Upregulation of tachykinin NK-1 and NK-3 receptor binding sites in the spinal cord of spontaneously hypertensive rat: impact on the autonomic control of blood pressure.
1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK-1 receptor ([(125)I]HPP[Arg(3),Sar(9),Met(O(2))(11)]SP (3-11)) and NK-3 receptor ([(125)I]HPP-Asp-Asp-Phe-N-MePhe-Gly-Leu-Met-NH(2)). 2 The NK-1 agonist [Sar(9),Met(O(2))(11)]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65-6500 pmol) and more sustained tachycardia. The NK-3 agonist senktide (6.5-65 pmol) evoked marked increases in MAP and HR (SHR>>>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar(9),Met(O(2))(11)]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK-1 antagonist, 65 nmol) and SB235375 (NK-3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK-1 and -3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK-1 (K(d)=2.5 nM) and NK-3 (K(d)=5 nM) receptors. 4 Data highlight an upregulation of NK-1 and -3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension.
Cloutier
Frank
F
Department of Physiology, Faculty of Medicine, Université de Montréal C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada H3C 3J7.
Ongali
Brice
B
Deschamps
Kathleen
K
Brouillette
Jonathan
J
Neugebauer
Witold
W
Couture
Réjean
R
D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology*; D001345:Autoradiography; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate; D006973:Hypertension / Q000503:physiopathology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000032:analysis / Q000096:biosynthesis* / Q000187:drug effects; D018042:Receptors, Neurokinin-3 / Q000032:analysis / Q000096:biosynthesis* / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013904:Thoracic Vertebrae; D015854:Up-Regulation
C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D000085:Acetates; D007211:Indoles; C444647:N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide; D010446:Peptide Fragments; D010880:Piperidines; D011804:Quinolines; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; C054724:senktide; C062618:substance P, Sar(9)-Met(O2)(11)-; D013373:Substance P