Role of spinal GABA receptors in depressor responses to chemical stimulation of the A5 area in normal and hypertensive rats

Abstract

Chemical stimulation of neurons in the pontine A5 area by microinjection of L-glutamate lowers arterial blood pressure. The mechanism of this 'A5 depressor response' is not well-established. Here, we examine the involvement of spinal cord gamma-aminobutyric acid (GABA) receptors in this depressor response in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Experiments were conducted in male WKY and age-matched SHR anaesthetised with sodium pentobarbitone and chloral hydrate. An intrathecal catheter was implanted with the tip located between T9 and L2. Three days later, rats were re-anaesthetised and 10 nl of 40 mM L-glutamate was injected into the A5 area before, during and after, blockade of spinal cord GABA-A receptors by intrathecal injection of bicuculline methiodide (1 mM in 10 microliters phosphate-buffered saline). Injection of L-glutamate (10, 20, 40, 80 mM in 10 nl) produced depressor responses that were similar in WKY (n = 6) and SHR (n = 6). Intrathecal injection of bicuculline elicited a pressor response that was greater in SHR (n = 7, 28.5 +/- 7.6% increase in mean arterial pressure) than WKY (n = 11, 11.6 +/- 3.6%, p < 0.05). After bicuculline, the depressor response to injection of L-glutamate into the A5 area was eliminated in both WKY (n = 7) and SHR (n = 6). Intrathecal injection of vehicle had no effect on either resting arterial blood pressure or the depressor response to A5 stimulation. Basal blood pressure and control responses to A5 stimulation were fully restored by around 90 min after bicuculline injection in each animal. In separate groups of rats, intrathecal injection of muscimol elicited depressor responses that were greater in SHR (n = 6, -32.0 +/- 6.2%) than WKY (n = 6, -17.3 +/- 1.5%, p < 0.05). Our results suggest that the A5 depressor response is due to a projection from the A5 area to the spinal cord. This projection acts directly, or through a spinal interneuron and uses GABA as a neurotransmitter. Furthermore, our results indicate a hyper-responsiveness to GABA-A receptor stimulation in SHR since intrathecal bicuculline elicited much greater increases and intrathecal muscimol elicited much greater decreases, in blood pressure in SHR than in WKY. Finally, it seems likely that the A5-spinal depressor pathway is less effective in SHR than WKY under physiological conditions since chemical stimulation of the A5 area with L-glutamate produced a comparable depressor response in both strains.