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Two receptors mediating relaxant responses to 5-hydroxytryptamine (5-HT) were studied comparatively in rings of rabbit jugular vein contracted with U-46619 (10 nmol/l). At low concentrations of 5-HT (0.001-0.1 mumol/l) vascular relaxation was mediated indirectly by the endothelial 5-HT receptor previously described by Leff et al. (1987). In preparations denuded of endothelium, higher concentrations of the amine (0.03-30 mumol/l) caused relaxation responses directly, presumably via a receptor located on the smooth muscle cells. Similarity between the receptors was evident in that both were susceptible to antagonism by methysergide, but resistant to blockade by ketanserin and MDL 72222. In these respects, the receptors qualified for a '5-HT1-like' classification. Consistent with this, 5-carboxamidotryptamine demonstrated a higher agonist potency than 5-HT at the receptor mediating relaxation directly. However, in endothelium-intact jugular vein rings this potency order was reversed, showing that the endothelial 5-HT receptor did not satisfy completely the criteria for a '5-HT1-like' designation. When the activities of a single set of tryptamines were compared in endothelium-intact and -denuded jugular vein rings, different affinity and relative efficacy estimates were obtained, confirming that two distinct 5-HT receptors mediate relaxation responses in this tissue. The most striking difference between these two receptor types was demonstrated by alpha-methyl-5-HT since it expressed a high affinity comparable to 5-HT at the endothelial receptor, but was inactive at the receptor in endothelium-denuded preparations at concentrations up to 30 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

The release of cytokines following administration of endotoxin and the contribution of nitric oxide (NO) to the subsequent haemodynamic profile were investigated in the conscious mouse. Administration of endotoxin (E. Coli, 026:B6, 12.5 mg kg−1, i.v.) elevated the concentration of tumour necrosis factor‐α (TNF‐α) in the plasma within 0.5 h, reaching a maximum at 2 h and returning to control concentrations by 4 h. In addition, the concentration of interleukin‐6 (IL‐6) in the plasma was also elevated within 1 h, reaching a maximum at 3 h and remaining elevated throughout the 12 h of study. Endotoxin (12.5 mg kg−1, i.v.) induced the expression of a Ca2+‐independent (inducible) NO synthase in the mouse heart and elevated the concentrations of nitrite and nitrate in the plasma within 4 h, reaching a maximum at 12 h. This was accompanied by a progressive fall in blood pressure over the same period. The vasopressor effect of noradrenaline (0.5–4 μg kg−1 min−1, i.v.) administered as a continuous infusion was significantly attenuated 7 h after endotoxin (12.5 mg kg−1, i.v). The NO synthase inhibitor NG‐monomethyl‐L‐arginine HCl (L‐NMMA; 1–10 mg kg−1, i.v. bolus) reversed the fall in blood pressure when administered 7 h after endotoxin (12.5 mg kg−1, i.v.). In an attempt to maintain a constant blood concentration, L‐NMMA was administered as a continuous infusion (10 mg kg−1 h−1, i.v.), beginning 4 h after a lower dose of endotoxin (6 mg kg−1, i.v.). Such treatment prevented the fall in blood pressure and the elevation of nitrite and nitrate in the plasma throughout the 18 h of observation. The fall in blood pressure following endotoxin (3 mg kg−1, i.v.) was significantly reduced throughout the 18 h of observation in homozygous mutant mice lacking the inducible NO synthase. In summary, we have developed a model of endotoxin shock in the conscious mouse in which an overproduction of NO by the inducible NO synthase is associated with the haemodynamic disturbances. This model, which exhibits many of the characteristics of septic shock in man, will enable the study of the pathology of this condition in more detail and aid the investigation of potential therapeutic agents both as prophylactics and, more importantly, as treatments.

1 In anaesthetized dogs, intra-left atrial administration of 5-hydroxytryptamine (5-HT) and selected tryptamine analogues (5-carboxamidotryptamine, 5-CT; 5-methyl tryptamine, 5-MT; a-methyl 5-hydroxytryptamine, a-HT; sumatriptan, Sum) in the presence of ketanserin and MDL72222 (5-HT2 and 5-HT3 receptor antagonists, respectively), produced dose-related changes in carotid, coronary 5 The coronary (and carotid) vasodilator responses to 5-CT were antagonized by the 5-HTI-like receptor antagonists, spiperone (1 mg kg-') and methiothepin (0.1 mg kg-'), whereas the renal vasoconstrictor responses to this tryptamine analogue were antagonized only by methiothepin. 6 It is concluded from these studies that agonist finger-printing in vivo, using tryptamine analogues, identifies and confirms the functional presence of at least two pharmacologically distinct subtypes of the 5-HTI-like receptor in the intact canine cardiovascular system. These two subtypes are located on the vascular smooth muscle and mediate direct vasoconstriction and vasodilatation responses in vivo. 7 In addition, these studies confirm that the distribution of these subtypes within the major vascular beds, shows a marked heterogeneity. The carotid vascular responses to the tryptamine analogues indicate the presence of both the vasodilator and the vasoconstrictor subtypes. The coronary vascular responses to these analogues are, however, consistent with presence of the vasodilator subtype, only. By contrast, the renal vascular responses to these analogues indicates only the presence of the vasoconstrictor subtype.

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