Cardiovascular and endocrine effects of endothelin-1 at pathophysiological and pharmacological plasma concentrations in conscious dogs.

BACKGROUND

Increased plasma concentrations of endothelin-1, a potent vasoconstrictor produced by the endothelium, have been reported in various pathological conditions. This study was conducted to evaluate effects of endothelin-1 at pathophysiological and pharmacological plasma concentrations.

METHODS AND RESULTS

Endothelin-1 was infused at increasing doses (2.5, 5, 10, and 20 ng/kg.min for 1 hour each) in nine conscious dogs. During endothelin-1 infusion, plasma endothelin-1 rose from a basal value of 1.8 +/- 0.4 pmol/l to 5.8 +/- 1.1 (pathophysiological), 20.8 +/- 3.9 (pathophysiological), 85.4 +/- 18.9 (pharmacological), and 311.4 +/- 55.7 (pharmacological) pmol/l at each dose, respectively. Heart rate increased at 2.5 ng/kg.min (from 129 +/- 7 to 146 +/- 12 beats/min) but decreased at 20 ng/kg.min (97 +/- 7 beats/min) (p less than 0.001). Such a biphasic response was also observed for peak (+)dP/dt and (dP/dt)/DP40 (p less than 0.005). Left ventricular systolic pressures, mean aortic pressure, and left atrial pressure increased over time (p less than 0.05, p less than 0.005, and p less than 0.001, respectively). The time constant of early isovolumic relaxation rose progressively (p less than 0.001). The percent systolic shortening decreased at 10 and 20 ng/kg.min (p less than 0.005). Pressure-segment length loops showed a reduction in systolic shortening associated with an increase in left ventricular systolic pressure at 20 ng/kg.min. Atrial natriuretic factor rose after 5 ng/kg.min from 28.5 +/- 6.5 to 92.0 +/- 18.2 pmol/l (p less than 0.005). Angiotensin II and catecholamines did not change significantly. Serum urea and creatinine rose progressively (p less than 0.05), whereas glucose decreased (p less than 0.05). The above results differed significantly from measurements obtained in a time-control group of six dogs.

CONCLUSIONS

A fourfold increase of plasma endothelin-1 obtained after doubling the infusion rate suggests a reduction in endothelin-1 clearance or endothelin-1 endogenous production. The biphasic response of heart rate is consistent with baroreflex-mediated effects resulting from vasodilation at the pathophysiological level and vasoconstriction at the pharmacological level. Hemodynamic data suggest an increase followed by a decrease in contractility at both levels, respectively. Finally, endothelin-1 is a stimulator of atrial natriuretic factor.