Alteration in calcium metabolism as a mechanism for pyridine aldoxime methochloride (2-PAM) cardiac action in rabbit atria.

Pyridine aldoxime methochloride (2-PAM) increased the force of contraction of stimulated rabbit left atria in vitro. The threshold concentration was 2.3 times 10- minus 3 M whereas 9.2 times 10- minus 2 M produced the absolute maximum increase in tension of 83%. Pretreatment of rabbits with reserpine (2.5 mg/kg/day for 3 days) had no significant influence on the positive inotropic action of 2-PAM. In addition, propranolol (10- minus 8 and 10- minus 6 M) had no effect. Time to peak tension and the time to complete relaxation during each contraction cycle was significantly prolonged. 2-PAM increased the isometric tension developed by isolated aortic strips. The maximum tension developed by the control aortas to 2-PAM was 1.54 plus or minus 0.17 g and after 10- minus 6 M phentolamine, it remained 1.46 plus or minus 0.19 g. The rate of tension decline of stimulated atria was increased in the presence of 2-PAM from 49.7 plus or minus 2.40 to 28.50 plus or minus 1.32 seconds when the atria were placed in a low calcium (Ca)-containing Ringer's solution (0.24 mM CaCl2). When the bathing medium was changed from a low Ca (0.24 mM CaCl2) Ringer's back to normal Ca (2.4 mM CaCl2) Ringers solution, 2-PAM had no influence on the rate of recovery of the initial tension response of the atria. The 34-Ca uptake and efflux studies demonstrated that 2-PAM had no influence on the inward movement of Ca through the membrane but increased the rate of efflux during the phase II process. 2-PAM depressed the rate of uptake of 45-Ca by the isolated rabbit sarcoplasmic reticulum. The T1/2 for the control uptake was 1.80 plus or minus 0.07 minutes and in the presence of 2-PAM (2 times 10- minus 2, 5 times 10- minus 2, 1 times 10- minus 1 M) the T1/2 was increased to 4.50 plus or minus 0.22, 7.20 plus or minus 0.36 and 11.6 plus or minus 0.44 minutes, respectively. It is concluded from these studies that 2-PAM has a positive inotropic effect on isolated rabbit atria which is probably not related to the autonomic nervous system. The evidence obtained strongly suggests that the mechanism of the positive inotropic action is related to the effect of 2-PAM on the homeostasis of intracellular Ca storage sites.