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 vera- pamil. Doses of mibefradil that gave low (M1; 0.45  0.02 g/mL) and high (M2; 0.93  0.05 g/mL) plasma concen- trations, or verapamil (0.059  0.004 g/mL; n = 6 each) were chosen to mimic clinically observed therapeutic levels. 3. At steady state infusion over 30–90 min, MAP was signifi- cantly lower in M2 (– 7 mmHg) and verapamil (– 6 mmHg) treat- ments, 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 hypo- tension. We conclude that T-type VOCC may play an important role in the venoconstrictor reflex in response to tilt in the rabbit. Key words: baroreflex, Bezold–Jarisch-like reflex, L-type calcium channel, mibefradil, nasopharyngeal reflex, orthostatic hypotension, T-type calcium channel (+/–)-verapamil. INTRODUCTION Voltage-operated Ca 2+ channels (VOCC) have been classed as L-, T-, N-, P- and Q-subtypes based on electrophysiological criteria and the pharmacology of relatively selective antagonists. 1–3 Only L- and, more recently, T-type channels are thought to occur on vascular and cardiac smooth muscle cells. 4 While the location and roles of L-type VOCC are well characterized, there is a paucity of similar data for T-type VOCC. In electrophysiological studies, T-type VOCC have been found in a variety of tissues, including the sinoatrial node, atrioventricular node, conducting tissue in the heart and in smooth muscle cells. 5,6 Until recently, more detailed studies have been hindered by the lack of a selective antagonist for these channels. Mibefradil is a novel tetrazol developed by Roche (Basle, Switzer- land) from over 500 analogues of the phenylalkylamine verapamil. It shares coronary vasodilator activity with verapamil, but not the depression of myocardial contractility until much higher concen- trations are reached. 7 In a recent analytical pharmacology study in human isolated tissue, the vascular dilatation to cardiac depression selectivity ratio of mibefradil, estimated from pIC50 values, was 41-fold. 8,9 This ratio was some 200-fold higher than that found for verapamil (ratio 0.5) and threefold higher than for the dihydro- pyridine felodipine (ratio 12). Part of this vascular selective action of mibefradil could be due to the estimated 17-fold concentration selectivity of T- versus L-type VOCC antagonism measured from whole-cell voltage-clamp studies in guinea-pig atrial myocytes 10 and 30-fold selectivity in guinea-pig azygous vein smooth muscle cells. 11 In addition, the tissue density of T- versus L-type channels or their role in entry of ‘trigger’ calcium 12 may be more important in vascular smooth muscle rather than cardiac myocytes. Pharmacodynamic studies have shown that mibefradil causes a negative chronotropic but not negative inotropic action until higher concentrations are reached. 7,13,14 Indeed, in dogs with chronic heart failure, mibefradil decreased peripheral vascular resistance at plasma concentrations that did not depress myocardial contractility. 15 In clinical studies, mibefradil, unlike L-type VOCC antagonists, did not cause increases in neurohumoral or cardiac sympathetic reflex activity in response to hypotension; effects associated with a signifi- cant incidence of mortality or myocardial infarction. 16,17 A possible reason for the lack of baroreceptor-mediated sympathetic activity following mibefradil could be the blockade of T-type VOCC mediating noradrenaline release from cardiac sympathetic nerves. If this also occurred on sympathetic varicosities in veins, some impairment of the venoconstrictor reflex to postural adaptation may occur, particularly if patients are elderly or in chronic heart failure, where sympathetic reflexes are attenuated. 18 ACUTE EFFECTS OF L- AND T-TYPE CALCIUM CHANNEL ANTAGONISTS ON CARDIOVASCULAR REFLEXES IN CONSCIOUS RABBITS Mark G Devlin, James A Angus, Kathryn M Wilson and Christine E Wright Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia Correspondence: Dr Christine E Wright, Department of Pharmacology, University of Melbourne, Victoria 3010, Australia. Email: cewright@unimelb.edu.au Received 18 July 2001; revision 25 October 2001; accepted 30 October 2001. Clinical and Experimental Pharmacology and Physiology (2002) 29, 372–380