Evidence for a sympatholytic effect of mibefradil in the pithed rat preparation

Objective The T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this parti cular type of calcium channel is known to be crucially involved in the neur onal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug. Methods To evaluate the sympathoinhibitory action, the effects of 3 and 10 mu mol/kg MIB on the tachycardic effect of electrical stimulation of the pr eganglionic cardioaccelerator nerves in the pithed rat were investigated. T he effect of MIB on the dose-response curve of externally applied noradrena line was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 mu mol/kg ver apamil (VER). Results The maximal increase in heart rate in response to electrical nerve stimulation was 96 +/- 7 bpm (control, n = 6), 70 +/- 6 bpm (3 mu mol/kg MI B, n = 8), 57 +/- 6 bpm (10 mu mol/kg MIB, n = 5), 93 +/- 5 bpm (3 mu mol/k g VER, n = 6) and 46 +/- 7 bpm (10 mu mol/kg VER, n = 5). The tachycardic r esponse to electrical stimulation at 1, 5 and 10 Hz was completely blocked by 5 mg/kg intravenous guanethidine. The maximal increase in heart rate in response to noradrenaline was 96 +/- 4 bpm (control, n = 6), 103 +/- 6 (3 m u mol/kg MIB, n = 6), 42 +/- 9 bpm (10 mu mol/kg MIB, n = 5), 73 +/- 5 bpm (3 mu mol/kg VER, n = 5) and 40 +/- 7 bpm (10 mu mol/kg VER, n = 6). Under control conditions and in the presence of 3 mu mol/kg MIB and VER the maxim al effect of noradrenaline was reached at 0.1 mu mol/kg whereas in the pres ence of 10 mu mol/kg MIB and VER it was reached at a dose of 1 mu mol/kg. MIB at a dose of 3 mu mol/kg was significantly more effective in reducing t he chronotropic response to electrical stimulation compared with externally applied noradrenaline. For VER the opposite holds true. These differences were not observed with doses of 10 mu mol/kg MIB and VER. Conclusion Mibefradil, besides its direct effect on cardiac T- and L-type c alcium channels, reduces the release of noradrenaline from sympathetic nerv e endings, most probably by inhibition of presynaptic N-type calcium channe ls. In the model used this effect is only observable at relatively low conc entrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade. J Hypertens 2000, 18:203-207 (C) L ippincott Williams & Wilkins.