Evaluation of Pulmonary and Cardiovascular Effects of Drugs of Military Interest

The purpose of these experiments was to establish the effects of intravenous infusions of WR-228,258 on the rhythm, electrical activity, and function of the heart, the pulmonary blood pressure and circulation, the systemic blood pressure and circulation, and the pulmonary ventilation. WR 228,258, when infused at doses rates fo 0.7, 1.0, and 1.3 micromoles/kg/min for 20 minutes, produced changes in several pulmonary and cardiovascular variables. These dose-rates are in the same range as those employed for a recent study of primaquine . 2 H3PO4 and a fourfold lower range than those employed in the previous studies of mefloquine and quinine. The dose-cardiopulmonary response relationships for WR-228,258 are the steepest observed in our studies of candidate or clinically used antimalarial agents. The major effects of WR 228,258 seen at these dose levels include: 1) increase in respiratory rate (40 - 120%), 2) increase in minute volume (10 - 55%), 3) and increase in heart rate at the high dose only (25%), 4) decrease in LV dP/dt (30 - 50%), 5) a transient fall in both systolic and diastolic blood pressure (10 - 20%), and 6) an increase in pulmonary wedge pressure (50 - 100%). We do not have data which defines the mechanisms of these effects, but it seems likely that