The Negative Inotropic Effect of [small beta, Greek]3-Adrenoceptor Stimulation Is Mediated by Activation of a Nitric Oxide Synthase Pathway in Human Ventricle

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[small beta, Greek]1-and [small beta, Greek]2-adrenoceptors in heart muscle cells mediate the catecholamine-induced increase in the force and frequency of cardiac contraction. Recently, in addition, we demonstrated the functional expression of [small beta, Greek]3-adrenoceptors in the human heart. Their stimulation, in marked contrast with that of [small beta, Greek]1- and [small beta, Greek] (2-adrenoceptors), induces a decrease in contractility through presently unknown mechanisms. In the present study, we examined the role of a nitric oxide (NO) synthase pathway in mediating the [small beta, Greek]3-adrenoceptor effect on the contractility of human endomyocardial biopsies. The negative inotropic effects of a [small beta, Greek]3-adrenoceptor agonist, BRL 37344, and also of norepinephrine in the presence of [small alpha, Greek]- and [small beta, Greek]1-2-blockade were inhibited both by a nonspecific blocker of NO, methylene blue, and two NO synthase (NOS) inhibitors, L-N-monomethyl-arginine and L-nitroarginine-methyl ester. The effect of the NOS inhibitors was reversed by an excess of L-arginine, the natural substrate of NOS, but not by D-arginine. Moreover, the effects of the [small beta, Greek]3-adrenoceptor agonist on contractility were associated with parallel increases in the production of NO and intracellular cGMP, which were also inhibited by NOS inhibitors. Immunohistochemical staining of human ventricular biopsies showed the expression of the endothelial constitutive (eNOS), but not the inducible (iNOS) isoform of NOS in both ventricular myocytes and endothelial cells. These results demonstrate that [small beta, Greek]3-adrenoceptor stimulation decreases cardiac contractility through activation of an NOS pathway. Changes in the expression of this pathway may alter the balance between positive and negative inotropic effects of catecholamines on the heart potentially leading to myocardial dysfunction. (J. Clin. Invest. 1998. 102:1377-1384.)

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