Nitric oxide (NO) and prostacyclin (PGI2) were determined in effluents of Langendorff-perfused rabbit hearts subjected to 2 h of global low-flow ischemia and subsequent reperfusion. PGI2 release [6-oxo-prostaglandin (PG) F1 alpha] was significantly enhanced during early reperfusion and remained elevated. NO formation was reduced during ischemia but did increase substantially during reperfusion. Indomethacin (3 microM) significantly suppressed ischemia-related 6-oxo-PGF1 alpha and NO release. This was accompanied by severely diminished myocardial recovery. NG-nitro-L-arginine (L-NNA) (100 microM) suppressed NO generation without major effects on 6-oxo-PGF1 alpha generation and cardiac dysfunction but with a remarkable increase in coronary perfusion pressure. These effects of L-NNA were antagonized by L-arginine, whereas the effects of indomethacin were not. There was a substantial loss of creatine kinase specific activity from reperfused ischemic hearts, which was further aggravated by indomethacin but not by L-NNA. These data demonstrate a cardioprotective and endothelium-protective role of PGI2 in myocardial ischemia, which also involves preservation of NO generation. Endogenous NO appears to be important for local regulation of coronary flow.
This study determines the release of nitric oxide (NO) from the coronary circulation of Langendorff hearts of rabbits, subsequent to administration of glyceryl trinitrate (GTN) and SIN-1. NO was measured on-line in the coronary effluent by the oxyhaemoglobin technique. Infusion of either GTN (10-40 mumoles/l) or SIN-1 (0.1-2.3 mumoles/l) into the coronary inflow resulted in a concentration-dependent NO release into the coronary effluent and a decrease in the coronary vascular resistance. NO generation from SIN-1 was identical with and without passage of the coronary circulation whereas NO generation from GTN was only detected after passage of the coronary vascular bed. NO generation by both substances was in the same range as endogenous NO release by two endothelium-dependent vasodilators, bradykinin (0.05 mumoles/l) and substance P (0.05 mumoles/l). Oxyhaemoglobin used for the assay of NO, inhibited the relaxation by SIN-1, but did not reduce vessel relaxations induced by GTN or iloprost, a stable prostacyclin analogue. Removal of the coronary endothelium by trypsin or pretreatment with L-NG-Monomethylarginine (30 mumoles/l) did neither affect NO release from GTN and SIN-1 nor the vasodilatory effect of both substances. These data are the first to directly demonstrate endothelium-independent NO release from organic nitrates during passage of an intact organ circulation. They additionally suggest a subendothelial site of metabolic NO formation from GTN.
1 Langendorff hearts, perfused at constant volume, were prepared from rabbits fed a cholesterolenriched diet for 4 months. Coronary perfusion pressure and nitric oxide (NO) release (oxyhaemoglobin technique) into the coronary effluent were measured continuously. Prostacyclin (PGI2) in the effluents was determined by radioimmunoassay (6-oxo-PGFIj).2 Basal NO release was not different between control and hypercholesterolaemic rabbits. However, the coronary vasculature of hypercholesterolaemic rabbits showed a considerably (>50%) reduced endothelium-dependent relaxation in response to short-term (3 min) infusion of bradykinin (50 nM) and substance P (50 nM) (P<0.05, n = 8-9). Under these conditions, NO release into the vessel lumen was increased, by 26%, in hypercholesterolaemic hearts (P< 0.05, n = 8-9). N0-nitro-L-arginine (L-NOARG, 30 pM) significantly attenuated both bradykinin-induced NO formation and vessel relaxation in control hearts but only NO release in hypercholesterolaemia. L-Arginine (200 pM) restored the response to that before L-NOARG but did not improve the reduced endothelium-dependent relaxation in cholesterol-fed rabbits. 3 Superoxide dismutase (10 u ml-') significantly improved vessel relaxation without changing the hypercholesterolaemia-related coronary dysfunction. Vasodilatation in response to exogenous NO donors (linsidomine) was diminished in hypercholesterolaemia as compared to controls. 4 Basal PGI2 release was unchanged in hypercholesterolaemic hearts. There was a tendency in these hearts for greater PGI2 formation after stimulation by substance P and bradykinin (P> 0.05). The coronary relaxation to iloprost was unchanged. 5 The data demonstrate impaired endothelium-dependent relaxation of coronary arterial resistance vessels in hypercholesterolaemia. This diminished vascular response was not due to reduced NO generation but probably a reduced action of released NO, either by accelerated degradation and/or disturbed signal transduction pathways to vascular smooth muscle cells. There was no significant change in PGI2 related pathways of vasomotor control in hypercholesterolaemia.
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