Role of endothelin-1 in the central neural cardiovascular control

In acute experiments on cats, endothelin-1 (ET-1) was injected into the sympathoexcitatory neuronal structures of the ventrolateral medulla (VLM) and the effects of injections on the peripheral mechanisms of circulation control were studied. Effects of ET-1 appeared to be dose-dependent. Injections of 200 pmol ET-1 into the structures of the tested brain zone resulted in considerable regular hypertensive responses due to an increase in the common peripheral vascular resistance (PVR), which corresponds to vasospasm. ET-1 in a smaller dose (100 pmol) could cause either hypertensive or, in some cases, hypotensive responses. Hemodynamic responses induced by injections of 100 pmol ET-1 into the sites of localization of vasomotor neurons in the VLM were based on less expressed shifts in the peripheral vascular resistance, as compared with the effects of ET-1 in the dose of 200 pmol. The effects were related to either facilitation or suppression (in the cases of hypertensive or hypotensive responses, respectively) of descending sympathoexcitatory influences from the VLM on different vascular pools. The threshold for excitation of vasomotor neurons in the tested brain area is likely to be considerably lower as compared with that for medullary “cardiac” neurons, because injections of 200 pmol ET-1 in the site of localization of cardiac neurons were followed by either enhancement, or suppression of the contractile myocardiac activity, while the heart rate usually decreased. The effects of ET-1 were facilitated after blocking of GABAa receptors with bicuculline and attenuated after preliminary application of GABA to the ventral surface of the medulla. The results indicate the possibility of interaction ET-1 and GABA on the neurons in the VLM. Such interaction is likely to be directed toward providing an optimum mode of regulation of the blood circulation.     

Impact of Swimming Exercise Training on the Effects of Modulation of Mitochondrial Permeability Transition and NOS-1 Activation in Medullary Cardiovascular Neurons of Rats

Physical inactivity can be considered one of the major risk factors related to cardiovascular diseases. There are reasons to believe that the positive effect of exercise training is, to a large extent, mediated by modulation of the nervous control of the circulation system. In our previous studies, we showed that modulation of mitochondrial permeability transition in medullary cardiovascular neurons significantly contributes to the hemodynamic reactions in both the norm and a number of pathological states. In this study, we examined in acute experiments on urethane-anesthetized rats the hemodynamic effects mediated by either modulation of mitochondrial permeability transition in medullary neurons, or activation of neuronal NO synthase (NOS-1) in these neuronal populations after preliminary moderate exercise training (everyday swimming sessions of increased duration carried out for four weeks). It was shown that, after exercise training had been completed, the effects of injections of an inductor of mitochondrial permeability transition pore (MPTP) opening, phenylarsine oxide (PAO, 0.5 to 1.5 nmol), into populations of cardiovascular neurons in the medullary autonomic nuclei (nucl. tractus solitarius and paramedian and lateral reticular nuclei) were less expressed, as compared with those in control (untrained) animals. The data obtained suggest that exercise training can exert a protective action on functional activity of medullary neurons due to the decreased sensitivity of MPTPs to their opening. Injections of an inhibitor of MPTP opening, melatonin (0.7 to 2.1 nmol), into populations of medullary neurons under study in trained rats induced a decrease in the systemic arterial pressure (SAP), in contrast to untrained animals demonstrating mostly hypertensive responses following injections of melatonin into the above nuclei. Injections of an activator of neuronal NO synthase (NOS-1), L-arginine, into the medullary nuclei of swimming-trained rats resulted in more expressed hemodynamic shifts than in control animals, which suggests an increase in the activity of neuronal NO synthase in medullary neurons of such animals.     

Hemodynamic responses induced by modulation of the nitric oxide system and mitochondrial permeability in the medullary cardiovascular nuclei of rats

In acute experiments on normotensive rats and those with genetically determined hypertension (urethane anesthesia), we studied hemodynamic effects resulting from modulation of the activities of neuronal NO synthase (NOS-1), arginase II, and superoxide dismutase, and also of the mitochondrial permeability in medullary cardiovascular neurons. Unilateral microinjections of either a nitric oxide (NO) donor, sodium nitroprusside, or a substrate for endogenous NO synthesis, L-arginine, into the medullary cardiovascular nuclei (nucl. tractus solitarius, NTS, nucl. ambiguous, AMB, paramedian nucleus, PMn, and lateral reticular nucleus LRN) were shown to induce hemodynamic responses with rather similar dynamics in both normotensive and spontaneously hypertensive rats, although in the latter the reactions were more intense. Injections of an antagonist of NOS-1, N^G nitro-L-arginine (L-NNA), into the medullary nuclei under study in spontaneously hypertensive rats resulted in shifts of the systemic arterial pressure (SAP), which did not differ dramatically from those observed in normotensive animals. The data obtained serve as the background for the suggestion that the functional activity of NOS-1 is not fundamentally impaired under hypertension conditions, but, probably, the amount of the substrate for adequate synthesis of NO via the NO-synthase pathway of metabolism of L-arginine is insufficient. Considering this, we examined the functional activity of arginase, an enzyme that also, similarly to NOS, uses L-arginine for metabolic transformation. Injections of antagonists of arginase, norvaline or α-difluoromethylornithine hydrochloride (DFMO), into populations of the medullary neurons under study induced similar shifts of the SAP in normotensive and spontaneously hypertensive rats, and those responses did not differ significantly from the effects of inhibition of the NOS-1 activity. Thus, both the above-mentioned enzymes are potentially active in normotensive and spontaneously hypertensive rats; so, a possibility for their competition for L-arginine in certain situations does exist. Modulation of the mitochondrial permeability in medullary cardiovascular neurons in normotensive and spontaneously hypertensive rats induced significant hemodynamic effects. In particular, an increase in the mitochondrial permeability in the medullary cardiovascular nuclei by injections of an inductor of mitochondrial permeability transition pore (mPTP) opening, phenylarsine oxide (PAO), was accompanied by SAP drops in both normotensive and spontaneously hypertensive rats; the effects were dose-dependent and, in some cases, irreversible. A decrease in the mitochondrial permeability in the neurons under study by injections of an inhibitor of mPTP, melatonin, induced mostly hypertensive responses, although in some experiments we observed hypotensive and two-phase responses. Neirofiziologiya/Neurophysiology, Vol. 39, No. 3, pp. 232–244, May–June, 2007.     

Involvement of Nitric Oxide in the Medullary Control of Circulation in Normotensive Rats

In acute experiments on anesthetized (urethane) normotensive rats, we studied the hemodynamic effects of unilateral microinjections of a nitric oxide (NO) donor, sodium nitroprusside, into the medullary nuclei participating in central cardiovascular control. We studied also the effects of modulation of the intensity of NO production: enhancing its synthesis by intramedullary injections of exogenous L-arginine or inhibiting this process with an inhibitor of neuronal NO synthase (nNOS), L-NNA, or with an inhibitor of arginase, norvaline. Intramedullary injections of the above agents were confined to the nucleus of the tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguous, and lateral reticular nucleus. We tried to evaluate the possibility of production of NO from L-arginine in central neurons of normotensive rats via not only the well-known NO synthase pathway, but also via an alternative arginase-mediated pathway of metabolism of the above amino acid. Our results demonstrated that both enzymes are potentially active: injections of the mentioned inhibitors of the enzymes into the medullary neuronal structures induced marked shifts in the systemic arterial pressure (SAP), the integrative parameter characterizing the state of the cardiovascular system. After preliminary administration of an nNOS inhibitor, 7-nitroindazole (30 mg/kg, i.p.) or an inhibitor of arginase, norvaline (2 g, i.v.), injections of L-arginine into the medullary nuclei failed to evoke significant shifts in the SAP. We suggest that the comparative degree of activation of nNOS or arginase in the medullary nuclei depends on different factors, first of all on the level of oxygenation of the nerve tissue. An inverse dependence is likely to exist between the levels of activation of the above enzymes.     

Changes in the mitochondrial permeability in medullary cardiovascular neurons influence the hemodynamics in rats

In acute experiments on anesthetized rats, we studied the effects of modulation of the mitochondrial permeability in medullary cardiovascular neurons (nucl. tractus solitarii, NTS, nucl. ambiguus, AMB, paramedian reticular nucleus, PMn, and lateral reticular nucleus, LRN) on the systemic arterial pressure (SAP). We were the first to show that the mitochondrial permeability is essential for medullary cardiovascular control. An increase in the mitochondrial permeability with injections of an inductor of mitochondrial transition pore opening, phenylarsine oxide (PAO, 0.5 to 504 nmol), into the medullary nuclei resulted in long-lasting decreases in the SAP; at high doses of PAO, these drops could be irreversible and led to the animal’s death. Injections of an inhibitor of mitochondrial transition pore opening, melatonin (0.7 to 70.0 nmol), into the medullary nuclei induced dose-dependent increases in the SAP. Melatonin and L-arginine were shown to demonstrate neuroprotective effects due to their ability to attenuate the consequences of increased mitochondrial permeability in medullary cardiovascular neurons. Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 392–395, July–October, 2007.     

Nitric oxide mediates depressor responses by activation of N-methyl-D-aspartate receptors in the nucleus tractus solitarius of cat

Nitric oxide (NO) is involved in cardiovascular regulation and sympathetic nerve activity of the central nervous system (CNS). The nucleus tractus solitarius (NTS) is important to cardiovascular regulation. However, the physiological role of NO in cardiovascular regulation effecting through the NTS remains unclear. The purpose of this study is to investigate the effect of NO measured by in vivo voltammetry on the cardiovascular responses in NTS induced by N-methyl-D-aspartate (NMDA) in anesthetized cats. Extracellular NO concentration was monitored through a Nafion- and porphyrin-coated carbon fiber electrode, which has previously been demonstrated sensitive and selective to NO responses. Microinjection of NMDA into NTS elicited a dose-dependent decrease in cardiovascular responses associated with NO release. Following the dose-response curve, a dose of 3 nmol of NMDA was selected. Microinjection of NMDA into NTS produced depressor responses and NO release. These responses in NTS to NMDA were attenuated by pretreatment with a competitive antagonist, 2-amino-5-phosphonopentanoat (AP-5, 1 nmol), and methylene blue (MB, 1 nmol), an inhibitor of guanylate cyclase. These results suggest that NO is formed from NMDA activation in NTS and that NO diffuses out of neurons into the nearby target neurons to produce depressor response and NO release through cyclic guanosine monophosphate (cGMP) formation. In conclusion, NO mediates depressor response consequent to activation of NMDA receptors in neurons of NTS.     

Nitric oxide: Involvement in the nervous control of cardiovascular function

Identification of nitric oxide (NO) as a neurotransmitter in the CNS resulted in initiation of numerous studies aimed at elucidating the roles of NO not only at a cellular level, but also in regulation of the activity of specific physiological systems coordinated by the brain. In this lecture, we will discuss the state of current knowledge about cellular events in the brain realized with the involvement of NO, distribution of NO-producing neurons in cerebral structures providing central cardiovascular control, peculiarities of NO production, and mechanisms underlying NO-mediated neuromodulatory effects on cardiovascular function. Activation of the NO system in the lower brainstem modulates a variety of neuronal pathways; NO was shown to induce GABA and glutamate releases within the medulla. The NO system in the brain is activated in the states of homeostatic imbalance, including hypertension and stress.Neirofiziologiya/Neurophysiology, Vol. 36, Nos. 5/6, pp. 466–478, September–December, 2004.This revised version was published online in April 2005 with a corrected cover date and copyright year.     

Does angiotensin II have a significant tonic action on cardiovascular neurons in the rostral and caudal VLM?

The peptidic ANG II receptor antagonists [Sar(1),Ile(8)]ANG II (sarile) or [Sar(1),Thr(8)]ANG II (sarthran) are known to decrease arterial pressure and sympathetic activity when injected into the rostral part of the ventrolateral medulla (VLM). In anesthetized rabbits and rats, the profound depressor and sympathoinhibitory response after bilateral microinjections of sarile or sarthran into the rostral VLM was unchanged after prior selective blockade of angiotensin type 1 (AT(1)) and ANG-(1---7) receptors, although this abolished the effects of exogenous ANG II. Unlike the neuroinhibitory compounds muscimol or lignocaine, microinjections of sarile in the rostral VLM did not affect respiratory activity. Sarile or sarthran in the caudal VLM resulted in a large pressor and sympathoexcitatory response, which was also unaffected by prior blockade of AT(1) and ANG-(1---7) receptors. The results indicate that the peptidic ANG receptor antagonists profoundly inhibit the tonic activity of cardiovascular but not respiratory neurons in the VLM and that these effects are independent of ANG II or ANG-(1---7) receptors.     

Evidence That Adrenergic Ventrolateral Medullary Cells Are Activated whereas Precerebellar Lateral Reticular Nucleus Neurons Are Suppressed during REM Sleep

Rapid eye movement sleep (REMS) is generated in the brainstem by a distributed network of neurochemically distinct neurons. In the pons, the main subtypes are cholinergic and glutamatergic REMS-on cells and aminergic REMS-off cells. Pontine REMS-on cells send axons to the ventrolateral medulla (VLM), but little is known about REMS-related activity of VLM cells. In urethane-anesthetized rats, dorsomedial pontine injections of carbachol trigger REMS-like episodes that include cortical and hippocampal activation and suppression of motoneuronal activity; the episodes last 4–8 min and can be elicited repeatedly. We used this model to determine whether VLM catecholaminergic cells are silenced during REMS, as is typical of most aminergic neurons studied to date, and to investigate other REMS-related cells in this region. In 18 anesthetized, paralyzed and artificially ventilated rats, we obtained extracellular recordings from VLM cells when REMS-like episodes were elicited by pontine carbachol injections (10 mM, 10 nl). One major group were the cells that were activated during the episodes (n = 10). Their baseline firing rate of 3.7±2.1 (SD) Hz increased to 9.7±2.1 Hz. Most were found in the adrenergic C1 region and at sites located less than 50 µm from dopamine β-hydroxylase-positive (DBH⁺) neurons. Another major group were the silenced or suppressed cells (n = 35). Most were localized in the lateral reticular nucleus (LRN) and distantly from any DBH⁺ cells. Their baseline firing rates were 6.8±4.4 Hz and 15.8±7.1 Hz, respectively, with the activity of the latter reduced to 7.4±3.8 Hz. We conclude that, in contrast to the pontine noradrenergic cells that are silenced during REMS, medullary adrenergic C1 neurons, many of which drive the sympathetic output, are activated. Our data also show that afferent input transmitted to the cerebellum through the LRN is attenuated during REMS. This may distort the spatial representation of body position during REMS.     

Responses of cortical neurons to local application of excitatory amino acids to their dendrites and soma

The efficacy of excitation induced by iontophoretic application of excitatory amino acids to the soma or different parts of the dendritic tree has been compared in experiments performed on parietal cortex slices. Spike activity was recorded extracellularly from single nerve cells of layer V. In total, the responses of 125 neurons were analyzed. Upon application of glutamate and aspartate to the neuronal soma and the majority of dendrites, latencies of excitatory responses did not exceed 500 msec. In 18% of cases, neuronal responses to transmitter application to basal and apical dendrites had longer (2–3 sec) latencies. The maximum intensity of responses was observed when excitatory amino acids had been applied to the soma or proximal parts of dendrites. If applied at a distance of over 100 µm to basal and 300 µm to apical dendrites, glutamate and aspartate elicited cellular responses whose intensity was 2–3 times lower than that of the responses induced by application to the soma. The maximum distances at which somatic spike responses could be recorded were 350 µm and 800 µm for basal and apical dendrites, respectively. Different latencies of the responses to somatic and dendritic applications of excitatory amino acids in some neurons, as well as high efficacy of responses to stimulation of remote parts of dendritic tree, may indicate nonidentity of electrical properties of dendritic and somatic membranes.Neirofiziologiya/Neurophysiology, Vol. 25, No. 6, pp. 437–446, November–December, 1993.     

Sympathoexcitatory CVLM neurons mediate responses to caudal pressor area stimulation

Neurons in the caudal pressor area (CPA) are a source of tonic sympathoexcitation that is dependent on activation of cardiovascular sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM). In the present study, we sought to clarify the mechanism through which CPA neurons elicit increases in RVLM neuronal discharge, vasoconstrictor sympathetic tone, and arterial pressure. In urethan-chloralose-anesthetized, paralyzed, and artificially ventilated rats, bilateral disinhibition of CPA with bicuculline (Bic) after bilateral disinhibition of caudal ventrolateral medulla (CVLM) caused increases in splanchnic sympathetic nerve activity (+277% control) and arterial pressure (+54 mmHg). Inhibition of CVLM neurons with muscimol abolished the pressor response to activation of CPA neurons, suggesting that neurons within CVLM mediate the excitatory responses from CPA. Disinhibition of CVLM and CPA with Bic enhanced the sympathoexcitatory responses to stimulation of CPA with DL-homocysteic acid, which were blocked by microinjections of kynurenic acid into CVLM. We conclude that the pathway from CPA to RVLM involves an obligatory glutamatergic activation of sympathoexcitatory neurons in the vicinity of CVLM.     

Distinct binding mode of I-AngII to AT1 receptor without the Cys-Cys disulfide bridge

Previous studies have shown that different parts of the septal area may have opposite roles in the control of water intake and cardiovascular responses. In the present study we investigated the effects of electrolytic lesions of the intermediate nucleus of the lateral septal area (LSI) on cardiovascular and dipsogenic responses to intracerebroventricular (icv) angiotensin II (ANG II) and water intake induced by other different stimuli. Male Holtzman rats (280–320 g of body weight, n = 6–16/group) with sham or electrolytic lesions of the LSI and a stainless steel cannula implanted into the lateral ventricle (LV) were used. The LSI lesions did not affect body weight or daily water intake. However, LSI lesions reduced water intake and pressor responses induced by icv ANG II (4.10^− 2 nmol). The LSI lesions also slightly reduced water intake induced by 24 h of water deprivation or isoproterenol (30 μg/kg) subcutaneously, but did not affect water intake induced by intragastric 2 ml of 2 M NaCl load. The results suggest that LSI is part of the forebrain circuitry activated by ANG II to produce pressor and dipsogenic responses. However, the same nucleus is not involved in the dipsogenic responses to central osmoreceptor activation.     

Nitric oxide modulates the cardiovascular effects elicited by acetylcholine in the NTS of awake rats

Microinjection of acetylcholine chloride (ACh) in the nucleus of the solitary tract (NTS) of awake rats caused a transient and dose-dependent hypotension and bradycardia. Because it is known that cardiovascular reflexes are affected by nitric oxide (NO) produced in the NTS, we investigated whether these ACh-induced responses depend on NO in the NTS. Responses to ACh (500 pmol in 100 nl) were strongly reduced by ipsilateral microinjection of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol in 100 nl) in the NTS: mean arterial pressure (MAP) fell by 50 +/- 5 mmHg before L-NAME to 9 +/- 4 mmHg, 10 min after L-NAME, and HR fell by 100 +/- 26 bpm before L-NAME to 20 +/- 10 bpm, 10 min after L-NAME (both P < 0.05). Microinjection of the selective inhibitor of neuronal nitric oxide synthase (nNOS), 1-(2-trifluoromethylphenyl) imidazole (TRIM; 13.3 nmol in 100 nl), in the NTS also reduced responses to ACh: MAP fell from 42 +/- 3 mmHg before TRIM to 27 +/- 6 mmHg, 10 min after TRIM (P < 0.05). TRIM also tended to reduce ACh-induced bradycardia, but this effect was not statistically significant. ACh-induced hypotension and bradycardia returned to control levels 30-45 min after NOS inhibition. Control injections with D-NAME and saline did not affect resting values or the response to ACh. In conclusion, injection of ACh into the NTS of conscious rats induces hypotension and bradycardia, and these effects may be mediated at least partly by NO produced in NTS neurons.     

Role of ventrolateral medulla in regulation of respiratory and cardiovascular systems

It is now widely accepted that the ventrolateral aspect of the medulla oblongata (VLM) plays an important role in regulation of the respiratory and cardiovascular systems. The VLM has been implicated as being involved in a number of different physiological functions, including central chemoreception, integration of afferent inputs from certain sense organs to the respiratory and cardiovascular controllers, the source of excitatory input to preganglionic sympathetic neurons in the spinal cord, and location of synaptic relay between the higher brain defense areas and spinal cord sympathetic elements. In recent years there have been a number of important findings concerning both the anatomical substrate and neurophysiological characteristics of VLM neurons involved in regulation of the respiratory and cardiovascular systems. New anatomical findings show that neuronal networks located in the VLM send projections to and receive projections from brain stem nuclei that have traditionally been associated with respiratory and cardiovascular regulation. Nevertheless, there are still many important questions concerning the role of the VLM in control of these vital systems that have yet to be answered. For instance, are the same VLM neurons involved in control of both systems? Is the VLM the only site for central respiratory chemoreception? This review will endeavor to examine new findings and to reexamine some older findings concerning the VLM.     

Gaba-ergic mechanisms in the caudal ventrolateral region of the cat medulla regulating vascular tonus and cardiac activity

In acute experiments on anesthetized cats data are obtained attesting to the fact that injections of GABA (0.5–50 µmoles/liter) into neuronal structures of the caudal ventrolateral medulla (CVLM) are accompanied by the development of hypertensive reactions caused by an increase in spontaneous activity in the sympathetic fibers of the renal and inferior cardiac nerves. An asymmetry is discovered in the realization of the inhibitory chrono- and inotropic influences on the heart emanating from the region investigated. Blocking of the GABA receptors with bicuculline (0.2–5.0 µmoles/liter) causes a sharp drop in the level of the systemic arterial pressure, a decrease in the strength and frequency of cardiac contractions, and a falling-off of the background activity in the peripheral symphathetic nerves. The findings suggest that the sympathoinhibitory CVLM neurons are under the constant inhibitory control of the GABA-ergic neurons.A. A. Bogomolets Institute of Physiology, Ukrainian Academy of Sciences, Kiev. Translated from Neirofiziologiya, Vol. 23, No. 6, pp. 698–703, November–December, 1991.     

Nitric Oxide Induction of Neuronal Endonuclease Activity in Programmed Cell Death

Neuronal survival is intricately linked to the maintenance of intact DNA. In contrast, neuronal degeneration following nitric oxide (NO) exposure is dependent, in part, on the degradation of DNA through programmed cell death (PCD). We therefore investigated in primary rat hippocampal neurons the role of endogenous deoxyribonucleases, enzymes responsible for metabolically derived DNA cleavage, during NO-induced neurodegeneration. Twenty-four hours following exposure to the NO generators sodium nitroprusside (300 μM) and SIN-1 (300 μM), neuronal survival was reduced from approximately 88 to 23%. Treatment with aurintricarboxylic acid (1–100 μM), an endonuclease inhibitor, during NO exposure increased neuronal survival from 23 to 80% and decreased DNA fragmentation from 70 to 30% over a 24-h period. Enhancement of endonuclease activity alone with zinc chelation actively decreased neuronal survival from approximately 80% to approximately 34%. DNA digestion assays identified not only two constitutively active endonucleases, an acidic endonuclease (pH 4.0–7.0) and a calcium/magnesium-dependent endonuclease (pH 7.2–8.0), but also a NO-inducible magnesium-dependent endonuclease (pH 8.0). In the absence of endonuclease activity, DNA degradation did not occur during NO application, suggesting that endonuclease activity was a requisite pathway for NO-induced PCD. In addition, NO independently altered intracellular pH in ranges that were physiologically relevant for the activity of the endonucleases responsible for DNA degradation. Our identification and characterization of specific neuronal endonucleases suggest that the constitutive endonucleases may play a role in the initial stages of NO-induced PCD, but the subsequent “downstream” degradation of DNA may ultimately be dependent upon the NO-inducible endonuclease.     

Role of glutamate in the rostral ventrolateral medulla in acupuncture-related modulation of visceral reflex sympathoexcitation

Visceral sympathoexcitatory reflexes induced by stimulation of the gallbladder with bradykinin (BK) are attenuated by electroacupuncture (EA) at Neiguan-Jianshi (P5-6) acupoints located over the median nerve. Previous studies have shown that neurons in the rostral ventrolateral medulla (rVLM) receive convergent input from visceral organs and somatic nerves (activated by EA). Glutamate (Glu), an important excitatory neurotransmitter in the rVLM, processes visceral sympathoexcitatory cardiovascular reflexes. In the present study, we determined the relation between EA-mediated opioidergic modulation of visceral cardiovascular responses and Glu. Reflex cardiovascular responses were evoked by application of BK to the gallbladder before and after EA in anesthetized cats. Glu concentrations ([Glu]) were measured by HPLC from samples collected by microdialysis probe(s) inserted unilaterally or bilaterally into the rVLM. BK-induced reflex responses and [Glu] were attenuated by 45% and 70%, respectively, after 30 min of EA (n = 6). EA alone did not change [Glu] in the rVLM (n = 6, P > 0.05). However, microdialysis of naloxone (100 mM) into the rVLM reversed EA-related inhibition of blood pressure and [Glu] (n = 5). Immunohistochemical visualization showed that delta-opioid receptors colocalized with, and were in close apposition to, vesicular Glu transporter 3- and c-Fos-double-labeled perikarya and processes of rVLM neurons after gallbladder stimulation with BK. These data suggest that EA attenuates BK-induced visceral sympathoexcitatory reflexes through opioid-mediated inhibition of Glu's action in the rVLM.     

Dissimilarity between prostaglandin E1 and nitric oxide donors as potentiators of plasma exudation in the rabbit skin in vivo

The ability of prostaglandin E₁ (PGE₁) and nitric oxide (NO) donor compounds such as sodium nitroprusside (SNP), glyceryl trinitrate (GTN), and 3-morpholino-sydnonimine (SIN-1) to modulate the histamine- and bradykinin-induced increase in microvascular permeability have been investigated in rabbit skin. The effect of the NO synthesis inhibitor N^ω-nitro- -arginine methyl ester ( -NAME) on the plasma exudation induced by histamine and bradykinin was also studied. Local edema formation was evaluated using [¹²⁵I]human serum albumin. New Zealand white rabbits received an intravenous injection of [¹²⁵I]human albumin followed immediately by the intradermal injection of edematogenic agents into the shaved dorsolateral skin. PGE₁ (0.1 nmol/site) significantly potentiated both histamine- and bradykinin-induced edema. In contrast, SNP (0.4–400 nmol/site), SIN-1 (0.4–400 nmol/site), and GTN (0.4–40 nmol/site) did not affect the edematogenic response induced by either histamine or bradykinin. GTN (0.4–40 nmol/site) also had no effect on the increase in plasma exudation induced by histamine and bradykinin in the presence of PGE₁. -NAME (50–400 nmol/site), but not its enantiomer -NAME, dose-dependently reduced the edema formation induced by a combination of either histamine or bradykinin with PGE₁. This inhibition was significantly reversed by SNP (4–400 nmol/site) and by high doses (2.5 μmol/site) of -arginine (but not by -arginine). Our results thus demonstrate that PGE₁, but not nitrovasodilators, can actually potentiate histamine- and bradykinin-induced edema in rabbit skin. This discrepancy cannot be explained by the lack of vasodilator activity of the nitrovasodilators since these were able to reverse the -NAME-induced inhibition of the edema provoked by histamine. Rather, this difference most likely reflects the ability of PGE₁ to modulate vascular permeability by mechanism(s) other than an increase in arterial flow.     

Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus

Physiological and anatomic methods were used to determine whether neurons in the rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), or hypothalamic paraventricular nucleus (PVN) mediate the cardiovascular response evoked from the dorsomedial hypothalamic nucleus (DMH), which is believed to play a key role in mediating responses to stress. In urethane-anesthetized rats, activation of neurons in the DMH by microinjection of bicuculline resulted in a large increase in arterial pressure, heart rate, and renal sympathetic nerve activity. The pressor and sympathoexcitatory responses, but not the tachycardic response, were greatly reduced after bilateral muscimol injections into the RVLM even when baseline arterial pressure was maintained at a constant level. These responses were not reduced by muscimol injections into the PVN or NTS. Retrograde tracing experiments identified many neurons in the DMH that projected directly to the RVLM. The results indicate that the vasomotor and cardiac components of the response evoked from the DMH are mediated by pathways that are dependent and independent, respectively, of neurons in the RVLM.     

Ultrastructural organization of the chemically sensitive cat ventrolateral medulla

Differences in the location of putative inhibitory (F-type) synapses were revealed during research into the ultrastructural organization of the chemically sensitive cat ventrolateral medulla (VLM). These synapses are made up of axonal terminals filled with flattened synaptic vesicles with the long axis measuring 60–80 nm. They are mainly located in the caudal portion of the test area, while S-type synapses with spherical electron-transparent synaptic vesicals, with a mean diameter of 50 nm, are distributed fairly evenly within the confines of the test area. It is postulated that neuronal structure of the chemically sensitive cat VLM have a different functional significance in the exerting of central neurogenous control over circulatory function.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 3, pp. 300–305, May–June, 1989.