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Role of nitric oxide in cardiac beta-adrenoceptor-inotropic response
L Sterin-Borda1, A Genaro, C Perez Leiros
1Centro de Estudios Farmacológicos y Bótanicos, Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina, Buenos Aires, Argentina.
Abstract:
We examined some of the signalling events in the negative modulation of isoproterenol-induced stimulation of contractility in rat isolated atria. Isoproterenol-mediated positive inotropic response is accompanied by the stimulation of nitric oxide synthase (NOS) and an increase in the production of cyclic GMP (cGMP). Inhibition of NOS and guanylate cyclase increased the dose-response curve of isoproterenol on contractility. Inhibitors of calcium flux or calcium calmodulin, but not of protein kinase C, abrogated these mechanisms. The existence of a modulatory negative inotropic-cyclic GMP-mediated mechanism limiting the effect of beta-adrenergic stimulation in myocardium is discussed.
Insights
A negative feedback loop involving nitric oxide synthase (NOS) and cyclic GMP (cGMP) limits beta-adrenergic stimulation in rat heart atria. This pathway, mediated by calcium, modulates cardiac contractility.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Beta-adrenergic stimulation, like isoproterenol, increases cardiac contractility.
- Nitric oxide synthase (NOS) and cyclic GMP (cGMP) are involved in cardiac signaling pathways.
- Understanding modulatory mechanisms is crucial for cardiac function research.
Purpose of the Study:
- To investigate the signaling events responsible for the negative modulation of isoproterenol-induced contractility in rat atria.
- To elucidate the role of nitric oxide synthase (NOS) and cyclic GMP (cGMP) in this negative feedback mechanism.
Main Methods:
- Isolated rat atria were used to study contractility.
- Pharmacological inhibitors were employed to block nitric oxide synthase (NOS), guanylate cyclase, calcium flux, calcium calmodulin, and protein kinase C.
- Dose-response curves for isoproterenol were analyzed under different inhibition conditions.
Main Results:
- Isoproterenol-induced positive inotropy was associated with NOS stimulation and increased cGMP production.
- Inhibition of NOS and guanylate cyclase shifted the isoproterenol dose-response curve upwards, indicating reduced negative modulation.
- Inhibitors of calcium flux and calcium calmodulin, but not protein kinase C, abolished these modulatory effects.
Conclusions:
- A cGMP-mediated negative inotropic mechanism exists, which limits the positive inotropic effects of beta-adrenergic stimulation in the myocardium.
- Calcium signaling plays a key role in this feedback loop, interacting with the NOS/cGMP pathway.
- This study highlights a critical counterbalance in cardiac adrenergic signaling.