Central Cardiovascular Regulation Research Articles

Neuropeptide FF distribution in the human and rat forebrain: A comparative immunohistochemical study

Neuropeptide FF (NPFF) is an octapeptide implicated in a variety of physiological functions, including nociception, cardiovascular responses, and neuroendocrine regulation. The NPFF gene and its mRNA are highly conserved across species. A comparative study of NPFF distribution in the human and rat forebrain was carried out by using single NPFF and double NPFF + vasopressin (VP) immunohistochemistry. NPFF is extensively localized within neurochemical circuits of human and rat forebrain. Semiquantitative analysis revealed that the densities of NPFF cells and fibers in many forebrain nuclei in the human correlate well with those observed for the same structures in the rat. High numbers of NPFF positive neurons in the dorsomedial hypothalamic nucleus and a dense plexus of NPFF fibers surrounding the fornix within the bed nucleus of the stria terminalis were identified in the human and rat forebrain. Within the hypothalamus of both species, dense NPFF innervation was observed in the perinuclear zone of the supraoptic nucleus (SO) just dorsolateral to the VP-positive neurons. Extensive NPFF innervation of ventricular ependyma and brain microvasculature were common for both species. At the same time, obvious differences in NPFF localization between the two species were also apparent. For example, in contrast to the rat SO, no NPFF- or NPFF- + VP-immunostained cells were observed in the human SO. Knowledge of NPFF neuroanatomical localization in the human brain and the relationship of these observations to those in the rat brain may provide insight into the role of this peptide in central cardiovascular and neuroendocrine regulation.

Induction of Heme Oxygenase-1 Is Involved in Carbon Monoxide-Mediated Central Cardiovascular Regulation

Carbon monoxide (CO) has been identified as an endogenous biological messenger in the brain. Heme oxygenase (HO) catalyzes the metabolism of heme to CO and biliverdin. Previously, we have shown the involvement of CO in central cardiovascular regulation, baroreflex modulation, and glutaminergic neuro-transmission in the nucleus tractus solitarii (NTS) of rats. In this study, we examined which HO isoform could be induced after hemin injection in the NTS. We also investigated their in situ distributions in the NTS after induction. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of hemin (1 nmol), a heme molecule cleaved by HO to yield CO, produced significant decrease in blood pressure and heart rate. These cardiovascular effects of hemin were attenuated by prior administration of HO inhibitor zinc protoporphyrin IX (ZnPPIX). Microinjection of hemin into NTS resulted in significant induction of HO-1 protein expression in situ. Pretreatment of ZnPPIX significantly inhibited the HO-1 induction after hemin injection. No significant changes of HO-2 expression were found after hemin injection and ZnPPIX pretreatment. The in situ inductions of the HO-1 protein expression were further confirmed to be in glial cells and neurons after hemin injections into the NTS. These results indicated HO-1 but not HO-2 might be responsible for the generation of CO and contribute to central control of cardiovascular effects.

Interactions between the histaminergic and angiotensinergic systems in the central cardiovascular regulation in rats

Interactions between the histaminergic and angiotensinergic systems in the central cardiovascular regulation in rats

Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain

Epithelial sodium channels (ENaC) are important for regulating sodium transport across epithelia. Functional studies indicate that neural mechanisms acting through mineralocorticoid receptors (MR) and sodium channels (presumably ENaC) are crucial to the development of sympathoexcitation and hypertension in experimental models of salt-sensitive hypertension. However, expression and localization of the ENaC in cardiovascular regulatory centers of the brain have not yet been studied. RT-PCR and immunohistochemistry were performed to study ENaC and MR expression at the mRNA and protein levels, respectively. Both mRNA and protein for alpha-, beta-, and gamma-ENaC subunits and MR were found to be expressed in the rat brain. All three ENaC subunits and MR were present in the supraoptic nucleus, magnocellular paraventricular nucleus, hippocampus, choroid plexus, ependyma, and brain blood vessels, suggesting the presence of multimeric channels and possible regulation by mineralocorticoids. In most cortical areas, thalamus, amygdala, and suprachiasmatic nucleus, notable expression of gamma-ENaC was undetectable, whereas alpha- and beta-ENaC were abundantly expressed pointing to the possibility of a heterogeneous population of channels. The findings suggest that stoichiometrically different populations of ENaC may be present in both epithelial and neural components in the brain, which may contribute to regulation of cerebrospinal fluid and interstitial Na+ concentration as well as neuronal excitation.

Respiratory and cardiovascular actions of orexin-A in mice

Ample evidence has been reported to show a probable contribution of orexin in the central cardiovascular regulation. Although cardiovascular and respiratory centers in the brain are located close to each other and are interconnected, the possible participation of orexin in respiratory regulation has not been fully documented. Here we examined the effects of intracerebroventricular administration of orexin-A on respiratory and cardiovascular parameters in urethane-anesthetized mice. Respiratory frequency and tidal volume were recorded simultaneously with blood pressure and heart rate. Orexin-A (0.003–3 nmol in 2 μL) or vehicle was administered into the lateral ventricle or cisterna magna. Lateral ventricular administration induced a rise in respiratory frequency (by 11% at the highest dose), tidal volume (76%), blood pressure (13%) and heart rate (6%) in a dose-dependent manner. With intracisternal administration, however, respiratory frequency did not change while a similar increase in tidal volume (75%) was observed. A relatively larger cardiovascular response was elicited with intracisternal administration (blood pressure 26%, heart rate 9%). On the other hand, with either administration route, orexin-A did not affect reflex increases in respiratory frequency and tidal volume in response to hypoxia and hypercapnia. These results show possible participation of orexin-A not only in the cardiovascular regulation but also in the respiratory control system. Moreover, orexin can affect the cardiorespiratory control system at multiple sites in different ways. Orexin-A seems not to be involved in respiratory reflex regulation in mice at least under anesthetized condition.

Responses of neuronal nitric oxide synthase expression in the brainstem to electroacupuncture Zusanli (ST 36) in rats

Recent studies have reported that l-arginine-derived nitric oxide (NO) in the gracile nucleus modifies the hypotensive responses to electroacupuncture (EA) stimulation of Zusanli (ST 36). The purpose of this study was to examine the influence of EA stimulation of ST 36 on neuronal NO synthase (nNOS) expression in the brainstem nuclei in rats. EA stimulation of ST 36 and a non-acupoint was performed using 3 Hz of stimulation for 10 s every 2 min for a period of 120 min in rats anesthetized with ketamine. Rats in the sham-treated group received surgery and EA needles were placed into the acupoints without performing the stimulation. After 2-h stimulation and sham treatment, animals were perfused with 4% paraformaldehyde. Sections of rat medulla were examined by immunolabeling with a polyclonal antibody directed against nNOS. The brainstem nuclei were also visualized by NADPH-diaphorase histochemistry, a marker of nNOS activity. nNOS expression and NADPH-diaphorase reactivity were quantified by using a microscope with reticule grid to count the number of positive cells over a nucleus. Unilateral EA stimulation of ST 36 in rats caused increases in nNOS immunostained cells in the rostral region of the ipsilateral gracile nucleus, but was not altered in the contralateral gracile nucleus compared with sham-treated rats ( P < 0.05, n = 6–7). NADPH-diaphorase-positive cells were also increased in the ipsilateral gracile nucleus of rats with EA stimulation. nNOS immunostaining and NADPH-diaphorase-positive neurons were significantly increased in both ipsilateral and contralateral sides of the medial nucleus tractus solitarius (mNTS) in rats receiving EA ST 36 compared with sham-treated animals ( P < 0.05). nNOS immunostaining and NADPH-diaphorase reactivity was neither altered in the gracile nucleus and mNTS of non-acupoint stimulated rats nor other brainstem nuclei in rats with EA ST 36. These results show that nNOS immunoreactivity and NADPH-diaphorase reactivity are consistently increased in the gracile nucleus and the mNTS by EA ST 36. We conclude that EA ST 36 induces nNOS expression in the gracile nucleus and mNTS, and enhanced nNOS-NO in the nuclei may modify central cardiovascular regulation, which contribute to hypotensive effects of acupuncture.

Role of galanin and galanin(1–15) on central cardiovascular control

Galanin and the N-terminal fragment Galanin(1-15) are involved in central cardiovascular regulation. The present paper reviews the recent cardiovascular results obtained by intracisternal injections of Galanin and Galanin(1-15) showing that: (A) the Galanin antagonist M40 blocks the central cardiovascular responses induced by Galanin(1-15) but not those elicited by Galanin; (B) both Galanin and Galanin(1-15) induce the expression of c-Fos in cardiovascular nuclei of the medulla oblongata with different temporal and spatial profiles; (C) the cardiovascular action of Galanin(1-15), but not Galanin, is mediated by peripheral beta-receptor stimulation; (D) and it is demonstrated an antagonistic Galanin/alpha2-adrenoceptors interaction as well as a differential modulation of central cardiovascular responses of Angiotensin II by Galanin or Galanin(1-15). All these data strengthen the involvement of both Galanin molecules as neuromodulators on central cardiovascular regulation.

Receptor-Independent Activation of GABAergic Neurotransmission and Receptor-Dependent Nontranscriptional Activation of Phosphatidylinositol 3-kinase/Protein Kinase Akt Pathway in Short-Term Cardiovascular Actions of Dexamethasone at the Nucleus Tractus Solitarii of the Rat

Whereas glucocorticoids are important blood pressure regulators via an action on peripheral circulation, their roles in central cardiovascular regulation are less known. This study evaluated the short-term cardiovascular effect of glucocorticoid in the nucleus tractus solitarii (NTS) and delineated the underlying molecular mechanisms. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection bilaterally into the NTS of a synthetic glucocorticoid, dexamethasone (Dex; 12.5, 25, 50, or 100 pmol), elicited hypertensive and tachycardiac responses. The initial cardiovascular responses, which lasted 15 to 30 min, were blunted by coadministration of a selective GABA(A) or GABA(B) receptor antagonist, bicuculline (15 pmol) or 2-hydroxy saclofen (150 pmol). The delayed responses, which endured at least 90 min and entailed maintained hypertension and tachycardia, were reversed by selective glucocorticoid type II receptor (GR) antagonist mifepristone (100 or 200 pmol), phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] (20 nmol), or nitric-oxide synthase inhibitor N(G)-monomethyl-l-arginine acetate (5 nmol), but not by the RNA synthesis inhibitor actinomycin D (20 nmol). Moreover, Dex induced an association of GR with the regulatory subunit of PI3K, p85alpha, in a ligand-dependent manner and promoted serine/threonine kinase Akt phosphorylation that was blocked by coadministration of mifepristone or LY294002. These cardiovascular and molecular responses occurred when translocation of activated GR into the nucleus was minimal. Our results indicate that Dex acts on the NTS to elicit hypertension and tachycardia via both a GR-independent interaction with GABA(A) and GABA(B) receptors and a GR-dependent but nontranscriptional mechanism that involves activation of PI3K/Akt pathway.

In situ Akt phosphorylation in the nucleus tractus solitarii is involved in central control of blood pressure and heart rate.

Previously, we have shown that nitric oxide (NO) plays a significant role in central cardiovascular regulation and modulates the baroreflex in the nucleus tractus solitarii (NTS) of rats. NO production is mediated by activation of NO synthase (NOS). Insulin signaling was involved in controlling peripheral blood pressure via the activation of endothelial NOS. Here, we investigated whether the insulin signal transduction pathway is involved in controlling central cardiovascular effects. Insulin was injected into NTS of urethane-anesthetized male Wistar-Kyoto (WKY) rats. Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8- and 16-week-old WKY rats. In addition, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the NOS inhibitor L-NAME into the NTS caused attenuation of the cardiovascular response evoked by insulin in either 8- or 16-week-old WKY rats. Western blot analysis showed a significant increase (2.6+/-0.4-fold; P<0.05) in Akt phosphorylation after insulin injection, whereas LY294002 abolished the insulin-induced effects. In situ Akt phosphorylation was found in NTS by immunohistochemistry analysis after injection of insulin. This in situ Akt phosphorylation was abolished significantly after injection of LY294002. Take together, these results suggest that the insulin-PI3K-Akt-NOS signaling pathway may play a significant role in central cardiovascular regulation.

The cardiovascular effects of nitric oxide and carbon monoxide in the nucleus tractus solitarii of rats.

Nitric oxide (NO) and carbon monoxide (CO) are endogenously synthesized gaseous molecules that act as neurotransmitters in both central and peripheral nervous systems. Previously, we have shown the involvement of NO and CO in central cardiovascular regulation and baroreflex modulation. In this study we investigated the possible interaction of NO and CO in the nucleus tractus solitarii (NTS) on cardiovascular effects in rats. Male Sprague-Dawley rats were anesthetized with urethane, and mean blood pressure (MBP) and heart rate (HR) were monitored intra-arterially. l-Arginine (3.3 nmol), the precursor of NO, or hematin (1 nmol), a heme molecule cleaved by heme oxygenase (HO) to yield CO, were microinjected unilaterally into the NTS. Cardiovascular effects were evaluated before and after microinjection of the HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG: 1 nmol) or the NO synthase (NOS) inhibitors N -monomethyl-l-arginine (l-NMMA: 10, 33 and 100 nmol) and N-nitro-l-arginine methyl ester (l-NAME: 10, 33 and 100 nmol). Unilateral microinjection of l-arginine or hematin into the NTS produced decreases in blood pressure and heart rate. These cardiovascular effects of both l-arginine and hematin were attenuated by prior administration of the NOS inhibitors l-NMMA or l-NAME in a dose-dependent manner. However, prior administration of ZnDPBG attenuated only the cardiovascular effects of hematin but not l-arginine. These results demonstrated that the HO/CO pathway might couple to the activation of NOS via the liberation of NO, to participate in central regulation of cardiovascular function. They also suggested a possible interaction between the NO/NOS and CO/HO systems in the NTS of rats.

Neurotransmission in Central Cardiovascular Control

In the article by Lin et al1 new information is provided concerning the central actions of the acetylated growth hormone secretagogue peptide, ghrelin.2–4 In this study the authors show that microinjection of ghrelin into the nucleus tractus solitarius caused small but significant changes in blood pressure and sympathetic nerve activity. To a certain extent, this study is a useful addition to our knowledge about central cardiovascular regulation. Many brain nuclei are now established to be important in the control of the circulation and the reflexes that maintain cardiovascular stability.5,6 However, the neurotransmitters that the neurons at these sites use, the receptors that they interact with, and the second messenger systems involved in transducing the effects of neurotransmitter release into intracellular events that range from channel opening to gene transcription are incredibly poorly understood. Each additional piece of information, such as that provided by Lin et al, is valuable. To their credit, they provide raw data showing the response and they used localized microinjection techniques to restrict the response to one brain nucleus. Most importantly, they used sympathetic nerve recording to prove that the effects observed are due, at least in part, to the effects of changes in sympathetic activity. Is this adequate? In examining the article by Lin et al, a number of areas for further investigation are presented. Lin et al raise some of these questions, such as a possible role for tonically released ghrelin. In this brief …

Interactions between the histaminergic and opioidergic systems in the central cardiovascular regulation - haemodynamic studies.

Interactions between the histaminergic and opioidergic systems in the central cardiovascular regulation - haemodynamic studies.

Geomagnetic field effect on cardiovascular regulation

The goal of the present research was try to explain the physiological mechanism for the influence of the geomagnetic field (GMF) disturbance, reflected by the indices of the geomagnetic activity (K, K(p), A(k), and A(p) indices), on cardiovascular regulation. One hundred forty three experimental runs (one daily) comprising 50 min hemodynamic monitoring sequences were carried out in rabbits sedated by pentobarbital infusion (5 mg/kg/h). We examined the arterial baroreflex effects on the short term blood pressure and heart rate (HR) variabilities reflected by the standard deviation (SD) of the average values of the mean femoral arterial blood pressure (MAP) and the HR. Baroreflex sensitivity (BRS) was estimated from blood pressure/HR response to intravenous (i.v.) bolus injections of vasoconstrictor (phenylephrine) and vasodilator (nitroprusside) drugs. We found a significant negative correlation of increasing GMF disturbance (K(p)) with BRS (P = 0.008), HR SD (P =0.022), and MAP SD (P = 0.002) signifying the involvement of the arterial baroreflex mechanism. The abrupt change in geomagnetic disturbance from low (K = 0) to high (K = 4-5) values was associated with a significant increase in MAP (83 +/- 5 vs. 99 +/- 5 mm Hg, P = 0.045) and myocardial oxygen consumption, measured by MAP and HR product (24100 +/- 1800 vs. 31000 +/- 2500 mm Hg. bpm, P = 0.034), comprising an additional cardiovascular risk. Most likely, GMF affects brainstem and higher neural cardiovascular regulatory centers modulating blood pressure and HR variabilities associated with the arterial baroreflex.

Interactions of carbon monoxide and metabotropic glutamate receptor groups in the nucleus tractus solitarii of rats.

Carbon monoxide has been shown to act as a neurotransmitter and neuronal messenger in the brain. Heme oxygenase catalyzes the conversion of heme to carbon monoxide and biliverdin. We have recently reported that carbon monoxide was involved in central cardiovascular regulation. Carbon monoxide modulated the baroreflex and may affect glutamatergic neurotransmission. In addition, metabotropic glutamate receptors may be coupled to the activation of heme oxygenase in the nucleus tractus solitarii of rats. The present study was designed to investigate the possible interactions of carbon monoxide and metabotropic glutamate receptor groups in the nucleus tractus solitarii. Unilateral microinjection of several agonists for metabotropic glutamate receptor groups such as (R,S)-3,5-dihydroxyphenylglycine (DHPG) (group I) (0.03 nmol), 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) (group II) (0.3 nmol), and l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) (group III) (0.3 nmol) produced a significant decrease in blood pressure and heart rate. Among the metabotropic glutamate receptor agonists, prior administration of zinc protoporphyrin IX, an inhibitor of heme oxygenase activity, significantly attenuated the cardiovascular effects of APDC and l-AP4, and failed to attenuate the cardiovascular responses of DHPG. These results indicated interactions between carbon monoxide and group II and III metabotropic glutamate receptors in central cardiovascular regulation.

Endogenous central histamine-induced reversal of critical hemorrhagic hypotension in rats: studies with L-histidine.

Activation of the histaminergic system is characteristic of response to the action of adverse or potentially dangerous stimuli that disturb circulatory homeostasis, such as dehydration and changes in blood pressure. Previous study demonstrates that inhibition of histamine N-methyltransferase, which catabolizes histamine released from neurons, leads to the increase in endogenous central histamine concentrations and to the reversal of critical hemorrhagic hypotension. In the present study, the influence of intraperitoneal loading with histamine precursor L-histidine on central cardiovascular regulation was studied in a model of irreversible pressure-controlled hemorrhagic shock. Experiments were carried out in male Wistar rats anesthetized with ketamine/xylazine subjected to critical hemorrhagic hypotension of 20 to 25 mmHg, which resulted in the death of all control saline-treated animals within 30 min. L-histidine administered in 5 min of critical hypotension produced dose-dependent increases in mean arterial pressure and heart rate (100-500 mg/kg), and a 100% survival rate of 2 h (500 mg/kg), whereas in normotensive animals, it did not influence cardiovascular parameters. The resuscitating effect of L-histidine (500 mg/kg) was associated with increases in histamine concentrations in the cerebral cortex (0.97 +/- 0.11 nmol/g of wet tissue vs. 0.67 +/- 0.22 nmol/g of wet tissue; P<0.05), hypothalamus (4.78 +/- 0.58 nmol/g of wet tissue vs. 4.08 +/- 0.43 nmol/g of wet tissue; P<0.01), and medulla oblongata (0.55 +/- 0.18 nmol/g of wet tissue vs. 0.34 +/- 0.09 nmol/g of wet tissue; P<0.05), as well as with no changes in plasma histamine concentrations in comparison with the saline-treated group 20 min after injection. Pretreatment with (S)-alpha-fluoromethylhistidine (alpha-FMH, 0.5 mg intracerebroventricularly), an irreversible inhibitor of L-histidine decarboxylase, produced a decrease in central histamine concentrations and diminished volumes of blood required to achieve critical hypotension. Moreover, alpha-FMH inhibited L-histidine-induced increases in central histamine concentrations and its resuscitating effect. In conclusion, the increase in central histamine concentrations after loading with L-histidine in rats subjected to critical hemorrhagic hypovolemia leads to the reversal of hypotension and the improvement in the survival rate of 2 h. On the other hand, inhibition of L-histidine decarboxylase activity, and thus histamine synthesis, produces a decrease in hemodynamic stability in hypotension, which suggests the histaminergic system-induced activation of compensatory mechanisms in hemorrhagic shock.

Interaction of carbon monoxide and adenosine in the nucleus tractus solitarii of rats.

Carbon monoxide has been identified as an endogenous biological messenger in the brain. Heme oxygenase catalyzes the metabolism of heme to carbon monoxide and biliverdin. Previously, we have shown the involvement of carbon monoxide in central cardiovascular regulation, baroreflex modulation, and glutamatergic neurotransmission in the nucleus tractus solitarii of rats. We also showed that adenosine increased the release of glutamate in the nucleus tractus solitarii. In this study, we investigated the possible interactions of carbon monoxide and adenosine in the nucleus tractus solitarii. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure were monitored intra-arterially. Unilateral microinjection of increasing doses of hemin (0.01 to 3.3 nmol), a heme molecule cleaved by heme oxygenase to yield carbon monoxide, produced a significant decrease in blood pressure and heart rate in a dose-dependent manner. In addition, similar cardiovascular effects were observed after injection of adenosine (2.3 nmol). These cardiovascular effects of hemin were attenuated by prior administration of the adenosine receptor antagonist 1,3-dipropyl-8-sulfophenylxanthine. Similarly, pretreatment of the heme oxygenase inhibitor zinc protoporphyrin IX or zinc deuteroporphyrin 2,4-bis glycol also attenuated the depressor and bradycardic effects of adenosine. These results indicate that the interaction between carbon monoxide and adenosine may contribute to the activation of heme oxygenase in central cardiovascular regulation.

CGMP/protein kinase G-dependent potentiation of glutamatergic transmission induced by nitric oxide in immature rat rostral ventrolateral medulla neurons in vitro.

Although both nitric oxide (NO) and glutamate within the rostral ventrolateral medulla (RVLM) are important mediators of the central cardiovascular regulation, little is known about the functional interactions between these two mediators. Herein, we investigated the possible role of NO on the glutamatergic transmission of RVLM neurons. Whole-cell patch-clamp recordings were performed on visualized RVLM neurons in the brainstem slice preparation of rats. We found that bath application of l-arginine, the substrate for NO production, significantly increased the amplitude of excitatory postsynaptic currents (EPSCs). This enhancement was completely abolished by coadministration of the NO synthase inhibitor 7-nitroindazole and mimicked by the NO donors 3-morpholinylsydnoneimine and spermine NONOate. Bath application of a NO-sensitive guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or a protein kinase G (PKG) inhibitor, Rp-8-bromo-guanosine 3',5'-cyclic monophosphorothioate, fully prevented the l-arginine-, 3-morpholinylsydnoneimine-, and N-[4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]-butyl]-1,3-propanediamin (spermine NONOate)-induced synaptic potentiation. Direct activation of PKG with 8-(4-chlorophenylthio)-cGMP mimicked the action of NO donors. Furthermore, the augmentation by spermine NONOate of EPSC was accompanied by a reduction of the paired-pulse facilitation and synaptic failure rate of EPSCs. Spermine NONOate also significantly increased the frequency of both spontaneous and miniature EPSCs without altering their amplitude distribution. Pretreatment with the N-type Ca2+ channel blocker omega-conotoxin GVIA selectively blocked the spermine NONOate-induced synaptic potentiation. These results suggest that NO acts presynaptically to elicit a synaptic potentiation on the RVLM neurons through an enhancement of presynaptic N-type Ca2+ channel activity leading to facilitating glutamate release. The presynaptic action of NO is mediated by a cGMP/PKG-coupled signaling pathway.

Angiotensin II modulates the cardiovascular responses to microinjection of NPY Y 1 and NPY Y 2 receptor agonists into the nucleus tractus solitarii of the rat

The aim of this work was to investigate the modulation of the cardiovascular effects of neuropeptide Y (NPY) in the nucleus tractus solitarii (NTS) by angiotensin II (Ang II) and to determine the NPY receptor subtype involved in this modulation. Anesthesized Sprague–Dawley rats received microinjections in the NTS of Ang II (threshold and ED 50 doses) with NPY Y 1 agonist Leu 31Pro 34NPY and NPY Y 2 agonist NPY(13–36) (threshold and ED 50 doses). The changes in mean arterial pressure (MAP) and heart rate (HR) recorded in the femoral artery were analyzed during 60 min after the microinjections. The injection of threshold doses of Ang II, Y 1 agonist or Y 2 agonist alone did not produce any change in cardiovascular parameters. However, the co-injections into the NTS of threshold doses of both Ang II and the Y 1 agonist elicited significant increases of MAP and HR of about 12 and 10%, respectively. The co-administration of threshold doses of Ang II with the Y 2 agonist also induced a significant vasopressor response. The vasodepressor and bradycardiac effect of an ED 50 dose of the Y 1 agonist was significantly counteracted ( P<0.01) by a threshold dose of Ang II. The vasopressor effect elicited by an ED 50 dose of the Y 2 agonist was significantly enhanced by a threshold dose of Ang II ( P<0.01). No significant change of cardiovascular responses elicited by an ED 50 dose of Ang II was observed in the presence of threshold doses of the Y 1 agonist or of the Y 2 agonist. The present study gives functional evidences for a differential modulatory activity of Ang II on the cardiovascular responses mediated by Y 1 and Y 2 receptor subtypes, which may be of relevance for central cardiovascular regulation in the NTS.

Modification of cardiovascular response of posterior hypothalamic adenosine A 2 receptor stimulation by adenylate cylase, guanylate cyclase and by K ATP channel blockade in anesthetized rats

Cardiovascular inhibitory effects induced by posterior hypothalamic adenosine A 2 receptors and their modulation by nitric oxide were suggested by our previous report. In this experiment, we examined the modulation of cardiovascular effects of adenosine A 2 receptor stimulation by adenylate cyclase, guanylate cyclase and ATP-sensitive K + channel in the posterior hypothalamus. Posterior hypothalamic injection of drugs was performed in anesthetized, artificially ventilated male Sprague–Dawley rats. Injection of adenosine A 2 receptor agonist 5′-( N-cyclopropyl)-carboxamidoadenosine (CPCA; 1, 2 and 5 nmol) produced a dose-dependent decrease of blood pressure and heart rate. Pretreatment with adenosine A 2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (10 nmol) blocked the depressor and bradycardiac effects of CPCA (5 nmol). Pretreatments with adenylate cyclase inhibitor MDL-12,330 (10 nmol) and guanylate cyclase inhibitor LY-83,583 (5 nmol) attenuated the depressor and bradycardiac effects of CPCA (5 nmol). In addition, pretreatment with ATP-sensitive K + channel blocker glipizide (20 nmol) attenuated the depressor and bradycardiac responses of CPCA (5 nmol). These results suggest that posterior hypothalamic adenosine A 2 receptors play an inhibitory role in the central cardiovascular regulation and that both adenylate cyclase and guanylate cyclase mediate the depressor and bradycardiac actions of adenosine A 2 receptors. Also, ATP-sensitive K + channel mediates the posterior hypothalamic cardiovascular regulations of adenosine A 2 receptors.

Chronic peripheral ouabain treatment affects the brain endothelin system of rats

Chronically administered ouabain increases the content of ouabain in several brain areas that are closely related to central cardiovascular regulation. However, the pattern of central changes induced by chronic infusion of ouabain is not completely understood. To investigate whether chronic peripheral ouabain treatment affects the brain endothelin system. By enzyme immunoassay, reverse transcription-polymerase chain reaction and autoradiography, we assessed brain endothelin and endothelin receptors contents following chronic (4 weeks) subcutaneous treatment of normotensive Sprague-Dawley rats with ouabain (OUA) (14 microg/kg per day). We also investigated the involvement of central endothelin receptors in increased sympathetic activity and hypertension induced by chronic OUA. Sympathetic activity was indirectly evaluated by recording changes in renal vascular resistance (RVR). Brains of Sprague-Dawley rats collected following OUA treatment showed increased levels of the endothelin-1, and a decrease in ET(A) receptor mRNA and receptor levels. These, following chronic treatment with the submaximal dose of 14 microg/kg per day OUA, were a three-fold augmentation (P < 0.05) of the endothelin-1 peptide and a 38% decrease in ET(A) receptor mRNA. In addition, dose-dependent increases in RVR and in the basal mean arterial blood pressure (MABP) were found when compared with the vehicle (saline)-treated blood pressure (i.e. RVR, 14 microg/kg per day OUA, +161 +/- 15%). Total renal blood flows were consequently decreased (14 microg/kg per day OUA, P < 0.01). Interestingly, increases in RVR and MABP elicited by the submaximal dose of 14 microg/kg per day chronic OUA were significantly (P < 0.01) reduced by intra-periaqueductal gray (PAG) microinjections of FR139317 (selective ET(A) receptor antagonist, 5 nmol) and SB209670 (ET(A)/ET(B) non-selective antagonist, 3 nmol), but not by BQ 788 (selective ET(B) receptor antagonist, 5 nmol). These data indicate that chronic treatment with OUA increases central endogenous synthesis/release of endothelin. This contributes to the peripheral OUA actions. As an example, an antagonism at the PAG endothelin receptors, mainly of the ET(A) type, reduced the effects of chronic OUA on both MABP and RVR.