INFLUENCE OF ENDOTHELIN-1 ON HUMAN ATRIAL MYOCARDIUM - MYOCARDIAL-FUNCTION AND SUBCELLULAR PATHWAYS

The influence of endothelin 1 on isometrically contracting human atria l muscle strip preparations was investigated under physiological condi tions (37 degrees C, 1 Hz, Ca2+ 2.5 mM). Endothelin dose-dependently i ncreased isometric tension from 3x10(-10)M to 1x10(-7)M. At 1x10(-7)M the inotropic effect of endothelin was maximum with isometric tension being increased by 32 +/- 6% (n = 11, p < 0.05). At 1x10(-7)M endothel in the positive inotropic effect was preceded by a transient negative inotropic effect with a decline in tension by - 5 +/- 1% (n = 11, p < 0.05). Endothelin prolonged time from peak tension to 50% relaxation ( RT50) by 29 +/- 5%. With BQ123 a competitive antagonist of the ET(A) r eceptor positive inotropic effect and the prolongation of relaxation w as significantly reduced and initial negative inotropic effect was abo lished, indicating a ET(A) receptor mediated effect. Preincubation wit h phorbolmyristateacetate (10(-5)M) to downregulate proteinkinase C (P KC) eliminated the positive inotropic effect of endothelin. Similarly, N-5,5-dimethylamiloride (10(-5)M) which inhibits Na+/H+-exchanger act ivity, abolished the positive inotropic effect of ET. However, with ei ther PMA or DMA the initial transient negative inotropic effect was st ill present(- 13 +/- 7%,n = 9, p < 0.05 and - 3 +/- 1%, n = 6, p < 0.0 5). Furthermore, both substances did not abolish the prolongation of t witch time parameters observed under endothelin. After preincubation w ith PMA, endothelin prolonged RT50 by 18 +/- 6% and with DMA by 11 +/- 2%. Using the photoprotein aequorin as an indicator for intracellular calcium concentrations showed that the positive inotropic effect was mainly mediated by an increase of systolic intracellular calcium conce ntrations. Thus, the present data indicate that the positive inotropic effect of endothelin in human atrial myocardium results from activati on of PKC with a subsequent activation of the Na+/H+-exchanger. Howeve r, the initial negative inotropic effects as well as the prolongation of relaxation seem to result from a different intracellular mechanism of endothelin.