Inhibitory effect of mibefradil on contractions induced by sympathetic neurotransmitter release in the rat tail artery

This study tested whether mibefradil exerts a stronger inhibitory effect than verapamil on sympathetic neurotransmitter release provoked by electrical field stimulation. Tail arteries (diameter 620+/-9 microm) were obtained from male Wistar rats. Ring segments of 2 mm length were mounted in an isometric wire myograph. After an appropriate period of equilibration and a priming procedure the vessels were either subjected to electrical field stimulation (EFS; frequency 0.25-4 Hz for 30 s) or a concentration-response curve was generated with either noradrenaline (concentration range 0.03-3 microM) or ATP (concentration 0.3 mM) which served as baseline parameters. EFS-induced contractions were stable and reproducible and were blocked by tetrodotoxin (1 microM), guanethidine (3 microM), and the combination of suramin (0.5 mM) and prazosin (3 microM). EFS-induced contractions (1 Hz) were almost completely inhibited by 10 microM mibefradil (97%) but only partly by 10 microM verapamil (73%). Log IC50 values were -5.6 for mibefradil and -6.6 for verapamil. Calcium antagonists were equipotent in inhibiting noradrenaline (maximum inhibition by mibefradil and verapamil by 70% and 75%, respectively; log IC50: -6.5 and -6.7, respectively) and ATP-mediated contractions (maximum inhibition by mibefradil and verapamil by 92% and 97%, respectively; log IC50: -6.5 and -7.0, respectively). Consequently mibefradil displays an additional effect on contractions provoked by EFS-induced sympathetic noradrenaline release which cannot be explained by L-type calcium channel blockade. Probably this effect of mibefradil is mediated by the blockade of prejunctional N-type calcium channels, thereby inhibiting sympathetic noradrenaline release. Since activation of the sympathetic nervous system in hypertension is both common and undesirable, a calcium antagonist displaying both L- and N-type calcium channel blocking activities, would have major advantages over calcium antagonists lacking N-type calcium channel blocking activities.