Kenichi Iwatsuki

A Weak Negative Inotropic Effect of Protamine Sulfate upon the Isolated Canine Heart Muscle

The direct effect of protamine sulfate upon myocardial inotropism was studied using an isolated canine heart muscle preparation. Isometric force (F) was decreased to 87.6 ± 1.2% of control values by a concentration of 50 × 10−3 g/L protamine, which is approximately equal to the estimated serum concentration of protamine when administered clinically in doses of 4 mg/kg. The decrease in F was accompanied by a decrease in the maximum velocity of force development (dF/dt) but no alteration in time to peak force. Administration of the preservative of protamine sulfate did not alter F and dF/dt. This suggests that protamine produces a direct negative inotropic effect, mediated by a decrease in intensity but not by a decrease in duration of the active state.

Inotropic Effects of Non-depolarizing Muscle Relaxants in Isolated Canine Heart Muscle

The inotropic effects of five non-depolarizing muscle relaxants were examined using an isolated canine heart muscle preparation. Except for fazadinium, all drugs were studied in their commercially available forms. d-Tubocurarine chloride (dTc) and metocurine iodide (MTC) produced dose-dependent decreases in isometric force (F) and the maximum velocity of force development (dF/dt) at concentrations greater than 22.5 × 10−3 g/L for dTc and greater than 15.0 × 10−3 g/L for MTC, concentrations which are 3 and 6 times higher than estimated clinical serum concentrations, respectively. Myocardial depression was about 3 times less with MTC than with dTc at equipotent concentrations. The degree of depression in F and dF/dt produced by MTC was almost identical with that produced by phenol, a preservative of MTC, indicating that MTC-induced myocardial depression may be due to the effect of the preservative. Pancuronium bromide (PC) produced a dose-dependent increase in F and dF/dt and decrease in the time to peak force. PC-induced changes in F, dF/dt, and time to peak force were inhibited by administration of propranolol 10−6 M. The results indicate that PC possesses a positive inotropic effect mediated by beta-adrenergic stimulation. Alcuronium chloride did not change F or dF/dt at concentrations from 5.0 × 10−3 to 60.0 × 10−3 g/L. Fazadinium bromide increased F and dF/dt slightly at a low concentration (1.875 × 10−2 g/L), but further increases in its concentration returned the values of F and dF/dt to control levels. F and dF/dt were not altered in vitro by concentrations of relaxants that would be anticipated in plasma in vivo in patients given clinically effective doses of 0.3 mg/kg of dTc, 0.1 mg/kg of MTC or PC, 0.2 mg/kg of alcuronium chloride, or 0.75 mg/kg of fazadinium bromide.

History of Muscle Relaxants in Japan

In summer 1950 the Joint Meeting of Japanese and American Medical Educators was held in Tokyo for 4 weeks under the sponsorship of UNICEF and eminent American scholars gave us lectures concerning the recent advances in the various fields of medicine. Fortunately I had an opportunity to attend the session of anesthesiology and heard the lectures by Dr. Meyer Saklad from Rhode Island Hospital. He opened our eyes to modern anesthesia. In December 1951 I was allowed to visit an American Naval Hospital in Yokosuka for 2 weeks and observed many cases of general anesthesia for the patients from the Korean battle field. Endotracheal intubation was performed very easily using decamethonium (Syncurine®). Without muscle relaxants, however, it was a very difficult procedure for us. Therefore, I was deeply impressed by the wonderful action of Syncurine®. The history of muscle relaxants in Japan, which actually started after World War II, is presented in the following, based mainly on my own experiences.