Effects Of Endogenous Vasoconstrictors Biology Essay

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Vasospasm has been associated with glaucoma, but the mechanism have not been clearly elaborated. A potent endogenous vasoconstrictor, endothelin (ET)-1 were increase in patient with glaucoma compared to normal subject. They also found that glaucoma patient with acral vasospasm, more likely to show deterioration in visual fields after cooling than patient without acral vasospasm. In other words, glaucoma patient with evidence of vasospasm have the risk of worsening visual fields under cooling induced than nonvasospastic patients. (Nicolela et al 2003). Vasospasm were also identified in migraine, which commonly found in females and associated with NTG. (Cursiefen et al 2000). McKendrick A.M. et. al (2000), suggest that migrainous pattern shares some features in early stages of glaucoma and this raises to the possibility that vascular involvement occur in these cases. Disability to remain constant of ocular blood flow during physiological condition, may categorized as having ocular vasospasm or dyregulation. NTG patient had significantly lower ophthalmic artery blood flow velocities and higher vascular resistance than normal subject. Reversible vasospasm in NTG is noticeable with elevated CO2 breathing compared to normal subject. (Harris et. al, 1994).

A inverse response pattern were found in ONH and choroidal with female that has vasospasm regarding blood gas perturbation compared to without vasospasm. (Gugleta et. al, 2005). A differentiation during blood gas perturbations and calcium channel blockers may demonstrate which persons are at greatest risk for vasospasm, impaired ocular blood flow and possibly OAG. Although, vasospasm is associated with multiple disease states including OAG with NTG patients and women appearing to be the most at risk for vasopastic contributions to disease processes. Fluctuations in ocular perfusion, ischemia, and/or reperfusion injury to the ocular tissues are possible vasospasm effect. Vasospasm also probably classified to be reversible (treatable). Blood gas perturbations test on OAG should be further explored, especially in patients that demonstrate a vasospastic criteria. Vascular endothelium secretes vasodilator nitric oxide (NO) and vasoconstrictor endothelin-1 (ET-1) that effect the microcirculation of the blood flow. (Adams J.A., 2006). Prostacyclins, acetylcholine, bradykinin, and histamine were activated by endothelium derivation. (Flammer and Orgul 1998; Adams 2006). Vasodilation were promoted on smooth muscle when secretion of NO from endothelial cells. (Toda and Nakanishi-Toda 2007). Velocity of lower diastolic and systolic ophthalmic artery blood flow of NTG has a decrease of cyclic GMP (indicator of NO) in plasma and aqueous humor of glaucoma patients. (Laude et al 2004). Blood flow reduction at anterior optic nerve were demonstrated when ET-1 applied on particular region of the anterior optic nerve. (Orgul et al 1996).

2.3 Ocular Blood Flow & Visual Field

Plange et. al found that asymmetric glaucomatous visual field loss was associated with asymmetric flow velocity in cetral retinal and ophthalmic arteries in POAG patients. (Plange et al, 2006). In addition, Zeitz et al found glaucoma progression to be associated with decreased blood flow velocities in the short posterior ciliary arteries. (Zeitz et. al, 2006). Zink et al Found an association between lower optic nerve laser Doppler blood volume measurement and glaucomatous visual field progression. (Zink et al, 2003). Galassi F. Et. al (2003), reported that patient with a stable visual field had a higher diastolic velocity and a lower resistivity index in the ophthalmic artery (OA) compared to those with a deteriorating visual field during the study. Patient with a vascular resistance greater than 0.78 in the OA had 6-times the risk of visual field deterioration.

Following research by Martinez et. al (2005), suggesting a correlation between RI greater than 0.72 in the OA and increased VF progression over a period of 3 years. Independent of the progression rate of glaucomatous visual field damage statistically correlates with retrobulbar hemodynamic variables as the faster rate in progression of glaucomatous damage, a lower baseline end diastolic blood flow velocity in the central retinal artery. (Satilmis M. et. al, 2003). The evaluation of glaucoma damage were also conducted between the extent of glaucoma damage and optic nerve blood flow, found that when both of the eyes have glaucoma, the hemidisk with greater damage showed significantly lower blood velocity than the hemidisk with less damage. (Lam A. et. al, 2005). This study provides additional evidence that impaired optic nerve circulation is associated with the extent of glaucomatous pathology. Sato and associates reported that reduction of capillary blood flow at neuroretinal rim in normal tension glaucoma patients was associated with regional visual field loss.

Sclera buckling for a rhegmatogenous retinal detachment (RPD) were also found to cause a reduction in blood flow at neuroretinal rim. Upon removing the buckle, the blood flow were improved to normal levels and a further worsening of the visual field was not detected. These result suggest that an encircling of sclera buckle may impair choroidal circulation and lead to visual field defects similar to eyes with normal tension glaucoma. (Sato E.A. et. al, 2008). Research done by Vassilos and associates with 13 male & 3 female with bilateral carotid stenosis, found that postoperatively peak systolic velocity had significantly improved in all vessels examined in the carotid that was operated on, but only in the OA and short posterior cilary artery in the fellow side.

Ocular blood flow deficits may therefore represent either a primary insult or are secondary to vascular regulatory dysfunction during diurnal fluctuations in vascular risk factors in certain OAG patients (Grieshaber and Flammer 2005).

2.4 Clinical therapeutic drug effect on optic disk blood flow with glaucomatous eye.

Some evidence of blood flow deficit in glaucoma derived from flourescein angiography since flourescein is a safe consistent drug to be use for staining and should be considered in high-risk patients. (Kwan A.S. et. al, 2006). Previous findings conducted by Harris A. et. al on NTG patients found that dorzolamide also accelerated retinal arteriovenous passage time (AVP) of flourescein dye, at constant retinal arterial and venous diameter, but failed to change flow velocities in any retrobulbar vessel. (Harris A. et al, 1999). Similar findings were found on healthy volunteers by using brinzolamide which reduction IOP level but showed no significant change in retrobulbar haemodynamics, but shortening of AVP. Since in glaucoma AVP is prolonged indicating vascular dysfunction this effect might be beneficial in glaucoma therapy. (Kaup M. et. al, 2004). Dorzolamide is a carbonic anhydrase inhibitor, an anti-glaucoma agent and topically applied in the form of eye drop was treated as placebo drug. Following study with dorzolamide found that there is no measureable vascular effects from topical dorzolamide treatment in previously untreated glaucoma eyes. (Bergstrand I.C. et. al, 2002). According to Ali S.H. et. al, reduction of IOP in OAG after therapeutic IOP reduction had a statistically significant improvement of blood flow in neuroretinal rim of the ONH, where as OHT patients does not demonstrate any changes. (Ali S.H. et. al, 2003).

Another topical drug can be use to reduce IOP elevation is latanoprost. A study has been conducted to evaluate the effect of a single instillation of latanoprost on human ONH and retinal circulation within certain time. Yasuhiro T. et. al found that tissue blood velocity in the ONH increased at least temporarily following a single instillation of topical latanoprost even the mechanism of the increases remain unclear. This may indicate that the effect of latanoprost on ONH tissue circulation in human may have clinical implication. (Yasuhiro et. al, 2004). The usage of topical nipradilol caused a transient, but significant increase in the ipsilateral ONH blood velocity after twice instillation in a week which indicate that the increase in ONH blood velocity in human was not a secondary effect accompanied by a decrease in IOP in the ipsilateral eye. (Ken M. et. al, 2002). This may be nipradilol attribute on vasodilative action. (Okamura T. et. al, 1996). It had been reported that topical nipradilol increases the ONH blood velocity in rabbits and suggest is partly attributable to local penetration of the drug. (Kanno K., 1998). Similar scenario also had been reported with topical betaxolol. (Araie M. et. al, 1997). Nipradilol also has been use in dogs, whereby reduction of IOP by nipradilol was similar to that by an existing β-adrenergic antagonist, timolol maleate, but nipradilol was associated with fewer systemic side effects in dogs. Nipradilol lowered IOP to an equivalent degree to timolol maleate but its hard enough to evaluate blood flow relationship between human and animal ocular haemodynamics. (Maehara S., 2004).

Findings through topical unoprostone also effect the tissue blood velocity in the ONH, the author recorded and increase temporarily following instillation of unoprostone twice daily for 7 days. The increment implication is unclear but the effect of topical unoprostone on human ONH circulation deserve further consideration. (Yasuhiro T. et. al, 2004).

Ocular blood flow appears to be related to any disease that involve blood circulation. As for epilepsy patients exhibit reduced neuroretinal capillary blood flow, volume, and velocity compared with normal subjects. A reduction in ocular perfusion may have implication for visual function in people with epilepsy. (Emma J.R.H., 2002).

Study also shows that the usage of dormolamide increase the blood flow in temporal neuroretinal rim and the cup of the optic nerve head, and fundus pulsation amplitude. (Fuchsjager-Mayrl G. Et. al, 2005). Recent study done by Andrzej S. et.al, additive effect of dorzolamide hydrochloride (Trusoft) and a morning dose of bimatoprost (Lumigan) on IOP and retrobulbar blood flow in patients with POAG reduces IOP significantly with these combined treatment whereby the vascular resistance in ophthalmic artery decreases. (Andrzej S. et. al, 2010). Vascular retinal artery in untreated or progressive POAG after treated with topical 2% of dorzolamide for 2 weeks show increase in diameter, velocity, and flow in response to normoxic hypercapnia. Similar trends were noted for ONH vascular reactivty too. (Subha T.V. et. al, 2010). Most of the study shows that the ocular blood flow is a good indicator for pathogenesis of glaucoma and it proves that blood flow measurement is a worthy findings to be exposed.

The goal for drug therapy originally to reduce IOP elevation or slow down the visual field loss progression. The visual field and optic nerve assessment can be evaluated through fundus photograph to confirm the sign of change regarding IOP elevation. There are several classification on IOP therapeutic drug such as beta blockers, prostaglandin, carbonic anhydrase inhibitors, adrenergic agonists, cholinergic blocking agents and a combination of products. For a drug to be fully effected, therapies must penetrate the anterior surface of the eye, reach at the tissue of interest, and execute the physiologic effect. The most common topical therapies being use is timolol whereby it blocks the β-adrenergic receptors on the ciliary epithelium to reduce the aqueous humour production. β-adrenergic receptors mediate relaxation of vascular smooth muscle. (Tsujimoto G. Et. al, 1985; Virginia P.A. et. al, 2006)). If β-adrenergic were blocked, this may cause vasoconstriction in the tissue and the receptor were found on retina and the optic nerve head. (Nies A.S. et. al, 1973; Elena P.P. et. al, 1987; Dawidek G.M.B., 1993). Timolol effect on ocular blood flow in glaucoma is still controversial and not consistent, so suggested to be limited in terms of ocular vasculature effect.

Topical carbonic anhydrase inhibitors (CAIs) like brinzolamide and dorzolamide were found to be helpful to reduce IOP elevation in the eye. By terms of pharmacology process, carbonic anhydrase is an enzyme that helps fluid balance in body and transform carbon dioxide along with water into carbonic acid. Finally dissociates into protons and bicarbonate whereby bicarbonates ions regulate the formation of aqueous humor via osmosis. CAI will bind to active site of the enzyme and prevent formation of carbon dioxide, water, bicarbonate and a proton. CA-II were inhibited by CAI which the concentration found at ciliary body. The inhibition process found to reduce IOP elevation. (Virginia P.A. et. al, 2006). According to various research, CAI were the found to be the most effective therapeutic drug to alter the ocular blood flow. (Fuchsjager-Mayrl G. et. al, 2005; Andrzej S. et. al, 2010; Subha T.V. et. al, 2010).

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