Hypertension is a multi-factorial, highly heritable and polygenic disease that involves complex interactions between genetically determined homeostatic control mechanisms and environmental factors. Hypertension is a chronic medical condition in which the arterial blood pressure is elevated (diastolic > 90mmHg, systolic >160mmHg). It is one of the risk factors for heart failure, ischaemic heart disease, cerebrovascular disease and renal failure. Hypertension can be classified into two categories, essential (primary) and secondary hypertension. Essential hypertension accounts for 90% of all cases. There is no obvious cause to explain the raise in arterial blood pressure. Secondary hypertension indicates that the raise in blood pressure is due to other conditions such as cancer, kidney disease and neurogenic stress. Mechanisms associated with secondary hypertension are generally fully understood however, those associated with essential hypertension are not. An increase in blood pressure is caused by an increase in cardiac output and/or total peripheral resistance (Page et al., 2006; Rang et al., 2007).
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Cardiovascular diseases cause a huge economic burden and are expensive for the world. It was reported that in 2003, the European Union spent â‚¬169 billion on the health system for cardiovascular disease treatments (Leal et al., 2006). It is the world's largest killers, estimated to kill 17.5 million lives a year, representing 30% of all global deaths (WHO report, 2005). Arterial hypertension is the most common cardiovascular disease, being a major public health problem in both developed and developing countries. Statistic shows that around 32% of men and 30% of women in the UK adult population have high blood pressure (Health Surveys Unit, 2004). Thereby, research to find preventions for this chronic disease is a vital investment.
II. Metabolic Syndrome
Today, there is a rise in obesity leading to the metabolic syndrome and in turn, to hypertension. "There are 400 million adults worldwide who are obese and 1.6 billion who are overweight. Children are getting fatter too. Worldwide, 155 million children are overweight, including 30-45 million obese children." (World Heart Federation)
What is metabolic syndrome: definition
Metabolic syndrome (MS) is a combination of metabolic abnormalities, characterized by several factors including obesity, hypertension and insulin resistance.(Fulop et al., 2006; Guize et al., 2008). It is considered as a constellation of abnormalities that is highly correlated with increased risk for cardiovascular diseases and diabetes type 2 (Eckel, 2007). MS is one of the major challenges to the health of the public all around the world. The World Health Organisation (WHO) was the first to put forward a proposed definition for the syndrome, in 1998. The main focus of this definition was based on glucose; with all patients defined as having diabetes or glucose intolerance or insulin resistance as well as high blood pressure, dyslipidemia, obesity or microalbuminuria. However, it was found that the definition proposed by WHO was better suited as a research tool rather than to be used in clinical settings (Eckel et al., 2005). More criteria for MS diagnosis emerged in 2001 and 2005 (See Table 1) from ATPIII and IDF. The ATPIII definition was more useful for clinical practice, emphasising on the importance of abdominal obesity (patient's waist circumference). The IDF definition placed abdominal obesity as the main focus of the syndrome. The definition reduces the threshold for waist circumference and glucose, and includes treated individuals and those with diabetes (Fulop et al., 2006; Cornier et al., 2008). These definitions are useful though, much research work is still needed to be done so the right definition is found, satisfying clinically and pathophysiologically.
Table 1: Criteria for MS diagnosis- There are continuous updates to the already existing definitions. (Fulop et al., 2006)
MS comprises of established risk factors for cardiovascular diseases. Researchers showed that the presence of the syndrome can be used to predict an increased risk of cardiovascular disease and coronary heart disease mortality (Cornier et al., 2008). However, its pathogenesis is still poorly understood. Nevertheless, abdominal obesity and insulin resistance are the most accepted and unifying hypothesis to describe the core pathophysiology of the metabolic syndrome (Fig 1).
Figure 1: The current proposed concept of the syndrome (Fulop et al., 2006)
Insulin resistance/abdominal obesity and Metabolic syndrome
Insulin resistance (IR) is the condition in which the normal amounts of insulin are produced by the body, though are inadequate to perform its physiological activities as it is not possible for the receptor to convey the necessary signal from them (Esteghamati et al., 2008). The various effects of insulin, such as its effects on lipoprotein lipase activity, muscle and adipose tissue glucose uptake or muscle and liver glycogen synthesis, indicates that for individuals who have insulin resistance, there are alterations within the body affecting glucose, lipid and protein metabolism (Fulop et al., 2006). Insulin is a pleiotropic molecule that is important to both anti-lipolysis and the stimulation of lipoprotein lipase (Steinberger et al., 2009). A major contributor to the development of insulin resistance is the overabundance of circulating fatty acids. There is a strong relationship between insulin resistance and obesity, though it is important to remember that insulin resistant can also be found in patients of normal weight. Studies showed that the major determinant of the metabolic risk profile is the distribution and localisation of the adipose tissue (Ruderman et al., 1998).
Hypertension and Metabolic Syndrome
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The majority of patient with hypertension are classed as overweight. The relationship between hypertension and insulin resistance has been widely studied, and several potentially different mechanisms have been related to it. When given intravenously to subjects of normal weight, insulin acts as a vasodilator. It also has secondary effects on sodium re-absorption by the kidney (Cornier et al., 2008; Steinberger et al., 2009). Due to insulin resistance, the vasodilatory effect of insulin on the subjects may be lost though its renal effect on sodium re-absorption is preserved. As well as the vasodilatory effect, the increased activity of the sympathetic nervous system due to insulin may also be preserved. It is believed that free fatty acids can help produce vasoconstriction (Eckel et al., 2005). Overall, the risk for hypertension in patients with metabolic syndrome is 6 times more frequent, than in lean men and women (Poirier et al., 2005). In an 8-years follow-up of middle-aged men and women in the Framingham Offspring Study, the population-attributable risk associated with metabolic syndrome for developing cardiovascular diseases was found to be 34% and 16% respectively (Wilson et al., 2005).
Type 2 diabetes mellitus (T2DM) and Metabolic Syndrome
Diabetes is a condition in which the body cannot produce enough or is not responding to insulin. In diabetic patients, the body fails to regulate the glucose metabolism, thereby is unable to maintain euglycaemia on its own. Type 1 diabetes mellitus is where the body fails to secrete insulin, where as insulin resistance in liver and muscle is a characteristic of Type 2 diabetes mellitus (T2DM). The progression from insulin resistance and impaired glucose metabolism to T2DM is now seen, and has been documented in both adults and children. Free fatty acids are predicted to be the main cause for the modification of the signals that generate glucose-dependent insulin secretion, due to insulin resistance in pancreatic islet beta-cells. Because of these alterations, lipotoxicity is therefore promoted through many different mechanisms, accounting for various manifestations of the metabolic syndrome. (Eckel et al., 2005; Steinberger et al., 2009). In an 8-years follow-up of middle aged men and women in the Framingham Offspring Study, the population-attributable risk associated with metabolic syndrome for developing type 2 diabetes mellitus was found to be 62% and 47% respectively (Wilson et al., 2005).
Low-grade inflammation and Metabolic Syndrome
Studies have shown an association of MS, leading to elevated levels of circulating inflammatory cytokines, with insulin resistance and obesity. Concentrations of inflammatory molecules such as C-reactive protein (CRP), which is an indicator of inflammation, as well as pro-inflammatory cytokines such as TNF-Î±, and IL6 appears to be elevated alongside with the increase in level of adipose tissue seen in patients with MS (Bastard et al., 2006; Berg et al., 2005). Obesity-linked TNF-Î± is secreted mainly from macrophages that accumulate in obese adipose tissue, research have shown its association with insulin resistance and components of MS. Like TNF-Î±, obesity-linked IL6 secreted by adipose tissue and skeletal muscle, are thought to be related to the development of T2DM and insulin resistance, but is negatively associated with High Density Lipoprotein-Cholesterol (HDL-C). Obesity is shown to be linked with these inflammatory molecules, signifying a chronic state of low-grade inflammation (Berg et al., 2005; Cornier et al., 2008; Steinberger et al., 2009). Many new hypotheses are being proposed questioning that inflammatory process may be involved in the initiation and development of hypertension.
III. Factors involved in blood pressure control
Blood pressure (BP) controlled by various physiological mechanisms such as the renin-angiotensin system, is the force that causes blood to flow through the arteries, capillaries, veins and back to the heart, ensuring an adequate tissue blood flow. BP is determined by the rate of blood flow produced by the heart (cardiac output), and the total peripheral resistance (TPR). Evidence shows that the systolic and diastolic pressures increase with age (fig 2) (Pinto E., 2007; Sharma S., 1992; Widmaier et al., 2006).
Figure 2: The graph shows systolic and diastolic blood pressure (mmHg) against age. (Sharma S. 1992)
In conclusion, blood pressure is controlled by several mechanism which acts together in combination. The responses from these mechanisms are achieved through short and long term actions, ensuring that the blood pressured is kept within normal set point, thereby providing an adequate perfusion to the body tissues.
Sympathetic Nervous System
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The sympathetic nervous system is the instantaneous responding regulator of the heart, monitoring changes in blood pressure, heart rate and activities of organs such as the kidney. It is also a long term regulator, acting through the renal sodium handling and the rennin-angiotensin system to maintain cardiovascular homeostasis. Deviation of blood pressure from a set point is detected by the baroreceptors, situated in the carotid sinus and the aortic arch. The sympathetic nervous system affects blood pressure through the binding of the noradrenaline to Î±1, Î²1 and Î²2 adrenergic receptors. An increase in blood pressure normally causes an inhibition of the sympathetic nervous system activity, resulting in vasodilation of the arterial and venous side of the body circulation, as well as a decreased in contractility of the heart. These mechanisms are set in place to restore homeostasis (Beevers et al., 2001; Rang et al., 2007; Widmaier et al., 2006). In conclusion, the sympathetic nervous system acts directly to regulate the renal sodium handling via the renal sympathetic nerves, and in doing so, indirectly activating the renin-angiotensin system.
Through the rennin-angiotensin system, the kidneys work to control the arterial pressure by inducing changes in the volume of extracellular fluids, increasing or decreasing the blood volume. The rennin-angiotensin system synergises with the sympathetic nervous system, being responsible for the long term maintenance of the blood pressure. Renin is a proteolytic enzyme that is secreted by the juxtaglomerular cells of the kidney when the blood pressure is low. Over-expression of renin and its metabolic products is thought to be the predisposing factor for individuals to develop hypertension (Zaman et al., 2002). Renin acts to cleave angiotensiongen, which gives angiotensin I (inactive form). Through biological processes, angiotensin I is converted to angiotensin II (active form), which can regulate the renal pressure natriuresis mechanism thus showing that angiotensin II is closely linked with arterial pressure control and volume homeostasis. An overactive renin-angiotensin system leads to vasoconstriction via the activation of AT receptors, and retention of sodium and water. This cascade of events causes an increase in blood volume leading to hypertension. (Rang et al., 2007; Wildmaier et al., 2006; Zaman et al., 2002).
The endothelium lines the entire circulatory system of the whole body. It regulates the vascular control mechanism by releasing vasodilators as well as vasoconstrictors substances such as nitric oxide (NO), prostacyclin (PGI2) and endothelin. Research suggests that a decrease in endothelium derived vasodilators leads to inability of vascular relaxation, which is believed to be one of the factors that cause an increase in vascular resistance and blood pressure as seen in patients with hypertension (Schiffrin, 2005). Endothelin-1 (ET-1), a vasoconstrictor peptide, is the most abundant and important of the endothelin family of peptides in blood vessels. ET-1 exert its vascular effects via stimulating the 3 known ET receptors; ETA, ETB, ETC. Using animal models of hypertension such as DOCA-salt rats, studies have been done to define the role of endothelin and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension. Endothelin antagonist showed promising therapeutic potential in hypertension however, currently endothelin antagonists that have been approved for clinical use is only for the treatment of primary pulmonary hypertension (Hynynen MM and Khalil RA, 2006; Schiffrin, 2005). .
IV. Treatments approaches/targets in hypertension
Diuretics are drugs which act on the kidney, directly on cells of the nephron. The drug acts to decrease the re-absorption of sodium ions at different parts of the nephron (fig 3), thus increasing the excretion of sodium ion and water. There are 3 main therapeutically useful types of diuretics acting on the thick ascending limb of Henle's loop, early distal convoluted tubule, and collecting tubules and ducts.
Figure 3: Actions of drugs on different sites of the Nephron (Mende 1990)
i) Mechanisms and actions of diuretics -
Benzothiadiazine (thiazides), an example of a type of diuretics, acts to inhibit the sodium transport by binding to the Cl- site of the Na+/Cl- co-transport system, as well as the Na+/H+ and Cl-/HCO3- exchanger in the distal convoluted tubule. The effect shows to decrease sodium re-absorption, causing 5-10% of filtered sodium by the glomerulus to be excreted (Padilla MC et al.,2007; Stanton BA, 1990). Loop diuretics such as furosemide, act primarily on the apical membrane of the thick ascending limb of Henle's loop to inhibit Na+/K+/2Cl- co-transporter. Due to the strong natriuretic effect, loop diuretics are the most effective diuretics, excreting 20-30% of filtered sodium (Musini VM et a., 2009). Potassium-sparing diuretics including, spironolactone and eplerenone, an aldosterone receptor blockers, and amiloride, an epithelial sodium channel blockers, act to inhibit sodium re-absorption at the connecting tubule and duct. It have a weak effect, 5%, therefore is only efficient when administered in combination with other diuretics.
ii) Uses of diuretics -
Loop diuretics are mainly prescribed in low doses to patients with renal impairment. It is advised to take loop diuretics with dietary salt restriction. Thiazides are less potent than loop diuretics, and are preferred over loop diuretics for patients with normal renal function. Potassium-sparing diuretics are used in combination with other diuretics, to help prevent K+ loss.
iii) Side effects of diuretics -
Side effects of diuretic drugs includes hypovolaemia and hypotension due to excessive Na+ loss and dieresis. Patients may also present with metabolic alkalosis and hypokalaemia, which is potentially fatal. Erectile dysfunction is the main unwanted effect for use of thiazides, though it is less commonly seen when thiazide is use in low doses.
i) Mechanisms and actions of sympatholytics -
Sympatholytic drugs work to block the sympathetic adrenergic system. There are four broadly use types of symphatholytics. Centrally-acting sympatholytics, such as methyldopa, and clonidine binds to Î±2-adrenoceptors, blocking the sympathetic activity. Secondly, peripheral-acting sympatholytics are Î±- and Î²-adrenoceptor antagonists, which are used to induce vasodilatation. Examples of this group of drugs are phentolamine (Î±1-selective antagonist), propranolo (Î²-selective antagonist), carvedilol (non-selective-antagonist). Thirdly, the ganglionic blockers, such as mecamylamine, are peripherally acting sympatholytic. Mecamylamine can antagonize the effects of nicotine, thereby blocking the transmission of impulse at the sympathetic ganglia. Lastly, drugs such as reserpine, guanethidine and metyrosine, are example of noradrenergic neuronal blockers. These drugs act to reduce the response of tissues such as the heart to sympathetic nerve stimulation, but do not affect the effects of circulating noradrenaline. (Hausberg M et al., 2004; Rang HP et al., 2007).
ii) Uses of sympatholytics -
Sympatholyic drugs are a known treatment of hypertension. Combination therapies of sympatholytics (Î²-blockers) with diuretics are commonly seen, giving a synergic effect thereby enhancing the treatment. However, precautions need to be taken on use of these drugs as patients with heart disease may rely on a degree of sympathetic drive to the heart, allowing the maintenance of cardiac output. Thus using these drugs, leading to blocking of Î²-receptors, can exacerbate cardiac failure. (Hausberg M et al., 2004; Rang HP et al., 2007).
iii) Side effects of sympatholyic -
Bronchoconstrction can occur, and the effect can be lethal in asthmatic patients. A decrease in glucose tolerance may sometimes be seen. This is because Î² blockers block the autonomic mediated release of insulin which leads to hypoglycaemia. Therefore, the uses of these drugs are avoided in patients with poorly controlled diabetes. Other side effects include bradycardia, fatigue, cold extremities, dry mouth and nasal as well as constipation and gastric upset. Clonidine can cause a rebound hypertension if there is a discontinuation of the drug in treatment. (Hausberg M et al., 2004; Rang HP et al., 2007).
c) Directly-acting vasodilators
i) Mechanisms and actions of directly-acting vasodilators -
Directly acting vasodilators act to increase local tissue blood low thus reducing arterial pressure and central venous pressure. Vasodilators such as minoxidil work to induce relaxation of smooth muscle by inducing hyperpolarisation, via increasing the membrane permeability to K+. Glyceryl trinitrate (nitroglycerin) is an example of a nitrovasodilators. The common mode of action of these drugs is as a source of nitric oxide, which can dilates blood vessels. Lastly, there is a large group of vasodilators such as verapamil, diltiazem and nifedipin, which acts as a calcium antagonist, blocking the cellular entry of Ca+ through calcium channels in response to depolarization, causing generalized arterial vasodilatation (Koch-Weser J, 1974).
ii) Uses of directly-acting vasodilators -
Due to its rapid cause in a fast drop of the blood pressure, vasodilators are generally use in combination with other first-line antihypertensive drugs such as with a diuretics, they are rarely ever used on its own.
iii) Side effects of directly-acting vasodilators -
The unwanted effects that have been reported on using of the drug is mainly due to the significant drop in blood pressure over a short period of time. These side effects include fainting, palpitations, hypotension as well as constipation due to the effects on Ca2+ channels in the gastrointestinal nerves and smooth muscle. (Koch-Weser J, 1974; Rang HP et al., 2007)
d) Indirectly-acting vasodilators
i) Mechanisms and actions of indirectly-acting vasodilators -
Angiotensin-converting enzyme inhibitors (ACE) such as captopril and enalapril, targets the renin-angiotensin system causing a reduce in angiotensin II leading to a decrease in peripheral vascular resistance. Thus, causes relaxation of blood vessel leading to a decrease in blood pressure. ACE however, do not affect cardiac contractility therefore, there will be no reduce in the cardiac output. Losartan and valsartan are examples of Angiotensin II receptor antagonists. These groups of drugs also work to block the effect of angiotensin II, though through different pharmacological pathway than ACE inhibitors.
ii) Uses of indirectly-acting vasodilators -
The angiotensin II receptor antagonists are usually well tolerated and are widely use in younger patients with hypertension, as well as hypertensive diabetic patients. However, ACE inhibitors cannot be used to treat patients with certain types of kidney and artery problem nor with hypertensive pregnant patients.
iii) Side effects of indirectly-acting vasodilators -
Common side effects include dry cough and hyperkalaemia due to reduced aldosterone secretion. (Zaman et al., 2002)
Figure 4 summarizes actions of all four types of antihypertensive drug that are currently available for treatments.
Figure 4: Primary and secondary effects of therapies (Koch-Weser J, 1974)
V. Why new drug?
There are a variety of antihypertensive agents that are available for use as a treatment to lower blood pressure in hypertensive patients. Factors to be considered by physicians in selecting antihypertensive agents before drawing up a treatment regimen, is to balance out the efficacy of the agent against adverse side effects. Despite the availability of numerous antihypertensive agents, a concerted research effort to develop new approaches to hypertension treatment is necessary.
There are still hypertensive patients who are truly refractory to the four-drug treatment types that are available; diuretics, symphatolytics, vasodilators and ACE. Patients present with secondary cause to hypertension such as those with renal artery stenosis, are also refrained from taking any of these antihypertensive agents. Secondly, it was estimated that 15-25% of the patients stop taking their antihypertensive drugs due to the unbearable side effects. For example, those that are taking diuretics may experience impaired glucose tolerance and/or gout, while those on propranolol may feel nauseous and/or dizziness. These side effects are lowering the quality of life of the patients. All of these concerns taken together, answer the question of why yet another antihypertensive agent may be needed in the pharmacologic armamentarium (Wilson TW, 1987).
VI. Transient Receptor Potential (TRP)
Drosophila, a fruit flies, with mutations in a particular gene lacking a specific Ca2+ entry pathway into photoreceptors, exhibiting abnormal responsiveness to continuous light. Because of the electrical phenotype associated with this mutation, this gene was named trp, which stands for 'transient receptor potential'. The trp gene mammalian related family is therefore referred to as the TRP superfamily of cation channels (Tominaga M et al., 2005). There are 28 known member of the mammalian TRP family, which can be subdivided into 7 subfamilies; TRPC, TRPV, TRPM, TRPP, TRPML, TRPA, TRPN. These channels are widely distributed and participate in a wide variety of physiological processes including detection of sensory stimuli, osmoregulation, chemo taxis, etc (Wang DH, 2008).
a) Characterization of TRPV1
i) Structure of TRPV1
Two studies were carried out to determine the structure of TRPV1, also known as a transient receptor potential vanilloid-1 (VR1) or a capsaicin receptor. One study was carried out by using single-particle electron cryomicroscopy and the other was done by performing a cystein accessibility study. TRPV1 , is predicted to have six transmembrane domains, a pore region between transmembrane five and transmembrane six forming hydrophobic stretch, and cytoplasmic N- and C- termini (Moiseenkova-Bell VY et al., 2008; Salazar H et al., 2009. TRPV1, as it name suggested, belongs to the TRPV subfamily of the large TRP ion channel super family. It is closely involved in a broad array of sensory pathways and responds to environmental stimuli including altered pH, temperature, mechanical and osmotic stress, as well as altered levels of lipid metabolites. Notice, that these changes may all be involved or result in cardiovascular regulation.
ii) Capsicin action
In 1997, a study was carried out to demonstrate that capsaicin can selectively bind to TRPV1. Results showed that capsaicin can cause the TRPV1 to activate the opening of Ca2+ channel below the usual temperature that it would normally open at 37 degree Celsius (Caterina MJ 1997). Capsaicin is the active secondary metabolite component of chili peppers. Capsaicin and its analogues are lipophilic suggesting that they can passes though the cell membrane and act directly on binding sites present in the intracellular surface of TRPV1.
iii) Proton action
TRPV1 is known to respond to an acidification of the extracellular milieu exerting it effects in two ways. Firstly, the extracellular protons increase the potency of the agonists such as heat or capsaicin to TRPV1, via lowering the threshold for channel activation. Secondly, further acidification can leads to the channel being able to open at room temperature, thus extracellular protons can be viewed as agonists. Also, these proton causes intracellular acidification as the protons can permeate the non-selective TRPV1 pore in acidic extracellular solution (Tominaga M et al., 2005).
iv) Heat activation
The currents produced by TRPV1 that are evoked by heat, show properties similar to those of capsaicin-evoked currents. It is not clear how or where heat acts to open the TRPV1 channel, it is now accepted that several TRP family ion channels are thermosensitive. This suggests that the TRP family may have temperature sensor domains present in their channel proteins.
b) Interactions of TRPV1 with Pro-hypertensive System (Role of TRPV1)
TRPV1 is mainly localized to primary sensory neurons in the dorsal root ganglia (DRG) as well as in the trigeminal and nodose ganglia. It has a dual function of sensory perception and sensory efferent function. Binding of agonists that are mentioned before triggers the release of neuropeptide from the afferent neurons, which binds and causes influx of Na+ and Ca2+ions. Example of transmitters released from TRPV1-positive sensory neurons includes, substance P and calcitonin gene-related peptide (CGRP). CGRP is a potent vasodilator that also has positive chronotropic and ionotropic effects.TRPV1-positive sensory nerves are found around blood vessles and in all vascular beds. On activation of these sensory nerves, transmitter molecules found in nerve endings such as CGRP, will be released.
i) TRPV1 and increased salt sensitivity
Over 50% of patients present with essential hypertension is salt sensitive. Research has been carried out to see whether impairment of the TRPV1 system may contribute to increased salt sensitivity in these patients. Li J et al have shown that high salt intake activates the TRPV1 which, in turn stimulates the release of CGRP form sensory nerves, rendering the salt-induced increases in arterial pressure effect. Furthermore, high salt intake unregulated mesenteric and renal medullary TRPV1 expression which contributes to maintenance of normal salt sensitivity (Li J et al., 2003). Another study show that blockade of TRPV1 can render a Dahl-salt-resistant rat sat-sensitive, whereas Dahl salt-sensitive rats were not responding leading to a conclusion that activation of TRPV1 during high salt intake may prevent salt-induced increases in blood pressure. However, dysfunctional in the TRPV1 system may contribute to increased salt sensitivity (Wang Y et al., 2006).
ii) TRPV1 and the rennin-angiotensis-aldosterone system
On binding with its agonist or stimuli, TRPV1 releases its neuropeptides such as substance P and CGRP. It is known that Substance P and CGRP can mediate direct and indirect effects on tubular ion transport in the kidney, thereby helping to mediate diuresis and natriuresis actions. It was shown in a study that degeneration of TRPV1-positive sensory nerves leads to a depletion of neurotransmitter causing an increase in blood pressure in rats fed with high-salt diet (Wang DH et al.,1998).Further investigation was carried out to see the role of the type 1 (AT1) and 2 (AT2) angiotensin II (AII) using salt-induced hypertension in capsaicin-pretreated rats model (Wang DH et al., 1999). The rats were attenuated by candesartan and PD 123319, an antagonist, to prevent the development of hypertension. Both of these antagonists to the TRPV1 shows a protective and effective effect in lowering increased blood pressured that were induced in the capsaicin-pretreated rats.
iii)TRPV1 and inflammation
TRPV1 is believed to play a pivotal role in mediating the inflammatory process which present in various stages of hypertension. These inflammatory processes, if unmediated, may develop into end organ or tissue damage (Wang DH, 2008). TRPV1 can cause a signaling cascade to stimulate the release of inflammatory cytokines through the mitogen-activated protein kinase (MAPK) signaling pathway. Though, the sensitivity of TRPV1 can also be regulated via inflammatory mediators such as bradykinin and cytokine IL-1Î² (Veronesia B et al.,1999). Due to this complex interaction of regulatory mechanisms, future study into how inflammation and TRPV1 interact is needed.
iv) TRPV1 as targets of therapy for cardiovascular disease
Due to its interaction with variety of pro-hypertensive system, TRPV1 may have enormous therapeutic potential. However, lack of understanding of the TRPV1 structures, endogenous ligands and the complex nature of its activation and signaling pathways, not much research have been carried out to find effective therapeutic treatments to act at TRPV1.
Many research have indicates that TRPV1 plays a key role in cardiovascular health and disease. The study and trials of dysfunctional TRPV1 expression and release of sensory neurotransmitter provides an insight into the interactions that lead to hypertension and increased salt sensitivity. TRPV1 have shown of it ability act as a sensor and regulator of cardiovascular homeostasis thereby, the study of the TRPV1 system may, in the future, helps to improve our understanding of the molecular basis underlying human hypertension.
VII. Rodent Models
The ideal animal models for research are those models that have human-like anatomy, physiology and complications. However, no species can perfectly imitate human physiology therefore experimental design and other constraints often limit the choice of animal models for specific research applications use. The general categories of animal models of hypertension can be divided into two group, genetic and nongenetic models. The genetic models include those that are phenotype-driven such as natural variation among inbread strains (SHR-model), or genotype-driven such as genetics-based manipulation of gene expression (null mice). The non-genetic models include those that are surgically induced, or those obtained by endocrine/dietary induced.
a) Nongenetic models
i) Surgically induced hypertension
In 1934, Goldblatt et al. introduced the first model of renal hypertension in dogs. These models was called 2K,1C for 2 Kidneys 1 Clip, and 1K,1C for unilateral constriction of the renal artery. The procedure was later performed in rabbits, monkeys and rodents. (Goldblatt H et al., 1934) This type of model allows the understanding of the pathophysiological mechanism of hypertension through studying of the renin-angiotensin-aldosterone system. 2K,1C is widely used in mice. It induces a reduction of glomerular filtrates, leading to an over-expression of renin-angiotensin-aldosterone system. An increase of 20mmHg in mean blood pressure can be obtained (Pinto YM et al., 1998).
ii) DOCA/salt hypertension
Deoxycorticosterone acetate salt (DOCA salt) is commonly endocrine method of inducing hypertension in rodent. The renal mass of the rodent will be partially removed, and the rodent will be given a controlled high salt diet. Around 20-35mmHg increase in systolic blood pressure can be seen. This type of model is good for the study of hypertension in association with cardiac and renal hypertrophy.
iii) Salt-induced hypertension
It shown that an 8% increase in high salt diet can already induce hypertension on it on. This type of model is especially use for the study of a malignant hypertension with glomerular lesions (Lerman LO et al., 2005).
iv) Chronic NO-synthase inhibition
Nitric oxide, NO, is one of the most powerful regulators of blood pressure. In this model, the rodent is treated with chronic NO synthase inhibition which induces hypertension that can be amplified by a simultaneous high salt diet.
v) Obesity and hypertension
It is known that obesity plays a major role in cardiovascular diseases, therefore animal models of the metabolic syndrome will provide a good opportunity to understand the mechanisms that leads to hypertension. However, a high fat diet induced hypertension in mice has not been successfully used (Bergan JJ et al., 2008).
i) Phenotype-driven models: the spontaneously hypertensive mouse
This type of experimental model is the most abundantly use for hypertension research and is particularly important in the study of polygenic hypertension. The homozygous hypertensive rat strains are achieved by selective breeding of rodents that display the desired phenotype, generation over generations. Once the trait is fixed, mating is maintained for another 20 generations in order to achieve genetic homogeneity rodent model.
ii) Genotype-driven models
There are a wide range of transgenic mice that have been generated for hypertension research. Specific gene targeting is carried out so that it will allow researchers to study the role of a single gene, either by its over-expression or by its deleting the gene. (Pinto YM et al., 1998) It also allows researchers to study the end organ damage due to its susceptibility of the certain genes as well as analyzing the effects of naturally occurring gene variants to regulate blood pressure. It is unseemly though, that a modification of just a single gene will lead to the complete understanding of the mechanism of hypertension. An enormous use of transgenic mice is via a method call RAS. This method uses the over-expression of the 2 subtypes of the gene for AT1 in mice and the REN (renin) gene to develop high blood pressure. There are also ACE knockout mice that are hypotensive. The use of these genotype-driven model help researchers to find novel potential interactions that may generate hypertension (Lerman LO et al., 2005; Takahashi N et al., 2004).
Even though people are more aware of their hypertension, and more people are doing exercise, 30% of hypertensive patients are controlled. The global picture of hypertensive patients is changing. Before, most patients present with hypertension are of old age. However, obesity and aging are on the rise and will likely contribute to more hypertension. A lot of children are now overweight thereby more and more patients are present with hypertension at a younger age. Therefore, a research and trials for new drug targets that could obtain a better result, a well tolerated treatement is needed. Development of experimental models of hypertension allows a thorough investigation of factors associated with regulation of blood pressure, genetic basis of hypertension, inheritance of hypertensive traits, and cellular responses to injury. Investigating its causes, effects and interaction with other cardiovascular risk factors by virtue of these experimental models may not only shed light on the complex mechanisms triggered by hypertension, but it may also assist in development of novel therapeutic strategies to manage this common disease. There are searches for new drugs to treat hypertension every day. I am sure that in the next few years, there will be a rapid progress in our knowledge on the genetic basis of hypertension; this will lead us to new therapeutic strategies. The uses of animal models allow us to test these new drugs before it become available for human. TRPV1 have proven to play a pivotal role as it mediate most, if not all, of the mechanisms which are thought to be the underlying cause of hypertension. Therefore, further study needs to be carried out in search for the use of drugs which can provide a new therapeutic use of TRPV1.