Endothelin reverses the effects of acidosis on the intracellular Ca2+ transient and contractility in ferret myocardium.
Endothelin may play an important role in modulating myocardial contractility under certain pathophysiological conditions. To determine whether endothelin beneficially modulates myocardial contractility in the common clinical condition of acidosis, we compared the effects of endothelin-1 on intracellular Ca2+ transients and isometric contractions under normal (extracellular pH [pH(o)] 7.4) and acidotic (pH(o) 6.4) conditions in ferret papillary muscles (n = 33) loaded with the Ca(2+)-regulated bioluminescent indicator aequorin. A pH(o) of 6.4 was induced by replacing 92% of HCO3- with Cl- in the bathing medium. The effects of endothelin at pH(o) 6.4 differed from the effects at pH(o) 7.4 in that 1) the minimally effective concentration of endothelin was 30-fold lower (1 x 10(-10) M at pH(o) 6.4; 3 x 10(-9) M at pH(o) 7.4) and the concentration-response curve of endothelin was significantly shifted to the left with a decrease in log EC50 from -7.83 +/- 0.13 to -8.92 +/- 0.10 (p less than 0.001), indicating an increased sensitivity of myocardium to endothelin; 2) endothelin produced an increase of approximately 375% in tension development at pH(o) 6.4 (approximately 62% at pH(o) 7.4) (p less than 0.001) without increasing peak [Ca2+]i (approximately 13% increase at pH(o) 7.4, p less than 0.001), indicating an increase in myofilament Ca2+ responsiveness; and 3) endothelin significantly abbreviated (approximately -19%, p less than 0.001) the prolonged intracellular Ca2+ transient induced by acidosis (pH(o) 6.4). In addition, pretreatment with 10 microM of the Na(+)-H+ exchange inhibitor 5-(N-methyl-N-isobutyl)-amiloride significantly attenuated endothelin-induced effects on the intracellular Ca2+ transient and contraction during acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
J
J
Charles A. Dana Research Institute, Boston, MA.
Morgan
J P
JP
D000138:Acidosis / Q000378:metabolism*; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003327:Coronary Disease / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005289:Ferrets; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D016623:Ion Pumps; D009200:Myocardial Contraction / Q000187:drug effects*; D013997:Time Factors
D002316:Cardiotonic Agents; D016232:Endothelins; D016623:Ion Pumps; D000584:Amiloride; C056369:5-(N-methyl-N-isobutyl)amiloride; D002118:Calcium