Evaluation of different metrics as an index for the assessment of arterial stiffness.

Elevated intravascular pressure is a contributing factor to increased arterial stiffness, and is a risk factor for cardiovascular morbidity and mortality. Assessment of arterial stiffness is of importance in evaluating cardiovascular risk. Pulse wave velocity (PWV) has been broadly used in the assessment of arterial stiffness. We compared three different metrics of arterial stiffness to PWV. Hemodynamic recordings were carried out in anesthetized hypertensive and normotensive rats (n = 25; 13-14 weeks old). Four parameters were calculated (PWV, elastic modulus (Einc), stiffness index (ß), and pressure-strain modulus (Ep)) as metrics of arterial stiffness. Hypertensive in comparison to normotensive rats had significantly higher systolic and diastolic blood pressures. Metric for arterial stiffness were significantly (p < 0.002) higher in hypertensive animals: PWV (8.46 ± 2.01 vs. 6.39 ± 1.28 m/s), Ep (0.246 ± 0.019 vs. 0.137 ± 0.010 dyn/cm2 × 10-6), Einc (17.5 ± 1.8 vs. 10.1 ± 0.9 dyn/cm2 × 10-6), and ß (2.43 ± 0.11 vs. 1.98 ± 0.08) (mean±SE). Bland-Altman analysis revealed ß as the only metric aligned with PWV in hypertensive state. We find in state of reduced arterial compliance associated with high systemic pressure, ß but not Einc or Ep is an index of arterial stiffness showing agreement with PWV.

Angiotensin II control of regional haemodynamics in rats with aortocaval fistula.

NEW FINDINGS: What is the central question of this study? Hyperdynamic circulation because of arteriovenous fistula results in reduction of blood flow to organs but is a model of low circulatory resistance with activated renin-angiotensin system. The aim was to determine contributions of different subtypes of angiotensin II receptors to regional blood flow and vascular conductance in a hyperdynamic circulatory state. What is the main finding and its importance? The renin-angiotensin system plays a pivotal role in control of regional blood flow in animals with arteriovenous fistula and makes a major contribution to the maintenance of normal arterial blood pressure. In this hyperdynamic circulatory state model, angiotensin II type 1 receptors predominated in regulating regional haemodynamics. Regional perfusion is reduced and the renin-angiotensin system activated in rats with aortocaval fistula. The effects of captopril (angiotensin-converting enzyme inhibitor), losartan (angiotensin II type 1 receptor antagonist) and PD 123319 (angiotensin II type 2 receptor antagonist) on regional blood flow and vascular conductance were assessed in rats with aortocaval fistula and sham-operated rats. Control of blood flow and vascular conductance by angiotensin II was evaluated by serial bolus injections of captopril, losartan and PD 123319 in anaesthetized rats. In rats with fistula, PD 123319 significantly decreased, whereas captopril and losartan increased, mesenteric blood flow. The decrease in mesenteric blood flow induced by PD 123319 was significantly greater in rats with fistula compared with sham operation. Captopril and PD 123319 significantly decreased renal blood flow compared with losartan, which increased it. In sham-operated rats, captopril and losartan significantly increased, whereas PD 123319 decreased, mesenteric and renal conductance. In rats with fistula, captopril and losartan significantly increased, whereas PD 123319 decreased, mesenteric conductance. The significant increase produced by losartan on mesenteric conductance was greater in rats with fistula compared with sham operation. PD 123319 produced a significantly greater decrease in renal conductance of rats with aortocaval fistula compared with sham-operated rats. Captopril, losartan and PD 123319 did not significantly affect perfusion in the hindquarter in rats with fistula or sham-operated. The renin-angiotensin system is more active in the control of regional haemodynamics in rats with aortocaval fistula and acts as a mechanism of maintaining normal arterial blood pressure in these animals. In rats with fistula, angiotensin II type 1 receptors predominate in regulating regional haemodynamics.

Effects of vasoactive substances on biomechanics of small resistance arteries of male and female Dahl salt-sensitive rats.

Changes in vascular biomechanics leading to increase in arterial stiffness play a pivotal role in circulatory dysfunction. Our objectives were to examine sex-specific pharmacological changes related to the biomechanics and any structural modifications in small resistance arteries of Dahl salt-sensitive male and female rats. The composite Young modulus (CYM) was determined using pressure myograph recordings, and immunohistochemistry was used for the evaluation of any structural changes in the third-order mesenteric arteries (n = 6). Animals on high-salt diet developed hypertension with significant elevation in central and peripheral blood pressures and pulse wave velocity compared to those on regular diet. There were no significant differences observed in the CYM between any of the groups (i.e., males and females) in vehicle-treated time-control studies. The presence of verapamil (0.3 µM) significantly reduced CYM in hypertensive males without changes within females compared to vehicle. This effect was abolished by phenylephrine (0.3 µM). BaCl2 (100 µM), ouabain (100 µM), and L-NAME (0.3 µM) combined significantly increased CYM in vessels from in normotensive males and females but not in hypertensive males compared to vehicle. The increase in CYM was abolished in the presence of phenylephrine. Sodium nitroprusside (0.3 µM), in the presence of phenylephrine, significantly reduced CYM in male normotensive versus hypertensive, with no differences within females. Significant differences were observed in immunohistochemical assessment of biomechanical markers of arterial stiffness between males and females. Our findings suggest sex possibly due to pressure differences to be responsible for adaptive changes in biomechanics, and varied pharmacological responses in hypertensive state.

Sex differences in vascular endothelial function related to acute and long COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been at the forefront of health sciences research since its emergence in China in 2019 that quickly led to a global pandemic. As a result of this research, and the large numbers of infected patients globally, there were rapid enhancements made in our understanding of Coronavirus disease 2019 (COVID-19) pathology, including its role in the development of uncontrolled immune responses and its link to the development of endotheliitis and endothelial dysfunction. There were also some noted differences in the rate and severity of infection between males and females with acute COVID. Some individuals infected with SARS-CoV-2 also experience long-COVID, an important hallmark symptom of this being Myalgic Encephalomyelitis-Chronic Fatigue Syndrome (ME-CFS), also experienced differently between males and females. The purpose of this review is to discuss the impact of sex on the vasculature during acute and long COVID-19, present any link between ME-CFS and endothelial dysfunction, and provide evidence for the relationship between ME-CFS and the immune system. We also will delineate biological sex differences observed in other post viral infections and, assess if sex differences exist in how the immune system responds to viral infection causing ME-CFS.

Genetic Variants of the Beta-Adrenergic Receptor Pathways as Both Risk and Protective Factors for Retinopathy of Prematurity.

PURPOSE: There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in ß-adrenergic receptor (ADRß) pathways could protect against ROP. Antagonists for the ADRß are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADRß signaling pathways associate with risk of developing ROP. DESIGN: An observational case-control targeted genetic analysis. METHODS: A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADRß pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort. RESULTS: The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADRß pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1α (PRKAR1A), rap guanine exchange factor 3 (RAPGEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP (P < .05). The most significant SNV was found in PRKAR1A (P = .001). Multiple variants located in the 3'-untranslated region (3'UTR) of RAPGEF3 were also associated with ROP (P < .05). PCR/restriction enzyme analysis of the 3'UTR of RAPGEF3 methodologically validated these findings. CONCLUSION: SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPGEF3 may represent risk factors for ROP. PRKAR1α has previously been implicated in retinal vascular development whereas the RAPGEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP.

Analysis of the cardiac effects of sodium-glucose co-transporter 2 inhibitors in animals without diabetes and a clinical perspective.

Emerging evidence points to a positive impact of sodium glucose co-transporter 2 (SGLT-2) inhibitors on cardiac structure and function, acutely (as early as 15 days) and chronically (up to 2 years). Accordingly, data from clinical studies appear to support the beneficial effects of this class of drugs on the cardiovascular system. However, the extent to which such effects may directly and/or indirectly be responsible for the beneficial actions of this class of drugs remains unclear. Based on the data in the literature, the actions of SGLT-2 inhibitors on the cardiac tissue in the absence of SGLT-2 co-transporter sites would suggest possible direct effects on calcium/calmodulin-dependent kinase II (CaMKII), voltage-gated, Nav1.5 channels and sodium-calcium exchanger 1 (NCX1), Na+/H+ exchanger (NHX), the late INa associated with calcium transient, the rapid (IKr) and slow (IKs) delayed rectifier K+ currents, phosphorylated levels of myofilament regulatory proteins, xanthine oxidase activity and sarco(endo)plasmic reticulum calcium ATPase and/or intracellular, and/or possible genomic sites in the cardiac myocytes. Collectively, the experimental and clinical evidence as to the effects of SGLT-2 inhibitors on cardiac and vascular tissues appear multifaceted in nature with no consensus for definitive site(s) of actions. It is clear that further investigations both in animals and humans, in vitro and in vivo are needed to shed more light on the true nature of the pharmacological actions of this class of compounds, and the extent of their beneficial effects as reported in a population with heart failure.

Influence of hyperpolarization caused by high salt diet on ß-adrenoceptor-mediated responses in rat pulmonary artery.

The effect of high salt diet on ß-adrenoceptor-mediated response was assessed in rat-isolated pulmonary arteries. Isoprenaline-induced relaxations were not different in tissues from rats on either, high salt or regular diets. However, acidic buffer (pH 6.4) alone and in combination with Ba2+ or Nω-nitro-L-arginine methyl ester (L-NAME) significantly attenuated isoprenaline-induced relaxations in tissues from rats on high salt compared with those on a regular diet. Also, Ba2+ and ouabain together produced a significantly greater inhibition of isoprenaline-induced relaxation in tissues from rats on high salt when compared with those on the regular diet. The resting membrane potential of smooth muscle cells of pulmonary arteries of rats on high salt diet compared with regular diet was more negative (ie, hyperpolarized) than that on the regular diet. This hyperpolarization was reversed on exposure of blood vessels to acidic buffer and/or Ba2+ and ouabain combined but not L-NAME. Treatment with isoprenaline did not cause further hyperpolarization of smooth muscle cells of arteries from rats on the high salt diet. Taken together, the electrical changes due to the high salt diet can be attributed to the opening of K+ channels (2 pore acid-sensitive K+ channels and K(ir2.1)) and the activation of Na+/K+-ATPase. Furthermore, hyperpolarization observed after consumption of high salt diet seems to preserve ß-adrenoceptor-mediated vasorelaxation.

Pharmacognosy and Effects of Cannabinoids in the Vascular System.

Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.

Differential biomechanics in resistance arteries of male compared with female Dahl hypertensive rats.

BACKGROUND: Increase in vascular stiffness is associated with a higher risk of cardiovascular morbidity and mortality and is likely sex-specific. METHOD: Our objectives were to compare structural and functional alterations in small resistance arteries as related to vascular stiffness from Dahl salt-sensitive male and female rats (n = 8, mean ±â€Šs.e.m.). RESULTS: Arterial blood pressure and pulse wave velocity were significantly (P < 0.05) elevated in males (161 ±â€Š3 mmHg; 6.4 ±â€Š0.2 m/s) and females (147 ±â€Š2 mmHg; 5.5 ±â€Š0.1 m/s) on a high (H) salt compared with regular (R) diets but were significantly higher in males (H) than in all others. Significant increases in collagen and smooth muscle cell areas were evident in ultrastructure of mesenteric arteries of hypertensive males compared to normotensive or corresponding females. There were no significant differences in composite Young's modulus (CYM) between groups. Vasoconstriction resulted in significantly higher CYM in male (H: 8.6 ±â€Š1 KPa) than R (4.5 ±â€Š0.8 KPa), and the corresponding females (H: 5.6 ±â€Š0.6 KPa and R: 5 ±â€Š0.9 KPa). In contrast, vasodilation significantly reduced CYM in the male groups (H: 2.5 ±â€Š0.4 KPa and R: 2.7 ±â€Š0.5 KPa) compared with the corresponding values in females (H: 4.2 ±â€Š0.6 KPa and R: 5 ±â€Š0.5 KPa). Moreover, the slope of pressure-volume curves revealed significantly greater distended vascular compliance in male H than R, and the corresponding females. CONCLUSION: Our findings are supportive of a link between high salt intake and elevated blood pressure as being sex specific, likely involving sex-dependent changes in ultrastructure of the vessels, which ultimately may alter the biomechanics, and thus, the haemodynamic functions of both macro-circulation and micro-circulations.

Molecular mechanisms of adverse drug reactions in cardiac tissue.

The myocardium is the target of toxicity for a number of drugs. Based on pharmacological evidence, cellular targets for drugs that produce adverse reactions can be categorized into a number of sites that include the cell membrane-bound receptors, the second messenger system, ionic channels, ionic pumps, and intracellular organelles. Additionally, interference with the neuronal input to the heart can also present a global site where adverse drug effects can manifest themselves. Simply, a drug can interfere with the normal cardiac action by modifying an ion channel function at the plasma membrane level leading to abnormal repolarization and/or depolarization of the heart cells thus precipitating a disruption in the rhythm and causing dysfunction in contractions and/or relaxations of myocytes. It is now recognized that toxic actions of drugs against the myocardium are not exclusive to the antitumor or the so-called cardiac drugs, and many other drugs with diverse chemical structures, such as antimicrobial, antimalarial, antihistamines, psychiatric, and gastrointestinal medications, seem to be capable of severely compromising myocardium function. At present, great emphasis in terms of drug safety is being placed on the interaction of many classes of drugs with the hERG potassium channel in cardiac tissue. The interest in the latter channel stems from the simplified view that drugs that block the hERG potassium channel cause prolongation of the QT interval, and this can cause life-threatening cardiac arrhythmias. Based on the evidence in the current literature, this concept does not seem to always hold true.

Ilepatril (AVE-7688), a vasopeptidase inhibitor for the treatment of hypertension.

sanofi-aventis (formerly Aventis Pharma AG) is developing ilepatril (AVE-7688), a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, for the potential treatment of hypertension and diabetic nephropathy. Ilepatril is currently in phase IIb/III clinical trials for hypertension and phase II trials for diabetic nephropathy. The company had planned to file for approval for the use of ilepatril for hypertension in 2010. Ilepatril was previously being developed for cardiac failure; however, the compound was not listed on Aventis's 2003 pipeline.

Haemodynamic effects of vasoactive agents following chronic state of high cardiac output in anaesthetized rats.

The arteriovenous fistula model of circulation can produce a high output and low peripheral resistance situation. Here, we have examined the effects of noradrenaline, vasopressin and sodium nitroprusside on cardiac index, mean arterial blood pressure, venous tone, resistance to venous return, arterial resistance, and blood volume in chronically shunted anaesthetized rats. The cardiac index of rats with chronic arteriovenous fistula (AVF) was significantly higher (36.65+/-2.28 ml/min per 100 g; (mean+/-S.E.M.; n=24) in comparison to sham-operated rats (20.04+/-0.86 ml/min per 100 g; mean+/-S.E.M.; n=8). Cardiac index did not significantly change during the infusion of noradrenaline (1.0, 3.0 and 10 microg/kg per min), vasopressin (10, 30, 100 ng/kg per min) or sodium nitroprusside (0.1, 0.3 and 1.0 microg/kg per min) compared to saline infusion in AVF animals. Infusion of noradrenaline significantly increased heart rate, dP/dt, mean circulatory filling pressure (Pmcf) and resistance to venous return without affecting mean arterial blood pressure when compared to saline infusion. Administration of vasopressin significantly increased dP/dt, mean arterial blood pressure, and Pmcf without affecting heart rate, resistance to venous return or arterial resistance compared to saline infusion. Infusion of sodium nitroprusside did not significantly affect any haemodynamic parameter measured when compared to saline infusion. The results indicate that the presence of chronic AVF alters responsiveness of the various segments of the circulatory system to vasoactive agents. Moreover, it produces a major impediment to overall changes that can normally be induced following the infusion of such agents.

Transmural pressure and membrane potential in human saphenous vein.

OBJECTIVE: An increase in transmural pressure reportedly depolarizes myocytes in various arterial blood vessels. We have examined the relationship between transmural pressure and membrane potential (E(m)) in human saphenous veins with a view to determine whether contractile force generation, hence spasmogenesis in vein grafts, involves a similar process of mechanoelectrical excitation. METHODS: Intracellular recordings were made by sharp glass microelectrodes in human isolated saphenous veins and parallel measurements were performed in ring preparations. RESULTS: E(m) values obtained in pressurized vessels at four different pressure levels were (mean+/-SD): -74.4+/-5.5 mV (0-6 cm H(2)O; n=10), -72.6+/-6.5 mV (11-14 cm H(2)O; n=27), -72.1+/-6.5 mV (26-27 cm H(2)O; n=30), and -72.9+/-4.0 mV (50-54 cm H(2)O; n=38), demonstrating the lack of an overt pressure-dependence. Except at the lowest transmural pressure tested, these values were significantly different from E(m) obtained in ring preparations (-77.8+/-4.0 mV; n=30). Raising extracellular K(+) to 80 mM produced a comparable depolarization in tissues either pressurized to 50-54 cm H(2)O (-64.9+/-4.3 mV; n=27) or set up as ring preparations (-64.06+/-6.9 mV; n=35). CONCLUSIONS: Human saphenous veins respond to transmural pressure with a limited depolarization that lacks correlation with pressure. The absence of a pressure-induced graded depolarization suggests that pressure-dependent vasoconstriction does not play a primary role in blood flow regulation in lower limb large veins. Moreover, this raises doubts that mechanical stimuli per se would lead to development of vasospasm in the early stages of saphenous vein grafting into arterial vascular beds.

Role of ß2- and ß3-adrenoceptors in arterial stiffness in a state of hypertension.

An increase in arterial stiffness is associated with a high risk for morbidity and mortality in a state of elevated systemic pressure. The sympathetic nervous system plays an important role in the regulation of vascular tone via activation of ß-adrenoceptors. The aim of this investigation was to determine the involvement of ß-adrenoceptors in the control of arterial stiffness in a state of hypertension versus normotension. Pulse wave velocity (PWV), an index of vascular stiffness, was assessed in isoflurane-anaesthetized 13-14-week-old male spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats. At baseline, PWV was significantly higher in SH (9.2±0.9m/s) compared to WKY rats (6.7±0.4m/s). The stimulation of ß2- but not ß3-adrenoceptors significantly reduced PWV in SH rats despite comparable reductions in blood pressure. Stimulation of ß2- or ß3-adrenoceptors did not reduce PWV in WKY rats. The administration of sodium nitroprusside (SNP) also significantly reduced PWV in SH but not WKY rats. Immunofluorescence revealed the expression of ß2- and ß3-adrenoceptors in endothelial cells and vascular smooth muscle cells of the abdominal aorta. There were no significant differences in the distribution of the expression of ß2- and ß3-adrenoceptors in endothelial and/or smooth muscle cells in blood vessels of SH compared to WKY rats. The evidence suggests that ß2-adrenoceptor stimulation and SNP infusion reduce PWV independently from reduction in blood pressure in a state of high systemic arterial pressure. A reduction in vascular tone of the central arteries may play a key role in decreasing PWV that is elevated due to stiffer arterial wall.

Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The activation of PPAR-gamma, an isotype of PPARs, can either increase or decrease the transcription of target genes. The genes controlled by this form of PPAR have been shown to encode proteins or peptides that participate in the pathogenesis of insulin resistance. Insulin resistance is defined as a state of reduced responsiveness to normal circulating concentrations of insulin and it often co-exists with central obesity, hypertension, dyslipidemia, and atherosclerosis. There is substantial evidence that links obesity with insulin resistance and type-2 diabetes. The early phase of obesity-related insulin resistance has 2 components: (a) interruption of lipid homeostasis leading to the increased plasma concentration of fatty acids that is normally suppressed by the activation of PPAR-gamma, and (b) activation of factors such as cytokines depressed by PPAR-gamma that cause insulin resistance. Therefore, it is logical to suggest that activation of PPAR-gamma may partially reverse the state of insulin resistance. Evidently, activation of the nuclear receptor, PPAR-gamma, by thiazolidinediones has been reported to ameliorate insulin resistance. Although hepatotoxity and possibility to induce congestive heart failure (CHF) limit the widely use of thiazolodinediones, they are still powerful weapon to fight against insulin resistance and type-2 diabetes if use properly. This article reviews the physiology of PPAR-gamma and insulin-signaling transduction, the pathogenesis of insulin resistance in obesity-related type-2 diabetes, the pharmacological role of PPAR-gamma in insulin resistance, and additional effects of thiazolidinediones.

beta-adrenoceptor mediated responses in rat pulmonary artery: putative role of TASK-1 related K channels.

The effect of isoprenaline on tone, cyclic adenosine 3':5' monophosphate (cAMP), and smooth muscle membrane potential (E ( m )) were assessed in rat isolated pulmonary arteries. N(omega)-nitro-L-arginine methyl ester (10.0 microM) or removal of endothelium partially inhibited relaxant responses to isoprenaline, but glibenclamide (10.0 microM) and indomethacin (10.0 microM) did not. While Rp-8-Br-cAMP (30.0 microM), tetraethylammonium (0.3 & 1.0 mM), 4-aminopyridine (100 microM), anandamide (10.0 microM), charybdotoxin (0.1 microM), ouabain (100 microM), and barium chloride (100 microM), incompletely blocked relaxation to isoprenaline, cyclopiazonic acid (1.0 microM), apamin (3.0 microM) and zinc acetate (300 microM) were without effect. Increasing extracellular K(+) ([K(+)](e)) inhibited relaxant responses to isoprenaline, completely abolishing the response at 30 mM [K+](e). Vasorelaxant effects of isoprenaline were significantly attenuated in buffer pH 6.4, and concomitant presence of Rp-8-Br-cAMP (30.0 microM) in pH 6.4 produced significant additive inhibition when compared to pH 6.4 without Rp-8-Br-cAMP. Isoprenaline increased cAMP turnover (1.55+/-0.24 fold; mean +/- SEM), which was inhibited by propranolol (1.0 microM). Resting E ( m ) of smooth muscle cells was -63.0+/-0.50 mV, and isoprenaline (1.0 microM) produced hyperpolarisation (-73.3+/-0.80 mV). While glibenclamide failed to affect isoprenaline-induced hyperpolarisation, ICI 118,551 (1.0 microM), anandamide or buffer pH 6.4 prevented it, and barium chloride and oubain combined caused partial inhibition. Isoprenaline-mediated relaxation seems to arise from several processes, including the generation of nitric oxide, the cAMP-cascade and, more importantly, a hyperpolarisation that is not due to activation of ATP-sensitive K channels but possibly of two-pore domain K channels of the TASK family.

Influence of tangential stress on mechanical responses to vasoactive agents in human saphenous vein with and without perivascular adipose tissue.

AIM: Improvement in short-term patency of vein grafts harvested with the surrounding tissue and no distention has been noted. The influence of transient tangential stress on mechanical function to vasoactive agents in isolated human saphenous veins stripped or with attached perivascular adipose tissue was assessed. METHODS: Concentration-response curves to noradrenaline, 5-hydroxytryptamine, methylcholine, sodium nitroprusside and nicardipine were constructed for veins exposed to no, low (approximately 120 mmHg) or high (approximately 240 mmHg) tangential stress. RESULTS: Tangential stress did not affect contractile effects of noradrenaline or relaxant effects of methylcholine and sodium nitroprusside. Regression analysis of the concentration-response curve to 5-hydroxytryptamine revealed a significant (P=0.042) increase in sensitivity in saphenous veins without perivascular adipose tissue exposed to no tangential stress, compared with veins with attached adipose tissue. Exposure to high stress significantly (P=0.024) increased the potency of 5-hydroxytryptamine in blood vessels without perivascular adipose tissue, as opposed to veins with adipose tissue. Relaxant responses to nicardipine in veins with perivascular adipose tissue were significantly (P=0.001) affected by exposure to low tangential stress compared with no or high tangential stress. A parallel comparison revealed that intact veins compared with those without perivascular adipose tissue exposed to low stress were significantly (P=0.020) more resistant to the relaxant effects of nicardipine. CONCLUSION: The findings of the present report support the view that tangential stress has an impact on the actions of vasoactive agents, but this influence is variable and factor(s) released from perivascular adipose tissue may have a bearing on the observed effect.

The effect of inflammation on sympathetic nerve mediated contractions in rat isolated caudal artery.

Chronic inflammatory process(es) contributes to changes in vascular function in a variety of diseases. Sympathetic nerve-mediated responses in blood vessels play a pivotal role in regular physiological functions. We tested the hypothesis that sympathetic neuro-effector function will be altered as consequence of inflammatory state. Sympathetic nerve-mediated contractions and alpha adrenergic receptor expressions were evaluated in isolated caudal arteries of rats treated with saline and Complete Freund's adjuvant (CFA). While CFA-treated animals had significantly higher plasma levels of tumor necrosis factor-alpha compared to saline, blood pressure remained unchanged. Immunofluorescence revealed increased expression of ionized calcium adapter binding molecule-1 in the adventitia of blood vessels from CFA-treated animals compared to saline. In isolated arteries, electrical field stimulations between 1.25 and 40Hz resulted in frequency-dependent contractions that wasabolished by tetrodotoxin. Neurogenic contractions from CFA groups were significantly greater than saline. While the presence of alpha1-adrenoceptor antagonist (prazosin) significantly inhibited contractions at lower frequencies of stimulation (1.25-5Hz) in isolated arteries of CFA-treated rats compared to controls, alpha2-adrenoceptor antagonist (rauwolscine) had modest effects. Inhibition of neuronal reuptake by cocaine comparably enhanced field-stimulated responses in vessels of experimental and control animals. Immunofluorescence revealed a difference in expression of alpha1- and alpha2-adrenoceptors in the endothelium of blood vessels of CFA compared to saline controls. Collectively, our observations lend support to enhanced neurogenic contractions in blood vessels of inflamed animals possibly attributing to alterations in responsiveness and/or distribution of post-junctional alpha1-adrenoceptors.