Role of cyclic AMP in regulating cardiac muscle contractility: Novel pharmacological approaches to modulating cyclic AMP degradation by phosphodiesterase

Abstract

1988.The role of cyclic AMP in modulating the contractile function of cardiac muscle has been the subject of intensive investigation for more than two decades. These studies have shown that the positive inotropic response to cyclic AMP involves multiple components, including adenylate cyclase, the enzyme that catalyzes the conversion of ATP to cyclic AMP, activation of cyclic AMP-dependent protein kinases, which are responsible for phosphorylating key intracellular proteins, and phosphodiesterase, the enzyme that hydrolyzes cyclic AMP, thereby terminating the response. Several reports have shown, however, that increases in intracellular cyclic AMP are not always accompanied by increases in myocardial contractility, suggesting that cyclic AMP may be compartmentalized within cardiac cells and that only certain compartments are involved in modulating contractility. In addition, although cardiac muscle contains only one form of adenylate cyclase, multiple forms of phosphodiesterase have been identified in ventricular muscle, which vary in their substrate specificity and their response to allosteric effectors such as calmodulin. Recent studies have also shown that these various forms of phosphodiesterase can be located in different regions within the cardiac cell and that only certain forms of the enzyme are involved in modulating the inotropic response to cyclic AMP. This review summarizes the current state of knowledge regarding the involvement of cyclic AMP with cardiac contractile function and also explores several controversial aspects of this involvement.

Role of phosphodiesterases III and IV in the modulation of vascular cyclic AMP content by the NO/cyclic GMP pathway

“…Our previous results showing an endothelium-independent relaxation produced by PDE III inhibitors (Komas et al, 1991) support the role of PDE III in the regulation of cyclic AMP content and in vascular contraction. Additionally, the possibility cannot be excluded that an eventual local cyclic AMP variation could be detected in the whole aorta (Weishaar et al, 1988;Silver et al, 1989;Hohl & Li, 1991). Such a lack of correlation between cyclic AMP content and functional effects has often been reported (Napoli et al, 1980;Vegesna et al, 1986;Hei et al, 1990).…”

Interaction of neuromuscular blocking drugs with recombinant human m1–m5 muscarinic receptors expressed in Chinese hamster ovary cells

“…Based on the in vivo data described above we would predict that pancuronium would be a muscarinic antagonist and produce atropine like effects and that vecuronium would be an agonist and produce acetylcholine like effects. Cyclic AMP has been shown in many studies to be intimately linked with changes in cardiac activity, as cyclic AMP affects cardiac contractility by altering intracellular Ca 2+ movement and other cardiac muscle Ca 2+ related events (Weishaar et al , 1988). In an attempt to probe the nature of the interaction with the m2 receptor we examined the effects of pancuronium (an agent that produces a tachycardia), rocuronium (an agent that may produce a weak tachycardia) and vecuronium (an agent that produces a bradycardia).…”

Comparative electrostatic analysis of adenylyl cyclase for isoform dependent regulation properties

“…All isoforms are expressed in the central nervous system (CNS), where they integrate different neurochemical signals to generate the appropriate cellular responses . The AC‐cAMP system is known to play pivotal roles in several processes involved in heart muscle contractility, synaptic plasticity, for example in the NMDA‐dependent long‐term potentiation (LTP) of the hippocampus and LTP in striatum, and in insulin regulation in the pancreas …”