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Studies on the direct vascular actions of diuretics

University of British Columbia

Although thiazide diuretics have been a mainstay of the drug therapy for the treatment of hypertension for over 30 years, the exact mechanism by which they reduce blood pressure is not known. In this thesis, the direct vascular actions of a thiazide diuretic (hydrochlorothiazide) were compared with those of thiazide like diuretics (chlorthalidone and indapamide) and a loop diuretic (furosemide). The vascular actions of these four diuretics were studied in the presence and absence of plasma solutions on the following tissue preparations: rat aortic rings, rat pulmonary artery rings, human uterine artery rings, and the rat perfused mesenteric bed. Whole animal experiments were conducted in control and a hypertensive rat model (DOCA/salt treated). Acute hypotensive effects of the diuretics were measured in rats with ligated ureters to prevent any diuretic effect. Acute tissue blood flow effects were also measured using the reference sample method with radioactively-label led microspheres. Results: (1) Diuretics possess a direct vasorelaxant effect only in the presence of plasma on in vitro arterial preparations. (2) This in vitro relaxant effects is endothelium-independent. (3) Albumin was found to be the main plasma cofactor required by diuretics. (4) Preincubation with albumin enables tissues to retain their responsiveness to diuretics in Krebs solution alone. (5) Excess albumin appears to decrease the vasorelaxant action of diuretics, presumably due to binding of the diuretics to albumin. (6) Diuretics possess acute blood pressure lowering and vasodilating effects in hypertensive animals by a mechanism independent of diuresis. (7) These in vivo effects are due to decreased total peripheral resistance and increased blood flow to specific vascular beds (intestine and kidney). (8) The potency of the vasorelaxant actions of the four diuretics tested in the various preparations is reproducible (indapamide > hydrochiorothiazide > chiorthalidone > furosemide) and is consistent. with their clinical antihypertensive potency. (9) Hydrochlorothiazide and chiorthalidone in plasma directly relax vascular smooth muscle by acting on calcium-activated potassium channels whereas indapamide and furosemide act by a different mechanism which is not prostaglandin-dependent. These data suggest that diuretics possess a direct vasorelaxant action which may be important to the antihypertensive action of these drugs.

Thesis/Dissertation

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2009-04-15

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http://hdl.handle.net/2429/7127

Pharmacology and Therapeutics

University of British Columbia

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