The effect of various drugs and agonists on human platelet shape change

Jagroop, I. Anita (2000) The effect of various drugs and agonists on human platelet shape change. (MPhil thesis), Kingston University, .


The effect of various drugs and agonists on human platelet shape change (PSC) was assessed. PSC was expressed as the increase in median platelet volume (MPV). We developed a new sensitive and reproducible method to measure MPV using a high-resolution (0.07 fl) channelyzer coupled to a platelet counter. Scanning electron micrographs showed that the changes in platelet morphology were mirrored by the MPV. We also used human platelets to assess the serotonergic action of two appetite suppressants, fenfluramine (d, l-F) and dexfenfluramine (d-F), as well as the main metabolite of d-F, d-norfenfluramine (d-norF). There was an increase in MPV in response to d-norF. This action was probably mediated via the serotonin (5HT) (receptor-subtype 2), because a specific antagonist blocked it. This is the first demonstration, using human tissue, of the serotonergic action associated with a metabolite of d-F. This serotonergic activity may be involved in the pathogenesis of pulmonary hypertension and heart valve pathology reported in patients on d,l-F and d-F. We assessed two antihypertensive drugs, losartan and doxazosin. Doxazosin, a long acting [alpha][sub]1-adrenoceptor antagonist, inhibited SHT-induced PSC. This effect may have potential clinical importance, because patients with peripheral vascular disease (PVD) or diabetes mellitus can have elevated circulating levels of SHT. This bioamine exerts harmful effects like stimulating vascular smooth muscle proliferation and inducing vasoconstriction. Losartan an angiotensin type I receptor blocker inhibited PSC induced by angiotensin II and a thromboxane A[sub]2 mimetic (U46619). Therefore, losartan in addition to lowering blood pressure has antiplatelet activity. Endothelin-l (ET-l) is a potent endogenous vasoconstrictor. Naftidrofuryl inhibited platelet activation induced by ET-I alone or in combination with ADP or SHT. These actions may contribute to the beneficial effects of naftidrofuryl in patients with intermittent claudication. These findings confirm the usefulness of the PSC technique in investigating the effect of agonists and drugs on human platelets.

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