Elevated Endothelin-1 inHeartFailure and LossofNormalResponse toPostural Change

Venousbloodsamples wereobtained after 90minutes ofsupine restandserially during 30minutes of60°upright tilt. Endothelin-1 levels werecompared with those ofknownneurohumoral mediators ofcompensation. Innormalsubjects, theresting levels ofendothelin-1 werelow(0.74±0.11 pg/ml), andthere was arapid increase to1.37±0.07 pg/ml at5minutes ofupright tilting (p<0.05). Thisincrease was notsustained at10and15minutes oftilt, butthere was atrend toward asecond rise at30minutes (1.14±0.17 pg/ml;p=0.06). This biphasic pattern ofresponsewas sharedbydopamine andreflected theresponseofsystemic bloodpressuretopostural change. Incontrast, slower andmore sustained increases in circulating levels were observed fornorepinephrine, epinephrine, aldosterone, plasmarenin activity, andvasopressin, whereas atrial natriuretic peptide tended todecrease progressively. Patients withcongestive heartfailure hadmarkedly higher basallevels ofcirculating endothelin-1 thannormalsubjects (3.7±0.5 pg/ml; p<0.01), andthere was no further increase on postural change. Similar patterns were observed fortheotherneurohumoral mediators measured, withthedegree ofblunting oftheresponsetoupright tilting inheart failure being inversely related tothemagnitude ofincrease inbasal levels. Conclusions. Alterations inplasmalevels ofendothelin incongestive heartfailure andin responsetopostural change werequalitatively andquantitatively similar tothealterations of knownmediators ofneurohumoral compensation. Inaddition, theincrease inplasma endothelin-1 during upright tilting innormalsubjects preceded theincreases incirculating levels oftheothervasoconstrictor mediators, consistent witha roleofendothelin-1 in neurohumoral compensation forhemodynamic stress. (Circulation 1992;85:510-517)