Hypotensive effects of centrally and peripherally administered neurotensin and neurotensin derivatives in rats

Abstract We have evaluated and compared the hypotensive effects of intravenously (iv) and intracerebroventricularly (icv) injected NT, NT fragments and analogues in pentobarbital-anesthetized rats. The removal of the sequence pGlu 1 -Leu 2 -Tyr 3 -Glu 4 -Asn 5 -Lys 6 -Pro 7 reduced only slightly the hypotensive activity of NT injected iv and icv while the deletion of Leu 13 or of Tyr 11 -Ile 12 -Leu 13 -OH brought about a large decrease of potency (NT (1–12)) or a complete loss of hypotensive activity (NT (1–10)). The replacement of Tyr 11 with Trp produced a minor increase (∼8%) or decrease (15%) of the potency of NT when injected iv and icv respectively. NT analogues in which Tyr 11 was replaced with Phe, D-Phe or D-Tyr exhibited large decreases of potency when injected iv but only small reductions of potency when injected icv. [D-Trp 11 ]-NT and [Tyr(Me) 11 ]-NT were relatively weak agonists using both routes of injection. Our results indicate that the chemical groups responsible for the hypotensive effect of peripherally and centrally injected NT are located in the same sequence (e.g. Arg 9 -Pro 10 -Tyr 11 -Ile 12 -Leu 13 -OH). The results also suggest that the amino acid Tyr 11 contributes to a large extent to the hypotensive activity of peripherally injected NT. The importance of Tyr 11 for the hypotensive activity of centrally administered NT remains difficult to evaluate possibly because the receptors which subserve the hypotensive effect of centrally administered NT and/or the mechanisms responsible for the inactivation of NT in the brain and in the periphery, are different.