Pharmacological evidence that NK-2 tachykinin receptors mediate hypotension in the guinea pig but not in the rat.
Vascular NK-1 and NK-2 tachykinin receptors in the rat and the guinea pig were characterized pharmacologically by using available agonists and antagonists exhibiting varying degrees of selectivity for these receptors. Because the anesthetized guinea pig has unusually low blood pressure, these animals were pithed and vagotomized and infused, throughout the experimental procedure, with norepinephrine (6 micrograms/kg/min). This treatment raised their blood pressure to a level appropriate for the determination of dose-hypotensive response curves. The NK-1 receptor agonists substance P (SP) and septide (0.004 to 1 microgram/kg iv) decreased carotid artery blood pressure in a dose-dependent manner in both species, but they were more potent (13- and 33-fold, respectively) in guinea pigs than in rats. The NK-2 receptor agonist [beta Ala8]-NKA(4-10) (0.06 to 1 microgram/kg) also dose-dependently lowered blood pressure in the pithed guinea pig with noradrenaline-supported blood pressure, although it failed to do so in the same rat preparation. RP 67580, a selective NK-1 antagonist, antagonized the SP- or septide-induced hypotensive response in rats, but not in guinea pigs. Conversely, RPR 100893, a novel NK-1 receptor antagonist chemically related to RP 67580, dose-dependently inhibited hypotension induced by SP, and even more, that induced by septide only in guinea pigs. In the latter species, neither RP 67580 nor RPR 100893 affected decreases in blood pressure induced by [beta Ala8]-NKA(4-10). These decreases were, however, inhibited by the NK-2 receptor antagonist SR 48968. The selectivity of this compound for the latter receptor was confirmed by its failure to affect SP- or septide-induced hypotension in either guinea pigs or rats. These results confirm that the hypotensive responses to SP and septide are mediated by NK-1 receptors in the two species studied. However, functional NK-2 receptors appear to be present in the vascular bed of the guinea pig but not that of the rat, since in the former species the hypotensive responses induced [beta Ala8]-NKA(4-10) were inhibited by SR 48968 but not by the NK-1 receptor antagonists studied. This conclusion is, to our knowledge, drawn here for the first time from clear-cut pharmacological results.
Floch
A
A
Rhŏne-Poulenc Rorer SA, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Thiry
C
C
Cavero
I
I
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006168:Guinea Pigs; D007022:Hypotension / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000187:drug effects / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology
D001549:Benzamides; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C064218:neurokinin A (4-10), beta-Ala(8)-; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C089835:RPR 100893; D013373:Substance P; C073839:SR 48968; C054725:septide; D015288:Neurokinin A; D011761:Pyrrolidonecarboxylic Acid