Study of SR 142801, a new potent non-peptide NK3 receptor antagonist on cardiovascular responses in conscious guinea-pig

1 The cardiovascular responses to intravenous (i.v.) injection of natural tachykinins, substance P (SP), neurokinin A (NKA), neurokinin B (NKB) 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 assessed 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 mean arterial blood pressure (MAP) accompanied by increases in heart rate (HR). NKA evoked only weak hypotensive effects at high doses (3000 pmol 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 senktide (1-1000 pmol kg(-1)), produced dose-related hypertensive effects with the following rank order of potency: senktide > [MePhe(7)]NKB > NKB. 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 completely inhibited by the combination of the two compounds. Atropine (1.5 mu mol kg(-1)) suppressed the decrease in HR induced by senktide without 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) propyl)-4-phenyl-piperidin-4-yl)-N-methylacetamide), a potent and specific non-peptide NK3 receptor 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 administration. By contrast, SR 142806 (4.6 mu mol kg(-1), i.v.), the (R)-enantiomer 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 MAP 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 only after i.v. injection. 6 In conclusion, these results show evident differences in the functional role of tachykinin receptors in the peripheral control of the cardiovascular system. Furthermore, a clear presser effect of senktide, which was selectively blocked by SR 142801, was observed in conscious guinea-pigs. Hence, this antagonist appears suitable for investigating the functional role of NK3 receptors.