Tilt Training Increases Vasoconstrictor Reserve in Patients with Neurocardiogenic Syncope

Neurocardiogenic syncope (NCS) is a common clinical entity resulting from an excessive reflex autonomic response, particularly during orthostatism. Treatment options are controversial and of limited effectiveness. Tilt training (TT) is a promising option to treat these patients. However, its mechanism of action and clinical impact remain unclear. OBJECTIVE: To characterize hemodynamic and autonomic responses during a TT program in patients with NCS refractory to conventional measures. METHODS: We studied 28 patients (50% male, mean age 41±14 years) without structural heart disease, with NCS documented by tilt testing. The TT program included 9 tilt sessions (3 times a week, 30 min) (60° - 6 sessions, 70° - 3 sessions), under ECG and blood pressure monitoring combined with home orthostatic self-training and 10° head-up during sleep. Systolic volume, cardiac output, total peripheral resistance, baroreflex sensitivity and heart-rate variability were computed. Patients were reassessed at 1 month and every 6 months for a maximum of 36 months (24±12 months). RESULTS: Over the course of the TT program there was a significant increase in total peripheral resistance (1485±225 vs. 1591±187 dyn·s·cm(-5), p<0.05), with a decrease in standard deviation (206±60 vs. 150±42, p<0.05). During follow-up, syncope recurred in five patients (19%), with a significant reduction in the number of episodes (4.0±3.2/patient in the 12 months before TT vs. 1.4±0.8/patient post-TT, p<0.05). CONCLUSION: In refractory NCS, TT may be an effective therapeutic option, with long-term benefits. These results appear to be due to an increase in vasoconstrictor reserve combined with a reduction in its variance.

Schistosomiasis differentially affects vasoconstrictor responses: up-regulation of 5-HT receptor-mediated aorta contraction

Schistosomiasis, classified by the World Health Organization as a neglected tropical disease, is an intravascular parasitic disease associated to a chronic inflammatory state. Evidence implicating inflammation in vascular dysfunction continues to mount, which, broadly defined, reflects a failure in the control of intracellular Ca2+ and consequently, vascular contraction. Therefore, we measured aorta contraction induced by 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1), two important regulators of vascular contraction. Isometric aortic contractions were determined in control and Schistosoma mansoni-infected mice. In the infected animals, 5-HT induced a 50% higher contraction in relation to controls and we also observed an increased contraction in response to Ca2+ mobilisation from sarcoplasmic reticulum. Nevertheless, Rho kinase inhibition reduced the contraction in response to 5-HT equally in both groups, discarding an increase of the contractile machinery sensitivity to Ca2+. Furthermore, no alteration was observed for contractions induced by ET-1 in both groups. Our data suggest that an immune-vascular interaction occurs in schistosomiasis, altering vascular contraction outside the mesenteric portal system. More importantly, it affects distinct intracellular signalling involved in aorta contraction, in this case increasing 5-HT receptor signalling.

Correlation between vasoconstrictor roles and mRNA expression of alpha1-adrenoceptor subtypes in blood vessels of genetically engineered mice.

We examined the contribution of each alpha(1)-adrenoceptor (AR) subtype in noradrenaline (NAd)-evoked contraction in the thoracic aortas and mesenteric arteries of mice. Compared with the concentration-response curves (CRCs) for NAd in the thoracic aortas of wild-type (WT) mice, the CRCs of mutant mice showed a significantly lower sensitivity. The pD(2) value in rank order is as follows: WT mice (8.21) > alpha(1B)-adrenoceptor knockout (alpha(1B)-KO) (7.77) > alpha(1D)-AR knockout (alpha(1D)-KO) (6.44) > alpha(1B)- and alpha(1D)-AR double knockout (alpha(1BD)-KO) (5.15). In the mesenteric artery, CRCs for NAd did not differ significantly between either WT (6.52) and alpha(1B)-KO mice (7.12) or alpha(1D)-KO (6.19) and alpha(1BD)-KO (6.29) mice. However, the CRC maximum responses to NAd in alpha(1D)- and alpha(1BD)-KO mice were significantly lower than those in WT and alpha(1B)-KO mice. Except in the thoracic aortas of alpha(1BD)-KO mice, the competitive antagonist prazosin inhibited the contraction response to NAd with high affinity. However, prazosin produced shallow Schild slopes in the vessels of mice lacking the alpha(1D)-AR gene. In the thoracic aorta, pA(2) values in WT mice for KMD-3213 and BMY7378 were 8.25 and 8.46, respectively, and in alpha(1B)-KO mice they were 8.49 and 9.13, respectively. In the mesenteric artery, pA(2) values in WT mice for KMD-3213 and BMY7378 were 8.34 and 7.47, respectively, and in alpha(1B)-KO mice they were 8.11 and 7.82, respectively. These pharmacological findings were in fairly good agreement with findings from comparison of CRCs, with the exception of the mesenteric arteries of WT and alpha(1B)-KO mice, which showed low affinities to BMY7378. We performed a quantitative analysis of the mRNA expression of each alpha(1)-AR subtype in these vessels in order to examine the correlation between mRNA expression level and the predominance of each alpha(1)-AR subtype in mediating vascular contraction. The rank order of each alpha(1)-AR subtype in terms of its vasoconstrictor role was in fairly good agreement with the level of expression of mRNA of each subtype, that is, alpha(1D)-AR > alpha(1B)-AR > alpha(1A)-AR in the thoracic aorta and alpha(1D)-AR > alpha(1A)-AR > alpha(1B)-AR in the mesenteric artery. No dramatic compensatory change of alpha(1)-AR subtype in mutant mice was observed in pharmacological or quantitative mRNA expression analysis.

Effects of neuropeptide Y on the blood pressure response to various vasoconstrictor agents.

Neuropeptide Y (NPY) is known to potentiate the pressor effect of norepinephrine. In the present work, we evaluated in unanesthetized normotensive rats the effect of NPY on blood pressure responsiveness not only to norepinephrine, but also to tyramine, a sympathomimetic agent acting indirectly to B-HT933, a selective alpha-2 adrenoceptor stimulant, to angiotensin II and vasopressin. Dose-response curves to the various pressor agents were established starting at the 45th min of an i.v. infusion with either NPY (0.025 and 0.1 microgram/min) or its vehicle. The two doses of NPY increased blood pressure by an average of approximately 6 mm Hg, which was not significantly different from the vehicle-induced blood pressure changes. NPY significantly enhanced the pressor effect of norepinephrine, tyramine and angiotensin II, but not that of B-HT933 and vasopressin. We also tested whether NPY inhibits the enzyme activity of Na, K-adenosine triphosphatase using a purified toad kidney preparation. Concentrations of NPY from 10(-14) M up to 10(-6) M had no effect on the enzyme activity. It appears therefore that the blood pressure potentiating effect of NPY is not restricted to alpha adrenoceptor stimulation with norepinephrine, but involves also the vasoconstrictor hormone angiotensin II. This NPY-induced potentiation does not seem to depend upon stimulation of alpha-2 adrenoceptors or inhibition of Na,K-adenosine triphosphatase.

Orpotrin: A novel vasoconstrictor peptide from the venom of the Brazilian Stingray Potamotrygon gr. orbignyi

Characterization of the peptide content of venoms has a number of potential benefits for basic research, clinical diagnosis, development of new therapeutic agents, and production of antiserum. In order to analyze in detail the peptides and small proteins of crude samples, techniques such as chromatography and mass spectrometry have been employed. The present study describes the isolation, biochemical characterization, and sequence determination of a novel peptide, named Orpotrin from the venom of Potamotrygon gr. orbignyi. The natural peptide was shown to be effective in microcirculatory environment causing a strong vasoconstriction. The peptide was fully sequenced by de novo amino acid sequencing with mass spectrometry and identified as the novel peptide. Its amino acid sequence, HGGYKPTDK, aligns only with creatine kinase residues 97-105, but has no similarity to any bioactive peptide. Therefore, possible production of this peptide from creatine kinase by limited proteolysis is discussed. Taken together, the results indicate the usefulness of this single-step approach for low molecular mass compounds in complex samples such as venoms. (c) 2006 Elsevier B.V. All rights reserved.

Vasoconstrictor effect of Africanized honeybee (Apis mellifera L.) venom on rat aorta

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Norepinephrine responses in rat renal and femoral veins are reinforced by vasoconstrictor prostanoids

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Alterations in vasoconstrictor responses to the endothelium-derived contracting factor uridine adenosine tetraphosphate are region specific in DOCA-salt hypertensive rats

Uridine adenosine tetraphosphate (Up(4)A) has been recently identified as a novel and potent endothelium-derived contracting factor and contains both purine and pyrimidine moieties, which activate purinergic P2X and P2Y receptors. The present study was designed to compare contractile responses to Up(4)A and other nucleotides such as ATP (P2X/P2Y agonist), UTP (P2Y(2)/P2Y(4) agonist), UDP (P2Y(6) agonist), and alpha,beta-methylene ATP (P2X(1) agonist) in different vascular regions [thoracic aorta, basilar, small mesenteric, and femoral arteries] from deoxycorticosterone acetate-salt (DOCA-salt) and control rats. In DOCA-salt rats [vs. control uninephrectomized (Uni) rats]: (1) in thoracic aorta, Up(4)A-, ATP-, and UP-induced contractions were unchanged; (2) in basilar artery, Up(4)A-, ATP-, UTP- and UDP-induced contractions were increased, and expression for P2X(1), but not P2Y(2) or P2Y(6) was decreased; (3) in small mesenteric artery, Up(4)A-induced contraction was decreased and UDP-induced contraction was increased; expression of P2Y(2) and P2X(1) was decreased whereas P2Y(6) expression was increased; (4) in femoral artery, Up(4)A-. UTP-, and UDP-induced contractions were increased, but expression of P2Y(2), P2Y(6) and P2X(1) was unchanged. The alpha,beta-methylene ATP-induced contraction was bell-shaped and the maximal contraction was reached at a lower concentration in basilar and mesenteric arteries from Uni rats, compared to arteries from DOCA-salt rats. These results suggest that Up(4)A-induced contraction is heterogenously affected among various vascular beds in arterial hypertension. P2Y receptor activation may contribute to enhancement of Up(4)A-induced contraction in basilar and femoral arteries. These changes in vascular reactivity to Up(4)A may be adaptive to the vascular alterations produced by hypertension. (C) 2011 Elsevier Ltd. All rights reserved.

Pain and swelling after periapical surgery related to the hemostatic agent used: anesthetic solution with vasoconstrictor or aluminum chloride

To assess pain and swelling in the first 7 days after periapical surgery and their relationship with the agent used for bleeding control.

Influence of hemostatic agents upon the outcome of periapical surgery: dressings with anesthetic and vasoconstrictor or aluminum chloride

OBJECTIVE To evaluate the effects of different hemostatic agents upon the outcome of periapical surgery. DESIGN A retrospective study was made of patients subjected to periapical surgery between 2006-2009 with the ultrasound technique and using MTA as retrograde filler material. We included patients with a minimum follow-up of 12 months, divided into two groups according to the hemostatic agent used: A) dressings impregnated in anesthetic solution with adrenalin; or B) aluminum chloride paste (Expasyl). Radiological controls were made after 6 and 12 months, and on the last visit. The global evolution scale proposed by von Arx and Kurt (1999) was used to establish the outcome of periapical surgery. RESULTS A total of 96 patients (42 males and 54 females) with a mean age of 40.7 years were included. There were 50 patients in the aluminum chloride group and 46 patients in the anesthetic solution with vasoconstrictor group. No significant differences were observed between the two groups in terms of outcome after 12 months - the success rate being 58.6% and 61.7% in the anesthetic solution with vasoconstrictor and aluminum chloride groups, respectively (p > 0.05). CONCLUSION The outcome after 12 months of follow-up was better in the aluminum chloride group than in the anesthetic solution with vasoconstrictor group, though the difference was not significant.

Differential involvement of N-type calcium channels in transmitter release from vasoconstrictor and vasodilator neurons

1 The effects of calcium channel blockers on co-transmission from different populations of autonomic vasomotor neurons were studied on isolated segments of uterine artery and vena cava from guinea-pigs. 2 Sympathetic, noradrenergic contractions of the uterine artery (produced by 200 pulses at 1 or 10 Hz; 600 pulses at 20 Hz) were abolished by the N-type calcium channel blocker omega-conotoxin (CTX) GVIA at 1-10 nM. 3 Biphasic sympathetic contractions of the vena cava (600 pulses at 20 Hz) mediated by noradrenaline and neuropeptide Y were abolished by 10 nM CTX GVIA. 4 Neurogenic relaxations of the uterine artery (200 pulses at 10 Hz) mediated by neuronal nitric oxide and neuropeptides were reduced < 50% by CTX GVIA 10-100 nM. 5 Capsaicin (3 muM) did not affect the CTX GVIA-sensitive or CTX GVIA-resistant neurogenic relaxations of the uterine artery. 6 The novel N-type blocker CTX CVID (100-300 nM), P/Q-type blockers agatoxin IVA (10-100 nM) or CTX CVIB (100 nM), the L-type blocker nifedipine (10 muM) or the 'R-type' blocker SNX-482 (100 nM), all failed to reduce CTX GVIA-resistant relaxations. The T-type channel blocker NiCl2 (100-300 muM) reduced but did not abolish the remaining neurogenic dilations. 7 Release of different neurotransmitters from the same autonomic vasomotor axon depends on similar subtypes of calcium channels. N-type channels are responsible for transmitter release from vasoconstrictor neurons innervating a muscular artery and capacitance vein, but only partly mediate release of nitric oxide and neuropeptides from pelvic vasodilator neurons.

Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update

The endothelium plays a vital role in maintaining circulatory homeostasis by the release of relaxing and contracting factors. Any change in this balance may result in a process known as endothelial dysfunction that leads to impaired control of vascular tone and contributes to the pathogenesis of some cardiovascular and endocrine/metabolic diseases. Reduced endothelium-derived nitric oxide (NO) bioavailability and increased production of thromboxane A2, prostaglandin H2 and superoxide anion in conductance and resistance arteries are commonly associated with endothelial dysfunction in hypertensive, diabetic and obese animals, resulting in reduced endothelium-dependent vasodilatation and in increased vasoconstrictor responses. In addition, recent studies have demonstrated the role of enhanced overactivation ofβ-adrenergic receptors inducing vascular cytokine production and endothelial NO synthase (eNOS) uncoupling that seem to be the mechanisms underlying endothelial dysfunction in hypertension, heart failure and in endocrine-metabolic disorders. However, some adaptive mechanisms can occur in the initial stages of hypertension, such as increased NO production by eNOS. The present review focuses on the role of NO bioavailability, eNOS uncoupling, cyclooxygenase-derived products and pro-inflammatory factors on the endothelial dysfunction that occurs in hypertension, sympathetic hyperactivity, diabetes mellitus, and obesity. These are cardiovascular and endocrine-metabolic diseases of high incidence and mortality around the world, especially in developing countries and endothelial dysfunction contributes to triggering, maintenance and worsening of these pathological situations.

Monitorização materno-fetal durante procedimento odontológico em portadora de cardiopatia valvar

FUNDAMENTO: Os efeitos da anestesia local em odontologia com lidocaína e epinefrina, sobre parâmetros cardiovasculares de gestantes portadoras de valvopatias e seus conceptos, não estão esclarecidos. OBJETIVO: Avaliar e analisar parâmetros da cardiotocografia, de pressão arterial e eletrocardiográficos da gestante portadora de doença valvar reumática, quando submetida à anestesia local com 1,8 ml de lidocaína 2% sem vasoconstritor e com epinefrina 1:100.000, durante procedimento odontológico restaurador. MÉTODOS: Realizamos monitorização ambulatorial da pressão arterial, eletrocardiografia ambulatorial materna e cardiotocografia de 31 portadoras de cardiopatia reumática, entre a 28ª e 37ª semana de gestação, divididas em dois grupos conforme presença ou não do vasoconstritor RESULTADOS: Demonstrou-se redução significativa dos valores de frequência cardíaca materna nos dois grupos, durante o procedimento, quando comparado aos demais períodos (p < 0,001). Houve ocorrência de arritmia cardíaca em 9 (29,0%) pacientes, das quais 7 (41,8%) pertencentes ao grupo de 17 gestantes que recebeu anestesia com adrenalina. A pressão arterial materna não apresentou diferença quando comparamos períodos ou grupos (p > 0,05). O mesmo ocorreu (p > 0,05) com número de contrações uterinas, nível e variabilidade da linha de base e número de acelerações da frequência cardíaca fetal. CONCLUSÃO: O uso de 1,8 ml de lidocaína 2% associado à adrenalina mostrou-se seguro e eficaz em procedimento odontológico restaurador durante a gestação de mulheres com cardiopatia valvar reumática.

Effectiveness of local anaesthetics with and without vasoconstrictors for perineal repair during spontaneous delivery: Double-blind randomised controlled trial

Objective: to investigate the use of local anaesthetics, in the presence or absence of vasoconstrictors, for perineal repair during spontaneous delivery. Design: double-blind, randomised-controlled trial. Setting: a birth centre, in the city of Sao Paulo, Brazil. Participants: from June to December 2004, a total of 96 women were allocated into three groups (first-degree perineal lacerations, second-degree perineal lacerations or episiotomy), and treated with local anaesthesia (1% lidocaine or 1% lidocaine with epinephrine) (n = 16 per treatment per group). Interventions: an initial local infiltration of the anaesthetic solution was given so that episiotomy could be carried out (5 ml) and to suture spontaneous lacerations (1 ml), followed by repeated doses (1 ml) until pain was completely inhibited. Measurements and findings: the main outcome measurement was the volume of anaesthetic used during episiotomy and perineal suture. Our data suggest that the concomitant use of the vasoconstrictor resulted in a significantly lower average volume used in the treatment of first-degree (1 ml, 95% confidence interval (0) 0.4-1.6) and second-degree (3.7 ml, 95% CI 1.6-5.8) lacerations (p = 0.002 and 0.001, respectively). A 0.3 ml (95% CI 1.5-2.1) average decrease in anaesthetic volume was observed with episiotomy (p = 0.724). The maximum volume of anaesthetic used with and without vasoconstrictor was 1-2 ml in 95% and 3-4 ml in 50% of first-degree lacerations, respectively, and 1-6 ml in 88% and 7-15 ml in 81% of second-degree lacerations, respectively. For episiotomy, the maximum dose was 15 ml, regardless of anaesthetic solution used. Key conclusions: our data confirm the hypothesis that the use of anaesthetics in conjunction with vasoconstrictors is more effective than anaesthetics alone in the repair of perineal lacerations, but not for episiotomy. (C) 2007 Elsevier Ltd. All rights reserved.

Lercanidipine reduces matrix metalloproteinase-2 activity and reverses vascular dysfunction in renovascular hypertensive rats

Increased expression/activity of matrix metalloproteinases (MMPs), especially MMP-2, plays a role in the vascular alterations induced by hypertension, and increased oxidative stress is a major factor activating MMPs. Here, we hypothesized that lercanidipine, a calcium channel blocker, could attenuate the increases in oxidative stress and MMP-2 expression/activity in the two-kidney, one-clip (2K-1C) hypertensive rats. Sham-operated or 2K-1C hypertension rats were treated with lercanidipine 2.5 mg/kg/day (or vehicle) starting three weeks after hypertension was induced. Systolic blood pressure was monitored weekly. After five weeks of treatment, aortic rings were isolated to assess endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall were studied in hematoxylin/eosin sections. Aortic MMP-2 levels were determined by gelatin zymography. Aortic MMP-2/tissue inhibitor of metalloproteinases (TIMP)-2 mRNA levels were determined by quantitative real-time RT-PCR. Plasma thiobarbituric acid reactive substances concentrations were determined using a fluorometric method. Lercanidipine attenuated 2K-1C hypertension (224 12 versus 183 11 mm Hg in 2K-1C rats and 2K-1C + Lercandipine rats, respectively; P < 0.01) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Increased MMP-2 and Pro-MMP-2 levels were found in the aortas of 2K-1C rats (all P < 0.05). Lercandipine attenuated 2K-1C-induced increases in MMP-2 by more than 60% and blunted 2K-1C-induced increases in oxidative stress (both P < 0.001). While hypertension-induced significant aortic wall hypertrophy and approximately 9-fold increases in the ratio of MMP-2MMP-2 mRNA expression (both P < 0.05), lercandipine did not affect these changes. These results suggest that lercanidipine produces antihypertensive effects and reverses the endothelial dysfunction associated with 2K-1C hypertension, probably through mechanisms involving antioxidant effects leading to lower MMP-2 activation. (C) 2008 Elsevier B.V. All rights reserved.