GLUCAGON REVERSES THE EFFECT OF NIFEDIPINE ON CONTRACTIONS IN NEONATAL VENTRICULAR MYOCYTES. † 152

Glucagon has been shown to reverse the negative inotropic effects of Ca²⁺ channel blockers in adult dogs, rats, mice, and humans. The mechanism for this action of glucagon remains unclear, but one hypothesis proposes it is related to an increase in circulating cAMP, resulting in increased Ca²⁺ release from the sarcotubular system. To test this hypothesis and to determine if glucagon reverses the effect of Ca²⁺ channel blockers on contractions in immature cells, we studied the effects of glucagon on neonatal rabbit ventricular myocytes. Previous studies show sarcotubular development (and its contribution to contractions) is diminished in these cells. Cell shortening was measured in field-stimulated ventricular cells from neonatal (1-4 day old) New Zealand White rabbits using a video edge detector. The cells were bathed at 24°C., initially in normal Tyrodes solution containing (in mM) NaCl 138, Dextrose 11.0, MgCl₂ 1.0, KCl 4.4, CaCl₂ 2.7 and HEPES 12.0 (pH adjusted to 7.4 with NaOH). Maximum inhibition of contractions was achieved in the neonatal cells using 20 μM nifedipine. Contractions after nifedipine were 6.9±2.0%(mean±SEM) of baseline, but returned to 71.4±8.3% of baseline within 2 minutes of infusion with Tyrodes containing 1 μM glucagon (n=9). In contrast, contractions in cells treated with nifedipine and perfused for 2 minutes with Tyrodes alone (n=8) remained small compared to contractions in cells glucagon-treated (12.8±3.7% of baseline, P≤0.001), without significant increase from measurements after nifedipine. In conclusion, glucagon appears to affect mechanisms other than cAMP-induced Ca²⁺ release from the sarcotubular system. Since glucagon reverses the negative inotropic effect of nifedipine in neonatal myocytes, it may be useful clinically in infants requiring therapy with Ca²⁺ channel blockers.