The modification of endothelin effects by the calcium antagonist isradipine was investigated by infusion of 1.0 n M/kg endothelin. a dose known to cause profound vasoconstriction, into eight anesthetized rabbits, followed by an infusion of 10 μg/kg isradipine or its vehicle into four rabbits each. In a second series of experiments, only isradipine (same dose) or its vehicle was infused into six rabbits each. Endothelin increased blood pressure and caused systemic vasoconstriction. marked bradvcardia, and cardiodepression (measured with a strain gauge), yet decreased central venous pressure. The regional vascular effects (measured with microspheres) encompassed widespread vasoconstriction (especially to the kidneys. adrenals, stomach, cecum, and heart), but also a tendency for vasodilatation (hepatic artery). Isradipine decreased blood pressure in endothelin-treated and normal animals. It increased cardiac output more in the endothelin group. The interaction between endothelin and isradipine in the peripheral circulation was generally additive. Isradipine blunts many, but not all, endothelin effects, thus resembling the antivasoconstrictor effects of calcium antagonists against a variety of vasoconstrictor agents such as angiotensin II (Ang 11) or vasopressin. Similar to these, endothelin appears to cause vasoconstriction by several mechanisms, one of which apparently involves L-channel activation. A specific interaction of endothelin with the L-channel appears unlikely.
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