EFFECTS OF VASODILATORS AND PERFUSION-PRESSURE ON CORONARY FLOW AND SIMULTANEOUS RELEASE OF NITRIC-OXIDE FROM GUINEA-PIG ISOLATED HEARTS

Objective: The aims were to validate the use of a direct reading NO el ectrode, to compare the effects of diverse acting drugs on altering co ronary flow (CF) and NO release, and to examine the effects of altered perfusion pressure on flow-induced changes in NO concentration [NO] i n the hemoglobin free effluent of guinea pig isolated hearts. Methods: Hearts were isolated and perfused initially at a constant perfusion p ressure (55 mmHg) with a modified Krebs-Ringer's solution equilibrated with 97% O-2 and 3% CO2 at 37 degrees C. Heart rate, left ventricular pressure, CF, and effluent pH, pCO(2), pO(2), and NO generated curren t were monitored continuously on-line. Effluent was sampled for L-citr ulline. Percent O-2 extraction and O-2 consumption were calculated. [N O] was quantitated with a sensitive amperometric sensor (sensitivity g reater than or equal to 1 nmol/l approximate to 3 pA) and a selective gas permeable membrane. Results: The electrode was not sensitive to ch anges in solution pO(2), flow, or pressure. The electrode was sensitiv e to pCO(2) (-0.50 nmol/l/mmHg) and temperature (+24.5 nmol/l/degrees C), so coronary effluent pCO(2) was measured to compensate for a small decrease in pCO(2) that occurred with an increase in coronary flow, a nd effluent temperature was rigidly controlled. Serotonin, bradykinin, and nitroprusside increased NO release along with CF, whereas nifedip ine, butanedione monoxime, zaprinast, and bimakalim comparably increas ed CF but did not increase [NO] or NO release. Increases in CF (ml/g/m in) and NO release (pmol/g/min), respectively, were 5.0 +/- 1 and 100 +/- 17 for 1 mu mol/l serotonin, 7.5 +/- 1 and 148 +/- 18 for 100 nmol /l bradykinin, and 7.8 +/- 1 and 173 +/- 28 for 100 mu mol/l nitroprus side. The increases ia effluent NO by bradykinin were proportional to the increases in L-citrulline. Tetraethylammonium decreased CF, but di d not change NO release, indomethacin changed neither CF nor NO releas e, and N-G-nitro-L-arginine methyl ester (L-NAME) reduced CF by 2.6 +/ - 1 ml/g/min and NO release by 25 +/- 8 pmol/g/min. An increase of CF of 8.0 +/- 0.3 ml/g/min, produced by increasing perfusion pressure fro m 25 to 90 mmHg, increased [NO] by 30 +/- 4 nmol/l; L-NAME but did not reduce the pressure-induced increase in CF, but reduced the increase in [NO] to 10 +/- 5 nmol/l. Conclusions: This study demonstrates in in tact hearts real-time release of NO by several vasodilator drugs and b y pressure-induced increases in flow (shear stress) and attenuation of these effects by L-NAME. (C) 1998 Elsevier Science B.V. All rights re served.