Mechanism of the vasodilating action of etozoline and its metabolites in guinea-pig aorta.
The mechanism of the vasodilating action of the diuretic etozoline and of its metabolites d- and l-ozolinone was studied in isolated aortic strips from reserpine-treated guinea-pigs. Etozoline (10 microM to 1 mM) induced a concentration-dependent inhibition of the contraction evoked by increasing K+ concentrations (15 to 45 mM) in the perfusion medium. The inhibition was of a noncompetitive type. Etozoline also inhibited contractions induced by increasing Ca++ concentrations in the perfusion medium of aortic strips depolarized by 40 mM K+. The inhibition was concentration-dependent and of a noncompetitive type. Tetraethylammonium, at concentrations reported to increase Ca++ influx into smooth muscle cells by closing K+ channels, induced contractions of aortic strips that were highly sensitive to inhibition by etozoline. Analysis of the concentration-response curves for tetraethylammonium showed that the antagonism by etozoline was of a competitive type. The pA2 value for etozoline was 5.01 +/- 0.16. Also arterial spasm, obtained by prolonging the exposure of vascular strips to tetraethylammonium (30 min), was completely suppressed by etozoline. l- and d-Ozolinone antagonized tetraethylammonium-induced contractions of aortic strips in an apparently competitive manner, but only at very high concentrations (1 and 3 mM, respectively). These results suggest that the vasodilating action of etozoline and of its metabolites is mediated by an inhibition of Ca++ influx into smooth muscle cells following a specific opening of K+ channels, but only etozoline may act through this mechanism at concentrations likely to be operative in vivo.
Dorigo
P
P
Department of Pharmacology, Padua University, Italy.
Belluco
P
P
Corradi
L
L
Gaion
R M
RM
Maragno
I
I
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D013237:Stereoisomerism; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014665:Vasodilator Agents
D000959:Antihypertensive Agents; D013757:Tetraethylammonium Compounds; D013844:Thiazoles; D014665:Vasodilator Agents; C018121:ozolinone; D012110:Reserpine; D011188:Potassium; D002118:Calcium; C015208:etozolin