Chronic treatment with FK506 increases p70 S6 kinase activity associated with reduced nitric oxide synthase activity in rabbit hearts.

FK506, an immunosuppressant, modulates phosphorylation of nitric oxide (NO) synthase, and induces cardiac hypertrophy in clinical settings. Having recently reported that chronic treatment with an inhibitor of NO synthase induces cardiac hypertrophy associated with the activation of 70-kD S6 kinase (p70S6K), which plays an important role in cardiac hypertrophy by regulating protein synthesis, we investigated the effects of chronic administration of FK506 on NO synthase and p70S6K activities in hearts. Twenty rabbits were divided into four groups: untreated rabbits, those treated with low-dose FK506 (0.10 mg/kg), those treated with medium-dose FK506 (0.20 mg/kg), and those treated with high-dose FK506 (0.40 mg/kg). FK506 was administered intravenously twice a day. After 4 weeks of treatment with FK506, calcium-dependent NO synthase activity in myocardium in the high-dose FK506 group was lower (P < 0.05) than in the untreated group. p70S6K activity in myocardium in the high-dose group was higher (P < 0.05) than in the untreated group. There was a significant (P < 0.05) inverse correlation between NO synthase and p70S6K activities in myocardium. However, the endothelial-dependent vasodilation of aortic rings or plasma levels of NO metabolites during experimental protocols did not differ among the groups studied. These findings suggest that chronic treatment of FK506 activates p70S6K and reduces NO synthase activity in rabbit hearts. Reduced NO synthase and/or activated p70S6K activities in hearts might contribute to the cardiac hypertrophy observed in some patients receiving FK506.

Nisoldipine selectively induces coronary vasodilation and improves mild myocardial ischemia in dogs: a potential role of cellular acidosis.

We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter. First, we administered nisoldipine into a systemic vein in the ischemic and nonischemic hearts. Second, nisoldipine was administered into the canine coronary artery of the ischemic myocardium, with and without administration of either sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine (0.25-4.0 mg/kg, i.v.) increased CBF by 59% in the ischemic myocardium more than the nonischemic myocardium (by 34%) without reducing AoP. The infusion of nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the ischemic myocardium with increases in fractional shortening (FS; 11 +/- 2% to 21 +/- 2%) and lactate extraction ratio (LER; -19 +/- 4% to 15 +/- 2%). Increases in CBF, FS, and LER were markedly attenuated during administration of nisoldipine with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent of increases in CBF (54 +/- 2 mL/100 g/min), FS (13 +/- 2%), and LER (-17 +/- 4%) were also markedly attenuated due to the concomitant treatment with amiloride. We conclude that myocardial cellular acidosis plays an important role in mediating coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may modulate the property of voltage-dependent Ca channels via Na(+)-H+ exchange.

Beneficial effect of OPC-8212 (3,4-dihydro-6-(4-(3,4-dimethoxy benzoyl)-1-piperazinyl)-2(1H)-quinolinone on myocardial oxygen consumption in dogs with ischemic heart failure.

The effect of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative), on myocardial oxygen consumption (MVO2) following intravenous administration (1 and 3 mg/kg/min) was studied in normal and ischemic failing hearts in open chest dogs. Ischemic failing heart was obtained by intracoronary injection of 15-micron microspheres and volume loading. OPC-8212 significantly increased LV max dP/dt and decreased mean aortic pressure, whereas heart rate was not altered in both normal and failing hearts. Despite the remarkable positive inotropic effect, this agent did not increase MVO2 in the normal hearts and even decreased MCO2 in the ischemic failing hearts associated with a decrease in LV end-diastolic pressure and hence, LV chamber size. These results indicate that OPC-8212 does not increase myocardial oxygen demand, probably because the increase in MVO2 by positive inotropic effect is offset by a decrease in MVO2 due to a decrease in chamber size. Thus, OPC-8212 may be promising for the treatment of congestive heart failure with reduced coronary flow reserve.