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Acute Effects Of L- And T-Type Calcium Channel Antagonists On Cardiovascular Reflexes In Conscious Rabbits

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SUMMARY

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° 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 μg/mL) and high (M2; 0.93 ± 0.05 μg/mL) plasma concentrations, or verapamil (0.059 ± 0.004 μg/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 mmHg) 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° tilt, vehicle- and verapamil-treated rabbits responded with small rises in MAP of 4 ± 2 and 8 ± 2 mmHg, respectively, 5 s into the upright posture, while M1 and M2 caused falls in MAP of 6 ± 4 and 9 ± 3 mmHg, 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.
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Keywords: Bezold–Jarisch-like reflex; L-type calcium channel; T-type calcium channel (+/–)-verapamil; baroreflex; mibefradil; nasopharyngeal reflex; orthostatic hypotension

Document Type: Research Article

Affiliations: Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia

Publication date: May 1, 2002

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