EFFECTS OF CONTINUOUS-INFUSION OF ENDOTHELIN-1 IN PREGNANT SHEEP

Plasma concentration of endothelin-1, a potent vasoconstrictor produce d by the vascular endothelium, has been observed to be significantly i ncreased in a number of pathophysiological states, including preeclamp sia. In the present study we have evaluated the effects of elevated pl asma endothelin-1 in pregnant sheep by continuous exogenous endothelin -1 administration. Nine pregnant ewes (110+/-5 days: gestation) were i nstrumented for measurements of maternal mean arterial pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1 was infused intravenously for 4 hours at a dose that was adjusted to raise mean arterial pressure by approximate to 20 mm Hg by the end of the f irst hour (range 5 to 20 ng/kg per minute). Mean arterial pressure, re nal blood flow, uterine blood flow, urinary protein excretion, hematoc rit, and plasma endothelin-1 concentration were measured hourly, and r enal and uterine vascular resistances were calculated. Endothelin-1 pr oduced significant increases (% change from baseline at t=4 hours) in mean arterial pressure (45+/-8%), renal vascular resistance (353+/-66% ), and uterine vascular resistance (59+/-21%). Endothelin-1 also incre ased microvascular permeability both systemically and within the kidne y, as suggested by marked increases in hematocrit (0.27+/-0.01 to 0.32 +/-0.01) and urinary protein concentration (0.95+/-0.1 to 7.9+/-3.2 mg /mL per mg creatinine). There was a highly significant correlation (P< .0001) between plasma endothelin-1 and mean arterial pressure, renal v ascular resistance, uterine vascular resistance, hematocrit, and urina ry protein content in all sheep studied. In addition, plasma endotheli n-1 corresponded well with the time course of the changes in cardiovas cular parameters and urinary protein excretion observed. These results provide evidence to suggest that elevation of circulating endothelin- 1 in pregnant sheep can produce cardiovascular and hemodynamic changes that in many ways resemble the human disease preeclampsia. This suppo rts the hypothesis that endothelial cell damage and/or dysfunction tha t is associated with increased production of endothelin-1 could direct ly contribute to the progression of preeclampsia.