Long-term calcium antagonist treatment of human hypertension with mibefradil or amlodipine increases sympathetic nerve activity

OBJECTIVES: Calcium antagonists are vasodilating drugs, which may cause reflex activation of the sympathetic nervous system with potentially untoward effects. We studied the effects of long-term treatment with amlodipine, a long-acting dihydropyridine-type calcium antagonist, and mibefradil, a phenylalkylamine-type calcium antagonist, on sympathetic nerve activity. METHODS: Fourteen patients with primary hypertension participated in a double-blind, cross-over study comparing the effects of 6 weeks of treatment with mibefradil 100 mg daily and amlodipine 10 mg daily. Heart rate, direct arterial blood pressure and cardiac output by echocardiography were registered. Global sympathetic activity was estimated using a [3H]noradrenaline isotope dilution method with arterial and venous sampling; cardiac sympathetic activity was assessed indirectly by heart rate variability and tissue velocity echocardiography. RESULTS: Both drugs lowered mean arterial pressure; the decrease was more pronounced with mibefradil (from 118 +/- 3 to 99 +/- 2 mmHg, compared to 118 +/- 3 to 104 +/- 2 mmHg for amlodipine, P < 0.01 between drugs). Mibefradil decreased heart rate (66 +/- 2 to 57 +/- 2 bpm), whereas amlodipine caused a slight increase (66 +/- 2 to 70 +/- 2 bpm; P < 0.001 between drugs) and tended to increase cardiac output. Noradrenaline spillover increased similarly with the two drugs, from 3.44 +/- 0.27 to 5.20 +/- 0.48 nmol/min per m2(P < 0.01) during mibefradil and to 5.72 +/- 0.49 nmol/min per m2 (P < 0.001) during amlodipine. There were minor effects on cardiac sympatho-vagal balance, but systolic and diastolic myocardial velocities were increased similarly by both drugs. CONCLUSIONS: Mibefradil and amlodipine treatment increase global sympathetic nerve activity similarly during long-term treatment, despite opposite effects on heart rate. Increases in myocardial velocities suggest concomitant cardiac sympathetic activation.