In vivo evidence for endothelin-1-mediated attenuation of alpha1-adrenergic stimulation

Experiments were designed to determine the influence of endothelin A (ET(A)) receptors on the pressor response to acute environmental stress in Dahl salt-resistant (DR) and Dahl-sensitive (DS) rats. Mean arterial pressure (MAP) was chronically monitored by telemetry before and after treatment with the selective ET(A) receptor antagonist ABT-627. Rats were restrained and subjected to pulsatile air jet stress (3 min). In untreated animals, the total pressor response (area under the curve) to acute stress was not different between DR vs. DS rats (8.1 +/- 1.7 vs. 15.6 +/- 2.6 mmHg x 3 min, P = 0.10). Conversely, treatment with ABT-627 potentiated the total pressor response only in DR rats (36.3 +/- 6.2 vs. 22.6 +/- 5.9 mmHg x 3 min, DR vs. DS, P < 0.05). Treatment with ABT-627 allowed greater responses in anesthetized DR rats to exogenous phenylephrine (1-4 microg/kg) during ganglionic blockade (P < 0.05) and produced a significant increase in plasma norepinephrine at baseline and during stress in conscious DR rats compared with untreated animals (P < 0.05). ET(A) receptor blockade had no effect on these responses in DS rats. Our results suggest that endothelin-1 can inhibit alpha-adrenergic-mediated effects in DR, but not DS rats, consistent with the hypothesis that ET(A) receptor activation functions to reduce sympathetic nerve activity and responses in vascular smooth muscle to sympathetic stimulation.