Endothelin-1 has a unique oxygen-saving effect by increasing contractile efficiency in the isolated rat heart.
BACKGROUND
The effect of endothelin (ET)-1 on cardiac energetics is not fully understood.


RESULTS
In isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (E(max)), pressure-volume area (PVA), and myocardial oxygen consumption (MVO(2)) before and after administration of ET-1 (1x10(-)(9) mol/L). ET-1 increased E(max) by 48+/-16% (P<0.01) and the total MVO(2) by 24+/-11% (P<0.01). The MVO(2)-PVA relations were linear both before and after ET-1 (r>0.99). ET-1 shifted MVO(2)-PVA upward, increasing the MVO(2) intercept by 24+/-13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46+/-5% before and 56+/-5% after ET-1 (P<0.01). ET-1-induced increases in E(max) and in contractile efficiency were abolished by an ET(A) receptor blocker (S-0139) but not by an ET(B) blocker (BQ-788). Although high [Ca(2+)] perfusion increased E(max) and the intercept to the same extent as ET-1, it did not change S. N(G)-Nitro-L-arginine (an inhibitor of nitric oxide synthase) increased the coronary perfusion pressure as much as ET-1, but S again remained unchanged. Dimethylamyloride (Na(+)/H(+) exchanger inhibitor) partially blocked the positive inotropic effect of ET-1 but not the ET-1-induced increase in the contractile efficiency.


CONCLUSIONS
Agonistic effects of ET-1 on the ET(A) receptor economized the chemomechanical conversion efficiency of the left ventricular unit myocardium by a mechanism independent of the Na(+)/H(+) exchanger. This unique oxygen-saving effect of ET-1 may play an adaptive role in the failing myocardium, in which local accumulation of ET-1 is present.
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Y
Y
Takeuchi
Y
Y
Kihara
K
K
Inagaki
T
T
Yoneda
S
S
Sasayama
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000209:etiology; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; D002109:Caffeic Acids; D002316:Cardiotonic Agents; D019332:Endothelin-1; D009842:Oligopeptides; D010880:Piperidines; C086421:S 0139; C039465:5-dimethylamiloride; C086539:BQ 788; D009828:Oleanolic Acid; D000584:Amiloride; D010100:Oxygen