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Involvement of cAMP-dependent protein kinase in the regulation of heart contractile force. II
Insights
Histamine increases heart cAMP levels and protein kinase activity, leading to enhanced contractile force and phosphorylase activity in guinea pig hearts. These effects are mediated via H2-receptors, not beta-adrenergic pathways.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Histamine is known to affect cardiovascular function.
- The precise molecular mechanisms underlying histamine's cardiac effects require further elucidation.
Purpose of the Study:
- To investigate the impact of histamine on key cardiac signaling pathways and functional parameters.
- To determine the receptor subtype involved in histamine's cardiac actions.
Main Methods:
- Utilized perfused guinea pig heart model.
- Measured cyclic adenosine monophosphate (cAMP) levels, cAMP-dependent protein kinase activity, phosphorylase activity, and contractile force.
- Administered histamine, propranolol (beta-blocker), and metiamide (H2-receptor antagonist).
Main Results:
- Histamine induced a dose-dependent rise in cardiac cAMP and protein kinase activity.
- These molecular changes correlated with increased contractile force and phosphorylase activity.
- Metiamide significantly blocked histamine's effects, while propranolol did not.
Conclusions:
- Histamine enhances cardiac contractility and phosphorylase activity through a cAMP-dependent protein kinase pathway.
- The H2-receptor is primarily responsible for mediating histamine's positive inotropic and phosphorylase-activating effects in the heart.
Abstract:
The effects of histamine on heart cAMP-dependent protein kinase activity, cAMP levels, phosphorylase activity, and contractile force was investigated in the perfused guinea pig heart. To accurately determine the protein kinase activity ratio in guinea pig heart, it was necessary to measure kinase activity in whole homogenates immediately after homogenization of the tissue. Histamine produced a rapid dose-dependent increase in cAMP and the protein kinase activity ratio followed by increased in contractile force and phosphorylase activity. There was a good correlation between the degree of protein kinase activation and the increase in phosphorylase and force. The beta-adrenergic blocking agent propranolol did not reduce the effects of histamine, but metiamide, a potent H2-receptor antagonist, greatly attenuated all the effects of histamine. The data support the hypothesis that increases in heart cAMP-dependent protein kinase activity produce corresponding increases in contractile force and phosphorylase activity.