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Biomedical subjects

J Krimmer

Publications and source records attributed to J Krimmer.

3 recordsLinked to original sources
PubMed1990

Dual sensitization of the adrenergic system in early myocardial ischemia: independent regulation of the beta-adrenergic receptors and the adenylyl cyclase.

Acute myocardial ischemia provokes sensitization of the adenylyl cyclase system. This sensitization can be differentiated in a receptor-specific and an enzyme-specific sensitization. The receptor-linked sensitization is characterized by an increase of beta-adrenergic receptors in the plasma membranes after 15 mins of global ischemia (49.8 +/- 3.6 to 67 +/- 6 fmol/mg protein) followed by a further increase (89 +/- 4 fmol/mg protein) after 50 min of ischemia in isolated perfused hearts. Concomitantly functionally coupled receptors which are able to bind the beta-agonist with high affinity, increased by 32% after 15 min and by 57% after 50 min of ischemia. The affinities of the receptors for their agonists or their antagonists remain unchanged. Maximally isoproterenol-stimulated adenylyl cyclase activity rose from 66 +/- 7 to 101 +/- 10 pmol cAMP/min/mg protein after 15 min of global ischemia indicating the beta-receptor-specific sensitization of the beta-adrenergic system. This sensitization was followed by a gradual decline of the adenylyl cyclase activity after 30 and 50 min of global ischemia. Additionally, 15 min of myocardial ischemia induced an enzyme-linked sensitization of the adenylyl cyclase activity as indicated by an increase of the forskolin-stimulated activity by about 25% (300 +/- 20 vs 378 +/- 25 pmol cAMP/min/mg protein). In contrast after 50 min of ischemia the total adenylyl cyclase activity declined (232 +/- 24 pmol cAMP/min/mg protein) despite the persistent increase of beta-adrenergic receptors in the plasma membranes. These data demonstrate that the enzyme-specific sensitization is only transient. The early sensitization and late inactivation of the adenylyl cyclase activity occurred independently of receptor activation and could not be prevented by beta-blockade (10(-6) M alprenolol). Cyanide perfusion (1 mM), used to block energy metabolism, lead to energy depletion similar to acute myocardial ischemia. This resulted in an increase of functionally coupled receptors with a time course comparable to that of global ischemia. Additional perfusion with desensitizing concentrations of the beta-agonist isoproterenol did not induce uncoupling or internalization of beta-adrenergic receptors in cyanide treated hearts, suggesting that the rise in functionally coupled receptors is due to a redistribution in part caused by the abolition of continuous receptor internalization. In contrast, the enzyme-linked sensitization is independent of cellular localization of the beta-adrenergic receptors. The increased activity was carried by the enzyme even after partial purification with solubilization and wheat germ affinity chromatography. These data suggest an ischemia-induced, covalent modification of the adenylyl cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1988

Regulation of beta-adrenergic receptors: impaired desensitization in myocardial ischemia.

The dynamic regulation of the adrenergic system plays an important role in the adaptation of the cardiovascular system in health and in disease. In myocardial infarction, large quantities of catecholamines are presynaptically released. The mechanisms of adaptive regulation of the beta-adrenergic receptors to beta-agonist stimulation involves functional uncoupling of the beta-adrenergic receptors from stimulatory guanine nucleotide binding protein Gs by local sequestration with the domain of the plasma membranes and by internalization of the beta-adrenergic receptors. During this course of adaptive regulation, also called desensitization, the beta-adrenergic receptors become phosphorylated by the newly discovered beta-adrenergic receptorkinase in a cAMP-independent process. In myocardial infarction, however, large quantities of beta-adrenergic agonists are contrasted by an increased number of functionally coupled beta-adrenergic receptors. The increase of functionally coupled beta-adrenergic receptors is dependent on the loss of high energy phosphates like ATP. This loss occurring in myocardial ischemia can be mimicked by the perfusion of isolated hearts with cyanide. The perfusion with cyanide results in an increase of functionally coupled receptors, additionally demonstrating that the loss of high energy phosphates is responsible for the increase of the beta-adrenergic receptors in acute myocardial ischemia. For the first time it could be demonstrated that in myocardial ischemia the processes of beta-agonist-induced receptor uncoupling and internalization are abolished. They lead to the functional sensitization of the beta-adrenergic system and are at least in part responsible for the occurrence of malignant arrhythmias in myocardial infarction.

Animals↗