title: Long-term calcium antagonist treatment of human hypertension with mibefradil or amlodipine increases sympathetic nerve activity.
abstract: OBJECTIVE
  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.
authors.affiliation: Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Clinical Physiology, S-182 88 Stockholm, Sweden. madeleine.lindqvist@ds.se
authors.forename: Madeleine
authors.initials: M
authors.lastname: Lindqvist
authors.forename: Thomas
authors.initials: T
authors.lastname: Kahan
authors.forename: Anders
authors.initials: A
authors.lastname: Melcher
authors.forename: Mikael
authors.initials: M
authors.lastname: Ekholm
authors.forename: Paul
authors.initials: P
authors.lastname: Hjemdahl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002302:Cardiac Output / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006321:Heart / Q000294:innervation; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D020748:Mibefradil / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology*; D013997:Time Factors; D014463:Ultrasonography
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017311:Amlodipine; D020748:Mibefradil; D009638:Norepinephrine