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Nitric oxide enhances the inotropic response to beta-adrenergic stimulation in the isolated guinea-pig heart
B D Prendergast1, P MacCarthy, J F Wilson
1Department of Cardiology, University of Wales College of Medicine, Cardiff, United Kingdom.
Abstract:
Nitric oxide (NO) exerts several effects on myocardial contraction, including enhancement of relaxation and diastolic function, modulation of beta-adrenergic inotropic responses, and inotropic effects in the absence 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 range of responses that can manifest in most mammalian species. We therefore examined the effects of NO on the inotropic response to beta-adrenergic 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 ejecting hearts were perfused with Krebs buffer at constant placed heart rate (1 microM) indomethacin, 37 degrees C, constant loading conditions), and high fidelity LV pressure was monitored by an apical 2 F Millar catheter. All hearts were initially treated with dobutamine (0.1 microM) and then, once the peak inotropic and chronotropic response had been established, with either (a) no further treatment (n = 6), (b) the NO donor sodium nitroprusside (1 microM, n = 6; 10 microM, n = 6), or (c) the specific agonist for NO release, substance P (0.1 microM, n = 6). Dobutamine (0.1 microM) produced a rapid positive inotropic and chronotropic response, associated with a fall in LV end-diastolic pressure (LVEDP) and a rise in coronary flow. The positive inotropic effect of dobutamine declined over 20-28 minutes, while the chronotropic response persisted over this period. Low dose sodium nitroprusside (1 microM) delayed the decline in the inotropic response to dobutamine and exaggerated the fall in LVEDP. Similar effects were observed with substance P (0.1 microM). In contrast, a higher dose of sodium nitroprusside (10 microM) did not alter the response to dobutamine. These data indicate that "low dose" NO augments the inotropic response to beta-adrenergic stimulation in the isolated ejecting guinea-pig heart, in addition to its previously reported effects on basal LV relaxation in the same preparation.
Insights
Low doses of nitric oxide (NO) enhance the inotropic response to beta-adrenergic stimulation in guinea-pig hearts. This finding clarifies NO
Area of Science:
- Cardiovascular Physiology
- Pharmacology
Background:
- Nitric oxide (NO) has varied effects on myocardial contraction, including relaxation and modulation of beta-adrenergic responses.
- Previous studies show species-specific effects of NO, necessitating further investigation in different mammalian models.
Purpose of the Study:
- To investigate the effects of NO on the inotropic response to beta-adrenergic stimulation in isolated guinea-pig hearts.
- To determine if NO's effects are dose-dependent and species-specific.
Main Methods:
- Isolated ejecting guinea-pig hearts were perfused and monitored for left ventricular (LV) pressure.
- Hearts were stimulated with dobutamine, followed by administration of sodium nitroprusside (NO donor) or substance P (NO agonist) at varying doses.
Main Results:
- Low-dose sodium nitroprusside (1 microM) and substance P (0.1 microM) delayed the decline in dobutamine's inotropic effect and increased LV end-diastolic pressure reduction.
- A higher dose of sodium nitroprusside (10 microM) did not alter the dobutamine response.
- Dobutamine initially caused positive inotropic and chronotropic effects, with the inotropic effect declining over time.
Conclusions:
- Low-dose nitric oxide augments the inotropic response to beta-adrenergic stimulation in the guinea-pig heart.
- These findings suggest that NO's modulatory role in cardiac contractility can be dose-dependent and may extend to beta-adrenergic responses in this species.