Mechanism of vasoselective action of mebudipine, a new calcium channel blocker.
In previous studies, mebudipine, a newly synthesized dihydropyridine calcium channel blocker, showed a considerable vasoselective action. To investigate the mechanism of this property, the pattern of inhibitory action on the KCl-induced contraction in isolated rat aortic rings and the effect of changing resting membrane potential on the potency of this compound were considered. In addition, its chronotropic and inotropic actions were also studied. Mebudipine inhibited KCl-induced contractions. Its inhibitory effect was progressive and needed time to reach maximum. Incubation of the aortic rings in depolarizing physiological solution (high potassium, zero calcium) resulted in the augmentation of mebudipine effect. The potency of mebudipine in inhibiting aortic contractions and its time- and voltage-dependent action were significantly greater than those of nifedipine. In comparison with nifedipine, mebudipine showed a greater negative chronotropic effect, but in the case of negative inotropism, the reverse relation was observed. It is concluded that mebudipine has a greater time- and voltage-dependent inhibitory effect, as compared to nifedipine and this property could explain its prominent vasoselective action. It has also marked negative chronotropic effect and minor negative inotropic action. With regard to the above findings, mebudipine might have a selective and protective calcium channel blocking effect in ischemic regions (ischemia-selectivity), and the potential to be used in cardiovascular diseases without causing harmful effects such as reflex tachycardia and heart failure which have sometimes been seen with the older agents.
Mirkhani
Hossein
H
Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, P.O. Box 71345-1649, Shiraz, Iran. mirkhanh@sums.ac.ir
Dirin
Mehrdad
M
Youssef-Zayeh
Iris
I
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000639:trends; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004338:Drug Combinations; C110812:mebudipine; D011189:Potassium Chloride; D009543:Nifedipine