Plasticity of GABA function in the nucleus tractus solitarius in hypertension

Alan F. Sved, Judith C. Sved
2003 American Journal of Physiology. Regulatory Integrative and Comparative Physiology  
THE BRAIN PLAYS AN IMPORTANT role in the normal regulation of arterial pressure, and alteration in the regulation provided by the brain may chronically influence arterial pressure leading to hypertension or hypotension. Indeed, substantial evidence suggests that human hypertension frequently has a neurogenic basis (5, 7), and certain drugs used to treat hypertension act on central neural systems controlling arterial pressure. Experiments comparing central neural control of arterial pressure in
more » ... terial pressure in animal models of hypertension with their normotensive controls represent a frequently used approach to study the mechanisms underlying hypertension. However, a corollary of this approach that is often overlooked is that in studying altered states of regulation, insight into the mechanisms involved in the physiological regulation of arterial pressure may be gained. Physiological control systems are often remarkably plastic and can alter their operating characteristics depending on the prevailing conditions. The study by Mei et al. (8) in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology nicely illustrates this point, as their study may inform us as much about the normal control of arterial pressure as it does about hypertension. The study by Mei et al. (8) is the most recent in a series of reports by Mifflin and colleagues (4, 13, 14) having their roots in studies we reported 15 years ago (1, 2, 9, 11) . Because baroreceptor reflex regulation of the autonomic nervous system is essential for the normal control of arterial pressure and the first central synapse in this reflex arc is located in the nucleus tractus solitarius (NTS) in the dorsomedial brain stem, it is not surprising that researchers interested in the central neural control of cardiovascular function have focused on this region. In a seminal report, Doba and Reis (3) described a marked increase in arterial pressure resulting from destruction of the NTS. Because inhibition of the NTS might be analogous to its destruction and GABA is the dominant inhibitory neurotransmitter in the brain, we began to study the role GABA plays in the NTS in the regulation of arterial pressure (1). Our naive hypothesis was that enhancement of GABA-mediated inhibition of NTS function may lead to increased arterial pressure and might be a mechanism underlying at least some forms of hyper-tension. We demonstrated that potentiating the actions of GABA in the NTS of anesthetized rats increased arterial pressure through actions on both GABA A and GABA B receptors (10). Furthermore, in a rat model of genetic hypertension, the spontaneously hypertensive rat (SHR), we noted that stimulation of GABA B receptors in the NTS, by injection of the GABA B agonist baclofen into the NTS, produced exaggerated increases in arterial pressure when compared to normotensive control rats (2). This observation provided some of the first evidence that cardiovascular responses elicited from the brain of SHR could be different from those of control rats and stood in marked contrast to the lack of difference in the pressor response cause by stimulation of GABA A receptors in the NTS (2). The potentiated increase in arterial pressure seen in SHR in response to injection of GABA B agonists but not GABA A agonists was one of the first demonstrations that a specific neural substrate involved in brain control of arterial pressure was altered in a model of hypertension. Subsequent studies demonstrated that potentiated pressor responses to GABA B agonists but not GABA A agonists also occurred in other rat models of hypertension (4, 12, 13) and may occur quite quickly in response to elevated arterial pressure (13). However, the relationship of this enhanced pressor action of GABA in the NTS to specific cellular responses in the NTS remained unclear, and the relationship to the baroreceptor reflex uncertain. Zhang and Mifflin (14) recently showed baclofen to be relatively ineffective at inhibiting baroreceptordriven activity of NTS neurons receiving monosynaptic baroreceptor input (based on electrophysiological criteria). Baclofen does, however, inhibit the activity of neurons receiving baroreceptor input polysynaptically (14); baclofen may also act presynaptically to inhibit baroreceptor transmission (14). In contrast, the GABA A agonist muscimol inhibited the activity of NTS neurons that received baroreceptor input either monosynaptically or polysynaptically (14). Mei et al. (8) now demonstrate that in a model of renal hypertension produced by removing one kidney and compressing the other, a model in which pressor responses to baclofen injected into NTS are enhanced (4, 13), neuronal responses to the iontophoretic application of GABA B and GABA A receptor agonists are modified in a complex manner. At both 1 and 4 wk after the onset of hypertension, the effectiveness of baclofen at inhibiting aortic depressor nerve (ADN) evoked responses in NTS neurons receiving monosynaptic input was markedly increased, making it comparable to the response in the Address for reprint requests and other correspondence:
doi:10.1152/ajpregu.00441.2003 pmid:14615397 fatcat:a3yj35wqa5dxfihl5yzo73uory