ANALYSIS OF THE VASOCONSTRICTOR RESPONSES TO POTASSIUM DEPOLARIZATION AND NOREPINEPHRINE AND THEIR ANTAGONISM BY DIFFERING CLASSES OF VASODILATORS IN THE PERFUSED RAT HINDQUARTERS

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Abstract
Although the role of Ca in activation of vascular smooth muscle has received considerable attention, few studies have analyzed responses of resistance vessels. The role of Ca in vasoconstriction induced by norepinephrine (NE) and by high K depolarization was evaluated in the resistance vessels of the Krebs''-perfused rat hindquarters. Responses to vasodilators of differing classes were assessed. Injection of NE (0.3-100 .mu.g) into the hindquarters increased perfusion pressure in a dose-related manner. Perfusion of the hindquarters with a depolarizing salt solution (80 mM K+) produced a sustained vasoconstriction (perfusion pressure = 143 .+-. 4 mm Hg). Vasoconstriction to NE and high K+ was abolished during perfusion with a Ca-free salt solution containing 2 mM ethylene glycol bis(.beta.-aminoethyl ether)-N,N''-tetraacetic acid. The K-induced vasoconstriction was slightly reduced (perfusion pressure = 119 .+-. 4 mm Hg) in animals pretreated with reserpine (5 mg/kg i.p.) indicating a slight neurogenic contribution to the response. The Ca channel blockers nifedipine (0.03-10 .mu.g), diltiazem (0.3-30 .mu.g) and verapamil (0.1-10 .mu.g) produced dose-related vasodilation of hindquarters constricted with either NE (7.1 .mu.M) or high K. These drugs were 4-10-fold more potent against K-induced vasoconstriction. Reserpine pretreatment enhanced the vasodilator response to nifedipine in K-depolarized preparations. Nitroprusside and nitroglycerin relaxed both NE and K-constricted hindquarters. The calmodulin blockers trifluoperazine and W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfamide] produced vasodilation; trifluoperazine was 12.5 times more potent against NE-induced vasoconstriction. These experiments demonstrate with respect to the resistance vessels of the rat hindquarters that extracellular calcium is critical to the vasoconstrictor response to both NE and K+; NE- and K+-induced vasoconstriction is highly sensitive to Ca blockers, nitrates, W-7 and trifluoperazine; and NE release masks the sensitivity of the K-depolarized preparations to Ca channel blockade by nifedipine. The hindquarters resistance vessels apparently differ from larger arteries (e.g., rabbit aorta) in terms of the source of activator Ca for NE and the relative sensitivity of the NE response to Ca channel blockade.