Cardiopulmonary effects of endothelin-1 in man.
OBJECTIVE
Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vasoconstriction such as congestive cardiac failure and primary and secondary pulmonary hypertension. The aim of the present study was to assess the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal man.


METHODS
Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study and 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 and pulmonary haemodynamic parameters were monitored non-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin-angiotensin and natriuretic peptide system activity were also measured.


RESULTS
Endothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increased from 1156 +/- 57 to 1738 +/- 115 dyn.s.cm-5, and total pulmonary vascular resistance (TPR) increased from 142 +/- 12 to 329 +/- 22 dyn.s.cm-5. Endothelin-1 caused significant impairment of left and right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic pressor effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impaired. Activity of the renin-angiotensin system was suppressed by endothelin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were unchanged.


CONCLUSIONS
Thus, in addition to systemic and pulmonary pressor effects our results suggest that endothelin-1 impairs overall cardiovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compensatory changes in the renin-angiotensin system.
Kiely
D G
DG
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, UK.
Cargill
R I
RI
Struthers
A D
AD
Lipworth
B J
BJ
D000328:Adult; D009320:Atrial Natriuretic Factor / Q000097:blood*; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D003864:Depression, Chemical; D003971:Diastole; D004311:Double-Blind Method; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D019332:Endothelin-1 / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D010701:Phonocardiography; D011667:Pulmonary Veins / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012083:Renin / Q000097:blood; D013318:Stroke Volume / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D016276:Ventricular Function / Q000187:drug effects*
D019332:Endothelin-1; D009320:Atrial Natriuretic Factor; D012083:Renin