Response Of Vascular Smooth Muscle Research Articles

Cryptostrobin and catechin isolated from Eugenia mattosii D. Legrand leaves induce endothelium-dependent and independent relaxation in spontaneously hypertensive rat aorta.

Considering the therapeutic potential of phenolic compounds, the purpose of the present study was to investigate the mechanisms involved in the relaxation induced by cryptostrobin and catechin, isolated from Eugenia mattosii D. Legrand leaves, in the aorta of spontaneously hypertensive rats (SHR). The thoracic aorta was isolated from SHR and kept in the organ bath system by recording contractile or relaxant responses. The addition of cumulative concentrations of cryptostrobin and catechin induced endothelium-dependent and-independent relaxation in aorta rings from SHR, as well as both compounds were effective in reducing phenylephrine-induced contraction. Pretreatment of aortic rings with Nω-nitro-l-arginine methylester (L-NAME, an inhibitor of nitric oxide synthase) or 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, an inhibitor of soluble guanylate cyclase), resulted in a significant change of relaxant effect induced by catechin, and a slight influence on cryptostrobin-induced relaxation. Muscarinic receptor and potassium channels are involved in catechin-induced relaxation as assessed using atropine (a muscarinic receptor antagonist), tetraethylammonium (a non-selective K+ channel blocker) and glibenclamide (an ATP-sensitive K+ channel blocker). Conversely, cryptostrobin, but not catechin, blunted the contraction induced by the addition of phenylephrine in a calcium-free solution. Besides that, cryptostrobin attenuated the contraction of rat aorta rings induced by internal Ca2+ release and external Ca2+ influx. These findings indicated that cryptostrobin and catechin alter vascular smooth muscle reactivity, and this effect may be involved, at least in part, by enhancing the endothelium NO/cGMP pathway and potassium channels activation. In addition, cryptostrobin reduced the phenylephrine, KCl and CaCl2-induced contractions in a calcium-free solution.

Ventilasi dan Perfusi, serta Hubungan antara Ventilasi dan Perfusi

Lung is a place for gas exchange where ventilation and perfusion occurs. Ventilation is the first step where sequential process of inhalation and exhalation take place. Meanwhile perfusion as the other step facilitates the gas exchange and tissue supply need. Blood flows through the lungs are equals as the amount of cardiac output where the factors that control cardiac output are mainly peripheral factors, also control pulmonary blood flow. In general condition, pulmonary blood vessels act as a passive tube, which can be increased with the increasing pressure and narrowed the pressure drop. Oxygen absorption level from lungs into bloodstream is a critical determinant for functional capacity, and an important factor wheter in normal conditions (including exercise) or even in illness state. Lung diffusion capacity is influenced by several geometric and functional factors. Gravitation influence systematic gradient in ventilation and perfusion distribution. Ventilation and blood flow variations at horizontal level also occur due to intrinsic anatomic variations and vascular geometry, as well as the differences in airway and vascular smooth muscle response which modifies the distribution. The change of integrity intrapleural chamber, hydrostatic pressure and osmotic imbalance, malfunction of surfactants, other intrinsic weakness of the branching system in the form of a progressive airway, and all the things that could potentially damage the structure of the lung can cause ventilation and diffusion dysfunction.

Paying the Toll for Inflammation

Paying the Toll for Inflammation

CME Accreditation Page

Meconium aspiration syndrome (MAS) is a major cause of respiratory insufficiency in the term and post-term newborns. There are several pathomechanisms participating in this disorder, particularly the airway obstruction, surfactant dysfunction, inflammation, lung edema, pulmonary vasoconstriction and bronchoconstriction. Inflammatory changes resulting from meconium aspiration cause severe impairment of lung parenchyma and surfactant, and influence the reactivity of both vascular and airway smooth muscle. Therefore, anti-inflammatory drugs may be of benefit in the management of MAS. This article reviews the pharmacological actions and side effects of various anti-inflammatory drugs used up to now in the experimental models of MAS and in the treatment of newborns with meconium aspiration.

Sustained exercise hyperemia during prolonged adenosine infusion in humans.

The contribution of Adenosine (ADO) to exercise hyperemia remains controversial and it is unknown whether ADO can evoke the prolonged vasodilation seen during exercise bouts. Therefore, we tested hypotheses in the human forearm during 3 h of intra‐arterial high dose ADO infusion: (1) skeletal muscle blood flow would wane over time; (2) exercise hyperemic responses during ADO administration would be unaffected compared to baseline. Using sodium nitroprusside (SNP), we tested parallel hypotheses regarding nitric oxide (NO) in a separate group of participants. Seventeen young healthy participants (ADO: n = 9; SNP: n = 8) performed multiple rhythmic handgrip exercise bouts (20% of maximum), two during saline and five during 3 h of continuous drug infusion. Five minutes of ADO infusion resulted in a ~5‐fold increase in forearm vascular conductance (FVC; 4.8 ± 0.6 vs. 24.2 ± 3.2 mL/min/100 mmHg, P < 0.05). SNP caused a ~4‐fold increase (4.4 ± 0.6 vs. 16.6 ± 2 mL/min/100 mmHg, P < 0.05). FVC did not wane over time with ADO (24.2 ± 3.2 and 22 ± 1.2 mL/min/100 mmHg [P > 0.05]) or SNP (16.6 ± 2 and 14.1 ± 2.4 mL/min/100 mmHg [P > 0.05]) at 5 versus 150 min. Superimposed exercise during ADO or SNP infusions evoked marked and consistent additional dilation over the course of the infusions. Our findings demonstrate that in humans there is no reduction in endothelial or vascular smooth muscle responsiveness to the exogenous vasodilatory metabolites ADO and NO. Additionally, even in the presence of an exogenous vasodilator, superimposed exercise can cause significant hyperemia.

The effect of intrauterine growth restriction on Ca2+ -activated force and contractile protein expression in the mesenteric artery of adult (6-month-old) male and female Wistar-Kyoto rats.

Intrauterine growth restriction (IUGR) is known to alter vascular smooth muscle reactivity, but it is currently unknown whether these changes are driven by downstream events that lead to force development, specifically, Ca2+‐regulated activation of the contractile apparatus or a shift in contractile protein content. This study investigated the effects of IUGR on Ca2+‐activated force production, contractile protein expression, and a potential phenotypic switch in the resistance mesenteric artery of both male and female Wistar‐Kyoto (WKY) rats following two different growth restriction models. Pregnant female WKY rats were randomly assigned to either a control (C; N = 9) or food restriction diet (FR; 40% of control; N = 11) at gestational day‐15 or underwent a bilateral uterine vessel ligation surgery restriction (SR; N = 10) or a sham surgery control model (SC; N = 12) on day‐18 of gestation. At 6‐months of age, vascular responsiveness of intact mesenteric arteries was studied, before chemically permeabilization using 50 μmol/L β‐escin to investigate Ca2+‐activated force. Peak responsiveness to a K+‐induced depolarization was decreased (P ≤ 0.05) due to a reduction in maximum Ca2+‐activated force (P ≤ 0.05) in both male growth restricted experimental groups. Vascular responsiveness was unchanged between female experimental groups. Segments of mesenteric artery were analyzed using Western blotting revealed IUGR reduced the relative abundance of important receptor and contractile proteins in male growth restricted rats (P ≤ 0.05), suggesting a potential phenotypic switch, whilst no changes were observed in females. Results from this study suggest that IUGR alters the mesenteric artery reactivity due to a decrease in maximum Ca2+‐activated force, and likely contributed to by a reduction in contractile protein and receptor/channel content in 6‐month‐old male rats, while female WKY rats appear to be protected.

TRPV4 activation in rat carotid artery in DOCA hypertension involves eNOS and endothelium-derived contractile factor (EDCF)

ABSTRACTAim: Role of TRPV4 channel in regulation of endothelial function in the carotid artery in deoxycorticosterone acetate (DOCA) model of hypertension in rat was studied.Methods: 8–10 weeks old albino Wistar rats divided into three groups namely Control, UNX and hypertensive animals. Vascular smooth muscle response was studied in isolated carotid artery of rat with acetylcholine, sodium nitroprusside, GSK1016790A (GSK) in presence and absence of L-NAME and indomethacin.Results: At the end of the 6th week, the mean systolic blood pressure was increased in DOCA-treated hypertensive rats (166 ± 8 mm Hg) compared to Control and UNX (125 ± 5 mm Hg). ACh (10–9 to 10–5 M) produced almost 100% relaxation in Control (Emax = 97.48 ± 1.06 %) and UNX animals (Emax = 93.16 ± 2.33 %) which was attenuated in DOCA-treated hypertensive animals (Emax = 70.85 ± 1.65 %). No significant changes seen in SNP (10–12 to 10–5 M) induced relaxation. GSK1016790A (10–12 to 10–7 M)-mediated relaxation was significantly attenuated in DOCA-treated hypertensive animals (Emax = 25.58 ± 13.60%) compared to the control (Emax = 80.59 ± 6.86%) and UNX (Emax = 87.32 ± 2.01%) animals. L-NAME (10–4 M) potently blocked GSK-induced relaxation, and a contractile response to GSK was observed in presence of L-NAME in all the three groups of animals which was sensitive to indomethacin (10–5 M).Conclusion: TRPV4 may regulate the vascular tone of rat carotid artery through an attenuated NO pathway and stimulation of the release of contractile prostanoids in the DOCA hypertensive rats.

Effect of reperfusion on vascular smooth muscle reactivity in three contraction models

BackgroundIschemia and reperfusion remain inseparable elements of numerous medical procedures such as by-pass surgery, organ transplantation or other cardiology and intervention radiology. The contraction of the smooth muscle of the vessel is considered to be one of the basic components leading to impaired perfusion, an increase in the oxygen deficit of the endothelium of the vessel, and subsequently also to tissues vascularized by the vessel.Main aim of this study was to evaluate the effect of ischemia and reperfusion on vascular smooth muscle cells stimulated pharmacologically with mastoparan-7 (direct G-protein activator) in comparison to stimulation of G-protein coupled receptor agonist - phenylephrine, and direct calcium channel activator - Bay K8644. Material and methodsExperiments were performed on isolated and perfused tail artery of Wistar rats. Contraction force in our model was measured by increased level of perfusion pressure with a constant flow. ResultsConcentration-response curves obtained for phenylephrine, mastoparan-7 and Bay K8644 presented a sigmoidal relation. Ischemia induced hyporreactivity of vessels, whereas during reperfusion the significant time related hyperreactivity for phenylephrine and mastoparan-7 only but not for Bay K8644. These reactions were secondary to the modulation of calcium influx from intra- and extracellular calcium stores. ConclusionsResults of our experiments suggest that mastoparan-7 significantly induces contraction of vascular smooth muscle cells not only for controls but in the presence of ischemia and reperfusion too. Potential therapeutic applications of the observed reactions are important. They may include regenerative processes within the nervous system, studies on the improvement of blood flow within the microcirculation, or antimicrobial activity. Modulation of the G protein-phospholipase C response may also be an interesting point of action of future drugs modifying the response to stimulation during ischemia in particular, such activities could take place during the transport of organs for transplantation.

Evaluation of systemic microvascular reactivity in adults with congenital heart disease.

Adults with congenital heart disease share some features with those with chronic heart failure. Although microvascular endothelial dysfunction has been described in chronic heart failure, evaluation of the microcirculation in adults with congenital heart disease is lacking. The present study aimed to investigate systemic microvascular reactivity in adults with congenital heart disease. The patients initially underwent cardiopulmonary exercise testing. Then, the cutaneous microvascular reactivity was evaluated in these patients using a laser speckle contrast imaging system coupled with skin iontophoresis of endothelial-dependent (acetylcholine) or -independent (sodium nitroprusside) vasodilators and postocclusive reactive hyperemia (PORH) and compared with healthy controls matched for age and sex. Thirty-one patients and 29 healthy controls were evaluated. The basal microvascular flow (P<.0001) and area under the curve in response to acetylcholine (P<.0001) were higher in the patients than in the healthy volunteers. The increase in cutaneous vascular conductance in response to sodium nitroprusside was reduced in the patients compared to the healthy volunteers (P=.0031). No difference in the microvascular response was observed during postocclusive reactive hyperemia. The basal microvascular flow of patients with peak oxygen consumption below 16.0mL kg-1 min-1 was superior to that of patients with values greater than 16.0mL kg-1 min-1 (P=.0046). Adults with congenital heart disease present a higher baseline cutaneous microvascular blood flow than healthy controls and do not present systemic microvascular endothelial dysfunction. Nevertheless, endothelium-independent microvascular reactivity is blunted, suggesting an altered vascular smooth muscle response or vascular structural alterations. Finally, patients with a lower functional capacity presented a greater microvascular basal blood flow than subjects with a higher functional capacity.

Vascular effects of apelin: Mechanisms and therapeutic potential.

Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions of the brain. A growing body of evidence now demonstrates a regulatory role for the apelin/APJ receptor system in cardiovascular physiology and pathophysiology, thus making it a potential target for cardiovascular drug discovery and development. Indeed, ongoing studies are investigating the potential benefits of apelin and apelin-mimetics for disorders such as heart failure and pulmonary arterial hypertension. Apelin causes relaxation of isolated arteries, and systemic administration of apelin typically results in a reduction in systolic and diastolic blood pressure and an increase in blood flow. Nonetheless, vasopressor responses and contraction of vascular smooth muscle in response to apelin have also been observed under certain conditions. The goal of the current review is to summarize major findings regarding the apelin/APJ receptor system in blood vessels, with an emphasis on regulation of vascular tone, and to identify areas of investigation that may provide guidance for the development of novel therapeutic agents that target this system.

Sodium Nitroglycerin Induces Cerebrovascular Vasodilation in Patients with Ischemic Heart Disease

Aging patients with ischemic heart disease (IHD) have impaired cerebrovascular vasodilation in response to hypercapnia, but whether this is due to endothelial dysfunction or impairment in the vascular smooth muscle remains unknown. Further, despite being a standard drug given to patients with cardiovascular disease, the role of an exogenous nitric oxide donor (sodium nitroglycerin – NTG, which acts independently of the endothelium) in the cerebrovasculature in these patients is not known. This study tested the hypothesis that age and IHD impair nitric oxide‐mediated dilation (sodium nitric oxide, 0.4 mg spray) of the nine larger cerebral arteries in the Circle of Willis (3 Tesla MRI), as well as mean flow velocity [transcranial Doppler ultrasound; right middle cerebral artery (MCA)] and calculated MCA cerebral blood flow. These measures were made in groups of IHD (n=10, 49–77 years), older controls (CTL; n=5, 51–78 years) and young healthy (YH; n=10, 20–26 years) individuals. Compared to baseline, right MCA velocity [V (cm/s)] decreased similarly in all three groups [ΔIHD: −5.8 ± 5.0 cm/s; ΔCTL: −5.8 ± 3.2 cm/s; ΔYH: −6.3 ± 4.4: all p&lt;0.05 versus baseline; mean ± S.D.]. However, a main effect of drug indicated that NTG induced artery dilation in all six basal and the three extracranial arteries [average range of cross sectional area values for all vessels provided here: BL: 3.3 – 16.5 mm2; NTG: 3.9 – 17.9 mm2, p&lt;0.05, mean], and this dilation was similar across all 3 groups [e.g. right MCA CSA – ΔIHD: 1.3 ± 1.4 mm2; ΔCTL: 0.7 ± 1.2 mm2; ΔYH: 1.3 ± 0.9 mm2, p&gt;0.05 versus baseline; mean ± S.D.]. As a result, NTG exerted no change in MCA blood flow versus baseline. These results demonstrate that age and IHD have little impact on vascular smooth muscle responses to exogenous nitric oxide.Support or Funding InformationSupported by Canadian Institute for Health Research (201503MOP‐342412‐MOV‐CEEA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired Inferior Vena Cava Relaxation but not Contraction in Two Models of Murine Acute Deep Venous Thrombosis

Venous thrombosis (VT) damages the vein wall, both physically with prolonged distention and from inflammation. These factors underlie post-thrombotic syndrome (PTS). Interleukin 6 (IL-6) may play a role in experimental PTS and vein wall responses. Prior assessment of post-thrombotic vein wall injury has used static measures such as histology and immunologic assays. The purpose of this study was to use myography to quantify the changes in contraction and relaxation of murine vessels exposed to an acute thrombus. Wild-type (WT) C57BL/6 mice were used to determine baseline vein wall passive tension on a DMT 610M myograph (DMT, Ann Arbor, Mich), including dosing concentrations of phenylephrine (Phe) and acetylcholine (Ach). WT and IL-6 knockout mice underwent VT using inferior vena cava (IVC) ligation (complete stasis) and stenosis (partial stasis), and no-surgery mice were used as controls. Mice were harvested at 2 days (2D) and analyzed using a myograph. Vessels were stimulated with Phe and Ach to stimulate a contraction and relaxation response. Immunohistochemistry for CD31 was used to identify endothelial cells on WT no-surgery and WT 2D ligation vessels. Optimal passive tension was determined to be 2 mN, with the optimal concentrations of Phe and Ach being 7E-3M and 1E-5M, respectively. There was no significant difference in contraction on exposure to Phe between the WT no-thrombus mice, WT 2D ligation, and WT 2D stenosis mice and the IL-6 knockout mice with or without thrombus (all P > .05). When mice were treated with Ach, there was significantly more relaxation in the nonthrombosed control IVC segments than in those mice IVC segments that had a 2D thrombus of either ligation- or stenosis-derived mechanisms (Fig). The CD31 staining confirmed the presence of endothelium in the WT 2D IVC thrombus mice, ruling out tissue lost during harvesting. Compared with controls, acute thrombosis with total or partial stasis did not impair IVC contractile responses, suggesting no effect on medial vascular smooth muscle response. The relaxation response, however, was significantly reduced in the post-thrombotic groups. These findings suggest that at acute time points, VT impairs the endothelial function of a vein wall while retaining the vascular smooth muscle cell function and may be a mechanism that promotes PTS.

Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide-Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model.

Pulmonary vasoreactivity could determine the responsiveness to vasodilators and, in turn, the prognosis of pulmonary hypertension (PH). We hypothesized that pulmonary vasoreactivity is impaired, and we examined the underlying mechanisms in the Sugen-hypoxia rat model of severe PH. Male Sprague-Dawley rats were injected with Sugen (20 mg/kg s.c.) and exposed to hypoxia (9% O2) for 3 weeks, followed by 4 weeks in normoxia (Su/Hx), or treated with Sugen alone (Su) or hypoxia alone (Hx) or neither (Nx). After hemodynamic measurements, the heart was assessed for right ventricular hypertrophy (Fulton's index); the pulmonary artery, aorta, and mesenteric arteries were isolated for vascular function studies; and contractile markers were measured in pulmonary arteries using quantitative polymerase chain reaction (PCR). Other rats were used for morphometric analysis of pulmonary vascular remodeling. Right ventricular systolic pressure and Fulton's index were higher in Su/Hx versus Su, Hx, and Nx rats. Pulmonary vascular remodeling was more prominent in Su/Hx versus Nx rats. In pulmonary artery rings, contraction to high KCl (96 mM) was less in Su/Hx versus Nx and Su, and phenylephrine-induced contraction was reduced in Su/Hx versus Nx, Hx, and Su. Acetylcholine (ACh)-induced relaxation was less in Su/Hx versus Nx and Hx, suggesting reduced endothelium-dependent vasodilation. ACh relaxation was inhibited by nitric oxide synthase (NOS) and guanylate cyclase blockade in all groups, suggesting a role of the NO-cGMP pathway. Nitrate/nitrite production in response to ACh was less in Su/Hx versus Nx, supporting reduced endothelial NO production. Sodium nitroprusside (10-8 M) caused less relaxation in Su/Hx versus Nx, Hx, and Su, suggesting a decreased responsiveness of vascular smooth muscle (VSM) to vasodilators. Neither contraction nor relaxation differed in the aorta or mesenteric arteries of all groups. PCR analysis showed decreased expression of contractile markers in pulmonary artery of Su/Hx versus Nx. The reduced responsiveness to vasoconstrictors and NO-mediated vasodilation in the pulmonary, but not systemic, vessels may be an underlying mechanism of severe PH in Su/Hx rats and appears to involve attenuation of the NO relaxation pathway and a switch of pulmonary VSM cells to a synthetic less reactive phenotype.

Morphological and growth responses of vascular smooth muscle and endothelial cells cultured on immobilized heparin and dextran sulfate surfaces.

Heparin has shown promise as a component of various biomaterial formulations, but its variable properties and inhibitory effects on some cell types have raised interest in use of dextran sulfate as an alternative. In this study, we characterized the interactions of vascular smooth muscle (SMC) and endothelial cells (EC) with heparin and dextran sulfate immobilized onto chitosan-based films. Films were modified by blending chitosan with type I collagen and covalently attaching heparin or dextran sulfate at various levels. Cell-material interactions were evaluated by quantifying cell spreading, shape and proliferation rate. ECs proliferated well on chitosan, but the polymer was a mediocre substrate for SMC growth. Immobilizing heparin on chitosan further inhibited SMC proliferation. However, blending collagen reversed the heparin inhibition of SMC growth, resulting in a pro-proliferative effect of heparin immobilized on chitosan-collagen films. Dextran sulfate surfaces supported both SMC and EC proliferation with or without the presence of collagen. The results indicate that inhibitory effects of heparin on SMC are reversed by immobilization in the presence of collagen, and that dextran sulfate may be superior to heparin as a biomaterial additive for promoting vascular cell growth in chitosan-based scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1725-1735, 2017.

Modeling of the mechanobiological adaptation in muscular arteries

Abstract The growth and remodeling of arteries, as controlled by the local stress state and the sensory input from the endothelial cells of the artery wall, is given a novel theoretical framework incorporating the active behavior of vascular smooth muscle. We show that local sensory input maps uniquely to the ratio between a target arterial wall cross-section area corresponding to homeostatic conditions and the current arterial wall area. A growth law is formulated by taking the production rates of individual constituents of the arterial wall to be functions of this target-to-current wall area ratio. We find that a minimum active stress response of vascular smooth muscle is necessary to achieve stable adaptation of the artery wall to dynamic flow conditions. With a sufficient active stress alteration in response to stretch, stable growth toward a homeostatic state can be observed for finite step changes or ramp changes in the transmural pressure or the flow rate.

2,4,6-Trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide increases calcium influx in lipopolisaccharide-pre-treated arteries.

It has been demonstrated that 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide (m-3M3FBS) activates phospholipase C (PLC) and stimulates apoptosis in smooth muscle cells, which may increase vascular reactivity. The primary aim of the present study was to evaluate the physiological effects of the direct stimulation of PLC by m-3M3FBS on vascular smooth muscle reactivity in arteries pre-treated with lipopolysaccharides (LPS) as a model of septic shock. Experiments were performed on isolated and perfused tail arteries of Wistar rats. The contraction force in the model was measured by assessing increases in perfusion pressure at a constant flow. Parameters describing the concentration-response curves (CRCs) obtained for phenylephrine and arginine-vasopressin in the presence of LPS confirmed a decrease in vessels reactivity. In comparison with the controls, m-3M3FBS treatment caused a significant increase in LPS-untreated as well as pre-treated arteries. Furthermore, in the presence of m-3M3FBS, calcium influx from intra- as well as extracellular calcium stores was significantly higher for LPS-untreated and pre-treated arteries. The results of the present study suggested that m-3M3FBS significantly increased the reactivity of vascular smooth muscle cells pre-treated with LPS by increasing the calcium influx from intra- and extracellular calcium stores. Further studies investigating this mechanism are required to evaluate whether this pathway may be a potential therapeutic strategy to treat sepsis.

Distinct and complementary roles for α and β isoenzymes of PKC in mediating vasoconstrictor responses to acutely elevated glucose.

We investigated the hypothesis that elevated glucose increases contractile responses in vascular smooth muscle and that this enhanced constriction occurs due to the glucose-induced PKC-dependent inhibition of voltage-gated potassium channels. Patch-clamp electrophysiology in rat isolated mesenteric arterial myocytes was performed to investigate the glucose-induced inhibition of voltage-gated potassium (Kv ) current. To determine the effects of glucose in whole vessel, wire myography was performed in rat mesenteric, porcine coronary and human internal mammary arteries. Glucose-induced inhibition of Kv was PKC-dependent and could be pharmacologically dissected using PKC isoenzyme-specific inhibitors to reveal a PKCβ-dependent component of Kv inhibition dominating between 0 and 10 mM glucose with an additional PKCα-dependent component becoming evident at concentrations greater than 10 mM. These findings were supported using wire myography in all artery types used, where contractile responses to vessel depolarization and vasoconstrictors were enhanced by increasing bathing glucose concentration, again with evidence for distinct and complementary PKCα/PKCβ-mediated components. Our results provide compelling evidence that glucose-induced PKCα/PKCβ-mediated inhibition of Kv current in vascular smooth muscle causes an enhanced constrictor response. Inhibition of Kv current causes a significant depolarization of vascular myocytes leading to marked vasoconstriction. The PKC dependence of this enhanced constrictor response may present a potential therapeutic target for improving microvascular perfusion following percutaneous coronary intervention after myocardial infarction in hyperglycaemic patients.

Vascular Smooth Muscle Reactivity in Old Spontaneously Hypertensive Stroke-Prone Rats: Effects of Prolonged Cold Ischemia Followed by Warm Reperfusion in an In Vitro Model

Vascular Smooth Muscle Reactivity in Old Spontaneously Hypertensive Stroke-Prone Rats: Effects of Prolonged Cold Ischemia Followed by Warm Reperfusion in an In Vitro Model

Antihypertensive drugs

Antihypertensive drugs

Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults

Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1years; mean±SE, 53–79years) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4mg) following eplerenone (100mg/dose, 2 doses, 24h between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6%, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOSSer1177 to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5%, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77±4/2mmHg, P≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure.