Endotoxin-induced impairment of vasopressor and vasodepressor responses in the pithed rat

1. Effects of E. coli endotoxin on vascular responsiveness to a variety of agents were compared with those of the calcium channel blocking drug nicardipine in pithed rats. 2. Infusion of endotoxin (250 micrograms kg-1 h-1) produced a fall in mean arterial blood pressure (8 mmHg). A similar fall (11 mmHg) was seen in rats receiving nicardipine (1.0 mg kg-1). 3. Endotoxin impaired responsiveness to vasopressin, phenylephrine and cirazoline, producing a shift to the right in the dose-response curves without any change in the maximum response. Responsiveness to 5-hydroxytryptamine (5-HT) and to the alpha 2-adrenoceptor agonists clonidine and BHT 933, was also impaired with a marked reduction in their maximum responses. The dose-response curve to the pressor effects of endothelin was not significantly modified. 4. Nicardipine produced a similar pattern of impairment of responsiveness to these agents to that produced by endotoxin. However, nicardipine also shifted the pressor dose-response curve to endothelin to the right with no significant alteration in its maximum response. 5. The pressor responses to endothelin and to 5-HT were, respectively, preceded and followed by dose-dependent depressor responses, which were markedly reduced by endotoxin and nicardipine. 6. The concomitant infusion of arginine vasopressin (0.64 iu kg-1 h-1) prevented endotoxin-induced hypotension and also prevented the impairment in responsiveness to cirazoline and to BHT 933. 7. The similarity of the pattern of impaired pressor responsiveness (except in relation to endothelin) and depressor responsiveness produced by endotoxin and nicardipine may be consistent with a common mechanism of action.