Peripheral vasodilation and plasma extravasation are part of the mechanism of neurotensin-induced hypotension in the anesthetized rat

Abstract

The mechanism underlying the hypotensive effect of neurotensin (NT) was investigated in pentobarbital-anesthetized rats. In a first series of experiments we measured the pressor effects of dimethylphenylpiperazinium (DMPP), noradrenaline (NA), physostigmine (PHYS) and angiotensin II (AT II) in control normotensive rats and in rats made hypotensive with NT, hexamethonium (C6), prazosin (PRZ), clonidine (CLO) or nitroprusside (NTP). The results showed that in rats made hypotensive with NT or NTP the pressor effects of DMPP, NA, PHYS and AT II were similar in amplitude to those measured in control rats. In contrast the pressor effects of DMPP were either reduced or reversed in C6-, PRZ-, or CLO-treated rats as compared to control rats. The pressor effects of NA were reduced, potentiated or unaltered, in PRZ-, C6-, or CLO-treated rats respectively, when compared to control rats. The pressor effects caused by PHYS were smaller in C6-, CLO-, or phentolamine-treated rats than in control rats. The level of hypotension reached in NT-treated rats being larger than in C6-, PRZ-, or CLO-treated rats, the lack of inhibition of the pressor effects of DMPP and NA by NT clearly suggests that the mechanism by which NT and its mast cell mediators cause hypotension in rats cannot be attributed to autonomic ganglion blockade, alpha adrenergic receptor blockade or to a CLO-like action. Moreover, the absence of inhibition of PHYS-induced pressor effects by NT in atropine-treated rats suggests that NT and its mast cell mediators are unlikely to interfere with acetylcholine release from preganglionic cholinergic nerves or with ganglion nicotinic receptors. The results obtained with AT II also ruled out the possibility for NT and its mast cell mediators to act as AT II receptor antagonists. In a second series of experiments we measured the influence of NT on the pressor effects of NA, AT II and vasopressin in C6-treated rats. The results showed that in these conditions NT inhibited the pressor effects of NA, AT II, and VSP. These results indicate that a non-specific, direct vasodilating action is likely to be part of the mechanism by which NT and, more importantly, its mast cell mediators, cause hypotension in rats. In the last series of experiments we have assessed the influence of plasma volume expansion on the rate of normalization of blood pressure in rats made hypotensive by NT or other hypotensive drugs. The results showed that plasma volume expansion was more effective in raising the blood pressure back to normal in rats made hypotensive with NT than in rats made hypotensive with either C6 or hydralazine. Taken together, these results indicate that peripheral vasodilation (most likely due to a direct effect of mast cell mediators liberated by NT on vascular smooth muscle cells) and plasma extravasation (due to the action of mast cell mediators liberated by NT on microvessels), are likely to play an important role in the mechanism by which NT produces hypotension in anesthetized rats.