title: Endogenous nitric oxide and myocardial adaptation to ischemia.
abstract: Ischemic myocardium does not inevitably undergo necrosis but rather can survive through downregulation of contractile function, ie, "hibernate." To study the role of endogenous NO in this adaptation, 41 enflurane-anesthetized swine were subjected to 90 minutes of moderate left anterior descending coronary artery hypoperfusion and assigned to placebo (P), to 30 mg/kg N(G)-nitro-L-arginine (L-NNA) IV to inhibit NO synthase, or to aortic constriction (AO) to match the increased left ventricular pressure observed with L-NNA. During normoperfusion, a regional myocardial external work index (WI, mm Hg. mm, sonomicrometry and micromanometry) was reduced with L-NNA (from 326+/-27 [SEM] to 250+/-19, P<0.05) but increased with AO (from 321+/-16 to 363+/-19, P<0.05 versus L-NNA). At 10 minutes of ischemia, WI was lower with L-NNA (109+/-10, P<0.05) than P (180+/-22) and AO (170+/-11) and did not change further at 85 minutes of ischemia. Relationships between WI and transmural myocardial blood flow and oxygen consumption were shifted rightward by L-NNA versus P and AO at both 10 and 85 minutes of ischemia. The maximal increment in calcium-activated external work was not different during normoperfusion among groups but was decreased during ischemia with L-NNA. L-NNA transiently increased myocardial contractile calcium sensitivity along with systemic pressure but reduced it during ongoing ischemia. The free-energy change of ATP hydrolysis after an early ischemic decrease recovered toward baseline values in all groups, and necrosis was absent after 2 (triphenyltetrazolium chloride staining) or 8 (histology) hours of reperfusion. Thus, endogenous NO contributes to hibernation by reducing oxygen consumption and preserving calcium sensitivity and contractile function without an energy cost during ischemia.
authors.affiliation: Abteilungen für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums, Essen, Germany. gerd.heusch@uni-essen.de
authors.forename: G
authors.initials: G
authors.lastname: Heusch
authors.forename: H
authors.initials: H
authors.lastname: Post
authors.forename: M C
authors.initials: MC
authors.lastname: Michel
authors.forename: M
authors.initials: M
authors.lastname: Kelm
authors.forename: R
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007773:Lactates / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D007773:Lactates; D019335:Nitroarginine; D009569:Nitric Oxide