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

Abstract

The T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this particular type of calcium channel is known to be crucially involved in the neuronal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug. To evaluate the sympathoinhibitory action, the effects of 3 and 10 micromol/kg MIB on the tachycardic effect of electrical stimulation of the preganglionic cardioaccelerator nerves in the pithed rat were investigated. The effect of MIB on the dose-response curve of externally applied noradrenaline was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 micromol/kg verapamil (VER). The maximal increase in heart rate in response to electrical nerve stimulation was 96 +/- 7 bpm (control, n = 6), 70 +/- 6 bpm (3 micromol/kg MIB, n = 8), 57 +/- 6 bpm (10 micromol/kg MIB, n = 5), 93 +/- 5 bpm (3 micromol/kg VER, n = 6) and 46 +/- 7 bpm (10 micromol/kg VER, n = 5). The tachycardic response 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 micromol/kg MIB, n = 6), 42 +/- 9 bpm (10 micromol/kg MIB, n = 5), 73 +/- 5 bpm (3 micromol/kg VER, n = 5) and 40 +/- 7 bpm (10 micromol/kg VER, n = 6). Under control conditions and in the presence of 3 micromol/kg MIB and VER the maximal effect of noradrenaline was reached at 0.1 micromol/kg whereas in the presence of 10 micromol/kg MIB and VER it was reached at a dose of 1 micromol/kg. MIB at a dose of 3 micromol/kg was significantly more effective in reducing the 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 micromol/kg MIB and VER. Mibefradil, besides its direct effect on cardiac T- and L-type calcium channels, reduces the release of noradrenaline from sympathetic nerve endings, most probably by inhibition of presynaptic N-type calcium channels. In the model used this effect is only observable at relatively low concentrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade.