Modulation of the pacemaker current by beta-adrenoceptor subtypes in ventricular myocytes from post myocardial infarction rat hearts.

The remodeling of the infarcted heart is accompanied by alterations in the expression and function of membrane channels and receptors. These abnormalities may lead to the deterioration of cardiac function and/or to arrhythmias. We studied the expression and modulation of the pacemaker current, If by β1- and β2-adrenoceptor (AR) subtypes in ventricular myocytes isolated from the heart of post-myocardial infarction (PMI) rats (i.e., 6 months after coronary ligation) and in sham-operated control (CTR) rats. Patch-clamped cells were superfused with a modified Tyrode's solution (1,2). The membrane capacitance was (M±SEM) 241±16 pF in PMI (n=39) and 226±11 pF in CTR (n=26, n.s.). Maximum specific conductance of If was significantly higher in PMI (33±5 pS/pF, n=31) than in CTR (18±4 pS/pF, n=22) (p<0.03). Activation curve was sigmoidal, with a midpoint (VH) of -94±2 mV in PMI (n=31) and -90±3 mV in CTR (n=20, n.s.). β1AR stimulation with norepinephrine (NE, 1 µM) caused a rightward shift of VH in PMI (10±2 mV) significantly smaller than in CTR (16±2 mV, p<0.05). Incubation with pertussis toxin (PTX) restored the effect of β1AR in PMI (16±2 mV, p<0.05 vs. not PTX-treated cells), while did not affect β1AR response in CTR. β2AR stimulation with isoprenaline (1 µM) in the presence of the β1AR antagonist CGP 20712A (0.1 µM) caused a similar positive shift of VH in both PMI (4.6±1 mV) and CTR (5.1±1 mV, n.s.). PTX-pretreatment significantly and equally increased β2AR response by 94% and 87% in both CTR and PMI, respectively. Thus, If is significantly enhanced in ventricular myocytes from PMI rat hearts; its modulation by β1AR is significantly depressed, probably due to an increased activity of PTX-sensitive Gi proteins.