Anti-vasoconstrictor effects of the K+ channel opener cromakalim on the rabbit aorta--comparison with the calcium antagonist isradipine.
1. Contractile responses of rabbit aortic rings elicited by KCl-depolarization, angiotensin II (AII), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) have been investigated in the presence of cromakalim (BRL 34915) and isradipine (PN 200-110). 2. Above 10(-6)M, cromakalim inhibited contractile responses to low (less than or equal to 32 mM) but not to higher KCl concentrations. The 5-HT and AII concentration-response curves were antagonized noncompetitively by cromakalim (10(-7)-10(-5)M) and the maximal responses were inhibited by 40 and 55%, respectively. 3. Isradipine caused less inhibition of AII and 5-HT contractile responses than cromakalim, and in the presence of isradipine (10(-7)M), cromakalim was still able to antagonize further the contractions to AII in this vessel. 4. NA-induced contractions were relatively insensitive to inhibition by cromakalim and isradipine, both drugs causing a small rightward shift of the NA concentration-response curve. This result suggests that NA utilizes different Ca2+ pools from those involved in AII- and 5-HT-induced contractions of this vessel. 5. The sustained (tonic) part of the NA response was inhibited in a concentration-dependent manner by cromakalim (10(-7)-10(-5)M), but not by isradipine. 6. In aortic rings partially depolarized with 3.5 x 10(-2)M KCl, the ability of cromakalim, but not of sodium nitroprusside, atriopeptin III or hydralazine, to inhibit AII- and tonic NA-induced contractions was abolished. 7. Antivasoconstrictor activity of cromakalim on the rabbit aorta appears to involve factors in addition to an indirect inhibition of Ca2+ entry through dihydropyridine-sensitive Ca2+ channels. 8. The ability of cromakalim to open K+ channels and thereby modify the membrane potential would appear to underlie these antivasoconstrictor effects. This mechanism of action of cromakalim clearly differs from that of other vasodilators such as sodium nitroprusside and hydralazine.
Cook
N S
NS
Cardiovascular Department, Sandoz Ltd., Basel, Switzerland.
Weir
S W
SW
Danzeisen
M C
MC
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D019806:Cromakalim; D005260:Female; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D012413:Rubidium / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D002121:Calcium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D000804:Angiotensin II; D012413:Rubidium; D009638:Norepinephrine; D017275:Isradipine