Prostanoids hypertension

A new initiative is a prostaglandin analogue latanoprost, a synthetic derivative of PGFja, used topically in open-angle glaucoma and ocular hypertension in patients unresponsive to other drugs (see prostanoid receptor AGONIST), antihaemophilic factor factor VIII. 

In comparison to the n-6 series, much less attention has been paid to the involvement of n-3 fatty acids in diabetic neuropathy, although the beneficial effects offish-oil supplements, a rich source of these fatty acids, in the prevention of atherosclerosis and hypertension in animal models and patients with vascular complications is well known (Lands et al. 1992). Proposals for the mechanisms by which n-3 fatty acids act include serving as precursors of vasoactive prostanoids and acting as shmulants for production of relaxing factors, such as nitric oxide (Lands etal. 1992 Boulanger 1990 McVeigh etal. 1993). 

The inhibition of distal nephron Na" reabsorption by 5,6-EET " the induction of kidney CYP2C23 and EET biosynthesis by excess dietary salt 123 and EET-induced dilation of micro-circulatory beds " suggested antihypertensive functions for the EETs In agreement with this (a) clotrimazole inhibition of the rat kidney epoxygenases caused reductions in renal EET biosynthesis , and the development of clotrimazole-dependent, salt-sensitive hypertension , (b) high salt diets failed to induce the activity of the kidney AA epoxygenase in hypertensive DS rats , and (c) the EETs contribute to the prostanoid- and NO-independent dilation pf renal afferent arterioles " In summary,... 

Studies constrasting normotensive and hypertensive subjects in terms of renal prostanoid excretion and prostanoid production by vascular and renal structures are abundant and provide compelling evidence that hypertension, both clinical and experimental, is commonly associated with disturbances in the arachidonic acid-prostanoid system. 

Many studies indicate an association between high blood pressure in experimental animals and abnormalities in urinary prostanoid excretion, a presumed index of the balance between renal prostanoid production and catabolism in vivo, and in rates of prostanoid synthesis and catabolism by renal structures and subcellular fractions in vitro. The urinary excretion of PGE2 is unchanged or decreased in spontaneously hypertensive rats, decreased in genetically hypertensive mice, in female genetically hypertensive rats (New Zealand strain) and in hypertensive Dahl salt-sensitive rats and either unchanged" or increased" in rats with two kidney-one clip... 

Abnormalities in renal prostanoids have been detected in several forms of clinical hypertension, including essential hypertension, renovascular hypertension and eclampsia. 

Effect of inhibitors of prostanoid synthesis on blood pressure in hypertensive animals and man... 

The net blood pressure response to treatment with inhibitors of prostanoid synthesis is determined by the sum of the alterations in cardiovascular and renal functions resulting from the deficit in prostanoid-mediated prohypertensive and antihypertensive mechanisms. In general, augmentation of blood pressure during chronic treatment with inhibitors of prostanoid synthesis is a response more frequent in hypertensive than in normotensive states and is usually accompanied by deterioration of renal haemodynamic and excretory... 

Reduction of blood pressure during the administration of inhibitors of prostanoid synthesis is noted in both normotensive and hypertensive conditions characterized by elevated plasma renin activity and is accompanied by marked lowering of plasma renin . Since renal prostanoids promote renin secretion , the reduction in blood pressure elicited by prostanoids synthesis inhibitors is probably the manifestation of a deficit in prostanoid-mediated renin release. Reduced synthesis of thromboxane also may contribute to lowering of blood pressure during treatment with inhibitors of prostanoid synthesis. This possibility is supported by the demonstration that specific inhibitors of thromboxane synthetase can lower blood pressure in spontaneously hypertensive rats. ... 

That therapy with various types of antihypertensive agents causes prostanoid levels to increase, raises the possibility that the accompanying blood pressure lowering effect is related to the increase in prostanoids. Pertaining to this point, several studies have demonstrated that indomethacin treatment at 75-200 mg day consistently raises blood pressure, sometimes by as much as 30mmHg, in hypertensive patients undergoing therapy with... 

DHA has been shown to induce endothelium-independent vasodilation. The meehanism(s) underlying DHA-induced vasodilation are 1) aetivation of ATP-sensitive channels in VSMCs by prostanoids (DHA metabolite) [30], 2) inhibition of L-type Ca channel and intracellular calcium release in VSMCs [30], Ingestion of -3 fatty acid supplements (e.g. fish oil and com oil) in rats reduced norepinephrine or vasopressin-mediated aortic vasoconstriction and enhanced endothelium-dependent vasodilation via acetylcholine. Furthermore, DHA-mediated vasodilation was prevalent in spontaneous hypertensive rat aorta suggesting that dietary intake of DHA is beneficial to counteract hypertension [30, 31], Similarly, ALA causes coronary arterial vasodilation via activation of VSMC Na /K -ATPase-mediated hyperpolarization [32]. Administration of ALA ean also increase CBF and vasodilation of rodent basilar artery (via activation of TREK-1 potassium chaimel) [33] indicating that ALA may also have therapeutic value used to eombat stroke/ischemia by increasing eerebral eirculation. 

Currently, prostanoids are administered for various therapeutic interventions e.g., 1) treprostinil, beraprost, and iloprost (Fig. 3) are analogs of PGI2 (prostacychn) which are used to treat pulmonary arterial hypertension (PAH) to overcome the drawback of short circulation... 

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