SYSTEMIC HEMODYNAMICS AND RENAL-FUNCTION DURING LONG-TERM PATHOPHYSIOLOGICAL INCREASES IN CIRCULATING ENDOTHELIN

Although recent studies have reported endogenous plasma endothelin lev els to be elevated two- to fivefold in chronic pathophysiological stat es, whether such an increase in circulating endothelin levels alone ca n lead to significant long-term alterations in cardiovascular and rena l function is not known. The purpose of this study was to examine the long-term systemic hemodynamic and renal effects of a pathophysiologic al increase in plasma endothelin concentration in chronically instrume nted, conscious dogs (n = 7). Infusion of endothelin-l (2.5 ng.kg(-1). min(-1)) for 8 days increased plasma concentration of immunoreactive e ndothelin approximately two- to threefold from 6.7 +/- 0.4 to 16.0 +/- 2.2 pg/ml. Mean arterial pressure increased 21% from a control value of 86.7 +/- 2.1 to 105.0 +/- 2.5 mmHg during the endothelin infusion p eriod. Cardiac output averaged 2,200 +/- 205 ml/min during control and fell by 33% on day 4 of endothelin infusion (1,484 +/- 146 ml/min) an d was still 14% below control after day 8 of endothelin infusion (1,88 5 +/- 154 ml/min). Endothelin increased total peripheral resistance fr om 42.0 +/- 8.1 to 80.3 +/- 9.1 mmHg.l(-1).min. Increasing plasma endo thelin two- to threefold was associated with an increase in renal vasc ular resistance and decreases in glomerular filtration rate and renal plasma flow. Endothelin-1 had no long-term effect on plasma renin acti vity or aldosterone concentration. These data indicate the importance of pathophysiological levels of endothelin in controlling renal and ca rdiovascular function in chronic conditions. Furthermore, the results indicate that endothelin may play a role as a mediator of chronic hype rtension in pathophysiological states associated with endothelial dysf unction.