STUDY OF SR-142801, A NEW POTENT NONPEPTIDE NK3 RECEPTOR ANTAGONIST ON CARDIOVASCULAR-RESPONSES IN CONSCIOUS GUINEA-PIG

1 The cardiovascular responses to intravenous (i.v.) injection of natu ral tachykinins, substance P (SP), neurokinin A (NKA), neurokinin B (N KB) and selective tachykinin (NK) receptor agonists, [Sar(9), Met(O-2) (11)]SP, [beta Ala(8)]NKA(4-10), [MePhe(7)]NKB and senktide were asses sed in conscious, freely moving, guinea-pigs. 2 SP and [Sar(9), Met(O- 2)(11)]SP (1-1000 pmol kg(-1)) induced dose-dependent decreases in mea n arterial blood pressure (MAP) accompanied by increases in heart rate (HR). NKA evoked only weak hypotensive effects at high doses (3000 pm ol kg(-1)) whereas [beta Ala(8)]NKA(4-10) (1-3000 pmol kg(-1)) had no effects. By contrast, NKB [MePhe(7)]NKB (1-10000 pmol kg(-1)) and senk tide (1-1000 pmol kg(-1)), produced dose-related hypertensive effects with the following rank order of potency: senktide > [MePhe(7)]NKB > N KB. Bradycardia occurred simultaneously with the increases in arterial pressure. 3 The presser response to intravenous injection of senktide (300 pmol kg(-1)) was partially reduced by pretreatment with prazosin (0.7l mu mol kg(-1)), or clonidine (0.38 mu mol kg(-1)) and was compl etely inhibited by the combination of the two compounds. Atropine (1.5 mu mol kg(-1)) suppressed the decrease in HR induced by senktide with out altering the blood pressure response. These findings suggest that the blood pressure response to senktide is an indirect effect mediated by noradrenaline released from sympathetic nerve endings, whereas the bradycardia is of vagal reflex origin. 4 SR 142801, ((S)-(N)-(1-(3-(1 -benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) opyl)-4-phenyl-piperid in-4-yl)-N-methylacetamide), a potent and specific non-peptide NK3 rec eptor antagonist dose-dependently (0.46-4.6 mu mol kg(-1) i.v.; 4.6-46 mu mol kg(-1), p.o.) inhibited the cardiovascular effects of senktide and displayed a long-lasting inhibitory effect after oral administrat ion. By contrast, SR 142806 (4.6 mu mol kg(-1), i.v.), the (R)-enantio mer of SR 142801 had no effect on the responses to senktide. SR 142801 at a high dose (15 mu mol kg(-1), i.v.) was inactive toward the [Sar( 9), Met(O-2)(11)]SP-induced hypotension. 5 SR 142801 did not modify MA P in conscious guinea-pigs both after i.v. (4.6 and 15 mu mol kg(-1)) and oral (46 and 150 mu mol kg(-1)) administration, showing a lack of agonistic properties. However, a slight reduction in HR was observed o nly after i.v. injection. 6 In conclusion, these results show evident differences in the functional role of tachykinin receptors in the peri pheral control of the cardiovascular system. Furthermore, a clear pres ser effect of senktide, which was selectively blocked by SR 142801, wa s observed in conscious guinea-pigs. Hence, this antagonist appears su itable for investigating the functional role of NK3 receptors.