Spectrum of hypertension in one fourth of people

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Hypertension affects approximately one fourth of the world's population and contributes substantially to worldwide cardiovascular morbidity and mortality. About 49% ischemic heart disease and 62% cerebrovascular disease are caused due to suboptimal blood pressure according to world health report, 2002 (1). According to the results of Kearney etal (2) 29% of the world population will be hypertensive by 2025. High blood pressure is a constant risk factor for myocardial infarction (MI), Heart failure (HF), and stroke and kidney disease (3). Each 20-mm Hg increment in systolic BP and 10-mmHg increment in diastolic BP doubles the risk for cardiovascular complications in adults across the BP range from 115/75 to 185/115 mm-Hg (4). These observations indicate that BP related end organ damage may manifest for years before the patient reaches the threshold for hypertension. Treatment of hypertension and its associated complications will increase the burden on the health care system and loss in the quality of life for millions of patients. Hypertension is associated with several physiological and biochemical changes in the vessel wall, including excessive vessel contraction and hypertrophy and hyperplasia of smooth muscle cells, resulting in increased peripheral vascular resistance. The exact causes of essential hypertension and its associated complications are largely unknown despite the investigative efforts of the scientists worldwide. The renin angiotensin system (RAS) is a major homeostatic system that controls body fluid volume, electrolyte balance, blood pressure, and neuronal and endocrine functions related to cardiovascular control. RAS regulates the vascular response to injury and inflammation (5). Chronic activation of RAS leads to hypertension and perpetuates a cascade of pro inflammatory, prothrombotic and atherogenic effects associated with end organ damage. There is increasing evidence that elevated role of interleukin-6 and its related cytokines may be an independent risk factor for hypertension. Although, clinically considered to be a biomarker of cardiovascular diseases, recent studies have shown that IL-6 signaling plays a significant role in hypertension (6). Elevated levels of inflammatory mediators in pregnancy may lead to placental ischemia, which contributes to increased vascular resistance and hypertension of pregnancy (7). High salt diet is one of the major risk factors in the development and maintenance of hypertension. The effects of high salt diet are related to the alteration in the functioning of RAS, which is normally suppressed by a high salt diet (8). Recent genetic studies using nonparametric linkage analyses have suggested that several chromosomal regions linked with hypertension. Quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressures identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous hypertension (9). The gene for Cd36 is a known target for peroxisome proliferator -activator receptor -γ. In the vascular system, PPARs influence cell growth and migration oxidative stress and inflammation and have been implicated to be vasculoprotective (9). Angiotensin II receptor blockers with the ability to selectively modulate activity of peroxisome proliferator-activated receptor-γ and expression of genes in these fat metabolism pathways may represent useful prototypes for a new class of transcription modulating drugs aimed at treating patients with hypertension. To summarize, hypertension is a disease of multiple etiologies, RAS regulates BP and vascular response to injury. Lowering BP and providing end organ protection are the two important goals of anti hypertensive therapy. Further studies will help in early interventions that prevent or delay end organ damage and reduce the CV risk associated with this disease.

Renin-Angiotensin System (RAS) in Hypertension

Renin-angiotensin system is a prime candidate for the maintenance of blood pressure. The effector molecule of RAS is angiotensin II (AngII), which binds to specific membrane-bound angiotensin receptors located in multiple tissues, including the vasculature (10, 11). The enzymatic cascade of RAS is initiated by release of renin, an aspartyl protease by the juxtaglomerular cells located in the afferent and efferent arterioles of the renal glomerulus in response to a variety of stimuli, including decreased renal perfusion pressure (8), increased activity of renal sympathetic nerves and decreased NaCl delivery to the macula densa of the juxtaglomerular apparatus (12). Renin cleaves angiotensinogen, a glycoprotein consisting of 429 amino acids which is synthesized by hepatocytes (13) to the decapeptide angiotensin I (8) Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase further cleaves angiotensin I to octapeptide angiotensin II that is the main effector hormone of the RAS. Angiotensin II is also formed via non-ACE pathways, such as chymase, cathepsin G and other serine proteases which can lead to a phenomenon called 'angiotensin escape' in some patients treated with ACE inhibitors. Alternative non-ACE angiotensin II-forming pathways are particularly relevant because circulating levels of angiotensin II return to normal in these patients despite continuing therapy with ACE inhibitors (14) Almost all vascular effects of Ang II are mediated via its seven transmembrane G-protein protein coupled angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptor. AT1 receptor activation leads to vasoconstriction by mobilization of intercellular Ca2+ levels, release of aldosterone from adrenal gland, increase in the activity of sympathetic nervous system , vascular remodeling, stimulating smooth muscle proliferation, inhibits nitric oxide synthase and salt and water retention as well as increase in oxidative stress and levels of transforming growth factor β which further stimulates the proinflammatory, atherogenic and prothrombotic environment. AT2 receptor activation appears to counteract the effects of AT1 receptors on cardiovascular tissue (15,16), as it induces vasodialtion, apoptosis and natriuresis. Increased expression of AT2 and cGMP via angiotensin receptor blocker (ARB) reduces vascular remodeling, whereas ACE inhibition mediated a similar decrease via a distinct AT2 independent mechanism. It is possible to have improved outcomes in treating hypertension by dual inhibition of RAS. Although binding of angiotensin with AT1 is a major source of deleterious effects of RAS activation, there are several biologically active angiotensin metabolites, including angiotensin III, angiotensin IV and angiotensin-(1-7), which stimulate the AT1 and AT2 receptors with low affinity (17,18). The biological relevance of the different metabolites in various tissues is still under investigation. Traditionally Ang II induces several intercellular transduction pathways, such as the phospholipase C-diacylglycerol- inositol triphosphate and the mitogen- activated protein (MAP) kinase signaling pathways which may be involved in development of renal and vascular dysfunction. More recently, the JAK/STAT signaling pathway has been shown to be activated by Ang II via stimulation of the AT1 receptor in cardio fibroblasts, vascular smooth muscle cells (VSMC) and the kidney.(19,20) Janus Kinases (JAKs) are cytoplasmic tyrosine kinases initially identified as essential components of interferon receptor signaling(21). In VSMC, Ang II stimulation leads to activation of JAK family members JAK2 and TYK 2 and subsequently leads to phosphorylation of STAT1-3, STAT5 and STAT6 (22,23). The phosphorylated STAT protein dimerizes and translocate to the nucleus to regulate the expression of the target gene. The JAK/STAT pathway can also be activated by interaction with G beta subunit of the heterotrimeric G - protein. The electroporation of antibodies against STAT1 and STAT3 abolished VSMC proliferation in response to Ang II and growth factors suggesting an important role for STAT signaling pathway in Ang II induced cell proliferation (21). Ang II activates the vascular NADP(H) oxidase system resulting in increased production of reactive oxygen species(ROS). Clinical and experimental evidence have indicated that ROS plays a critical role in development of hypertension. RAS influences blood pressure via various mechanisms.(23) RAS induces O2 and NO production in the kidney, where O2 acts as vasoconstrictor and enhances tubular sodium reabsorption and NO exhibits opposite effects. Rapid interaction of O2 with NO diminishes the bioavailability of NO resulting in impairment of organ function. It has been suggested that imbalance between RAS, NO and O2 contributes to pathophysiology of hypertension. The above observations indicate that RAS influences blood pressure via various mechanisms. Ang II produce via systemic RAS and local RAS induces the synthesis and secretion of IL-6, which in turn induces the synthesis and secretion of angiotensinogen through the gp130/JAK/STAT signaling pathway(23). Enhanced angiotensinogen activates vascular RAS and may prolong hypertension. Multiple studies have shown that changes in angiotensinogen levels influence long term activity of RAS. In summary, RAS plays a pivotal role as one of the critical regulators of the detrimental effects in arterial hypertension.

Interleukin 6 Knockout prevents angiotensin II induced hypertension

Interleukin-6(IL-6) is a multifunctional cytokine produced by a spectrum of cell types in the cardiovascular system.IL- 6 secretion is upregulated in response to inflammation, vasoconstrictors, oxidative stress and vascular injury. Plasma IL-6 levels are strongly associated with a number of cardiac risk factors including atherosclerotic disease, cardiomyopathies and metabolic syndromes.(24,25) Multiple measures of blood pressure strongly correlate with IL-6 levels in apparently healthy aged men. (26)The mechanisms by which IL-6 potentially affects hypertension or hypertrophy are not clearly understood. Interleukin 6 (IL-6) is released from vascular tissue in response to angiotensin II (Ang II). Recent work has shown that an Ang II type 1 receptor antagonist lowers blood pressure and aortic mRNA expression of proinflammatory cytokines IL-1β TNF-α and IL-6, as well as plasma levels of IL-6 and IL-1β in spontaneously hypertensive rats (27). It has been reported that chronic Ang II-induced hypertension, depended on IL-6 and showed significant attenuation in IL-6 knockout (KO) mice (6). Moreover, there was a 10 fold increase in secretion of plasma IL-6 in the wild type mice infused with AngII. It is possible that there is a direct link between IL-6 and Ang II, as loss of IL-6 had no effect on blood pressure under control conditions as well as during high salt intake. A separate study shows that Ang II infusion in WT mice with normal salt intake caused a significant increase in hypertension, and dose dependant decreases in RBF and afferent arteriole, whereas although knock out of IL-6 completely abolished hypertension. (Figure 1.), it did not significantly attenuate the decrease in RBF and diameter of afferent arteriole suggesting that renal vasoconstriction is not the primary explanation of blood pressure effect.

However significant activation (phosphorylation) of JAK2 and STAT3 in renal cortex of WT mice infused with Ang II at 800ng/kg/min still implicates a role for the kidneys. Satou et al have shown that showed that Ang II alone did not cause STAT3 phosphorylation in a cultured human proximal tubular cell line but did potentiate the stimulatory action of IL-6(28).This suggests that IL-6 could play a role in the effect of Ang II on tubular sodium reabsorption, and it is consistent with evidence that IL-6 activates the collecting duct epithelial sodium channel and STAT3 phosphorylation in primary cultured renal proximal tubular cells.(29)Further studies are warranted to understand whether the invitro evidence supporting renal tubular actions of IL-6 can translate to effects of Ang II induced increases in sodium reabsorption in vivo

Figure 1. MAP (mean±SEM) in WT and IL-6 KO mice infused with Ang II at 800 ng/kg per minute and in control WT and KO mice during the control (C) period and Ang II treatment (T) period. *P<0.05 vs baseline (within group).

(Michael W. Brands etal , Hypertension 2010;56;879-884)

Differential control of Angiotensin II-dependent hypertension by classic Interleukin-6 receptor signaling and Interleukin-6 trans-Signaling

Classic binding of lL-6 to membrane bound cognate receptor (IL-6 R) activates gp130 to transmit its signal; many of the biological activities assigned to IL-6 are mediated via a naturally occurring soluble IL-6 receptor (sIL-6R)(29). The resulting IL-6/sIL-6R is then able to directly activate gp130 through a process termed" IL-6 transsignaling" (30). sgp130Fc, a recombinant protein selectively blocks IL-6 trans- signaling without ablation of classical IL-6R signaling.IL-6 trans-signaling, thus affords IL-6 with the capacity to trigger responses in cell types that would remain unresponsive to IL-6 itself (31). Molecular mechanisms by which IL-6 potentially affects Ang II-mediated responses via its receptor-dependent signaling are not clearly understood. It is reported that BP increases in WT mice were significantly suppressed by sgp130Fc. However, cardiac and aortic hypertrophy was unaffected suggesting a role for IL-6 signaling through the cognate IL-6R. In addition, the antihypertensive effect of sgp130 was mimicked by IL-6 deficiency. Therefore, the most likely effect to account for the bioactivity of sgp130 is inhibition of IL-6/sIL-6R signaling. These data indicate that both forms of IL-6 signaling participate in Ang II vascular effects and, furthermore, show that IL-6 signaling for hypertrophy is independent of its pressor effects(29).It is reported that, IL-6 deficiency is associated with decreased expression of both cognate IL-6R and plasma sIL-6R, suggesting that IL-6 regulates expression of IL-6R at the gene level. Ang II elevates plasma sIL-6R in IL-6-/- but not WT mice. These data show that Ang II regulates sIL-6R in a manner that is antagonized by IL-6.Elevated expression of AT1R expression is observed in IL-6-/-/ aortae, however responses to Ang II in this strain were either lower or unaffected. The elevation in AT1R could represent an attempt to compensate for attenuated Ang II responses in IL-6 deficiency, eg, by up-regulating components of the Ang II-signaling pathway. However, Ang II significantly decreased AT1R expression in WT. These data indicate that IL-6 acting via the cognate IL-6R mediates Ang II-dependent down-regulation of AT1R in vivo.It can be summarized that. In summary, Ang II-dependent hypertension and hypertrophy are mediated by different IL-6R signaling pathways with IL-6 trans-signaling controlling Ang II-dependent hypertension but classic IL-6R signaling regulating hypertrophy, down-regulation of AT1R. Future studies will answer the questions regarding the site of action of sIL-6R signaling and will help better understand the control of hypertension by this pathway.

Hypertension in Pregnancy- Preeclampsia

Preeclampsia is defined as new hypertension (diastolic blood pressure ≥90mm Hg) and substantial proteinurea (≥ 300 mg in 24 hours) at or after 20 weeks of gestation (7). It complicates 2 -8% of pregnancies and is a major contributor of maternal and neonatal morbidity and mortality worldwide (32). Recent studies have shown that women who endure preeclampsia are at a greater risk for cardiovascular disease than nonpreeclamptic women and the men who fathered those preeclamptic pregnancies (33). Although the pathophysiology of preeclampsia remains largely unknown, the leading hypotheses strongly rely on disturbed placental function in early pregnancy. Inadequate trophoblast invasion leads to incomplete remodeling of the uterine spiral arteries and is considered to be a primary cause of placental ischemia (34). It is hypothesized that chronic reduction in uterine perfusion pressure (RUPP) leads to synthesis and release of increased amounts of vasoactive factors such as soluble fms-like tyrosine kinase-1 (sFlt-1), and cytokines. The maternal vascular endothelium appears to be an important target of factors that are triggered by placental ischemia/ hypoxia in preeclampsia. Imbalance between endothelium-derived relaxing and contracting factors disrupts the vascular homeostasis resulting in vasoconstriction, leukocyte adherence, mitogenesis, prooxidation, and vascular inflammation (35,36).

Fig. 2 Pathways by which reduced uterine perfusion pressure (RUPP) and placental ischemia may lead to endothelial and cardiovascular dysfunction during pregnancy. Placental ischemia results in increased synthesis of soluble fms-like tyrosine kinase-1 (sFlt-1), TNF-_ and IL-6, angiotensin II type 1 receptor autoantibodies (AT1-AA), and thromboxane (TX). Elevations in these factors are proposed to result in endothelial dysfunction by decreases in bioavailable nitric oxide (NO) and increased reactive oxygen species (ROS) and endothelin-1 (ET-1), which in turn

results in altered renal function, increased total peripheral resistance (TPR), and ultimately hypertension. PlGF, placental growthfactor.

(Joey P. Granger etal Am J Physiol Heart Circ Physiol 294: H541-H550, 2008.)

Role of endothelial markers in preeclampsia

The markers of endothelial dysfunction are often elevated weeks before observance of clinical manifestations in preeclampsia and therefore may serve as predictors of the syndrome in women that develop the syndrome.

1) Nitric Oxide: Substantial evidence indicates that elevated nitric oxide (NO) production in normal pregnancy a plays an important role in the renal vasodilatation and studies from several laboratories indicate that chronic NO synthase inhibition in pregnant rats produces hypertension. Chronic reduced uterine perfusion pressure (RUPP) in pregnant rats also decreases renal protein expression of neuronal NO synthase but not urinary nitrite/nitrate excretion relative to control pregnant rats. It is not clear whether there is a reduction in NO production in this spontaneous model of pregnancy-induced hypertension.(37)

2) Endothelin: Endothelial damage stimulates endothelin (ET-1) synthesis and it has been reported that ET-1 increases oxidative stress in placental villi (38). Thus endothelin may have additional effects on the maternal cardiovascular system not only by direct actions on the vasculature but also indirectly via oxidative stress. Granger etal have investigated the role of endothelin in mediating RUPP hypertension in conscious, chronically instrumented pregnant rats (39) and they have also shown that RUPP elicits increased renal cortical and medullary expression of preproendothelin and that chronic administration of the selective endothelin type A (ETA) receptor antagonist (ABT- 627, 5 mg/kg/day for 10 days) markedly attenuates the increased mean arterial pressure in these rats (39). In contrast, ETA receptor blockade had no significant effect on blood pressure in the normal pregnant animal, suggesting that ET-1 plays an important role in mediating the hypertension produced by chronic RUPP pregnant rats (39).

3) Renin Angiotensin System and preeclampsia: Plasma renin concentration, renin activity, and ANG II levels are elevated in normal pregnancy, although vascular responsiveness to ANG II appears to be reduced (40). In contrast, during preeclampsia, there appears to be a marked increase in the sensitivity to ANG II (40).Recent studies in preeclamptic women by AbdAlla and colleagues have shown that the AT1 receptor forms heterodimers with the bradykinin B2 receptor in abundance, suggesting that this heterodimerization may play a part in the long-observed increased ANG II sensitivity in preeclampsia.(41)Another intriguing observation regarding the involvement of the RAS in the pathophysiology of preeclampsia is the demonstration of increased circulating concentrations of an agonistic angiotensin II type 1 receptor autoantibodies ( AT1-AA) in preeclamptic women (43). The angiotensin II (ANG II) type 1 receptor autoantibodies (AT1-AA) (43) induce widespread dysfunction of the maternal endothelium in vessels of the kidney and other organs that ultimately results in hypertension. Recently, Li etal have shown that AT1 receptor antagonism attenuated the blood pressure response to placental ischemia (43). Exposure of serum from pregnant rats to reductions in uterine perfusion enhances endothelin production by endothelial cells via AT1 receptor activation.However, chronic oral administration of converting enzyme inhibitor enalapril (250 mg/l for 6 days) decreased MAP to a similar extent in pregnant rats with RUPP and normal pregnant rats, suggesting that the RAS does not play a major role in mediating the hypertension produced by chronic reductions in uterine perfusion pressure in pregnant rats . It is speculated that AT1 is a central mediator of several pathways in preeclampsia, further investigation will help to understand the mechanism by which AT1-AA and RAS contribute to the pathophysiology of preeclampsia.

4) Cytokines: Placental ischemia during pregnancy is associated with elevated levels of plasma cytokines such as IL-6, and TNF -α which may contribute to increased vascular resistance and hypertension of pregnancy. Chronic infusion of TNF-α or IL- 6 into pregnant rats at concentrations similar to what is observed in preeclamptic women increases arterial pressure and decreases renal plasma flow and glomerular filtration rate .Additionally, low-dose infusion of TNF-α results in decreases renal neuronal NO synthase expression (44) while also increasing ET-1 mRNA in the kidney, placenta, and vasculature Cytokines further add to the complications of preeclampsia by increasing the activity of sympathetic nervous system, however it is yet to be determined whether chronic elevation of cytokines increase sympathetic activity in preeclampsia.

5) Angiogenic factors: Strong clinical evidence suggests that preeclampsia is strongly linked to an imbalance between proangiogenic (VEGF and PlGF) and antiangiogenic (sFlt-1) factors in the maternal circulation. The actions of VEGF are regulated by mainly by two receptors, VEGF receptor-1 and -2, also known as Flt-1 and the kinase domain region (Flk/KDR), respectively. Alternative splicing in the plasma results in the production of soluble and endogenously secreted form of Flt-1.sFlt-1 disrupts VEGF signaling either by binding VEGF and PlGF or by forming heterodimers with the KDR receptor (45). sFlt-1 significantly inhibits the dilatory actions of both VEGF and PlGF in vitro. Intraperitoneal delivery of sFlt-1 via osmotic minipump in pregnant rats resulted in hypertension, proteinurea and impaired vascular function. (J. P. Granger, unpublished observations). Recent data suggest that circulating sFlt-1 concentrations may presage the clinical onset of preeclamptic symptoms; further studies are needed to better understand the mechanism governing the expression and action of this protein.

There has been a 40%increase in preeclampsia in recent years. Available strategies to manage this disorder are poor and currently limited to the delivery of baby and placenta. Hypertension associated with preeclampsia remits after delivery or termination of pregnancy, suggesting that placenta is the central culprit in the disease. Better understanding of the molecular pathways associated with this disease will expand the therapeutic strategies associated with this disease.

Pathophysiology of salt induced hypertension

Dietary salt intake is a known risk factor for hypertension. The exact mechanism by which the increase in salt intake leads to hypertension is not completely understood, it is known that high salt diet alters the functioning of renin - angiotensin system. It was proposed by Guyton et al. (46) that pressure-natriuresis mechanism regulates the sodium balance after salt intake to explain the link between sodium intake and hypertension. Sodium loading is associated with a transient increase in blood pressure which returns to primary values after pressure-natriuresis and regulation of extracellular volume (ECV). Thus, impairments of sodium elimination mechanism results in development of higher blood pressure. Autoregulatory vasoconstriction by peripheral tissue vasculature causes further increase in peripheral resistance(46). The above observations as well as studies performed on transplanted kidney patients, places the kidney in a central position in the regulation of blood pressure (47). High sodium concentrations may have direct hypertensive actions, such as induction of cardiac myoblast and smooth muscle cell hypertrophy (48), activation of NF-Kappa B in proximal tubular cells (leading to renal inflammation) (49), changes in the RAS, induction of oxidative stress, and others. A dysregulation of sodium metabolism can also be related to changes in genes and receptors associated with mineralocorticoid synthesis and function. Experiments on Sprague-Dawley rats fed with a high salt diet resulted in development of hypertension with increased renal injury and decreased renal expression of vascular endothelial growth factor (VEGF) (50). Epidemiologic and clinical studies have confirmed that high salt intake is a significant factor in determining the blood pressure levels. There is no age related increase in blood pressure in Neolithic tribes who still eat food which contains very low salt (less than 50 m mol NaCl ) whereas an increase in blood pressure was observed in populations who migrated to the western societies were sodium intake is several fold higher. Salt sensitive hypertension results in decreased ability of an individual to properly excrete sodium and water. A high-salt diet normally suppresses angiotensin II level through physiological blood pressure level control mechanisms. Adrenal and renal vascular responses to angiotensin II do not exhibit the expected changes predicted by changes in sodium intake in 40-50% of the essential hypertensive population (51). If the difference in blood pressure between a salt-loaded state (after administration of 2 liters of saline) and a salt-depleted state (low-sodium diet, about 10 mmol/day of Na plus oral furosemide) is > 10 mm Hg, it can be defined as 'salt sensitivity', whereas a difference of < 5 mm Hg can be defined as 'salt resistance' (52).Reduction of sodium intake in diet by 80-100mmol/day from an initial intake of around 180 mmol /day reduces blood pressure by an average of 4-6 mm Hg, although results were different for different populations. The effect of low sodium effect on blood pressure was greater in African Americans and Asians as compared to the Caucasians. Some studies have shown that African American RAS is more salt sensitive and they have a tendency to develop hypertension even with less sodium intake (53-55). Various rat strains on high salt diet show changes in the local RAS in different tissues. Downregulation of aortic AT1 receptor density and aortic and renal (AT 1 ) receptor mRNA was detected in Dahl salt-sensitive rats(56) on a high-salt diet, whereas (AT 1 ) receptor mRNA was upregulated in the brain. (AT1) mRNA levels increase in both in the aorta and in mesenteric resistance arteries of Wistar rats fed a high-salt diet (57), and that (AT1) receptor density increased in the renal cortex of spontaneously hypertensive rats after chronic high salt intake (58). Bayorh et al [78] detected a reduction in both plasma angiotensin II and aldosterone levels while an increase in the heart levels in Dahl salt-sensitive rats on a high-salt diet. The above studies hint that high dietary salt induces improper activation of the local renin angiotensin-aldosterone systems, and the tissue levels of angiotensin II and aldosterone may be more reflective of the severity of vascular maladaptations than plasma levels and may play a greater role in the maintenance of hypertension (59). Reduction in the salt intake by prehypertensive population will significantly reduce the number of hypertensive patients in the future Better understanding of the mechanisms involved in the interaction of sodium intake and blood pressure will prove beneficial for successful therapeutic interventions.

5 -HT in hypertension: A controversy

Serotonin (5-hydroxytryptamine) is a hormone/neurotransmitter synthesized by the essential amino acid tryptophan in the enterochromaffin cells of the intestine, raphe´ nuclei of the brain, and other discrete sites. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, it exists in two forms and synthesizes the intermediate 5-hydroxytryptophan (5-HTP)(60,61). 5-HT acts on postsynaptic receptors and can be taken back up into the neuron by the serotonin transporter (SERT), to be restored, or metabolized into 5-hydroxyindole acetic acid. (62)Circulating free 5-HT in the vasculature is largely controlled by the platelet through SERT(63). It can also be taken up and stored by the sympathetic neurons through actions of norepinephrine transporter. Although 5-HT has a long history in cardiovascular physiology, the role 5-HT plays in the cardiovascular system is still a puzzle. 5-HT exerts its biological effects mainly through activation of receptors in the cell membranes. Seven major types for 5 -HT (5-HT1-5-HT7)receptors and subtypes of several members exist.5-HT interacts with 5-HT1A,5-HT1B/1D,5HT 2 receptor family (5-HT2A and 5-HT 2B),5-HT3,5-HT-4 and 5-HT 7 coupled with G proteins to bring about changes in the cardiovascular system (64).It has been difficult to understand the role played by 5-HT in vascular control of blood pressure due to contradictory experimental evidence Varied responses are observed in different species on acute administration of 5-HT. Intravenous 5-HT shows a classic triphasic effect within seconds in anesthetized normal rats: Bezold Jarisch reflex via 5 -HT 3 receptor, arterial smooth muscle contraction via 5-HT2 receptor and a longer depressor response (activation of 5-HT7 arterial receptors and/or ganglionic inhibition).Acute administration of 5-HT decreases blood pressure in broiler chicken, and increases blood pressure in healthy calves and conscious sheep (65,66). Elevated levels of free 5-HT is consistently found in human and experimental models of hypertension. However, it is not known whether 5-HT mediates increase in blood pressure or is responding to hypertension in either a pathological or adaptive ameliorative manner. The following studies support the argument on both the sides in an attempt to speculate the complicated role of 5-HT in hypertension.

5-HT is not important in maintaining blood pressure

1) The circulating plasma levels of 5-HT in normal individuals are relatively low (nM vs. μM levels in whole blood) [100]. Modest elevation of these concentrations of 5-HT, in hypertension, are insufficient to activate 5-HT receptors normally expressed in the cardiovascular system.

2) Recent studies have shown that 5-HT can be synthesized, taken up, metabolized and released (serotonergic system) by systemic vasculature in a neuron independent manner by arteries and veins, indicating that vasculature has close relationship with 5-HT (67,68), however, the existence of serotonergic nerves (nerves that synthesize 5-HT) innervating systemic blood vessels is still not clear.

3) Depletion of 5-HT by parachlorophenylalanine (PCPA), an irreversible inhibitor of TPH, does not lower the blood pressure of SHR.

4) Studies using 5-HT2A/2C receptor antagonist, Ketanserin lowered BP of normal and hypertensive subjects, including humans, however reduction in BP has been largely attributed to α1 adrenergic receptor blockade, not 5-HT2 receptor blockade, however ritanserin did not lower blood pressure in hypertensive human (69) and SHR (70)[ritanserin lacks affinity for the α1 adrenoceptor receptor and has a high affinity for the 5-HT2A, 5-HT2B, and 5-HT7 receptor)(71)

These studies raise a question over the involvement of 5-HT in initiating or maintaining elevated levels of BP, however it is possible that 5-HT exerts equal pressor and depressor activities resulting in no change in blood pressure.

5-HT is important in maintaining blood pressure Although the above mentioned points refute the importance of 5-HT in maintaining blood pressure, powerful evidence exists that 5-HT modulates vascular smooth muscle tone, total peripheral resistance (TPR) and BP.

1) Acute and chronic administration of 5-HTP, an intermediate of 5-HT reduced blood pressure of the normal Sprague - Dawley, spontaneously hypertensive and Dahl salt sensitive rats in three independent studies(64)Fregly etal demonstrated that chronic treatment with 5-HTP prevented the development of DOCA-salt hypertension.(64).

2) In vitro studies have demonstrate that 5-HT is a vasoconstrictor in isolated arteries and arteries from hypertensive humans and animals are hyper reactive, however experiments conducted in vivo based on the hypothesis that elevated level of 5-HT would increase arterial contraction and cause an increase in blood pressure showed opposite results. Figure shows that 5-HT has a lower threshold, is more potent in arteries from hypertensive animals (DOCA salt hypertension) as compared to normotensive rats. Chronic administration of 5-HT through minipumps reduced blood pressure in normotensive rat and lowered blood pressure of the DOCA salt hypertensive rat over 50 mm of Hg.

3) Aggregation of platelets result in high(micromolar) local concentration of 5-HT (72) which is considered sufficient to activate endogenous 5-HT receptors, in particular the 5-HT1B/1D and 5-HT2B receptors for which 5-HT has high affinity.

4) It is known that blood vessels have a serotonergic system and they can synthesize, metabolize and release 5-HT, increasing the possibility of interaction of 5-HT with a local receptor. It is possible that serotonergic nerves may not exist in the vasculature thus 5-HT is taken up by the adrenergic nerves through the norepinephrine transporter(NET) and released upon neuronal stimulation (73,74).

5) Amplified arterial contractions to vasoconstrictors such as Angiotensin II ,endothelin -1 and NE were observed with subcontractile concentrations of 5-HT (low nM) (75,76) and similar action could potentially occur with vasorelaxants.

6) LY272015, the 5-HT2B receptor antagonist reduces experimental forms of rodent hypertension, but elevated blood pressure in the normal sham rat (77, 78). These results suggest that 5-HT2B receptor may serve opposing actions based on its location within the vasculature.

Figure 3: Top: Effect of 5-HT on isolated arteries (in vitro) from normal and hypertensive rats. Points are mean ± SEM for number of animals in parentheses. Bottom: Effect of 5-HT, given in vivo in a miniosmotic pump (25µg/kg/min), on blood pressure of a rat with a mineralocorticoid (deoxycorticosterone acetate or DOCA) dependant form of hypertension. Point represents mean ± SEM for number of animals in parentheses.

(Watts SW, etal Cardiovasc Ther. 2010) (64)

The relaxant 5-HT2B receptor predominates in the sham animal, while the contractile smooth muscle 5-HT2B receptor is dominant in the DOCA salt. Studies have shown that 5-HT reduces sympathetic activity through ganglionic transmission, in consistency with the knowledge that sympathetic activity is elevated in many forms of hypertension. Hypotensive actions of 5-HT can be blocked by inhibiting nitric oxide synthase (NOS), indicating that 5-HT depends on NOS activity for its function (79-81).

There is huge evidence supporting the role of 5-HT in hypertension but it is not known how 5-HT acts in the cell, how does it decrease blood pressure, is the elevated level of 5-HT the cause of disease or an adaptation to decrease blood pressure. The different behavior of 5-HT in vitro and in vivo is an enigma, and the role of different 5-HT receptors in regulating blood pressure is still not clear. Future studies will answer these questions and help understand the complex role of 5-HT in regulating B.P.

Role of Cd36 in the genetic control of blood pressure

Genetic studies of human and experimental hypertension provide a means to identify key pathways that predispose individuals to increased blood pressure and associated risk factors for cardiovascular and metabolic diseases and identify new drug targets for BP reduction. Quantitative trait loci (QTL) are set of genes involved in the pathogenesis of complex clinical disorders including essential hypertension and the metabolic syndrome. QTL-regulating BP or related cardiovascular and metabolic phenotypes in SHR and Dahl models (82) has been successfully identified on many chromosomes by Rapp and other investigators. However, it was challenging to identify specific DNA variants involved in polygenic forms of hypertension and related complex traits (83) because environmental and genetic factors play an important role in determination of phenotypes. Identification of mutations in the coding sequence of the gene for 11 β- hydroxylase in Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats lead to the initial discovery of specific DNA sequence variants. These variants encoded 5 amino acid substitutions in 11β-hydroxylzhydroxylase that cosegregated with Mendelian effects on the adrenal capacity to synthesize a mineralocorticoid hormone, 18-hydroxy-11-deoxycorticosterone, and with effects on BP (84). In contrast to the hypertensive Dahl SS/Jr strain, the normotensive Dahl SR/Jr strain carried a particular allele for 11β-hydroxylase that helped protect against salt-induced increases in BP.

Figure 4: Genome wide quantitative trait transcript analysis of cis eQTL in kidney with blood pressureThe renal expression of all cis eQTLs with diastolic and systolic blood pressure levels ware correlated in rat recombinant inbred strains derived from the SHR and the Brown Norway rat .For each cis e QTL mapped in the rat genome , the Pearson correlation coefficient with SBP or DBP is plotted against the location of the probe set (Mb).Empirical Significance thresholds(p<0.05) for the correlations are indicated by the horizontal lines. The cis eQTLs corresponding to the Cd 36 probe sets are indicated by the arrows. The cis -eQTL probe set closest to Cd 36 that also showed a significant correlation with blood pressure corresponds to Pmpcb(encoding mitochondrial processing peptidase- beta)

(Pravenec M et al. Nat Genet. 2008 Aug;40(8):952-4.)

Transfection studies and development of high resolution strains confirmed the functional effects of 11β hydroxylase mutations on synthesis of 18-hydroxy -11- deoxycorticosterone and BP regulation (85, 86). Studies by Lifton et al show that mutations in 11β-hydroxylase are involved in causing glucocorticoid remediable aldosteronism, a monogenic form of human hypertension (9). These studies indicate that genetic variants affecting BP typically involve mechanisms that regulate renal sodium chloride transport.

Expression QTL (eQTL) analysis of the kidney led to mapping of chromosome regions linked to renal expression of 15,923 transcripts in 30 recombinant inbred strains derived from the SHR and the normotensive Brown Norway rat (87) Linkage analysis showed 2,490 eQTLs in the kidney at a genome-wide significance level of P < 0.05. 780 eQTLs are regulated in cis by virtue of each having its linkage peak within 10 Mbp of the physical location of the probe set used to identify its transcript (87). Quantitative trait transcripts (QTT) analysis resulted in identification of high priority candidate genes for BP regulation (88) in the recombinant inbred strains by searching for correlations between renal expression of cis-acting eQTLs and direct measurements of arterial pressure. Out of 780 cis-eQTLs in the kidney, two probe sets for Cd36, the gene located on rat chromosome 4 encoding the Cd36 fatty acid transporter, shows the strongest correlation with diastolic BP (Fig. 4). The renal expression of Cd36 correlates inversely with both systolic BP and diastolic BP. The recombinant inbred strains inheriting the SHR variant of Cd36 show greater systolic and diastolic pressure than the recombinant inbred strains inheriting the Brown Norway variant of Cd36. The SHR/NIH (National Institute of Health) strain harbors a mutant form of Cd36 that generates aberrant transcripts and deficient membrane expression of functional Cd36 (9). There was a significant reduction in BP in congenic strain of SHR (SHR-Chr.4) which had a segment of chromosome 4 replaced including mutants Cd36 with the corresponding segment from the normotensive Brown Norway strain. Transgenic rescue of defective Cd36 improved glucose and lipid metabolism in multiple SHR transgenic lines but attenuated hypertension in only one transgenic line, therefore it was assumed that deficiency of wild type Cd36 is not a likely determinant hypertension. However, quantitative real-time RT-PCR analysis subsequently showed that renal expression of the wild-type Cd36 transgene was actually extremely low or undetectable in the transgenic lines that failed to show any improvement in BP, but clearly detectable in the SHR-TG19 line that showed a significant reduction in BP, therefore there is a possibility that genetically determined variation in the renal expression of Cd36 might influence BP in the SHR. .Furthermore, transplantation experiments performed in 2 groups of genetically identical SHRs that differed only in renal expression of Cd36 wherein kidneys from SHRs with mutant Cd36 or from transgenic SHRs with abundant renal expression of wild type Cd36 were transplanted in to bilaterally nephrectomized SHR congenic rats that expressed wild type Cd36 in extra renal tissues, showed significant reduction in BP of recipients that received a donor kidney expressing wild-type Cd36 as compared to those lacking wild-type Cd36. Similar results were observed in renal cross transplantation experiments using donor kidneys from the SHR congenic strain in which the wild-type form of Cd36 is normally expressed under control of its native promoter and transplantation experiments in younger rats with lower BP. Recent studies have shown that knockout of Cd36 can cause hypertension in mice as judged by tail cuff measurements of BP in 52 week old, unanesthetized animals with targeted deletion of Cd36 (89) The, BP of Japanese individuals with CD36 deficiency was reported to be greater than that in age-matched controls (90) CD36 deficiency occurs in 2-3% of Asian and African populations but less than 0.3% of Americans of European descent (91). Further understanding of additional downstream target genes in both the nuclear and mitochondrial genome may prove useful for a new class of transcription modulating drugs aimed at treating patients with hypertension.


Protective effect of PPAR-γ in Hypertension

Peroxisome proliferator-activated receptor-γ(PPAR-γ)is a member of the superfamily of nuclear receptor ligand-activated transcription factors that modulate genes involved in lipid and glucose metabolism (92).

Natural ligands for PPARγ are the prostaglandin D2 derivative 15-deoxy-Δ12,14-prostaglandin J2 and forms of oxidized linoleic acid, 9- and 13(S)-HODE (93). Synthetic ligands for PPARγ include the antidiabetic insulin sensitizers thiazolidinediones (glitazones), such as troglitazone, pioglitazone and rosiglitazone These insulin-sensitizing drugs decrease peripheral insulin resistance and thereby reduce blood glucose levels in patients with type 2 diabetes (94). PPAR γ is expressed in vascular smooth cells, endothelial cells and macrophages. In vascular smooth muscle cells, PPARγ agonists inhibit proliferation and migration, release of matrix degrading enzymes, oxidative stress and AT1R expression (95). PPARγ may also play a role in the induction of a differentiated phenotype in proliferating vascular smooth muscle cells, which could be important in vascular pathology (96). Thiazolidinediones, ligands of PPARγ prevent vascular smooth muscle cell proliferation by blocking activity of regulatory proteins. These observation indicate that antiproliferative effects of the PPAR-γ agonists play an important role in minimizing vascular injury, restenosis, and atherosclerosis (97).

PPARγ activators protect the endothelial cells against vascular inflammation by inhibiting the expression of tumor necrosis factor (TNF)α, interleukin (IL)-6 and IL-1β and attenuate TNF-induced VCAM-1 and ICAM-1 expression (98). They also act as vasorelaxants on the endothelium, because they enhance endothelial NO production and by inhibition of spontaneous and agonist-induced ET-1 synthesis (99). The different activators of PPARγ may inhibit or induce endothelial cell apoptosis, depending on the activator involved. Ciglitazone and 15d-PGJ2 were pro-apoptotic, other glitazones were found to be antiapoptotic It has been reported that PPARγ activators (rosiglitazone and pioglitazone) prevent development of hypertension, regressed vascular remodeling, reduced vascular inflammation and improved endothelial function in Ang II-infused rats and DOCA - salt hypertensive rats (100, 101). The gene for cd36 is a target of PPARγ in SHR. It was speculated that expression of PPARs could be decreased in blood vessels of SHR, which would exacerbate proliferation, migration, inflammation and fibrosis, as found in this hypertensive model. However, rather than decreased expression of PPARγ in blood vessels and cultured VSMC from SHR, their expression was increased. This may result from a feedback response to the decreased activity of the mutant Cd36 of SHR (102).

Although thiazolidinedione ligands of PPARγ are valuable transcription-modulating drugs for treating type 2 diabetes, insulin resistance, improving insulin sensitivity, decreasing fatty acid levels, and reducing BP (103). They are associated with certain adverse effects that may limit their use in clinical practice. The major side effects are fluid retention, and weight gain along with an increased incidence of congestive heart failure by as much as 500%, even in patients at relatively low risk for cardiovascular disease (104). It has been reported that clinically approved angiotensin receptor blocker (ARB), telmisartan, not only blocks binding of angiotensin II to the angiotensin II type 1 receptor but can robustly activate PPARγ. Janke et al 83 have demonstrated that telmisartan in concentrations as low as 1 mol/L can activate PPARγ target gene sequences in human fat cells. In contrast to the thiazolidinedione ligands of PPARγ,telmisartan is a partial agonist of PPARγ and belongs to a class of molecules known as selective PPAR modulators (SPPARMs) that may improve glucose and lipid metabolism without promoting fluid retention and weight gain. SPPARMs do not stimulate PPARγ as much as the glitazones and also have more selective effects on the recruitment of key transcription cofactors that influence PPARγ target gene expression profiles (105,106).

Figure 5: Potential antiatherosclerotic mechanisms of molecules that function both as ARBs and SPPARMs.

(Michal Pravenec et al, Hypertension 2007;49;941-952)

Molecules that serve as dual ARBs/SPPARMs could provide new opportunities for the prevention of diabetes in patients with hypertension and the metabolic syndrome PPARγ activators can decrease expression of the angiotensin II type 1 receptor gene, inhibit the effects of angiotensin II on intracellular signaling pathways, and may have additional beneficial vascular effects that go beyond their actions on glucose and lipid metabolism (9). Thus, multifunctional compounds that simultaneously block the angiotensin II type 1 receptor and selectively modulate the activity of PPARγ might also provide improved opportunities for preventing atherosclerosis and cardiovascular disease. Large scale clinical trials will assess the potential impact of dual ARB/SPPARM molecules. PPAR activation in the cardiovascular system has emerged as an interesting possibility to modulate pathological processes in the development of vascular disease. However their role in clinical medicine has not yet been clarified. There is still much to be learned about exactly how different PPARs mediate their cardiovascular actions and why some clinical studies have been associated with negative outcomes.


Hypertension has been ranked as one of the top 10 leading causes of worldwide disability adjusted life years. The pathogenesis of hypertension and molecular mechanisms involved in blood pressure remain poorly understood. Evaluation of the effect of ACE-inhibitor and ARB monotherapy as well as combination therapy by clinical trials in different patient populations have shown that combination therapy provides more extensive RAS inhibition and greater anti hypertensive efficacy and end organ protection. Increasing evidence suggests that inflammatory mediators play a very important role in hypertension and IL-6 signaling pathway differentially regulates hypertension. The cardiovascular effects of 5-HT are very complex and it is still not clear whether it is beneficial or detrimental in treatment of hypertension. Genetic studies of human and experimental hypertension have been instrumental to identify the key pathways that predispose individuals to increased blood pressure. Further research will help to better understand the complex etiology of this disease and lead to development of successful therapeutic interventions targeting patients at high risk of hypertension and prevention of its associated complications.