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 th an verapamil on sympathetic neurotransmitter release provoked by electrical field stimulation. Tail arteries (diameter 620+/-9 mu m) were obtained fro m male Wistar rats. Ring segments of 2 mm length were mounted in an isometr ic wire myograph. After an appropriate period of equilibration and a primin g procedure the vessels were either subjected to electrical field stimulati on (EFS; frequency 0.25-4 Hz fdr 30 s) or a concentration-response curve wa s generated with either noradrenaline (concentration range 0.03-3 mu M) or ATP (concentration 0.3 mM) which served as baseline parameters. EFS-induced contractions were stable and reproducible and were blocked by tetrodotoxin (1 mu M), guanethidine (3 mu M), and the combination of suramin (0.5 mM) a nd prazosin (3 mu M). EFS-induced contractions (1 Wt) were almost completel y inhibited by 10 mu M mibefradil (97%) but only partly by 10 mu M verapami l (73%). Log ICS, values were -5.6 for mibefradil and -6.6 for verapamil. C alcium antagonists were equipotent in inhibiting noradrenaline (maximum inh ibition by mibefradil and verapamil by 70% and 75%, respectively; log IC50: -6.5 and -6.7, respectively) and ATP-mediated contractions (maximum in; hi bition by mibefradil and verapamil by 92% and 97%; respectively; log IC50: -6.5 and -7.0, respectively). Consequently mibefradil displays an additiona l effect on con; tractions provoked by EFS-induced sympathetic noradrenalin e release which cannot be explained by L-type calcium channel blockade. Pro bably this effect of mibefradil is mediated by the blockade of prejunctiona l N-type calcium channels, thereby inhibiting sympathetic noradrenaline rel ease. 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.