Investigation of putative cardiac beta 3-adrenoceptors in man.

The purpose of the present study was to investigate the presence of putative cardiac beta 3-adrenoceptors mediating chronotropic and inotropic responses in normal subjects. Isoprenaline (a known beta 1, beta 2 and beta 3-agonist) was infused to stimulate cardiac beta-adrenoceptors in the presence of antagonists at beta 1 (atenolol 25 mg) and beta 1/beta 2 (nadolol 5 mg, 20 mg and 80 mg) adrenoceptor subtypes. Dose-ranging with nadolol was performed to evaluate the lowest dose required to produce significant beta 2-blockade, since the higher doses might conceivably cause beta 3-blockade. Doppler echocardiography was used to evaluate stroke distance and minute distance, which are the linear analogues of stroke volume and cardiac output respectively. Nadolol 5 mg produced almost complete blunting of finger tremor (beta 2-blockade) whilst atenolol 25 mg had no significant effect. Chronotropic and Doppler minute distance responses to isoprenaline were consistent with stimulation of both beta 1 and beta 2-adrenoceptors with no evidence of a beta 3-mediated effect. However, isoprenaline produced an increase in systolic blood pressure and left ventricular stroke distance that was not attenuated by a dose of nadolol (20 mg) which produced complete blunting of beta 1 and beta 2-mediated responses. This infers the possibility of functional inotropic or lusitropic beta 3-adrenoceptors in the human heart. This study also brings into question possible differences in the validity of using stroke distance and systolic blood pressure as measures of inotropic response to beta-adrenoceptor stimulation and advocates the use of Doppler echocardiography as an additional tool for this purpose.