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The effects of carbachol on cAMP and protein kinase A activity in rat ventricles Zhang, Jack Zhen


It has been shown that (CCH) antagonizes the positive inotropic response to forskolin (FSK) in rabbit ventricles without decreasing total cAMP levels elevated by FSK. Further reports proposed that only cAMP (Cyclic AMP) in the particulate fraction of myocardium determines the inotropic state and Ca2+ transients of the cell in the presence of cAMP elevating agents. In this investigation, we studied the effects of CCH on compartmental cAMP and PKA (protein kinase A) activity changed by cAMP-generating agents in rat ventricles. The elevation of particulate cAMP content was correlated with the LVP (left ventricle pressure) increased by isoproterenol (ISO) (10-7 M), and FSK (10-6 M) (r=0.90). Although PGE1 (prostaglandin E-\, 3x10-5 M) increased the total cAMP content and soluble PKA activity, it neither significantly affected the particulate cAMP content and PKA activity nor the LVP. Pre-perfusion with CCH (3x10-6 M) for 1 min, in addition to antagonizing the LVP elevated by ISO (122.8 ± 12.4 to 60.3 ± 8.4 mm Hg), decreased the total and particulate cAMP (26.8 ± 1.3 to 18.2 ± 1.6 and 16.4 ± 1.2 to 12.1 ± 0.8 pmol/mg protein respectively), lowered the soluble PKA ratio (0.60 ± 0.02 to 0.42 ± 0.03) and increased the percentage of particulate PKA (19.46 ±1.15 to 26.22 ± 0.54 %). CCH had no effect on either total and particulate cAMP levels or soluble and particulate PKA activity in the presence of FSK although the positive inotropic response to FSK was abolished by CCH (93.1 ±8.1 to 54.2 ± 8.5 mm Hg). The results support the hypothesis that particulate cAMP and PKA may determine the inotropic state of myocardium after cAMP-generating agent stimulation. However, the ability of CCH to antagonize the positive inotropic effect of FSK does not appear to be associated with a reduction in particulate cAMP or PKA activity.

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