The obese Zucker rat is resistant to insulin for glucose disposal, but it is unknown whether this insulin resistance is accompanied by alterations of insulin-mediated muscle protein synthesis. We examined rates of muscle protein synthesis either with or without insulin in lean and obese Zucker rats with the use of a bilateral hindlimb preparation. Additional experiments examined insulin's effect on protein synthesis with or without rapamycin, an inhibitor of protein synthesis. Protein synthesis in red and white gastrocnemius was stimulated by insulin compared with control (no insulin) in obese (n = 10, P<0.05) but not in lean (n = 10, P>0.05) Zucker rats. In white gastrocnemius, rapamycin significantly reduced rates of protein synthesis compared with control in lean (n = 6) and obese (n = 6) rats; however, in red gastrocnemius, the attenuating effect of rapamycin occurred only in obese rats. The addition of insulin to rapamycin resulted in rates of synthesis that were similar to those for rapamycin alone for lean rats and to those for insulin alone (augmented) for obese rats in both tissues. Our results demonstrate that insulin enhances protein synthesis in muscle that is otherwise characterized as insulin resistant. Furthermore, rapamycin inhibits protein synthesis in muscle of obese Zucker rats; however, stimulation of protein synthesis by insulin is not via a rapamycin-sensitive pathway.

Insulin-stimulated glucose transport has been shown to decline during maturation in lean rats. To determine whether this maturation-induced decrease occurred in the muscle of obese rats and whether the contraction-stimulated pathway for glucose transport was similarly affected, glucose transport rates were measured in insulin- and electrically stimulated skeletal muscle during hindlimb perfusion of 10- and 29-wk-old lean and obese male Zucker rats. Glucose transporter (GLUT-4) protein was also measured. Insulin-stimulated glucose transport rates were significantly decreased (36-56%) in 29-wk compared with 10-wk-old lean rats. There was no maturation-related decrease in GLUT-4. Insulin-mediated glucose transport was unaltered by maturation in skeletal muscle of obese rats. Differential effects of maturation on lean and obese rats caused the effect of obesity on maximally insulin-stimulated glucose transport to be much greater in 10- than 29-wk-old animals. Maturation had no effect on contraction-stimulated glucose transport rates in either lean or obese animals. The combined effect of maximal insulin plus contraction was not altered with maturity in lean animals but was significantly increased in 29- compared with 10-wk-old obese rats. Absence of a change in GLUT-4 content together with uncompromised contraction-stimulated glucose transport suggests that the maturation-induced decrease in insulin-stimulated glucose transport in lean rats is due to a defect in the insulin signaling pathway.

Verapamil can produce depression of left ventricular function, delayed atrioventricular conduction, and hypotension, which can be potentiated by hyperkalemia. We sought to investigate a direct cardiac interaction between verapamil and hyperkalemia. Studies utilized isolated guinea pig hearts (Langendorff) paced at 250 beats/min. Hearts were randomly assigned to perfusion (Krebs-Henseleit buffer) with potassium concentrations ([K]⁺) of 1.5, 3, 6 and 9 mmol/l. Infusion of verapamil at rates of 0.2 to 60 µg/min (approximately 3 × 10^–8 to 10^–5 mol/l) produced concentration-dependent reduction of isovolumic left ventricular developed pressure. As [K]⁺ increased, concentration response curves showed parallel shifts to the left. The ED₅₀ for reduction of left ventricular developed pressure significantly decreased: 8.2 ± 3.7, 2.9 ± 1.4, 1.2 ± 0.7, 0.6 ± 0.2 µg/min (mean ± SD), respectively. Nifedipine and diltiazem were also studied in hearts perfused with 3 and 9 mmol/l [K]⁺. Infusion of nifedipine 0.003-1 µg/min (approximately 10^–9 to 3 × 10^–7 mol/l) produced concentration-dependent reduction of left ventricular developed pressure but the ED₅₀ was not affected by [K]⁺: 0.06 ± 0.03 and 0.05 ± 0.04 µg/min, respectively. Nifedipine vehicle was without effect at the infusion rates tested. Infusion of diltiazem 2–200 µg/min (approximately 3 × 10^–7 to 3 × 10^–5 mol/l) also produced concentration-dependent reduction of left ventricular developed pressure. The ED₅₀ for diltiazem-induced reduction of left ventricular developed pressure was significantly reduced by elevated [K]⁺: 20.1 ± 6.7 and 3.5 ± 0.9 µg/min with 3 and 9 mmol/l [K]\ respectively. Conclusion, verapamil-induced reduction of left ventricular developed pressure was significantly influenced by buffer potassium concentration, showing a direct interaction between hyperkalemia and verapamil on the heart. A similar interaction was observed with diltiazem but not nifedipine, suggesting that the interaction was not general for all calcium entry blockers.