Inotropic agents exert their action through one of two major mechanisms. Catecholamines have an agonist effect at the b -,-adrenergic receptor in cardiac muscle (Fig.. 1). The brreceptor is located on the outer surface of the sarcolemma, where it is coupled via a G protein to adenylyl cyclase, an enzyme on the inner surface. Within the cytoplasm, ATP is catalyzed by adenylate cyclase to cAMP. The latter is the well-known second messenger, which is the fulcrum of all inotropic activity. The phosphodiesterase inhibitors exert their inotropic action by inhibiting the breakdown of cAMP by its specific enzyme phosphodiesterase III. Thus, whether the mechanism of inotropic effect is b-adrenergic stimulation or phosphodiesterase inhibition, the end result is elevation of cAMP levels within the cardiac muscle cell.
Fig. 1 The b-adrenergic receptor. The b-receptor (B) is coupled to adenylyl cyclase (AC) by G proteins (G s, stimulatory; Gi, inhibitory). Activation of adenylyl cyclase catalyzes the transformation of ATP to cAMP, which in turn converts protein kinase from its inactive form (PK) to its active form (PKa). Protein in the calcium channel is phosphorylated by PKa, which opens the 'gate' so that calcium (Ca2+) moves into the cell. Calcium enters the sarcoplasmic reticulum (SR), inducing it to release calcium which binds to troponin C (T) and allows activation of the actin-myosin complex. cAMP is inactivated by conversion to AMP by phosphodiesterase (PDE). Calcium is cycled out of the cell by calcium adenosine triphosphatase (Ca 2+ATPase). In contrast, the a-adrenergic receptor is coupled to phospholipase C, generates cGMP, and forms diacyl glycerol and inositol triphosphate. The net effect is similar—calcium entry via the sarcolemma and calcium release from the sarcoplasmic reticulum. However, the a-adrenergic receptor is independent of cAMP. (Reproduced with permission from Rpyster,(19l901.)
The activation of cAMP induces a protein kinase which opens a calcium gate in the sarcolemma and allows the ingress of calcium into the cardiac muscle cytoplasm. This in turn induces the release of large amounts of calcium from the sarcoplasmic reticulum. Released calcium binds to troponin and forms tropomyosin C which releases tropomyosin from its binding to actin and myosin. Thus the lateral movement of actin and myosin is facilitated, culminating in cardiac muscle contraction.
In vascular smooth muscle, cAMP activation has exactly the opposite effect; it induces an uptake of calcium into the sarcoplasmic reticulum. This results in smooth muscle relaxation. The contrasting effects of cAMP activation in cardiac muscle and smooth muscle explain the inodilator action of phosphodiesterase inhibitors, i.e. a cardiac inotropic effect combined with systemic and pulmonary vasodilation.
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