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.
van der Lee
R
R
Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands. R.vdlee@amc.uva.nl
Pfaffendorf
M
M
De Mey
J G
JG
van Zwieten
P A
PA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D020748:Mibefradil / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000294:innervation; D018377:Neurotransmitter Agents / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D013623:Tail / Q000098:blood supply; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D018377:Neurotransmitter Agents; D020748:Mibefradil; D000255:Adenosine Triphosphate; D014700:Verapamil; D009638:Norepinephrine