Endothelin-1 Facilitates Synaptic Transmission in the Nucleus Tractus Solitarii in Normotensive Rats but Not in Spontaneously Hypertensive Rats.

Abstract

We previously demonstrated that endothelin-1 (ET-1) increases the neuronal activity of neurons in the nucleus tractus solitarii (NTS) and augments the response to glutamate (Glu), using in vitro brainstem slice preparations of normotensive Wistar-Kyoto (WKY) rats. This study was designed to determine whether the effects of ET-1 on neuronal activity and synaptic transmission in the NTS are altered in spontaneously hypertensive rats (SHR). Experiments were performed with WKY rats and age-matched SHR. We recorded the extracellular single unit of neuronal activity of NTS neurons in response to electrical stimulation of the solitary tracts using in vitro brainstem slice preparations.ET-1 or Glu was iontophoretically applied to the recording neurons. ET-1 increased the neuronal activity of NTS neurons in SHR as well as WKY. The magnitude of the increase in the neuronal activity evoked by Glu was augmented by application of ET-1 in WKY rats (6.1 ± 0.6 to 11.1 ± 1.7 spikes/s, p < 0.05) but not in SHR (5.6 + 0.5 to 5.6 + 0.6 spikes/s). These results indicate that ET-1 increases the neuronal activity of the NTS in both SHR and WKY. However, the increase in neuronal activity in response to Glu is augmented by ET-1 in WKY but not in SHR, suggesting that reflex control is impaired in SHR. (Hypertens Res 1999; 22: 43-48) Key Words: endothelin, brain, hypertension, glutamate, baroreflexCentral endothelin-1 (ET-1) plays an important role in regulation of cardiovascular function (1-8) . ET is produced by endothelial cells and by non-endothelial cells, such as neurons, astrocytes, and glial cells (1, 9) . ET-like immunoreactivity is present in the paraventricular nucleus, supraoptic nucleus, hippocampus, cerebellum, and nucleus tractus solitarii (NTS) of the brain in rats as well as in humans (1, 10) . The distribution of ET and its binding sites throughout the brain suggests that, in addition to its role as a vasoconstrictor, ET may also act as an important neuromodulator in the central nervous system. ET binding is highest in the cardiovascular regulatory centers of the central nervous system, such as the brainstem including the NTS (11, 12). Radioreceptor binding studies have shown ET receptors to be down-regulated in the hypothalamus and ventrolateral medulla of spontaneously hypertensive rats (SHR), although no differences are seen in the dorsal medulla or NTS (13-15). The concentration of ET-1 was found to be lower in the central nervous system of SHR than in that of normotensive Wistar-Kyoto (WKY) rats (16). These studies suggest that the cardiovascular regulatory effect of central ET-1 may thus be altered in hypertension.Mutant mice deficient in ET-1 have been created using gene-targeting techniques, and ET-1 (+1) -heterozygous mice have elevated blood pressure; central nervous system mechanism(s) also appear to be involved (2). The systemic and regional circulatory effects of centrally administered ET-1 have been shown to be mediated through ETA receptors (5, 6).The intracerebroventricular administration of ET-1 produ...

Regulation of Blood Pressure and Salt Homeostasis by Endothelin

“…Bilateral microinjections of ET A antagonists into the NTS of rats elicited an initial pressor response (albeit followed by hypotension) (508). In agreement with this, ET-1 or glutamate applied to brain stem slices stimulated NTS neuronal discharge from both WKY and SHR rats (293, 693); notably, ET-1 enhanced the response to glutamate in WKY, but not in SHR, rats. Increased NTS neuronal activity would be expected to reduce sympathetic efferent activity and lower BP, thereby augmenting baroreflex buffering of BP.…”

Increased Cardiac Sympathetic Drive and Reduced Vagal Modulation Following Endothelin Receptor Antagonism in Healthy Conscious Rats

“…The administration of ET‐1, or the blockade of its receptors, has yielded contradictory results depending on the dose and central site studied. Injection of ET‐1 into the nucleus tractus solitarius seems to result in an increase in neuronal activity, 28–31 whereas ET‐1 injection into the Rostral ventrolateral medulla causes an increase in neuronal discharge 32–34 . In anaesthetized rats, injection of low doses of ET‐1 into the cisterna magna increases renal sympathetic nerve activity (RSNA), HR and arterial pressure, but injection of high doses of ET‐1 has the opposite effect 15 .…”