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 < 0.001). Such a biphasic response was also observed for peak (+)dP/dt and (dP/dt)/DP40 (p < 0.005). Left ventricular systolic pressures, mean aortic pressure, and left atrial pressure increased over time (p < 0.05, p < 0.005, and p < 0.001, respectively). The time constant of early isovolumic relaxation rose progressively (p < 0.001). The percent systolic shortening decreased at 10 and 20 ng/kg.min (p < 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 < 0.005). Angiotensin II and catecholamines did not change significantly. Serum urea and creatinine rose progressively (p < 0.05), whereas glucose decreased (p < 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.