Role of the spinal cord NO/cGMP pathway in the control of arterial pressure and heart rate

The modulatory effect of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway on sympathetic preganglionic neurons still deserves further investigation. The present study was designed to examine the role of the spinal cord NO/cGMP pathway in controlling mean arterial pressure and heart rate. We observed that intrathecal administration of the NO synthase inhibitor N omega-Nitro-L-arginine methyl ester hydrochloride (L-NAME) causes an increase in mean arterial pressure but does not affect heart rate. Intrathecal administration of the soluble guanylyl cyclase inhibitor 1H-[1,2,4] Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) does not change mean arterial pressure and heart rate. The precursor for NO synthesis, L-arginine, reduces both mean arterial pressure and heart rate while administration of ODQ before L-arginine impaired decreases in mean arterial pressure and heart rate. Administration of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) after L-NAME does not affect increases in mean arterial pressure promoted by NO synthase inhibition. Although the hypotensive and bradycardic responses induced by intrathecal administration of L-arginine depend on cGMP, our results indicate that NO acts to tonically inhibit SPNs, independent of either cGMP or NMDA receptors.

Effect of baroreceptor denervation on the autonomic control of arterial pressure in conscious mice

This study evaluated the role of arterial baroreceptors in arterial pressure (AP) and pulse interval (PI) regulation in conscious C57BL mice. Male animals, implanted with catheters in a femoral artery and a jugular vein, were submitted to sino-aortic (SAD), aortic (Ao-X) or carotid sinus denervation (Ca-X), 5 daysprior to the experiments. After basal recording of AP, the lack of reflex bradycardia elicited by administration of phenylephrine was used to confirm the efficacy of SAD, and cardiac autonomic blockade with methylatropine and propranolol was performed. The AP and PI variability were calculated in the time and frequency domains (spectral analysis/fast Fourier transform) with the spectra quantified in low-(LF; 0.25-1Hz) and high-frequency bands (HF; 1-5Hz). Basal AP and AP variability were higher after SAD, Ao-X or Ca-X than in intact mice. Pulse interval was similar among the groups, whereas PI variability was lower after SAD. Atropine elicited a slight tachycardia in control mice but did not change PI after total or partial denervation. The bradycardia caused by propranolol was higher after SAD, Ao-X or Ca-X compared with intact mice. The increase in the variability of AP was accompanied by a marked increase in the LF and HF power of the AP spectra after baroreceptor denervation. The LF and HF power of the PI were reduced by SAD and by Ao-X or Ca-X. Therefore, both sino-aortic and partial baroreceptor denervation in mice elicits hypertension and a remarkable increase in AP variability and cardiac sympathetic tonus. Spectral analysis showed an important contribution of the baroreflex in the power of LF oscillations of the PI spectra. Both sets of baroreceptors seem to be equally important in the autonomic regulation of the cardiovascular system in mice.

Modulation of arterial pressure by P2 purinoceptors in the paraventricular nucleus of the hypothalamus of awake rats

In the present study we evaluated the role of purinergic mechanisms in the PVN on the tonic modulation of the autonomic function to the cardiovascular system as well on the cardiovascular responses to peripheral chemoreflex activation in awake rats Guide-cannulae were bilaterally Implanted in the direction of the PVN of male Wistar rats Femoral artery and vein were catheterized one day before the experiments Chemoreflex was activated with KCN (30 mu g/0 05 ml iv) before and after microinjections of P2 receptors antagonist into the PVN Microinjection of PPADS a non selective P2X antagonist Into the PVN (n = 6) produced a significant increase in the baseline MAP (99 +/- 2 vs 112 +/- 3 mmHg) and HR (332 +/- 8 vs 375 +/- 8 bpm) but had no effect on the pressor and bradycardic responses to chemoreflex activation Intravenous injection of vasopres in receptors antagonist after microinjection of PPADS into the PVN produced no effect on the increased baseline MAP Simultaneous microinjection of PPADS and KYN into the PVN (n=6) had no effect in the baseline MAP HR or in the pressor and bradycardic responses to chemoreflex activation We conclude that P2 purinoceptors in the PVN are involved in the modulation of baseline autonomic function to the cardiovascular system but not in the cardiovascular responses to chemoreflex activation in awake rats (C) 2010 Elsevier B V All rights reserved

Dopamine microinjected into brainstem of awake rats affects baseline arterial pressure but not chemoreflex responses

Dopamine (DA) is a neuromodulator in the brainstem involved with the generation and modulation of the autonomic and respiratory activities. Here we evaluated the effect of microinjection of DA intracistema magna (icm) or into the caudal nucleus tractus solitarii (cNTS) on the baseline cardiovascular and respiratory parameters and on the cardiovascular and respiratory responses to chemoreflex activation in awake rats. Guide cannulas were implanted in cisterna magna or cNTS and femoral artery and vein were catheterized. Respiratory frequency (f(R)) was measured by whole-body plethysmography. Chemoreflex was activated with KCN (iv) before and after microinjection of DA icm or into the cNTS bilaterally while mean arterial pressure (MAP), heart rate (HR) and f(R) were recorded. Microinjection of DA icm (n = 13), but not into the cNTS (n = 8) produced a significant decrease in baseline MAP (-15 +/- 1 vs 1 +/- 1 mm Hg) and HR (-55 +/- 11 vs -11 +/- 17 bpm) in relation to control (saline with ascorbic acid, n = 9) but no significant changes in baseline f(R). Microinjection of DA icm or into the cNTS produced no significant changes in the pressor, bradycardic and tachypneic responses to chemoreflex activation. These data show that a) DA icm affects baseline cardiovascular regulation, but not baseline f(R) and autonomic and respiratory components of chemoreflex and b) DA into the cNTS does not affect either the autonomic activity to the cardiovascular system or the autonomic and respiratory responses of chemoreflex activation. (C) 2010 Elsevier B.V. All rights reserved.

GABA and nitric oxide in the PVN are involved in arterial pressure control but not in the chemoreflex responses in rats

GABAergic, nitrergic and glutamatergic mechanisms in the PVN on the baseline mean arterial pressure (MAP), heart rate (HR) and on the cardiovascular responses to chemoreflex activation in awake rat were evaluated. Chemoreflex was activated with KCN before and after microinjections into the PVN. Bicuculline into the PVN increased baseline MAP (94+/-3 vs 113+/-5 mmHg) and HR (350+/-9 vs 439+/-18 bpm) but had no effect on the pressor (49+/-5 vs 47+/-6 mmHg) or bradicardic (-213+/-23 vs -256+/-42 bpm) responses (n=7). Kynurenic acid into the PVN (n=6) produced no significant changes in the MAP (98+/-3 vs 100+/-3 mmHg), HR (330+/-5 vs 339+/-12 mmHg) or in the pressor (50+/-4 vs 42+/-4 mmHg) and bradicardic (-252+/-4 vs -285+/-16 bpm) responses to chemoreflex. L-NAME into the PVN (n=8) produced increase in the MAP (94+/-3 vs 113+/-5 mmHg) and HR (350+/-9 vs 439+/-18 bpm) but had no effect on the pressor (52+/-5 vs 47+/-6 mmHg) or bradicardic (-253+/-19 vs -320+/-25 bpm) responses to chemoreflex. We conclude that GABA(A) and nitric oxide in the PVN are involved in the maintenance of the baseline MAP but not in the modulation of the responses to chemoreflex. The results also show that Glutamate receptors in the PVN are not involved in maintenance of the baseline MAP, HR or in the cardiovascular responses to chemoreflex in awake rats. (C) 2008 Elsevier B.V. All rights reserved.

Heart rate and arterial pressure variability in the experimental renovascular hypertension model in rats

This study was conducted in one kidney, one clip (1K1C) Goldblatt hypertensive rats to evaluate vascular and cardiac autonomic control using different approaches: 1) evaluation of the autonomic modulation of heart rate (HR) and systolic arterial pressure (SAP) by means of autoregressive power spectral analysis 2) assessment of the cardiac baroreflex sensitivity; and 3) double blockade with methylatropine and propranolol. The 1K1C group developed hypertension and tachycardia. The 1K1C group also presented reduction in variance as well as in LF (0.23 +/- 0.1 vs. 1.32 +/- 0.2 ms(2)) and HF (6.6 +/- 0.49 vs. 15.1 +/- 0.61 ms(2)) oscillations of pulse interval. Autoregressive spectral analysis of SAP showed that 1K1C rats had an increase in variance and LF band (13.3 +/- 2.7 vs. 7.4 +/- 1.01 mmHg(2)) in comparison with the sham group. The baroreflex gain was attenuated in the hypertensive 1K1C (- 1.83 +/- 0.05 bpm/mmHg) rats in comparison with normotensive sham (-3.23 +/- 0.06 bpm/MmHg) rats. The autonomic blockade caused an increase in the intrinsic HR and sympathetic predominance on the basal HR of 1K1C rats. Overall, these data indicate that the tachycardia observed in the 1K1C group may be attributed to intrinsic cardiac mechanisms (increased intrinsic heart rate) and to a shift in the sympathovagal balance towards cardiac sympathetic over-activity and vagal suppression associated to depressed baroreflex sensitivity. Finally, the increase in the LF components of SAP also suggests an increase in sympathetic activity to peripheral vessels. (c) 2008 Elsevier B.V. All rights reserved.

Fluorescent indication that nitric oxide formation in NTS neurons is modulated by glutamate and GABA

Nitric oxide (NO) in NTS plays an important role in regulating autonomic function to the cardiovascular system. Using the fluorescent dye DAF-2 DA, we evaluated the NO concentration in NTS. Brainstem slices of rats were loaded with DAF-2 DA, washed, fixed in paraformaldehyde and examined under fluorescent light. In different experimental groups, NTS slices were pre-incubated with 1 mM L-NAME (a non-selective NOS inhibitor), 1 MM D-NAME (an inactive enantiomere of L-NAME), 1 mM kynurenic acid (a nonselective ionotropic receptors antagonist) or 20 mu M bicuculline (a selective GABA(A) receptors antagonist) before and during DAF-2 DA loading. Images were acquired using a confocal microscope and the intensity of fluorescence was quantified in three antero-posterior NTS regions. In addition, slices previously loaded with DAF-2 DA were incubated with NeuN or GFAP antibody. A semi-quantitative analysis of the fluorescence intensity showed that the basal NO concentration was similar in all antero-posterior aspects of the NTS (rostral intermediate, 15.5 +/- 0.8 AU: caudal intermediate, 13.2 +/- 1.4 AU; caudal commissural, 13.8 +/- 1.4 AU, n = 10). In addition, the inhibition of NOS and the antagonism of glutamatergic receptors decreased the NO fluorescence in the NTS. On the other hand, D-NAME did not affect the NO fluorescence and the antagonism of GABAA receptors increased the NO fluorescence in the NTS. It is important to note that the fluorescence for NO was detected mainly in neurons. These data show that the fluorescence observed after NTS loading with DAF-2 DA is a result of NO present in the NTS and support the concept that NTS neurons have basal NO production which is modulated by L-glutamate and GABA. (C) 2009 Elsevier Inc. All rights reserved.

Atenolol blunts blood pressure increase during dynamic resistance exercise in hypertensives

center dot Dynamic resistance exercise promotes a sizeable increase in blood pressure during its execution in non medicated hypertensives. WHAT THIS STUDY ADDS center dot Atenolol not only decreases blood pressure level but also mitigates the increase of blood pressure during dynamic resistance exercise in hypertensive patients. An increase in blood pressure during resistance exercise might be at least in part attributed to an increase in cardiac output. AIMS This study was conducted to determine whether atenolol was able to decrease BP level and mitigate BP increase during dynamic resistance exercise performed at three different intensities in hypertensives. METHODS Ten essential hypertensives (systolic/diastolic BP between 140/90 and 160/105 mmHg) were blindly studied after 6 weeks of placebo and atenolol. In each phase, volunteers executed, in a random order, three protocols of knee-extension exercises to fatigue: (i) one set at 100% of 1 RM; (ii) three sets at 80% of 1 RM; and (iii) three sets at 40% of 1 RM. Intra-arterial radial blood pressure was measured throughout the protocols. RESULTS Atenolol decreased systolic BP maximum values achieved during the three exercise protocols (100% = 186 +/- 4 vs. 215 +/- 7, 80% = 224 +/- 7 vs. 247 +/- 9 and 40% = 223 +/- 7 vs. 252 +/- 16 mmHg, P < 0.05). Atenolol also mitigated an increase in systolic BP in the first set of exercises (100% = +38 +/- 5 vs. +54 +/- 9; 80% = +68 +/- 11 vs. +84 +/- 13 and 40% = +69 +/- 7 vs. +84 +/- 14, mmHg, P < 0.05). Atenolol decreased diastolic BP values and mitigated its increase during exercise performed at 100% of 1 RM (126 +/- 6 vs. 145 +/- 6 and +41 +/- 6 vs. +52 +/- 6, mmHg, P < 0.05), but not at the other exercise intensities. CONCLUSIONS Atenolol was effective in both reducing systolic BP maximum values and mitigating BP increase during resistance exercise performed at different intensities in hypertensive subjects.

Mechanisms underlying the biphasic effect of vitamin K-1 (phylloquinone) on arterial blood pressure

Phylloquinone (vitamin K-1, VK1) is widely used therapeutically and intravenous administration of this quinone can induce hypotension. We aimed to investigate the mechanisms underlying the effects induced by VK1 on arterial blood pressure. With this purpose a catheter was inserted into the abdominal aorta of male Wistar rats for blood pressure and heart rate recording. Bolus intravenous injection of VK1 (0.5-20 mg kg(-1)) produced a transient increase in blood pressure followed by a fall. Both the pressor and depressor response induced by VK1 were dose-dependent. On the other hand, intravenous injection of VK1 did not alter heart rate. The nitric oxide synthase (NOS) inhibitor N-G-nitro-L-arginine methyl ester (L-NAME, 10 and 20 mg kg(-1)) reduced both the increase and decrease in blood pressure induced by VK1 (5 mgkg(-1)). On the other hand, indometacin (10 mg kg(-1)), a non-selective cyclooxygenase inhibitor, did not alter the increase in mean arterial pressure (MAP) induced by VK1. However, VK1-induced fall in MAP was significantly attenuated by indometacin. We concluded that VK1 induces a dose-dependent effect on blood pressure that consists of an acute increase followed by a more sustained decrease in MAP. The hypotension induced by VK1 involves the activation of the nitric oxide (NO) pathway and the release of vasodilator prostanoid(s).

Redução da pressão arterial e do duplo produto de repouso após treinamento resistido em idosas hipertensas

FUNDAMENTO: Em razão das controvérsias existentes na literatura quanto aos possíveis benefícios do treinamento resistido (TR) sobre a pressão arterial de repouso (PA) e por causa da escassez de estudos com indivíduos idosos e hipertensos, o TR é pouco recomendado como forma de tratamento não-farmacológico da hipertensão arterial. OBJETIVO: Verificar os efeitos do TR progressivo sobre a pressão arterial de repouso (PA), a freqüência cardíaca (FC) e o duplo produto (DP) em idosas hipertensas controladas. MÉTODOS: Vinte mulheres idosas (66,8 ± 5,6 anos de idade) sedentárias, controladas com medicação anti-hipertensiva, realizaram 12 semanas de TR, compondo o grupo do treinamento resistido (GTR). Vinte e seis idosas (65,3 ± 3,4 anos de idade) hipertensas controladas não realizaram exercícios físicos durante a pesquisa, constituindo o grupo-controle. RESULTADOS: Houve redução significativa nos valores de repouso da pressão arterial sistólica (PAS), da pressão arterial média (PAM) e do DP após o TR. Não foram encontradas reduções significativas na pressão arterial diastólica (PAD) e na FC de repouso após o TR em ambos os grupos. A magnitude da queda no GTR foi de 10,5 mmHg, 6,2 mmHg e 2.218,6 mmHg x bpm para a PAS, PAM e o DP, respectivamente. CONCLUSÃO: O TR progressivo reduziu a PAS, PAM e o DP de repouso de idosas hipertensas, controladas com medicação anti-hipertensiva.

Influência do bloqueador de receptor de angiotensina (Losartana potássica) na função renal e pressão arterial em cães GRMD

A distrofia muscular de Duchenne (DMD) é uma alteração neuromuscular caracterizada por contínua necrose muscular e degeneração, com eventual fibrose e infiltração por tecido adiposo. O aumento progressivo da fibrose intersticial no músculo impede a migração das células miogênicas, necessárias para a formação muscular. O modelo canino constitui-se nas melhores fenocópias da doença em humanos, quando comparados com outros modelos animais com distrofia. O tratamento antifibrose de pacientes DMD, tendo como alvo os mediadores da citocina, TGF-beta, e o tratamento com antiinflamatórios, podem limitar a degeneração muscular e contribuir para a melhora do curso da doença. O presente estudo teve como objetivo observar os possíveis efeitos adversos na fisiologia renal, por meio de avaliação bioquímica sanguínea e da pressão arterial, verificando a viabilidade do uso do Losartan (um inibidor de TGF-beta) nos cães afetados pela distrofia muscular. Foram utilizados quatro cães adultos, sendo dois machos e duas fêmeas. Utilizou-se a dose de 50mg de Losartan, administrada via oral, uma vez ao dia. Os exames clínicos, bem como alterações na função renal, o nível do potássio sérico e a pressão arterial não evidenciaram reação adversa durante todo o período do experimento. O uso de Losartan, por um período de 9 semanas, mostrou-se como uma terapia segura para o tratamento antifibrótico em cães adultos, não afetando a função renal ou pressão arterial dos animais.

Valores da pressão arterial em cães pelos métodos oscilométrico e Doppler vascular

Foram comparados dois métodos não-invasivos de medida da pressão arterial, o Doppler vascular e o oscilométrico, com o objetivo de estabelecer parâmetros que possam auxiliar no diagnóstico seguro da hipertensão arterial. Para tal, foram utilizados 45 cães, machos e fêmeas, distribuídos em três grupos de acordo com o peso, pequeno, médio e grande porte. Em cada animal, procedeu-se a mensuração por meio do Doppler vascular e, em seguida, do oscilométrico. Na obtenção da pressão arterial sistólica, não houve diferença entre os métodos nos três grupos de animais, porém, na obtenção da pressão arterial diastólica, houve diferença estatística entre o Doppler vascular e o oscilométrico nos grupos de animais de pequeno e médio porte. Pôde-se concluir que valores confiáveis de pressão sistólica podem ser obtidos tanto por meio do Doppler vascular quanto do oscilométrico. Os valores da pressão arterial diastólica obtidos pelos dois métodos não se correlacionam, principalmente nos animais de pequeno e médio porte.

Finger blood pressure during leg resistance exercise

Blood pressure (BP) assessment during resistance exercise can be useful to avoid high BP, reducing cardiovascular risk, especially in hypertensive individuals. However, non-invasive accurate technique for this purpose is not available. The aim of this study was to compare finger photoplethysmographic (FPP) and intra-arterial BP values and responses during resistance exercise. Eight non-medicated hypertensive subjects (5 males, 30-60 years) were evaluated during pre-exercise resting period and during three sets of the knee extension exercise performed at 80% of 1RM until fatigue. BP was measured simultaneously by FPP and intra-arterial methods. Data are mean +/- SD. Systolic BP was significantly higher with FPP than with intra-arterial: at pre-exercise (157 +/- 13 vs. 152 +/- 10 mmHg; p < 0.01) and the mean (202 +/- 29 vs. 198 +/- 26 mmHg; p < 0.01), and the maximal (240 +/- 26 vs. 234 +/- 16 mmHg; p < 0.05) values achieved during exercise. The increase in systolic BP during resistance exercise was similar between FPP and intra-arterial (+ 73 +/- 29 vs. + 71 +/- 18 mmHg; p = 0.59). Diastolic BP values and increases were lower with FPP. In conclusion, FPP provides similar values of BP increment during resistance exercise than intra-arterial method. However, it overestimates by 2.6 +/- 6.1% the maximal systolic BP achieved during this mode of exercise and underestimates by 8.8 +/- 5.8% the maximal diastolic BP.

Isolation and Characterization of a Natriuretic Peptide from Crotalus oreganus abyssus (Grand Canyon Rattlesnake) and its Effects on Systemic Blood Pressure and Nitrite Levels

Studies on the therapeutic potential of venom peptides have significantly advanced the development of new peptide drugs. A good example is captopril, a synthetic peptide drug, which acts as an anti-hypertensive and potentiating bradykinin, inhibiting the angiotensin-converting enzyme, whose precursor was isolated from the venom of Bothrops jararacussu. The natriuretic peptide (NPs) family comprises three members, ANP (atrial natriuretic peptide), BNP (B-type natriuretic peptide) and CNP (C-type natriuretic peptide), and has an important role in blood pressure regulation and electrolyte homeostasis. In this study, we describe, for the first time, the isolation and characterization of a novel natriuretic-like peptide (Coa_NP), isolated from Crotalus Oreganus abyssus venom. The peptide has 32 amino acids and its complete sequence is SKRLSNGCFGLKLDRIGAMSGLGCWRLINESK. The Coa_NP has an average molecular mass of 3510.98 Da and its amino acid sequence presents the loop region that is characteristic of natriuretic peptides (17 amino acids, NP domain consensus; CFGXXXDRIXXXSGLGC). Coa_NP is a natriuretic peptide of the ANP/BNP-like family, since the carboxy terminal region of CNP has its own NP domain. The functional experiments showed that Coa_NP produced biological effects similar to those of the other natriuretic peptides: (1) a dose-dependent decrease in mean arterial pressure; (2) significant increases in plasma nitrite levels, and (3) vasorelaxation in thoracic aortic rings that were pre-contracted with phenylephrine. The structural and biological aspects confirm Coa_NP as a natriuretic peptide isolated from snake venom, thus expanding the diversification of venom components.

Online monitoring of pulse pressure variation to guide fluid therapy after cardiac surgery

BACKGROUND: The arterial pulse pressure variation induced by mechanical ventilation (Delta PP) has been shown to be a predictor of fluid responsiveness. Until now, Delta PP has had to be calculated offline (from a computer recording or a paper printing of the arterial pressure curve), or to be derived from specific cardiac output monitors, limiting the widespread use of this parameter. Recently, a method has been developed for the automatic calculation and real-time monitoring of Delta PP using standard bedside monitors. Whether this method is to predict reliable predictor of fluid responsiveness remains to be determined. METHODS: We conducted a prospective clinical study in 59 mechanically ventilated patients in the postoperative period of cardiac surgery. Patients studied were considered at low risk for complications related to fluid administration (pulmonary artery occlusion pressure <20 mm Hg, left ventricular ejection fraction >= 40%). All patients were instrumented with an arterial line and a pulmonary artery catheter. Cardiac filling pressures and cardiac output were measured before and after intravascular fluid administration (20 mL/kg of lactated Ringer`s solution over 20 min), whereas Delta PP was automatically calculated and continuously monitored. RESULTS: Fluid administration increased cardiac output by at least 15% in 39 patients (66% = responders). Before fluid administration, responders and nonresponders were comparable with regard to right atrial and pulmonary artery occlusion pressures. In contrast, Delta PP was significantly greater in responders than in nonresponders, (17% +/- 3% vs 9% +/- 2%, P < 0.001). The Delta PP cut-off value of 12% allowed identification of responders with a sensitivity of 97% and a specificity of 95%. CONCLUSION: Automatic real-time monitoring of Delta PP is possible using a standard bedside rnonitor and was found to be a reliable method to predict fluid responsiveness after cardiac surgery. Additional studies are needed to determine if this technique can be used to avoid the complications of fluid administration in high-risk patients.