Amlodipine, a new 1,4-dihydropyridine calcium antagonist with a particularly strong antihypertensive profile.
The effects of a new 1,4-dihydropyridine derivative amlodipine have been compared with results from our previous work. Application of amlodipine at a concentration of 1.6 X 10(-6) M to isolated guinea-pig papillary muscle for 120 minutes produced a 50% reduction in tension development compared with a concentration of 3.7 X 10(-7) M nifedipine needed to produce the same result under identical conditions. This suggests that amlodipine has even weaker negative inotropic effects than nifedipine. In isolated porcine coronary strips, the K+-induced contractions were approximately 10,000 times more sensitive to the relaxing effects of nisoldipine, nitrendipine and nicardipine than to those of papaverine, whereas nifedipine and amlodipine were 3,000 times more potent than papaverine. However, in comparison with these in vitro actions, the efficacy of amlodipine appears to be greater in vivo: Simultaneous subcutaneous injection of nifedipine (20 mg/kg) and of equimolar doses of nisoldipine and felodipine attenuated the myocardial calcium uptake by rat hearts in situ (stimulated with a single subcutaneous dose of 30 mg/kg isoproterenol) with the same efficacy, whereas the actions of nitrendipine and nimodipine were considerably weaker. In contrast, amlodipine antagonized isoproterenol-stimulated myocardial calcium accumulation more effectively. Furthermore, amlodipine exhibited a high antihypertensive potency combined with rapid onset and long duration of action: Amlodipine (10 mg/kg orally [p.o.]) reduced the blood pressure of spontaneously hypertensive rats almost to the same extent as nifedipine, nitrendipine, verapamil and felodipine administered at the much higher doses of 100 mg/kg p.o. Amlodipine (20 mg/kg/day p.o.) maintained normal blood pressure during the whole life span of Dahl-S rats (5 months), but this dose is considerably lower than that reported for other 1,4-dihydropyridines. The survival of NaCl-loaded Dahl-S rats increased from 20 to 100% after administration of amlodipine (20 mg/kg/day p.o.) over 10 weeks: The effective dose of other calcium antagonists is approximately 5 times higher, but well tolerated as, e.g., demonstrated in long-term studies on Dahl-S rats with nitrendipine over 12 months. Increases in systemic arteriolar tone can be visualized in the ocular fundus of spontaneously hypertensive rats. After amlodipine (10 mg/kg p.o.) arteriolar spasm declines. Prophylaxis with 2 doses of 20 mg/kg amlodipine daily in NaCl-loaded Dahl-S rats abolished the macroscopic and histologic changes that are normally seen in branches of the mesenteric artery. With use of electron microscopy, calcium accumulation in the lamina elastica interna was demonstrated by the potassium-pyr-oantimonate technique.(ABSTRACT TRUNCATED AT 400 WORDS)
Fleckenstein
A
A
Physiological Institute, University of Freiburg, Federal Republic of Germany.
Frey
M
M
Zorn
J
J
Fleckenstein-Grün
G
G
D017311:Amlodipine; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008638:Mesenteric Arteries; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009543:Nifedipine / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012161:Retinal Artery; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D017311:Amlodipine; D009543:Nifedipine; D007545:Isoproterenol; D002118:Calcium