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Rolipram reduces the inotropic tachyphylaxis of glucagon in rat ventricular myocardium
Maria Jesús Juan-Fita1, Maria Luisa Vargas, Alberto J Kaumann
1Departamento de Farmacologia, Facultad de Medicina, Universidad de Murcia, Campus de Espinardo, 30100, Murcia, Spain.
Abstract:
Glucagon increases cardiac contractility through G(s) protein-coupled glucagon receptors, but the inotropic responses fade. The fade could be due to receptor desensitisation or to the action of phosphodiesterases (PDE), or to both mechanisms. We investigated the effects of the PDE4 inhibitor rolipram (1 microM) on the inotropic and cAMP-responses to glucagon in paced right ventricular strips of the rat heart. Responses to the partial agonist dobutamine, mediated through beta(1)-adrenoceptors, were studied for comparison. Glucagon increased contractility (-logEC(50)M=7.3 for maximum responses with E(max)=32% of the response to 9 mM Ca(2+)), but the responses tended to fade (-logEC(50)M=7.1 for faded responses with E(max)=11.5%). Dobutamine (-logEC(50)M=5.8, E(max)=56%) produced positive inotropic effects that did not fade. Rolipram did not affect basal contractility and cAMP levels. Rolipram enhanced the contractile responses to glucagon and reduced fade (-logEC(50)M=7.5 and 7.3 with E(max)=74% and 45% for maximum and faded responses respectively). The response to glucagon (0.1 microM) completely faded in the absence of rolipram, but only partially faded and then remained stable in the presence of rolipram (1 microM). Rolipram enhanced contractile responses to dobutamine (-logEC(50)M=6.0, E(max)=75%). Dobutamine (3 microM), but not glucagon (0.1 microM), increased tissue levels of cAMP. Consistent with the inotropic data, rolipram caused glucagon to augment cAMP and enhanced the effects of dobutamine. Thus, PDE4 activity limits the responses mediated through both glucagon receptors and beta(1)-adrenoceptors. PDE4-catalysed hydrolysis of cAMP contributes to the inotropic tachyphylaxis of glucagon.
Insights
The phosphodiesterase 4 (PDE4) inhibitor rolipram enhances glucagon-mediated cardiac contractility and reduces response fade. PDE4 activity limits responses to both glucagon and dobutamine, contributing to glucagon
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Physiology
- Enzyme Inhibition
Background:
- Glucagon increases cardiac contractility via G(s) protein-coupled receptors, but these effects diminish over time (fade).
- This fade may result from receptor desensitization, phosphodiesterase (PDE) activity, or both.
- Phosphodiesterase 4 (PDE4) enzymes hydrolyze cyclic AMP (cAMP), a key second messenger in cardiac function.
Purpose of the Study:
- To investigate the role of PDE4 in the fading inotropic responses to glucagon in rat cardiac tissue.
- To determine if inhibiting PDE4 with rolipram can enhance and stabilize glucagon-induced contractility.
- To compare the effects of PDE4 inhibition on glucagon and beta(1)-adrenoceptor-mediated responses (using dobutamine).
Main Methods:
- Isolated, paced rat right ventricular strips were used to measure contractility.
- The effects of glucagon and dobutamine (a beta(1)-adrenoceptor agonist) on contractility were assessed with and without the PDE4 inhibitor rolipram (1 microM).
- Cyclic AMP (cAMP) levels were measured in cardiac tissue under various conditions.
Main Results:
- Glucagon increased cardiac contractility, but the response exhibited significant fade.
- Rolipram enhanced the maximum contractile response to glucagon and substantially reduced the fade.
- Rolipram also enhanced dobutamine-induced contractility and, along with dobutamine, increased cAMP levels, indicating PDE4 limits both glucagon and beta(1)-adrenergic signaling.
Conclusions:
- PDE4 activity significantly contributes to the fading of glucagon-mediated positive inotropic effects in the rat heart.
- Inhibition of PDE4 with rolipram can augment and stabilize cardiac contractility stimulated by glucagon.
- PDE4 plays a crucial role in regulating cAMP levels and limiting responses mediated by both glucagon and beta(1)-adrenergic receptors in the heart.
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