The expression and pharmacological modulation of the pacemaker current in venticular myocytes from post myocardial infarction 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. To get insight into the mechanism of cellular remodeling in this setting, we studied If expression and modulation by 1- and 2-adrenoceptors (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 also containing (mM): KCl 25, BaCl2 , MnCl2 , 4-aminopyridine 0.5 to amplify If and reduce overlapping currents. The membrane capacitance was 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.). 1AR stimulation with norepinephrine (NE, 1 µM) caused a positive shift of VH in PMI (102 mV) significantly smaller than in CTR (162 mV, p<0.05). Incubation with pertussis toxin (PTX) (0.5 µg/ml, 3 hrs at 37°C) significantly increased the effect of 1AR in PMI cells. After incubation, the NE-induced positive shift of VH was 162 mV (p<0.05 vs. not PTX-treated cells). PTX-pretreatment did not have any effect in CTR cells, the NE-induced shift being 16±3 mV. 2AR stimulation with isoprenaline (1 M) in the presence of the selective 1AR antagonist CGP 20712A (0.1 M) caused a similar shift of VH in both PMI (4.61 mV) and CTR (5.11 mV, n.s.). PTX-pretreatment significantly and equally increased 2AR-induced shift of VH 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 1AR is significantly depressed, probably due to an increased activity of PTX-sensitive Gi proteins.