Blockade of endothelin-induced contractions by dichlorobenzamil: mechanism of action.
Contractions of intact rat aortic rings induced by endothelin were totally inhibited by the amiloride analogue dichlorobenzamil (DCB) at concentrations known to block Na-Ca exchange (IC50 = 30 microM). Amiloride (100 microM) was ineffective. Ca-channel blockers and a K-channel opener elicited only partial inhibition. These results could indicate that the Na-Ca exchanger plays an important role in endothelin-induced contractions. Endothelin, however, had no effect on the kinetics of the exchanger, and, in addition, contractions also occurred in Na-depleted vessels. The endothelin-induced contractions produced by Ca release from intracellular pools were also completely inhibited by DCB. In fact, the latter compound was found to block contractions induced by Ca itself in the presence of Ca ionophore or detergent. We conclude that DCB acts directly on Ca-induced activation of myofilaments in smooth muscle.
Criscione
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L
Cardiovascular Research Department, CIBA-GEIGY Limited, Basel, Switzerland.
Thomann
H
H
Rodriguez
C
C
Eglème
C
C
Chiesi
M
M
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology*; D004533:Egtazic Acid / Q000494:pharmacology; D016232:Endothelins; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010455:Peptides / Q000037:antagonists & inhibitors*; D051381:Rats; D019831:Sodium-Calcium Exchanger; D014661:Vasoconstriction / Q000187:drug effects*
D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D016232:Endothelins; D008565:Membrane Proteins; D010455:Peptides; D019831:Sodium-Calcium Exchanger; C041470:3',4'-dichlorobenzamil; D000001:Calcimycin; D004533:Egtazic Acid; D000584:Amiloride; D002118:Calcium