Figure 1

Schematic representation of the postulated mechanisms of intracellular action of catecholamines and phosphodiesterase inhibitors (PDEIs). Catecholamines activate β- or α-adrenergic receptors, which in turn are linked with different G regulatory proteins. The β-receptor is linked with a stimulatory Gs-guanidine triphosphate unit (Gs-GTP), which activates the adenyl cyclase system resulting in increased concentrations of cyclic AMP (C-AMP), which in turn activate calcium channels to lead to increased cytosolic calcium, which increases the contractility of the actin–myosin system through its binding with troponin C. Depending on the concentration of a C-AMP-dependent protein kinase, phospholambam is phosphorylated and the uptake of calcium by the sarcoplasmic reticulum (SR) is also affected. The concentration of C-AMP in the myocardium is also regulated by the activity of the type III phosphodiesterase enzyme. If this is inhibited by a PDEI, then C-AMP concentration rises, with effects on cytosolic calcium concentration. In the myocardium this leads to increased contractility, and in vascular smooth muscle to vasodilatation. The α-adrenergic receptor, on the other hand, activates a different regulatory G protein (Gq), which acts through the phospholipase C system and the production of 1,2-diacylglycerol (DAG) and, via phosphatidyl-inositol-4,5-biphosphate (PiP₂), of inositol 1,4,5-triphosphate (IP₃). IP₃ activates the release of calcium from the SR, which by itself and through the calcium–calmodulin dependent protein kinases influences cellular processes, which in vascular smooth muscle leads to vasoconstriction. DAG simultaneously activates protein kinase C, which leads to the phosphorylation of other proteins within the cell.