BLOCKADE OF ENDOTHELIUM-DEPENDENT RELAXATION BY THE AMILORIDE ANALOG DICHLOROBENZAMIL - POSSIBLE ROLE OF NA+/CA++ EXCHANGE IN THE RELEASE OF ENDOTHELIUM-DERIVED RELAXANT FACTOR

  • 1 December 1985
    • journal article
    • research article
    • Vol. 235  (3) , 644-650
Abstract
The importance of extracellular calcium for the expression of endothelium-dependent relaxation was examined in isolated rat aortic rings contracted by methoxamine. The endothelium-dependent relaxation generated by acetylcholine or the calcium ionophore A23187 was eliminated when rings were placed in physiological buffer to which calcium had not been added. The endothelium-independent relaxation to sodium nitroprusside was still elicited in the presence of this low calcium buffer. Pretreatment of aortic rings with high concentrations of nifedipine (5 .times. 10-7 M) or verapamil (10-5 M) caused a comparable displacement to the right (2-3 times) in the relaxant dose-response curve for acetylcholine, A23187 and sodium nitroprusside with little or no changes in the maximal relaxation obtained with these vasodilators. Increasing concentrations of dichlorobenzamil, an analog of amiloride and a recently described inhibitor of calcium influx via sodium-calcium exchange, functionally antagonized and abolished the relaxations elicited by acetylcholine and A23187, but had no apreciable effect on the relaxations to sodium nitroprusside or atrial natriuretic factor (an endothelium-independent vasodilator). Similar results were obtained using isolated rabbit aortic rings. Thus, although the presence of extracellular calcium is critically required for the expression of endothelium-dependent relaxation, the associated calcium translocation is not blocked by the organic calcium entry blockers. The results with dichlorobenzamil suggest that sodium-calcium exchange may be an important mechanistic step in the release of endothelium-derived relaxant factor.

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