CARDIOPULMONARY EFFECTS OF ENDOTHELIN-1 IN MAN

Objectives: Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vas oconstriction such as congestive cardiac failure and primary and secon dary pulmonary hypertension. The aim of the present study was to asses s the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal m an. Methods: Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study a nd received systemic infusions of either endothelin-1 (0.75, 1.5 and 3 pmol . kg(-1). min(-1) for 30 min each) or saline placebo. Systemic a nd pulmonary haemodynamic parameters were monitored noil-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin-angiotensin a nd natriuretic peptide system activity were also measured. Results: En dothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increase d from 1156 +/- 57 to 1738 +/- 115 dyn . s . cm(-5), and total pulmona ry vascular resistance (TPR) increased from 142 +/- 12 to 329 +/- 22 d yn . s . cm(-5). Endothelin-1 caused significant impairment of left an d right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic presser effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impair ed. Activity of the renin-angiotensin system was suppressed by endothe lin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were un changed. Conclusions: Thus, in addition to systemic and pulmonary pres ser effects our results suggest that endothelin-1 impairs overall card iovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compe nsatory changes in the renin-angiotensin system.