dizocilpine-maleate and Hypotension

It is known that enrichment of glutamatergic transmission in the nucleus tractus solitarii (NTS) plays an important role in central cardiovascular regulation. Our previous study demonstrated that nicotine decreased blood pressure and heart rate in the NTS probably acting via the nicotinic acetylcholine receptors (nAChRs)-Ca²⁺-calmodulin-eNOS-NO signaling pathway. The possible relationship between glutamate and nicotine in the NTS for cardiovascular regulation is poorly understood. This study investigated the involvement of glutamate receptors in the cardiovascular effects of nicotine in the NTS. Nicotine (a non-selective nAChRs agonist), MK801 (a non-competitive NMDA receptor antagonist), APV (a competitive NMDA receptor antagonist), or NBQX (a selective AMPA receptor antagonist) was microinjected into the NTS of anesthetized Wistar-Kyoto rats. Microinjection of nicotine (1.5 pmol) into the NTS produced decreases in blood pressure and heart rate. The hypotensive and bradycardic effects of nicotine were abolished by prior administration of MK801 (1 nmol) and APV (10 nmol), but was completely restored after 60 min of recovery. In contrast, prior administration of NBQX (10 pmol) into the NTS did not alter the cardiovascular effects of nicotine. The nitrate (served as total NO) production in response to nicotine microinjection into the NTS was suppressed by prior administration of APV. These results suggest that the hypotensive and bradycardic effects of nicotine in the NTS might be mediated through NMDA receptors, and that the nAChRs-NMDA receptor-NO pathway could be involved.

Topics: Animals; Blood Pressure; Bradycardia; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Glutamic Acid; Heart Rate; Hypotension; Male; Nicotine; Nicotinic Agonists; Quinoxalines; Rats; Rats, Inbred WKY; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Solitary Nucleus; Valine

Previous studies have observed that fluid percussion brain injury (FPI) impaired NMDA induced pial artery dilation (PAD) in an age dependent manner. Unrelated studies observed a similar age dependent impairment of hypotensive cerebral autoregulation after FPI. This study was designed to test the hypothesis that NMDA receptor activation contributes to impairment of cerebral autoregulation during hypotension after FPI in an age dependent manner. Therefore, the role of NMDA in impaired hypotensive cerebrovascular regulation after FPI was compared in newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of hypotension (10-15 ml blood/kg) decreased mean arterial blood pressure uniformly in both groups (approximately 44%). In the newborn, hypotensive PAD was blunted within 1 h of FPI but partially protected by pretreatment with the NMDA antagonist MK801 (1 mg/kg i.v.) (34+/-1 vs. 8+/-1 vs. 25+/-2% for sham control, FPI, and FPI-MK801, respectively). Cerebral blood flow (CBF) was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by MK801 in the newborn (56+/-5, 35+/-2, and 16+/-1 vs. 62+/-6, 45+/-3, and 30+/-2 ml/min 100 g for normotension, normotension-FPI, and hypotension-FPI in the absence and presence of MK801, respectively). In contrast, blunted hypotensive PAD was protected significantly less by MK801 in the juvenile (32+/-2 vs. 7+/-2 vs. 16+/-2% for sham control, FPI, and FPI-MK801, respectively). Similarly, MK801 had less protective effect on normotensive and hypotensive CBF values post FPI in the juvenile. These data indicate that NMDA receptor activation contributes to impaired hypotensive cerebral hemodynamics following brain injury in an age dependent manner.

Topics: Aging; Animals; Animals, Newborn; Blood Chemical Analysis; Brain Injuries; Cerebral Arteries; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Homeostasis; Hypotension; Male; Microspheres; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Swine

Previous studies have observed that hypotensive pial artery dilation was blunted after hypoxia-ischemia. In unrelated studies, the opioid nociceptin/orphanin FQ (NOC/oFQ) was observed to contribute to hypoxic ischemic impairment of N-methyl-D-aspartate (NMDA)-induced pial dilation. This study determined the contribution of NOC/oFQ and NMDA to hypoxic ischemic hypotensive cerebrovasodilation impairment in newborn pigs equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased PO(2) to 33 +/- 3 mm Hg. Topical NOC/oFQ (10(-10) M), the cerebrospinal fluid concentration after hypoxia-ischemia, had no effect on pial artery diameter by itself but attenuated hypotension (mean arterial blood pressure decrease of 44 +/- 2%) -induced pial artery dilation (35 +/- 2% versus 22 +/- 3%). Hypotensive pial artery dilation was blunted by hypoxia-ischemia, but such dilation was partially protected by pretreatment with the putative NOC/oFQ receptor antagonist, [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M; 29 +/- 2%, sham control; 7 +/- 2%, hypoxia-ischemia; and 13 +/- 2%, hypoxia-ischemia and [F/G] NOC/oFQ (1-13) NH(2)). Coadministration of the NMDA antagonist MK801 (10(-5) M) with NOC/oFQ(10(-10) M) partially prevented hypotensive pial dilation impairment. Similarly, pretreatment with MK801 partially protected hypoxic ischemia impairment of hypotensive pial dilation (35 +/- 2%, sham control; 7 +/- 1%, hypoxia-ischemia; 22 +/- 2%, hypoxia-ischemia + MK801). These data show that NOC/oFQ and NMDA contribute to hypoxic ischemic hypotensive cerebrovasodilation impairment. These data suggest that NOC/oFQ modulation of NMDA vascular activity also contributes to such hypotensive impairment.

Topics: Animals; Animals, Newborn; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Hypotension; Hypoxia-Ischemia, Brain; Intracranial Hypertension; Male; N-Methylaspartate; Narcotic Antagonists; Neuroprotective Agents; Nociceptin; Nociceptin Receptor; Opioid Peptides; Peptide Fragments; Pia Mater; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Shock, Hemorrhagic; Swine; Vasodilation

The effect of gamma-aminobutyric acid (GABA)A receptors and of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor blockade on clonidine hypotension was studied. The experiments were performed on spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. We found that the blockade of GABAA receptors line significantly (P < 0.01) reduced hypotensive responses to clonidine. Similarly, the NMDA receptor antagonist dizocilpine (MK-801) completely abolished the blood pressure lowering effect of clonidine. Our findings support the conclusion that clonidine hypotension is closely related to the functional state of both inhibitory GABAergic and excitatory glutamatergic systems.

Topics: Animals; Bicuculline; Blood Pressure; Clonidine; Dizocilpine Maleate; GABA-A Receptor Antagonists; Hypotension; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, N-Methyl-D-Aspartate

Endothelin-1 (ET-1) produces hypotension via an action at glutamate-sensitive medullary cardiovascular sites. Here, we used excitatory amino acid (EAA) receptor antagonists to examine the possible role of an endogenous EAA in this neural action of central ET-1. ET-1 (3 pmol) applied to the IV ventricle of anesthetized, artificially ventilated rats elicited a sustained decrease in blood pressure (27 +/- 6%). Pretreatment with two EAA receptor antagonists, APV and CNQX (or MK-801 and CNQX), significantly attenuated the hypotension to central ET-1 (11 +/- 4%). Since these antagonists do not interact with endothelin receptors, we conclude that release of an endogenous EAA may contribute to the hypotensive action of central ET-1.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Endothelins; Excitatory Amino Acid Antagonists; Hypotension; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, Glutamate