Acute effects of L- and T-type calcium channel antagonists on cardiovascular reflexes in conscious rabbits.
1. The effects of the relatively selective T-type voltage- operated calcium channel (VOCC) antagonist mibefradil were compared with verapamil, an L-type VOCC antagonist, on a range of autonomic reflexes in conscious rabbits. 2. Mean arterial pressure (MAP), heart rate (HR), the baroreceptor-HR reflex, postural adaptation reflex (90 degrees head-up tilt), Bezold-Jarisch-like reflex and the vasoconstrictor component of the nasopharyngeal reflex were assessed before and during i.v. infusion of vehicle (saline), mibefradil or verapamil. Doses of mibefradil that gave low (M1; 0.45 +/- 0.02 microg/mL) and high (M2; 0.93 +/- 0.05 microg/mL) plasma concentrations, or verapamil (0.059 +/- 0.004 microg/mL; n = 6 each) were chosen to mimic clinically observed therapeutic levels. 3. At steady state infusion over 30-90 min, MAP was significantly lower in M2 (- 7 mmHg) and verapamil (- 6 mm Hg) treatments, but only verapamil caused a significant tachycardia (+ 31 b.p.m.) compared with vehicle. Mibefradil (M2) and verapamil decreased the HR range of the baroreflex by 27 and 29%, respectively, but neither treatment affected the vagal or sympathetic constrictor components of the Bezold-Jarisch-like and nasopharyngeal reflexes, respectively. 4. In response to 90 degrees tilt, vehicle- and verapamil-treated rabbits responded with small rises in MAP of 4 +/- 2 and 8 +/- 2 mm Hg, respectively, 5 s into the upright posture, while M1 and M2 caused falls in MAP of 6 +/- 4 and 9 +/- 3 mm Hg, respectively, at 5 s. 5. Thus, both L- and T-type VOCC antagonists, at plasma concentrations in the clinical range, lowered MAP in the conscious rabbit, but only mibefradil caused postural hypotension. We conclude that T-type VOCC may play an important role in the venoconstrictor reflex in response to tilt in the rabbit.
Devlin
Mark G
MG
Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
Angus
James A
JA
Wilson
Kathryn M
KM
Wright
Christine E
CE
D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D020748:Mibefradil / Q000097:blood / Q000494:pharmacology; D009305:Nasopharynx / Q000187:drug effects / Q000502:physiology; D011187:Posture; D011817:Rabbits; D012018:Reflex / Q000187:drug effects*; D014700:Verapamil / Q000097:blood / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D014700:Verapamil