Central Pressor Research Articles

Interaction of Orexin A and Vasopressin in the Brain Plays a Role in Blood Pressure Regulation in WKY and SHR Rats.

BackgroundOrexin A (OXA) and vasopressin (AVP) exert a central hypertensive effect due to an increase in sympathetic nerve activity. To date, little is known about the interaction of these 2 neuropeptides in the central regulation of blood pressure. The present study compared the consequences of infusion into the left cerebral ventricle (ICV) of OXA on mean arterial blood pressure (MABP) in normotensive (WKY) and spontaneously hypertensive (SHR) rats, and explored whether the central pressor action of OXA in these 2 strains depends on activation of brain AVP V1a receptors (V1aR).Material/MethodsTen groups of experiments were performed on 12-week-old WKY and SHR rats implanted with ICV cannulas for infusion of OXA (3 nmol) and V1aR antagonist (V1aRANT, 500 ng), administered separately and together. Levels of V1aR and OXR in the medulla oblongata of WKY and SHR rats were compared in separate series.ResultsWe found that: 1) OXA significantly increased MABP only in WKY rats, 2) V1aRANT prevented an increase in MABP induced by OXA in WKY rats and decreased MABP in SHR rats, 3) OXA abolished the hypotensive action of V1aRANT in SHR rats, and 4) SHR rats had significantly higher levels of OX1R and V1aR proteins and OX1R mRNA in the brain medulla.ConclusionsThe present study shows that OXA and AVP can interact in the brain to affect blood pressure regulation, and that this interaction differs in normotension and hypertension.

Anti-hypertensive effect of hydrogen peroxide acting centrally.

Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2) or the increase of endogenous H2O2 centrally produced by catalase inhibition with 3-amino-1,2,4-triazole (ATZ) injected icv reduces the pressor responses to central angiotensin II (ANG II) in normotensive rats. In the present study, we investigated the changes in the arterial pressure and in the pressor responses to ANG II icv in spontaneously hypertensive rats (SHRs) and 2-kidney, 1-clip (2K1C) hypertensive rats treated with H2O2 injected icv or ATZ injected icv or intravenously (iv). Adult male SHRs or Holtzman rats (n = 5-10/group) with stainless steel cannulas implanted in the lateral ventricle were used. In freely moving rats, H2O2 (5 μmol/1 μl) or ATZ (5 nmol/1 μl) icv reduced the pressor responses to ANG II (50 ng/1 µl) icv in SHRs (11 ± 3 and 17 ± 4 mmHg, respectively, vs. 35 ± 6 mmHg) and 2K1C hypertensive rats (3 ± 1 and 16 ± 3 mmHg, respectively, vs. 26 ± 2 mmHg). ATZ (3.6 mmol/kg of body weight) iv alone or combined with H2O2 icv also reduced icv ANG II-induced pressor response in SHRs and 2K1C hypertensive rats. Baseline arterial pressure was also reduced (-10 to -15 mmHg) in 2K1C hypertensive rats treated with H2O2 icv and ATZ iv alone or combined and in SHRs treated with H2O2 icv alone or combined with ATZ iv. The results suggest that exogenous or endogenous H2O2 acting centrally produces anti-hypertensive effects impairing central pressor mechanisms activated by ANG II in SHRs or 2K1C hypertensive rats.

Activation of mGluR5 and NMDA Receptor Pathways in the Rostral Ventrolateral Medulla as a Central Mechanism for Methamphetamine-Induced Pressor Effect in Rats.

Acute hypertension produced by methamphetamine (MA) is well known, mainly by the enhancement of catecholamine release from sympathetic terminals. However, the central pressor mechanism of the blood-brain-barrier-penetrating molecule remains unclear. We used radio-telemetry and femoral artery cannulation to monitor the mean arterial pressure (MAP) in conscious free-moving and urethane-anesthetized rats, respectively. Expression of Fos protein (Fos) and phosphorylation of N-methyl-D-aspartate receptor subunit GluN1 in the rostral ventrolateral medulla (RVLM) were detected using Western blot analysis. ELISA was carried out for detection of protein kinase C (PKC) activity in the RVLM. MA-induced glutamate release in the RVLM was assayed using in vivo microdialysis and HPLC. Systemic or intracerebroventricular (i.c.v.) administration of MA augments the MAP and increases Fos expression, PKC activity, and phosphorylated GluN1-ser 896 (pGluN1-ser 896) in the RVLM. However, direct microinjection of MA into the RVLM did not change the MAP. Unilateral microinjection of a PKC inhibitor or a metabotropic glutamate receptor 5 (mGluR5) antagonist into the RVLM dose-dependently attenuated the i.c.v. MA-induced increase in MAP and pGluN1-ser 896. Our data suggested that MA may give rise to glutamate release in the RVLM further to the activation of mGluR5-PKC pathways, which would serve as a central mechanism for the MA-induced pressor effect.

Interaction of central angiotensin II and aldosterone on sodium intake and blood pressure

Recent studies demonstrated an important natriorexigenic mechanism activated by aldosterone acting in the hindbrain. Studies have also shown that aldosterone effects are intensified by angiotensin II (ANG II) and vice-versa. Thus, the aim of the present work was to test if angiotensinergic mechanisms in the forebrain are involved on sodium appetite to aldosterone infused into the 4th V and also if aldosterone into the 4th V might facilitate ingestive and cardiovascular responses to central ANG II. Male Holtzman rats with stainless steel cannulas implanted into the 4th ventricle (4th V) and lateral ventricle (LV) had access to 1.8% NaCl during 2 h/day. Chronic infusion of aldosterone (100 ng/h) into the 4th V for 7 days strongly increased 1.8% NaCl intake (16.1 ± 2.2 ml/2h/day). Losartan (AT1 receptor antagonist, 50 µg/1 µl) acutely injected into the LV reduced 1.8% NaCl intake induced by aldosterone infusion into the 4th V (8.8 ± 2.3 ml/2h/day). The pressor response to ANG II (50 ng/1 µl) into the LV increased in rats treated with aldosterone into the 4th V (45 ± 5 mmHg, vs. vehicle infusion: 26 ± 4 mmHg). Similarly, fluid intake (water + 1.8% NaCl) also increased when rats receiving aldosterone infusion were treated with ANG II acutely into the LV. These results suggest that forebrain angiotensinergic mechanisms are important for sodium intake produced by aldosterone acting in the hindbrain. In addition, aldosterone in the hindbrain produces sensitization of the central pressor mechanisms activated by ANG II acting in the forebrain.

Omapatrilat: penetration across the blood-brain barrier and effects on ischaemic stroke in rats.

Omapatrilat (OMA), which simultaneously inhibits the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (neprilysin (NEP)), is widely used in experimental protocols related to hypertension and heart failure. The penetration of OMA across the blood-brain barrier (BBB) and the effects of ACE/NEP inhibition on the recovery from ischaemic stroke have not yet been investigated. Angiotensin (Ang) I injected intracerebroventricularly (ICV) or intravenously (IV) is converted to Ang II by ACE and induces an immediate increase in blood pressure. The pressor responses to OMA administered ICV, orally or IV were studied in male Wistar rats instrumented with an ICV and arterial and venous catheters. OMA infused ICV rapidly appeared in the systemic circulation and more effectively attenuated the systemic than the central pressor responses to Ang I. OMA administered orally (5, 25, 100μmol/kg body weight) or IV (0.5, 1, 5, 25μmol/kg body weight) completely abolished increases in blood pressure to IV Ang I up to 2h after treatment. The pressor responses to ICV Ang I were not altered, indicating that systemically administered OMA does not cross the BBB. To study the effects of ACE and NEP inhibition in the brain on the recovery from ischaemic stroke, OMA was infused ICV over a 5-day period before and 24h after the occlusion of the middle cerebral artery (MCAO) for 90min. ICV application of OMA had no effect on infarction volume and marginally improved neurological outcome. We demonstrate for the first time that simultaneous inhibition of ACE and NEP in the brain tissue does not alter the recovery from ischaemic stroke.

High-fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats.

Central application of apelin elevates blood pressure and influences neuroendocrine responses to stress and food consumption. However, it is not known whether the central cardiovascular effects of apelin depend also on caloric intake or chronic stress. The purpose of the present study was to determine the effects of intracerebroventricular administration of apelin on blood pressure (mean arterial blood pressure) and heart rate in conscious Sprague-Dawley rats consuming either a normal-fat diet (NFD) or high-fat diet (HFD) for 12weeks. During the last 4weeks of the food regime, the rats were exposed (NFDS and HFDS groups) or not exposed (NFDNS and HFDNS groups) to chronic stress. Each group was divided into two subgroups receiving intracerebroventricular infusions of either vehicle or apelin. Apelin elicited significant increase of mean arterial blood pressure and heart rate in the NFDNS rats. This effect was abolished in the HFDNS, HFDS and NFDS groups. HFD resulted in a significant elevation of blood concentrations of total cholesterol, triglycerides glucose and insulin. Chronic stress reduced plasma concentration of total and high-density lipoprotein cholesterol, and increased plasma corticosterone concentration and APJ receptor mRNA expression in the hypothalamus, whereas a combination of a HFD with chronic stress resulted in the elevation of plasma triglycerides, total cholesterol and low-density lipoprotein cholesterol, and in increased plasma corticosterone concentration, apelin concentration and APJ receptor mRNA expression in the hypothalamus. It is concluded that a HFD and chronic stress result in significant suppression of the central pressor action of apelin, and cause significant though not unidirectional changes of metabolic and endocrine parameters.

Abstract 201: Overexpression of Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Potentiates Angiotensin II (AngII)-Mediated Signaling in Neurons

AngII signaling in the brain regulates systemic cardiovascular function. AngII modulates neuronal ion channel activity and neuronal firing via reactive oxygen species (ROS) and redox-sensitive proteins. Our recent studies indicate that in neurons AngII increases activity (i.e. phosphorylation) of CaMKII, a signaling intermediate known to inhibit potassium (K+) channel current. However, the potential cross-talk between AngII, ROS, and CaMKII in modulating neuronal K+ channel activity and the in vivo central AngII-induced pressor response remains unclear. Here, we tested the hypothesis that CaMKII overexpression exacerbates the AngII-dependent inhibition of K+ channel current and the acute central AngII-induced increase in blood pressure. The neuron specific isoform of CaMKII (CaMKIIα) was cloned, and CaMKIIα adenovirus was generated (AdCaMKIIα). Adenovirus-mediated overexpression of total and active CaMKII protein were assessed in differentiated mouse catecholaminergic (CATH.a) neurons by measuring total and phosphorylated CaMKII protein levels, respectively, via Western blot analysis. To investigate the effect of CaMKIIα overexpression on K+ channel activity, CATH.a neurons were transduced with AdCaMKIIα or control adenovirus, AdEmpty, and voltage-gated K+ current (IKV) was measured by the whole cell patch-clamp technique. Baseline IKV was measured followed by 5 mins of AngII (100 nM) superfusion. AngII lowered steady-state current (ISS) and peak current (Ipeak) in AdEmpty-transduced neurons (ISS by 20 ± 4%; Ipeak by 19 ± 3%), and this inhibitory response was significantly potentiated in AdCaMKIIα-transduced neurons (ISS by 40 ± 7%; Ipeak by 41 ± 5%; p< 0.05). Preliminary in vivo studies suggest that the central AngII-induced pressor response is exacerbated in mice intracerebroventricularly injected with AdCaMKIIα as compared to control virus-injected mice. These data indicate that CaMKIIα overexpression potentiates AngII-mediated inhibition of IKv and the central AngII-induced pressor response. Future studies will investigate the ROS-mediated post-translational modifications of CaMKIIα in AngII-stimulated neurons and the contribution of these modifications to ion channel activity and blood pressure regulation.

Essential role of mTORC1 in the hypertension induced by overactivation of the brain renin‐angiotensin system (1067.2)

Angiotensin II (Ang II) is a major effector peptide of the renin‐angiotensin system (RAS). Ang II‐induced activation of angiotensin type 1 receptor (AT1R) signaling in cardiovascular‐related brain nuclei such as the subfornical organ (SFO) is thought to be important for the development of hypertension. However, the molecular machinery underlying the central pressor actions of Ang II is poorly defined. We previously demonstrated the involvement of neuronal mammalian target of rapamycin complex 1 (mTORC1) in blood pressure (BP) regulation. Interestingly, using in vitro systems we also found that mTORC1 is a downstream element of neuronal AT1R signaling. To assess the relevance of mTORC1 for Ang II action, we first examined mTORC1 activity in the cardiovascular brain regions in hypertensive transgenic mice with brain‐specific hyperactive RAS (sRA mice). Strikingly, the number of phospho‐S6 positive cells (used as a readout of mTORC1 activity) was significantly higher in the SFO of sRA mice (64±6) relative to controls (36±8, p<0.05, n=5). Moreover, central administration of an adenovirus encoding a dominant negative S6 kinase (an mTORC1 substrate) lowered systolic BP in sRA (from 148±8 to 130±8 mmHg, p<0.05, n=3) to comparable levels as control mice receiving GFP adenovirus (from 125±7 to 126±1 mmHg, n=3). These results indicate that neuronal mTORC1 activation is a critical event in brain RAS‐induced BP elevation.

Blood pressure and the contractility of a human leg muscle

These studies investigate the relationships between perfusion pressure, force output and pressor responses for the contracting human tibialis anterior muscle. Eight healthy adults were studied. Changing the height of tibialis anterior relative to the heart was used to control local perfusion pressure. Electrically stimulated tetanic force output was highly sensitive to physiological variations in perfusion pressure showing a proportionate change in force output of 6.5% per 10 mmHg. This perfusion-dependent change in contractility begins within seconds and is reversible with a 53 s time constant, demonstrating a steady-state equilibrium between contractility and perfusion pressure. These stimulated contractions did not produce significant cardiovascular responses, indicating that the muscle pressor response does not play a major role in cardiovascular regulation at these workloads. Voluntary contractions at forces that would require constant motor drive if perfusion pressure had remained constant generated a central pressor response when perfusion pressure was lowered. This is consistent with a larger cortical drive being required to compensate for the lost contractility with lower perfusion pressure. The relationship between contractility and perfusion for this large postural muscle was not different from that of a small hand muscle (adductor pollicis) and it responded similarly to passive peripheral and active central changes in arterial pressure, but extended over a wider operating range of pressures. If we consider that, in a goal-oriented motor task, muscle contractility determines central motor output and the central pressor response, these results indicate that muscle would fatigue twice as fast without a pressor response. From its extent, timing and reversibility we propose a testable hypothesis that this change in contractility arises through contraction- and perfusion-dependent changes in interstitial K(+) concentration.

Abstract 185: Utilization of Nanoformulated Copper/Zinc Superoxide Dismutase (CuZnSOD) to Attenuate the Central Angiotensin II-Induced Pressor Response

Elevated levels of superoxide (O 2 .- ) in the brain and dysregulation of angiotensin II (AngII)-dependent neural mechanisms are associated with cardiovascular diseases, such as hypertension. For improved brain delivery of CuZnSOD protein, a O 2 .- -specific scavenging enzyme, we developed SOD nano, a polyion complex with a polyethylene glycol corona and polyethyleneimine core that electrostatically binds CuZnSOD protein. Our previous studies in cultured neurons indicate that SOD nano enters neurons through active endocytosis and localizes to various organelles where it scavenges O 2 .- and effectively inhibits AngII intra-neuronal signaling. Here, we hypothesized that centrally administered SOD nano ameliorates AngII-dependent neurogenic hypertension by delivering functional CuZnSOD protein to AngII sensitive brain regions. For these studies, C57Bl/6 male mice were instrumented with carotid catheter radiotelemeters to record mean arterial pressure (MAP). Intracerebroventricular (ICV) cannulae were implanted for the administration of SOD nano and daily injections of AngII (350 ng) before and after SOD nano treatment. The average AngII-induced increase in MAP for 3 days prior to treatment was 9.2 + 0.7 mmHg. ICV-administered SOD nano (113 U SOD activity) significantly inhibited the acute, central AngII pressor response for at least 3 days (ΔMAP D1= 1.3 + 1.4 mmHg; D2 = -2.7 + 3.7 mmHg; D3 = 3.4 + 4.1; n=3, p< 0.05 vs. AngII response 3 days prior). In contrast, ICV-administered saline did not alter the AngII-induced pressor response (ΔMAP D1 = 8.0 + 2.8 mmHg, D2 = 9.6 + 1.5, D3 = 7.3 + 1.2, n=4). Additionally, free CuZnSOD protein (ICV, 113 U SOD activity) did not attenuate the central AngII pressor response (ΔMAP D1 = 6.6 + 0.4 mmHg, D2 = 10.7 + 2.3, D3 = 16.3 + 8.4, n=2); thus, suggesting enhanced stability and/or cellular uptake of the SOD nano compared to free protein. Notably, the distribution of fluorescently labeled SOD nanozyme administered ICV was detected throughout the ventricular system, primarily in ependymal cells lining the brain ventricles and in the choroid plexus. These data suggest that this nanotechnology approach is effective in delivery CuZnSOD protein in vivo to AngII sensitive brain regions where it inhibits brain angiotensinergic signaling.

Involvement of Hypothalamic Periventricular GABAergic Nerves in the Central Pressor Response to Clonidine in Freely-Moving Conscious Rats

Microinjection of the α2-adrenoceptor agonist clonidine into the hypothalamic periventricular nuclei (PVN) induces the pressor response associated with bradycardia in freely-moving conscious rats. This study investigated the involvement of γ-aminobutyric acid nerves (GABAergic nerves) and glutamatergic nerves in the cardiovascular response to microinjection of clonidine in the PVN. Male Wistar rats were chronically implanted with a microinjection cannula into the PVN and an arterial catheter into the abdominal aorta through the femoral artery. Blood pressure and heart rate were measured under a conscious unrestrained state. PVN injection of clonidine induced a dose-dependent pressor response concomitant with bradycardia. PVN pretreatment with GABA, muscimol (GABAA-receptor agonist), or bicuculline (GABAA-receptor antagonist) significantly inhibited the pressor response to PVN-injected clonidine without affecting bradycardia. PVN pretreatment with baclofen (GABAB-receptor agonist), 2-hydroxysaclofen (GABAB-receptor antagonist), or kynurenic acid (non-selective NMDA-type glutamate–receptor and ionotropic glutamate–receptor antagonist) did not affect the pressor response to PVN-injected clonidine. These results suggest that clonidine induces a pressor response by stimulating the presynaptic α2-adrenoceptor of GABAergic nerves in the PVN, thereby inhibiting GABAergic nerve activity.

Central pressor activity of cimetidine in spontaneously hypertensive rats.

The systemic blood pressure effect of cimetidine given intracerebroventricularly (i.c.v.) in anaesthetized spontaneously hypertensive (SH) rats has been investigated. Cimetidine (250 micrograms i.c.v.) caused a gradual long lasting rise in mean arterial blood pressure with maximum of 31.6 +/- 4.5 mm Hg. Chemical degeneration of catecholaminergic neurons with 6-OHDA treatment, central administration of phentolamine and prazosin, and the bilateral adrenalectomy significantly inhibited the pressor response of cimetidine, while propranolol (i.c.v.) had no effect. From these results it appears that the hypertensive response of cimetidine is mediated by central catecholaminergic pathways and is due to an increase in efferent sympathetic outflow and release of catecholamine from the adrenal medulla.

Central Pressor Response by Olmesartan in the Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Objectives: The major aims of the present study were to evaluate the effect of chronic oral treatment with olmesartan on cardiovascular response to exogenous angiotensin II (Ang II), and its relationship with the AT1 receptor (AT1R) mRNA in rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHR). Methods: SHR (12 weeks old) were treated with olmesartan, 30 mg/(kg . day), in drinking water. 4 weeks later, Ang II (100 pmol) was microinjected into the RVLM, and arterial pressure and the heart rate were observed. Results: The blood pressure of all SHR-olme rats reach near normal level during breeding period. Ang IIresulted in an increase in mean arterial pressure (MAP) of each group. While, the increase of MAP in olmesartan-treated SHR was significantly smaller than that in untreated SHR(26.3 ± 0.75 mmHg vs. 47.2 ± 1.41 mmHg, n = 10, P < 0.01 ); however, it was still greater than that in WKY rats(26.3 ± 0.75 mmHg vs. 21.5 ± 0.72 mmHg, n = 10, P < 0.05). The heart rate (HR) of the each group was also increased, but there was no statistical significance among groups. In addition, AT1R mRNA in RVLM was measured by RT-PCR and analyzed with optic density. It demonstrated that the mean optic density (MOD) of AT1R mRNA in olmesartan-treated SHR was significantly reduced compared with untreated SHR(0.94 ± 0.41 vs. 2.41 ± 0.37, n = 10, P < 0.01); however, it was still higher than that in WKY rats(0.94 ± 0.41 vs. 0.81 ± 0.22, n = 10, P < 0.05). Conclusions: These results demonstrated that chronic oral treatment with olmesartan could obviously attenuate the exaggerated pressor response to exogenous Ang II and inhibit the excessive expression of AT1R in RVLM of SHR, so we presume olmesartan may attenuate central pressor response by reducing AT1R in RVLM of SHR.

Inhibition of central angiotensin II-induced pressor responses by hydrogen peroxide

Hydrogen peroxide (H2O2), important reactive oxygen species produced endogenously, may have different physiological actions. The superoxide anion (O2·−) is suggested to be part of the signaling mechanisms activated by angiotensin II (ANG II) and central virus-mediated overexpression of the enzyme superoxide dismutase (that dismutates O2·− to H2O2) reduces pressor and dipsogenic responses to central ANG II. Whether this result might reflect elevation of H2O2 rather than depletion of O2·− has not been addressed. Here we investigated the effects of H2O2 injected intracerebroventricularly (i.c.v.) or ATZ (3-amino-1,2,4-triazole, a catalase inhibitor) injected intravenously (i.v.) or i.c.v. on the pressor responses induced by i.c.v. injections of ANG II. Normotensive male Holtzman rats (280–320 g, n=5–13/group) with stainless steel cannulas implanted in the lateral ventricle were used. Prior injection of H2O2 (5 μmol/1 μl) or ATZ (5 nmol/1 μl) i.c.v. almost abolished the pressor responses induced by ANG II (50 ng/1 μl) also injected i.c.v. (7±3 and 5±3 mm Hg, respectively, vs. control: 19±4 mm Hg). Injection of ATZ (3.6 mmol/kg b.wt.) i.v. also reduced central ANG II-induced pressor responses. Injections of H2O2 i.c.v. and ATZ i.c.v. or i.v. alone produced no effect on baseline arterial pressure. Central ANG II, H2O2 or ATZ did not affect heart rate. The results show that central injections of H2O2 and central or peripheral injections of ATZ reduced the pressor responses induced by i.c.v. ANG II, suggesting that exogenous or endogenous H2O2 may inhibit central pressor mechanisms activated by ANG II.

Inflammation and Neurogenic Hypertension

See related article, pages 263–270 The brain renin–angiotensin system (RAS) plays a critical role in maintaining blood pressure regulation and volume homeostasis. Components of the RAS, including angiotensinogen, renin, angiotensin (Ang)-converting enzymes, and Ang receptors, are expressed in various nuclei located between the anteroventral region of the third ventricle (AV3V) and the brain stem.1,2 Accordingly, formation of the various Ang peptides, notably Ang II and Ang(1-7) can take place in the brain, independently of the endocrine RAS, and participate in the regulation of water intake, salt appetite, cardiac baroreflex and autonomic functions. Upregulation of Ang II type 1 (AT1) receptors in these nuclei has been shown to reduce baroreflex sensitivity and increase sympathetic tone, thus contributing to the development and maintenance of hypertension and heart failure, ultimately leading to end-organ damage.3 On the other hand, treatment with ACE inhibitors and Ang receptor blockers can prevent RAS overactivity and restore a normal cardiovascular function. In addition to Ang II generated in the brain, blood-borne Ang peptides can also enter the central nervous system via the circumventricular organs (CVOs) and contribute to the regulation of blood pressure and volume homeostasis.4 The CVOs are represented by the OVLT (organum vasculosum of the lamina terminalis), the subfornical organ (SFO), the median eminence and the neurohypophysis, …

CENTRALLY ADMINISTERED INSULIN POTENTIATES THE PRESSOR RESPONSE TO ANGIOTENSIN II BY MAPK ACTIVATION IN RATS: PP.34.406

Objectives: Insulin-resistance related hypertension could be due to insulin actions at central level. As insulin and angiotensin II (Ang II) exert some effects at hypothalamic level by MAPK intracellular pathway activation, we evaluated if insulin modifies the central pressor response to Ang II in control (C) and insulin-resistant rats. Methods: Two groups of male Sprague-Dawley rats were studied: C: tap water; fructose (F)-treated: F solution (10% w/v) to drink for 6 weeks (n = 20). A cannulae was inserted in one carotid artery to measure mean arterial pressure (MAP; mmHg). Vehicle or insulin (12 mU/h) was perfused intracerebroventricularly. Changes in MAP were evaluated in response to Ang II 5 pmol. Afterwards, hypothalami were removed to determine ERK1/2 phosphorylation levels. Results: MAP basal value was elevated in F rats (90 ± 3 vs. C: 75 ± 3, p < 0.05). Ang II increased MAP only in insulin pre-treated C animals (dMAP: 6.3 ± 0.8 vs. vehicle, p < 0.01); meanwhile it elevated MAP in a similar manner in insulin and vehicle pre-treated F rats (dMAP: 5.5 ± 1.1 and 4.0 ± 1.0 respectively, p < 0.01 vs. C vehicle). Basal phospho-ERK 1/2 hypothalamic levels were similar in both groups. In C and F Ang II or insulin infusion increased more than two fold phospho-ERK 1/2 hypothalamic levels (p < 0.05 vs. C vehicle). C animals that received insulin infusion followed by Ang II injection presented 4.5 higher values of phospho-ERK 1/2 than those receiving vehicle (p < 0.01) meanwhile F rats showed 3.5 higher levels (p < 0.05 vs. C vehicle). Both groups increased twice phospho-ERK 1/2 than those treated with Ang II without insulin pre-treatment (p < 0.05). Conclusions: Centrally administered insulin potentiates the pressor effects of Ang II in C rats, suggesting a novel mechanism, involving MAPK activation, by which insulin influences blood pressure control at central level. The existence of a pressor response to Ang II in F rats, and the absence of changes in this response after previous administration of insulin could be due to the chronic hiperinsulinemia present in this model.

Oral phycocyanobilin may diminish the pathogenicity of activated brain microglia in neurodegenerative disorders

There is considerable evidence that activated microglia play a central role in the pathogenesis of many prominent neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. The elevated NADPH oxidase activity of these microglia contributes importantly to their pathogenic impact, collaborating with increased iNOS activity to generate the cytotoxic oxidant peroxynitrite. Phycocyanobilin (PCB), a chromophore derived from biliverdin that constitutes up to 1% of the dry weight of spirulina, has recently been shown to be a potent inhibitor of NADPH oxidase. The possibility that orally administered PCB could reach the brain parenchyma in sufficient concentrations to influence microglial function is consistent with the findings of two rodent studies: orally administered C-phycocyanin (the spirulina holoprotein that includes PCB) suppresses the neurotoxic impact of the excitotoxin kainite in rats, and a diet high in spirulina ameliorates the loss of dopaminergic neurons in the MPTP-induced Parkinsonian syndrome in mice. Hence, supplemental PCB may have considerable potential for preventing or slowing the progression of a range of neurodegenerative disorders. Some of the central physiological effects of PCB may also reflect inhibition of neuronal NADPH oxidase, which is now known to have a modulatory impact on neuron function, and can mediate neurotoxicity in certain circumstances. Neuronal NADPH oxidase activation is an obligate mediator of the central pressor effect of angiotensin II, and there is suggestive evidence that it may also play a role in inflammatory hyperalgesia; these findings point to possible antihypertensive and analgesic applications for PCB. The likely favorable effects of PCB on vascular health may also protect the brain by decreasing stroke risk, and inhibition of NADPH oxidase in rodents has been shown to lessen the neurotoxic impact of temporary cerebral ischemia. PCB may thus have versatile potential for preserving the healthful function of the central nervous system into advanced old age--albeit optimal neuroprotection may require more complex regimens that incorporate PCB along with other well tolerated nutraceuticals and drugs, in conjunction with prudent lifestyle modifications.

Angiotensin II receptor 1 involved in the central pressor response induced by interleukin-1 beta in the paraventricular nucleus

Objective: To investigate the possible participation of angiotensin II receptor 1 (AT1 receptor) in pressor response induced by IL-1β in the paraventricular nucleus (PVN) of hypothalamus.Methods: The experiments were performed on adult Wistar rats. Mean arterial pressure (MAP) were recorded during microinjection of different doses of IL-1β, IL-1β together with Losartan, an AT1 receptor antagonist, or Ang II pre-treated with IL-1β into PVN. Rats microinjected with saline were served as controls in all experiments.Results: Microinjection of IL-1β (0.1 or 0.2 ng) resulted in increases in blood pressure in a dose-dependent manner, and the pressor effect caused by administration of IL-1β (0.2 ng) could be attenuated by pre-treatment with AT1 receptor antagonist (100 ng Losartan). A subpressor dose of IL-1β (0.05 ng) could augment the pressor response induced by microinjection of Ang II (10 ng).Discussion: The present results provide support that central infusion of IL-1β increases blood pressure and the pressor response requires stimulation of AT1 receptors. It is also shown that IL-1β has the effect of increasing the magnitude of pressor response induced by Ang II in PVN.

Exaggerated Blood Pressure Response to Exercise Is Associated With Augmented Rise of Angiotensin II During Exercise

The aim of this study was to investigate the association between an exaggerated blood pressure (BP) response to exercise and augmented angiotensin (Ang) II rise during exercise. Although a central pressor effect of Ang II has been implicated in the pathogenesis of hypertension, the relationship between Ang II and exaggerated BP response to exercise is unclear. Thirty-six subjects with an exaggerated BP response to exercise (18 men, age 50 +/- 16 years, Group II) were compared with 36 age- and gender-matched control subjects (18 men, age 50 +/- 16 years, Group I) with normal BP reactivity. The subjects who had resting BP >or=140/90 mm Hg or were treated with any antihypertensive drugs were excluded. The blood was sampled at rest and immediately after peak exercise for measurement of renin, Ang II, aldosterone, and catecholamine. At rest, there were no significant differences in BP, renin, aldosterone, and catecholamine levels between the 2 groups. The renin, aldosterone, and catecholamine were increased during exercise, but there were no significant differences between the groups. However, log Ang II at rest (0.78 +/- 0.32 vs. 0.98 +/- 0.38, p = 0.004) and peak exercise (0.84 +/- 0.35 vs. 1.17 +/- 0.51, p < 0.001) and the magnitude of the increment of log Ang II with exercise (0.06 +/- 0.12 vs. 0.19 +/- 0.20, p = 0.003) were significantly higher in the exaggerated BP response group. An exaggerated BP response to exercise was associated with augmented rise of Ang II during exercise.

Aminopeptidase A

Several decades of investigation have provided unequivocal support for the existence of an intrinsic brain renin-angiotensin (Ang) system (RAS) and its involvement in the control of cardiovascular functions.1,2 Essential components of the RAS, ie, renin, angiotensinogen, Ang-converting enzyme, Ang-converting enzyme 2, type 1 Ang II, and type 2 Ang II receptors, as well as various aminopeptidases, are synthesized within the brain, and the hyperactivity of RAS in the brain is implicated in the development and maintenance of hypertension.1,2 Moreover, interruption of the brain RAS activity by either pharmacological or genetic means is associated with a profound beneficial outcome in hypertension.1,2 Thus, the brain RAS may be an important target for hypertension with neurogenic origin. Many years ago it was proposed that the physiologically relevant peptide in the brain RAS that regulates blood pressure (BP) is Ang III rather than Ang II.3,4 Ang III, also called Ang-(2-8), is generated from Ang II by aminopeptidase A (APA), which cleaves the Asp1-Arg2 bond in Ang II. Persuasive evidence have been presented in support of this “Ang III hypothesis”: (1) Ang III, when centrally administrated, enhances BP; stimulates vasopressin release, thirst, and sodium appetite; and decreases baroreceptor reflex function3,5,6; (2) Ang III displays comparable affinity to Ang II for the type 1 Ang II receptor3; (3) specific inhibitors of APA …