ENDOTHELIN-1-INDUCED VASOPRESSOR RESPONSES IN ESSENTIAL-HYPERTENSION

The potential role of endothelin-l (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increm ents in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of h ypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensi n-converting enzyme inhibitor enalapril (20 mg BID) or the calcium cha nnel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET- 1 levels from 2.5+/-0.4 to 11.6+/-1.0 pmol/L (P<.05). Blood pressure r ose by approximately 10 mm Hg (P<.05). Cardiac index decreased by 21+/ -2%, whereas calculated systemic vascular resistance increased by 27+/ -6% (P<.05). Renal blood flow decreased from 1051+/-94 to 707+/-60 mL/ min at the end of the ET-1 infusion (P<.05), and calculated renal vasc ular resistance increased from 118+/-19 to 189+/-19 mm Hg.min/L (P<.05 ). Sodium excretion decreased from 227+/-39 to 111+/-15 mu mol/min (P< .05). Both enalapril and nifedipine treatment prevented the systemic e ffects of ET-1 infusion in these subjects. However, during enalapril t reatment, despite renal predilatation, ET-1 reduced renal blood flow ( from 1119+/-132 to 701+/-75 mL/min, P<.05) and increased renal vascula r resistance (from 111+/-16 to 187+/-28 mm Hg.min/L, P<.05) to the sam e levels as during ET-1 infusion alone. Nifedipine pretreatment attenu ated the ET-l-induced fall in renal blood flow (from 1088+/-93 to 907/-68 mL/min) and increase in renal vascular resistance (from 105+/-9 t o 133+/-10 mm Hg.min/L). Although neither drug modulated the antinatri uretic effect of ET-1, nifedipine increased basal sodium excretion (P< .05), which compensated for the decrease during ET-1 infusion. In conc lusion, essential hypertensive subjects are sensitive to the vasoconst rictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in atten uating the renal constrictor effects of ET-1.