Mueller, P. J., Foley, C. M., Vogl, H. W., Hay, M., & Hasser, E. M. (2005). Cardiovascular response to a group III mGluR agonist in NTS requires NMDA receptors. American journal of physiology. Regulatory, integrative and comparative physiology, 289(1), R198-208.
Previous studies have demonstrated that microinjection of the putative group III metabotropic glutamate receptor (mGluR) agonist, l(+)-2-amino-4-phosphonobutyric acid (L-AP4), into the nucleus tractus solitarius (NTS) produces depressor and sympathoinhibitory responses. These responses are significantly attenuated by a group III mGluR antagonist and may involve ionotropic glutamatergic transmission. Alternatively, a previous report in vitro suggests that preparations of L-AP4 may nonspecifically activate NMDA channels due to glycine contamination (Contractor A, Gereau RW, Green T, and Heinemann SF. Proc Natl Acad Sci USA 95: 8969-8974, 1998). Therefore, the present study tested whether responses to L-AP4 specifically require the N-methyl-D-aspartate (NMDA) receptor and whether they are due to actions at the glycine site on the NMDA channel. To test these possibilities in vivo, we performed unilateral microinjections of L-AP4, glycine, and selective antagonists into the NTS of urethane-anesthetized rats. L-AP4 (10 mM, 30 nl) produced sympathoinhibitory responses that were abolished by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP-5, 10 mM) but were unaffected by the non-NMDA antagonist 6-nitro-7-sulfamobenzoquinoxaline-2,3-dione (NBQX, 2 mM). Microinjection of glycine (0.02-20 mM) failed to mimic sympathoinhibitory responses to L-AP4, even in the presence of the inhibitory glycine antagonist, strychnine (3 mM). Strychnine blocked pressor and sympathoexcitatory actions of glycine (20 mM) but failed to reveal a sympathoinhibitory component due to presumed activation of NMDA receptors. The results of these experiments suggest that responses to L-AP4 require NMDA receptors and are independent of non-NMDA receptors. Furthermore, although it is possible that glycine contamination or other nonspecific actions are responsible for the sympathoinhibitory actions of L-AP4, our data and data in the literature argue against this possibility. Thus we conclude that responses to L-AP4 in the NTS are mediated by an interaction between group III mGluRs and NMDA receptors. Finally, we also caution that nonselective actions of L-AP4 should be considered in future studies.
Xue, B., Badaue-Passos, D., Guo, F., Gomez-Sanchez, C. E., Hay, M., & Johnson, A. K. (2009). Sex differences and central protective effect of 17beta-estradiol in the development of aldosterone/NaCl-induced hypertension. American journal of physiology. Heart and circulatory physiology, 296(5), H1577-85.
The present study tested the hypotheses that male and female rats respond differently to subcutaneous infusions of aldosterone (Aldo; 1.8 microg.kg(-1).h(-1), 1% NaCl to drink; 28 days) and that central estrogen plays a protective role against the development of hypertension. In rats with blood pressure (BP) and heart rate (HR) measured by Data Sciences International telemetry, chronic Aldo/NaCl treatment induced a greater increase in BP in males (Delta25.4 +/- 2.4 mmHg) than in females (Delta7.1 +/- 2.2 mmHg). Gonadectomy augmented Aldo/NaCl-induced hypertension in females (Delta18.2 +/- 2.0 mmHg) but had no effect in males (Delta23.1 +/- 2.9 mmHg). Immunohistochemistry for Fra-like activity was higher in the paraventricular nucleus of intact males, castrated males, and ovariectomized (OVX) females compared with intact females after 28 days of Aldo/NaCl treatment. In intact males, central 17beta-estradiol (E(2)) inhibited the Aldo/NaCl increase in BP (Delta10.5 +/- 0.8) compared with that in central vehicle plus systemic Aldo/NaCl (Delta26.1 +/- 2.5 mmHg) rats. Combined administration of E(2) and estrogen receptor antagonist ICI182780 (ICI) blocked the protective effect of E(2) (Delta23.2 +/- 2.4 mmHg). In intact females central, but not peripheral, infusions of ICI augmented the Aldo/NaCl (Delta20.4 +/- 1.8 mmHg) BP increase. Finally, ganglionic blockade after Aldo infusions resulted in a smaller reduction in BP in intact females (-23.9 +/- 2.5 mmHg) and in central estrogen-treated males (-30.2 +/- 1.0 mmHg) compared with other groups (intact males, -39.3 +/- 3.4; castrated males, -41.8 +/- 1.9; intact males with central E(2) + ICI, -42.3 +/- 2.1; OVX females, -40.3 +/- 3.3; and intact females with central ICI, -39.1 +/- 1.3 mmHg). Chronic Aldo infusion produced increases in NaCl intake and decreases in HR that were both similar in all groups. Taken together, the results indicate that central estrogen plays a protective role in the development of Aldo/NaCl-induced hypertension and that this may result from reduced sympathetic outflow.
Hay, M. (2001). Subcellular mechanisms of area postrema activation. Clinical and experimental pharmacology & physiology, 28(7), 551-7.
Hayward, L., Hay, M., & Felder, R. B. (1993). Acute resetting of the carotid sinus baroreflex by aortic depressor nerve stimulation. The American journal of physiology, 264(4 Pt 2), H1215-22.
The effect of prolonged aortic depressor nerve (ADN) stimulation on carotid sinus baroreflex regulation of arterial pressure (AP) and renal sympathetic nerve activity (RSNA) was examined in anesthetized rabbits. Ramp increases in carotid sinus pressure (CSP) were repeated before and after 5 min of bilateral ADN stimulation. One minute after ADN stimulation the curve relating AP to CSP had shifted up and to the right, characterized by significant increases (P 0.05) in the maximum (91 +/- 2 to 101 +/- 3 mmHg; mean +/- SE), midpoint (118 +/- 7 to 125 +/- 8 mmHg CSP), and minimum (45 +/- 3 to 53 +/- 4 mmHg) of the AP reflex curve. There was a parallel shift downward of the curve relating RSNA to CSP, characterized by significant decreases in the maximum [100 +/- 0 to 66 +/- 8% of maximum control RSNA value (%max)], the range (90 +/- 2 to 59 +/- 8%max), and the gain (-1.0 +/- 0.2 to -0.5 +/- 0.1%max/mmHg) of the RSNA reflex curve. Values returned to control within 10 min of cessation of ADN stimulation. These results suggest that central neurons processing baroreflex information from one set of mechanoreceptors can be reset by convergent signals arising from another baroreceptor site.
Hay, M., & Kunze, D. L. (1994). Calcium-activated potassium channels in rat visceral sensory afferents. Brain research, 639(2), 333-6.
The purpose of the present study was to describe, at the single-channel level, the activity of a calcium-sensitive potassium channel in rat visceral-sensory neurons which has been suggested to be involved in sensory neuron excitability. Single-channel recordings in the inside-out configuration identified a 220 pS conductance calcium-activated potassium channel (KCa). From a -20 mV holding potential, increasing [Ca2+]i from 0.01 microM to 1.0 microM increased the open probability of this channel 92% (from 0.12 to 0.23). However, from a +20 mV holding potential, increasing [Ca2+]i from 0.01 to 1.0 microM increased the open probability by 326% (from 0.15 to 0.64). In addition, this large conductance KCa channel was blocked by TEA (1.0 microM) and charybdotoxin (40 microM) when applied to the external surface. These results are the first to characterize a large conductance KCa channel in the sensory afferent neurons of the rat nodose ganglia and should further expand the understanding of the ionic currents involved in the regulation of sensory afferent neuronal activity.