Related Experiment Videos
Cyclic AMP in myocytes isolated from hypertrophied rat hearts
R Hilal-Dandan1, P A Khairallah
1Department of Heart and Hypertension Research, Cleveland Clinic Foundation, Ohio.
Insights
Cardiac hypertrophy impairs heart function differently in various rat models. In renal hypertensive rats, cyclic AMP production defects contribute to reduced responsiveness, unlike in spontaneously hypertensive rats.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Biochemistry
Background:
- Cardiac hypertrophy, often caused by pressure overload, can lead to impaired contractile function.
- Reduced inotropic responsiveness to beta-adrenergic stimulation is a hallmark of failing hypertrophied hearts.
Purpose of the Study:
- To investigate if impaired cyclic AMP (cAMP) production in cardiac myocytes underlies reduced inotropic responsiveness in two models of cardiac hypertrophy.
- To differentiate the biochemical mechanisms responsible for impaired contractility in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR).
Main Methods:
- Isolated ventricular myocytes from SHR and RHR were used to measure basal and isoproterenol-stimulated cAMP levels.
- cAMP accumulation was assessed with and without phosphodiesterase inhibition (using isobutyl-methyl-xanthine).
- Results were compared between hypertensive models and normotensive controls.
Main Results:
- Spontaneously hypertensive rats showed no significant changes in cAMP production, indicating other mechanisms are involved in their impaired response.
- Renal hypertensive rats exhibited significantly depressed basal and stimulated cAMP levels, suggesting a defect in cAMP synthesis or signaling.
- These findings highlight heterogeneity in the pathophysiological consequences of cardiac hypertrophy.
Conclusions:
- Impaired inotropic responsiveness in SHR is not due to defects in cAMP production.
- Reduced cAMP formation contributes to impaired contractility in RHR, pointing to signal transduction abnormalities.
- The underlying cause of cardiac hypertrophy influences its pathophysiological outcomes more than the hypertrophic response itself.
Abstract:
Impaired inotropic responsiveness to isoproterenol stimulation has been reported in the hypertrophied hearts of spontaneously hypertensive rats and renal hypertensive rats. This study was carried out in order to investigate the possibility that a defect in cyclic AMP production by cardiac myocytes is responsible for the impaired inotropic responsiveness of these hearts. Basal and isoproterenol stimulated cyclic AMP levels were measured in ventricular myocytes isolated from hypertrophied rat hearts. Cyclic AMP accumulation was also measured in the presence of isobutyl-methyl-xanthine, a phosphodiesterase inhibitor, and the results were compared to the appropriate controls. In the spontaneously hypertensive rat, no changes were detected in the basal or isoproterenol stimulated cyclic AMP formation. This suggests that the biochemical alterations leading to a diminished inotropic response in this model of cardiac hypertrophy involve abnormalities in mechanisms other than cyclic AMP production. In the renal hypertensive rat, basal and isoproterenol stimulated cyclic AMP levels were significantly depressed as compared to controls. This suggests that abnormalities in the signal transduction mechanism and formation of cyclic AMP are, at least in part, responsible for the impaired inotropic responsiveness seen in this model. These results confirm that cardiac hypertrophy is a heterogeneous process. Reduced inotropic responsiveness to isoproterenol stimulation in the hypertrophied hearts of the SHR and the RHR, both models of pressure overload hypertrophy, involve different biochemical alterations. Results of this study suggest that the physiologic response of cardiac hypertrophy may not be as important as the underlying cause of hypertrophic stimuli in determining the pathophysiological consequences.