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

Abstract

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 (250pgkg -h-') 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-'). 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 a2-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 dosedependent depressor responses, which were markedly reduced by endotoxin and nicardipine. 6 The concomitant infusion of arginine vasopressin (0.64iukg-'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.

Regional haemodynamic responses to acetylcholine, methoxamine, salbutamol and bradykinin during lipopolysaccharide infusion in conscious rats

“…Two hours after the beginning of LPS infusion, the diminished pressor and carotid, mesenteric and hindquarters vasoconstrictor effects of methoxamine are consistent with reports of vascular hyporeactivity to a variety of vasoconstrictor agents in other rat models (Fink et al, 1985;Schaller et al, 1985;Guc et al, 1990;Hollenberg et al, 1993) and in man (Chernow et al, 1982). It is generally agreed that NOmediated mechanisms are involved (see Moncada et al, 1991) and, if so, it is interesting that not all vascular beds responded uniformly and that the pattern of hyporesponsiveness changed with time during LPS infusion (see below).…”

The effects of aspirin, flurbiprofen, and NO-donating acetylsalicylic acid(NCX 4016) on mice models of endotoxic and septic shock

“…It is becoming clearer that NO may act both as friend and foe in septic states (15). Since many deleterious effects of endotoxins, such as hypotension (16) and vascular hyporesponsiveness (17) to vasoconstrictors (18) and vasodilators (19), could be explained by excess NO production (20), the inhibition of NO to combat septic shock was regarded as essential until recently. The usefulness of an NO-inhibiting drug for the treatment of human toxic shock syndrome in an isolated case report (21) has enhanced this belief.…”

Voltage-independent calcium channels mediate lipopolysaccharide-induced hyporeactivity to endothelin-1 in the rat aorta

“…SEPTIC SHOCK IS A COMPLEX pathological state characterized by systemic vasodilation and hyporesponsiveness to vasoconstrictor agents (12,32,38,39). Numerous experimental studies of sepsis have clearly documented the presence of both in vivo and in vitro vascular hyporesponsiveness to different vasoconstrictors, including ␣-adrenergic agonists (7,12), angiotensin II (38), KCl (38,39), endothelin-1 (ET-1) (4,17), and thromboxane A 2 (2).…”

“…Numerous experimental studies of sepsis have clearly documented the presence of both in vivo and in vitro vascular hyporesponsiveness to different vasoconstrictors, including ␣-adrenergic agonists (7,12), angiotensin II (38), KCl (38,39), endothelin-1 (ET-1) (4,17), and thromboxane A 2 (2).…”

“…Therefore, LPS induces hyporeactivity to ET-1 in rat aorta that depends on external Ca 2ϩ influx through non-voltage-operated Ca 2ϩ channels, but not on ET-1 receptor expression or Ca 2ϩ sensitization. calcium sensitization; sepsis; vascular smooth muscle SEPTIC SHOCK IS A COMPLEX pathological state characterized by systemic vasodilation and hyporesponsiveness to vasoconstrictor agents (12,32,38,39). Numerous experimental studies of sepsis have clearly documented the presence of both in vivo and in vitro vascular hyporesponsiveness to different vasoconstrictors, including ␣-adrenergic agonists (7, 12), angiotensin II (38), KCl (38, 39), endothelin-1 (ET-1) (4, 17), and thromboxane A 2 (2).…”