Evidence for a GABA(B) receptor component in the spinal action of Substance P (SP) on arterial blood pressure in the awake rat

Abstract

1 The activation of tachykinin NK(1) receptors in the rat spinal cord produced a transient drop in arterial blood pressure followed by a more prolonged pressor effect which is mediated by the stimulation of the sympatho-adrenal system. This study aims at characterizing the spinal mechanism of that initial hypotension occurring in awake unrestrained rats. 2 The initial hypotension (-18+/-2.0 mmHg at 1 min) and the tachycardia (110+/-10 b.p.m.) produced by the intrathecal (i.t.) injection of the stable NK(1) receptor agonist [Sar(9), Met(O(2))(11)]-SP (Sar9, 0.65 nmol) at T-9 spinal cord level was inhibited by the prior injection of 65 nmol LY306740 or LY303870 (NK(1) receptor antagonists). No inhibition was seen when a similar dose of antagonists was given intravenously. 3 The prior i.t. injection of the GABA(B) receptor antagonist CGP52432 (100 nmol) reduced the hypotension evoked by Sar9 (0.65 nmol) and by the GABA(B) receptor agonist baclofen (100 nmol). The GABA(A) receptor antagonist bicuculline (25 nmol, i.t.) was without effect against Sar9, and the GABA(A) agonist muscimol (100 nmol, i.t.) had no cardiovascular effect. 4 The putative involvement of other mediators (dopamine, serotonine, glycine and glutamate) in Sar9-induced hypotension was made unlikely on the basis of various pharmacological treatments. Thus data, suggest that the transient hypotension which occurs upon the activation of NK(1) receptors in the spinal cord is due to the release of GABA which in turn activates GABA(B) receptors to inhibit sympathetic pre-ganglionic fibres. This mechanism may have a physiological significance in the spinal reflex autonomic control of arterial blood pressure.

Figure 1

Time-course effects on changes in mean arterial blood pressure (Δ MAP) and heart rate (Δ HR) for a period of 45 min following the intrathecal injection of three increasing doses of Sar9 at T-9 spinal cord level in awake unrestrained rats. Each point represents the means±s.e.mean of eight rats. Baseline MAP and HR values are 90.6±4.3 mmHg and 418±11 b.p.m., respectively. Statistical comparison to vehicle values (aCSF) is indicated by ^*P<0.05; ^**P<0.01; ^***P<0.001.

Figure 2

Maximal changes in mean arterial blood pressure (Δ MAP) and heart rate (Δ HR) induced by 0.65 nmol Sar9 injected to T-9 spinal cord level of awake rats in the absence (prior to and 24 h later) and presence (15 min after) of 65 nmol of LY303870, LY306740 or LY306155 administered either i.t. (A–B) or i.v. (C–D). Data are means±s.e.means of six rats per antagonist. Statistical comparison to vehicle (aCSF/20% DMSO) values (^*) or to Sar9 without antagonist (†) is indicated by ^*P<0.05; ^**, ††P<0.01; ^***P<0.001. Baseline values are for MAP and HR: 103.6±8.3 mmHg and 371.7±14.0 b.p.m. (LY303870); 83.9±5.1 mmHg and 416.7±13.3 b.p.m. (LY306740); 104.7±8.6 mmHg and 373.3±17.8 b.p.m. (LY306155).

Figure 3

Maximal changes in mean arterial blood pressure (Δ MAP) and heart rate (Δ HR) induced by i.t. injection of 100 nmol baclofen or 0.65 nmol Sar9 injected prior to or 1 min after i.t. administration of 100 nmol CGP52432. Data are means±s.e.means of six rats. Statistical comparison to vehicle values (^*) or to agonists without CGP52432 (†) is indicated by ^*, †P<0.05; ^**, ††P<0.01; ^***P<0.001.