Calcium channel blocking properties of amlodipine in vascular smooth muscle and cardiac muscle in vitro: evidence for voltage modulation of vascular dihydropyridine receptors.
Amlodipine was twice as potent as nifedipine at inhibiting Ca2+-induced contractions in depolarised rat aorta (IC50 1.9 nM vs. 4.1 nM) but, unlike nifedipine, displayed a very slow onset of action. Contractions induced by depolarising steps with 45 mM K+ were much less potently blocked by amlodipine (IC50 19.4 nM), whereas the potency of nifedipine was little changed (IC50 7.1 nM). This difference may be explained by a modulated receptor hypothesis, similar to that described for cardiac muscle, in which block of vascular calcium channels by dihydropyridines is enhanced at depolarized membrane potentials, such voltage-dependence only being apparent with a slow-acting drug such as amlodipine. Recovery from amlodipine block of K+-responses in rat portal vein after drug washout was also very slow. Amlodipine and nifedipine blocked phenylephrine-induced contractions of the rat aorta with potencies similar to those against depolarisation-induced responses. Negative inotropic potencies of amlodipine and nifedipine in perfused guinea pig hearts were approximately one-tenth those against Ca2+-induced contractions in rat aorta. Amlodipine caused complete block of guinea pig papillary muscle single-cell slow action potentials at a concentration (5 microM) that had no effect on upstroke velocity of normal, fast potentials but reduced the duration of the plateau phase.
D000200:Action Potentials / Q000187:drug effects; D017311:Amlodipine; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011978:Receptors, Nicotinic; D017311:Amlodipine; D009543:Nifedipine; D011188:Potassium; D002118:Calcium