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The actions of calcium antagonists on systemic hemodynamics, blood flow distribution and venous tone of the rat

University of British Columbia

The purpose of my study was to determine and compare the effects of three calcium antagonists on systemic hemodynamics, ECG, blood flow distribution, tissue conductance and venous tone of the rat. The effects of a representative drug from Spedding's (1985) three subclasses of calcium antagonists on systemic hemodynamics, ECG, cardiac output and the distribution of blood flow were investigated by the microsphere technique in pentobarbital-anesthetized rats. The representative drugs were: I, nifedipine (12 and 35 µg/kg/min); II, verapamil (43 and 83 µg/kg/min) and III, flunarizine (174 and 275 µg/kg/min). Low and high doses were selected to give a decrease in mean arterial pressure of 10 and 20 mmHg, respectively, compared with control rats. At equal depressor levels, all the drugs similarly decreased total peripheral resistance while slightly but not significantly increasing cardiac output (CO) and stroke volume. Heart rate was decreased by verapamil and flunarizine, but increased by nifedipine. The high dose of nifedipine decreased contractility as measured by dP/dt and had no effect on PR-interval, while verapamil decreased dP/dt and prolonged the PR-interval. The low dose of nifedipine and both doses of flunarizine slightly but not significantly decreased dP/dt and had no effect on PR-interval. All three drugs similarly affected the distribution of blood flow. Blood flow to lungs, liver, and heart was increased while flow to the intestine, kidneys, spleen and skin was decreased. Arterial conductances in lungs, liver, heart and skeletal muscle were increased by the three drugs. These results show that representative drugs from the three subclasses of calcium antagonists had similar effects on the distribution of blood flow and arterial conductances but different chronotropic, dromotropic and inotropic effects. A final set of experiments were designed to evaluate calcium antagonist actions on venous tone, as venous tone is a primary determinant of CO and the calcium antagonists generally increase CO. The effects of three calcium antagonists, verapamil, nifedipine and flunarizine on mean arterial pressure (MAP), heart rate (HR) and mean circulatory filling pressure (MCFP), an index of total body venous tone, were investigated in the. conscious rat. Infusions of all three drugs caused a dose-dependent decrease in MAP and an increase in MCFP, compared with the corresponding values in control rats. HR was decreased by verapamil and flunarizine and slightly increased by nifedipine. Further experiments investigated whether the increase in MCFP by verapamil was indirectly caused by reflex activation of the autonomic nervous system. Rats were pretreated with a continuous infusion of the ganglionic blocker hexamethonium prior to infusion of verapamil. After treatment with hexamethonium, verapamil did not increase the MCFP. In fact the highest dose of verapamil significantly decreased MCFP. The results suggest that calcium antagonists have greater dilator effects in arterioles compared to veins. It appears that any direct venodilator effects of verapamil in conscious rats are masked due to reflex activation of the autonomic nervous system.

Text

2010-07-19

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http://hdl.handle.net/2429/26661

Pharmacology

University of British Columbia

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