Divergent Effects of Dihydropyridine and Phenylalkylamine Calcium Channel Antagonist Classes on Autonomic Function in Human Hypertension

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Abstract
Abstract Calcium channel antagonists differ by class in reported frequency of side effects that suggest reflex sympathoadrenal activation. Do such differences result from differential effects on autonomic and baroreflex function? The present study compared acute and chronic effects of two classes of calcium channel antagonists, the dihydropyridine type (felodipine) and the phenylalkylamine type (verapamil), on efferent sympathetic outflow and baroreflex slope in 15 essential hypertensive subjects. Blood pressure, heart rate, hemodynamics, and biochemistries were determined at baseline and after acute (first dose) and chronic (4 weeks) administration of the drugs versus placebo. Acutely, felodipine caused a greater decrease in blood pressure associated with a larger decline in systemic vascular resistance than the corresponding effects produced by verapamil. Chronically, there were similar, significant declines in blood pressure ( P =.001) and systemic vascular resistance ( P =.001) after each drug. Acutely, increased sympathetic activity after felodipine was suggested by reflex tachycardia (from 69±3 to 74±2 beats per minute, P =.014) and elevation of plasma norepinephrine (from 264±25 to 323±25 pg/mL, P =.037), whereas after verapamil the corresponding changes were closely similar to those after placebo. Chronically, verapamil suppressed sympathetic activity, as evidenced by a decrease in resting heart rate (from 76±2 to 69±3 beats per minute, P =.002), decrease in plasma norepinephrine (from 264±25 to 178±21 pg/mL, P <.001), decrease in chromogranin A (from 33.0±2.4 to 27.8±1.7 ng/mL, P <.001), and lessened response of mean arterial pressure ( P =.006) and heart rate ( P =.016) to phentolamine α-adrenergic blockade; after chronic felodipine, all of these variables were unchanged. Neither drug affected baroreflex slope. We conclude that felodipine and verapamil have qualitatively different, time-dependent actions on efferent sympathetic nervous system activity, actions that may in part explain the disparity in autonomic/hemodynamic side effect profiles of the dihydropyridine and phenylalkylamine classes of calcium channel antagonists.