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Cardiovascular improvement due to RA642, a pyrimido-pyrimidine derivative, in canine endotoxin shock
Abstract:
The cardiovascular effects of a pyrimido-pyrimidine derivative, RA642, were studied during endotoxin shock in pentobarbital-anesthetized dogs. In the control group, 30 min after intravenous administration of Escherichia coli endotoxin (1 mg/kg) mean blood pressure (MBP) and cardiac output (CO) fell significantly from 125 +/- 8 mmHg (mean +/- SE) to 65 +/- 8 mmHg and from 1.57 +/- 0.17 liter/min to 0.84 +/- 0.13 liter/min, respectively. Left ventricular (LV)dP/dtmax, renal blood flow (RBF), heart rate (HR), and central venous pressure (CVP) were also reduced significantly after endotoxin administration. Following the injection of vehicle 30 min after the endotoxin, all cardiovascular parameters in the control group remained decreased. A rapid significant rise in portal venous pressure (PoP) occurred and was maintained until the end of the experiment. Endotoxin caused an initial transient rise of total peripheral resistance (TPR) followed by a prolonged decrease. In the treated group, RA642 (0.25 mg/kg, IV), injected 30 min after the endotoxin, produced significant increases in MBP (from 62 +/- 6 mmHg to 93 +/- 7 mmHg), CO (from 0.92 +/- 0.111 liter/min to 1.28 +/- 0.18 liter/min), LVdP/dtmax (from 1600 +/- 100 mmHg/sec to 2100 +/- 300 mmHg/sec), and RBF (from 46 +/- 10 ml/min to 61 +/- 11 ml/min) within 15 min. There was a gradual return toward the pretreatment levels in each parameter 30 min after the endotoxin. The values of each parameter in the treated group were maintained significantly higher than those in the control group until the end of the experiment (90 min after the treatment). RA642 caused a rapid return of the reduced HR and the elevated PoP to the preendotoxin level. CVP recovered somewhat, though insignificantly, toward the preendotoxic value by the treatment. Following treatment, TPR was maintained at the pretreatment level. The results of this study provide evidence that RA642 exerts beneficial cardiovascular actions in endotoxin shock, restoring blood flow to vital organs without jeopardizing normal perfusion pressure and without increasing heart rate.