Modulation of the pacemaker current If by β-adrenoceptor subtypes in ventricular myocytes isolated from hypertensive and normotensive rats

Objective: Both beta(1)- and beta(2)-adrenoceptors (beta(1)-AR and beta(2)-AR) are functionally present in human and rat ventricular myocytes. The two receptor subtypes are differently regulated during the development of myocardial hypertrophy and failure. I-f is expressed in human and rat ventricular myocytes. In hypertrophied myocytes isolated from old spontaneously hypertensive rats (SHR) the density is much larger than in age-matched normotensive Wistar Kyoto (WKY). Due to the possible relevance of I-f as an arrhythmogenic mechanism in the rat and human ventricle, we studied and compared the effects of beta(1)-AR and beta(2)-AR stimulation on I-f in both hypertrophied and normal left ventricular myocytes of 18-month old SHR and WKY. Methods: The whole-cell configuration of the patch-clamp technique was employed. Noradrenaline (NA, 1 mu M) was used to stimulate beta(1)-AR and isoprenaline (LSO, 1 mu M) in the presence of the beta(1)-AR antagonist CGP 20712A (0.1 mu M) to stimulate beta(2)-AR. Results: In SHR, NA increased I-f by causing a 10.8+/-0.9 mV(n = 10)positive shift in the voltage of maximal activation (V-1/2); this effect was completely reversed by CGP 20712A. beta(2)-AR stimulation was effective in seven out of 13 cells tested, where it caused a small positive shift in V-1/2 (4.0+/-1.7 mV). Cyclopentyladenosine (CPA), a selective A(1)-receptor agonist, reversed the effect of NA; the antiadrenergic action of CPA was abolished in cells pre-incubated with pertussis toxin (PTX) to block inhibitory G proteins (Gi). In PTX-treated cells the shift in V-1/2 caused by both beta(2)-AR (9.6+/-1.7 mV, n=6, p<0.05) and beta(1)-AR (17.6+/-1.9 mV, n=7, p<0.05) was significantly greater than in control cells. Both beta-AR subtypes modulated I-f activation also in WKY: beta(1)-AR shifted V-1/2 by 16.0+/-1.4 mV (n=15) and beta(2)-AR by 4.2+/-1.1 mV (n=7). However, in PTX-treated WKY cells only the beta(2)-AR effect was potentiated (shift in V-1/2: 11.4+/-1.4 mV, n=9, p<0.01), while the beta(1)-AR response was unchanged (18.9+/-4.2 mV, n=5, n.s.). Condusions: I-f expressed in SHR hypertrophied ventricular myocytes is modulated by catecholamines mainly through the stimulation of the beta(1)-AR subtype. The beta(1)-AR response is, however, significantly lower than that observed in myocytes from normotensive rats, probably as a consequence of the presence of an increased inhibitory activity of Gi proteins. This post-receptorial control may be seen as a mechanism to limit the arrhythmogenicity of beta-AR stimulation in myocardial hypertrophy and failure. (C) 1999 Elsevier Science B.V. All rights reserved.