NITRIC-OXIDE ENHANCES THE INOTROPIC RESPONSE TO BETA-ADRENERGIC STIMULATION IN THE ISOLATED GUINEA-PIG HEART

Nitric oxide (NO) exerts several effects on myocardial contraction, in cluding enhancement of relaxation and diastolic function, modulation o f beta-adrenergic inotropic responses, and inotropic effects in the ab sence of agonist pre-stimulation. Different effects have been observed in different species and preparations, and it is unclear whether they are species- or preparation-specific or whether they represent a rang e of responses that can manifest in most mammalian species. We therefo re examined the effects of NO on the inotropic response to beta-adrene rgic stimulation in the isolated guinea-pig heart, a species in which we have previously shown that NO enhances basal left ventricular (LV) relaxation and modulates the Frank-Starling response. Isolated ejectin g hearts were perfused with Krebs buffer at constant paced heart rate (1 mu M indomethacin, 37 degrees C, constant loading conditions), and high fidelity LV pressure was monitored by an apical 2F Millar cathete r. All hearts were initially treated with dobutamine (0.1 mu M) and th en, once the peak inotropic and chronotropic response had been establi shed, with either (a) no further treatment (n = 6), (b) the NO donor s odium nitroprusside (1 mu M, n = 6; 10 mu M, n = 6), or (c) the specif ic agonist for NO release, substance P (0.1 mu M, n = 6). Dobutamine ( 0.1 mu M) produced a rapid positive inotropic and chronotropic respons e, associated with a fall in LV end-diastolic pressure (LVEDP) and a r ise in coronary flow. The positive inotropic effect of dobutamine decl ined over 20-28 minutes, while the chronotropic response persisted ove r this period. Low dose sodium nitroprusside (1 mu M) delayed the decl ine in the inotropic response to dobutamine and exaggerated the fall i n LVEDP. Similar effects were observed with substance P (0.1 mu M). In contrast, a higher dose of sodium nitroprusside (10 mu M) did not alt er the response to dobutamine. These data indicate that ''low dose'' N O augments the inotropic response to beta-adrenergic stimulation in th e isolated ejecting guinea-pig heart, in addition to its previously re ported effects on basal LV relaxation in the same preparation.