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PubMed2006

Intense vasoconstriction in response to aspirate from stented saphenous vein aortocoronary bypass grafts.

OBJECTIVES: We sought to identify soluble vasoconstrictor substances that are released during stent implantation into saphenous vein aortocoronary bypass grafts. BACKGROUND: Atherosclerotic saphenous vein aortocoronary bypass grafts are particularly vulnerable to plaque rupture. Protection devices prevent particulate debris from being embolized. Additional soluble vasoconstrictor substances possibly also contribute to impaired microvascular perfusion. METHODS: Peripheral venous blood (VB) and aspirate (AS) were obtained from 14 patients with a significant stenosis in a saphenous vein graft during stent implantation under protection with a distal balloon occlusion device. In five additional patients, arterial blood (AB) was also taken distal to the stented lesion before intervention. Vasomotor substances in VB, AB, and AS plasma were identified in a bioassay of rat mesenteric arteries with intact (+E) and denuded endothelium (-E). Vasoconstriction was normalized to that induced by potassium chloride depolarization (100%). RESULTS: Venous blood, AB, and AS plasma induced maximum vasoconstriction within six minutes. The AS plasma induced a vasoconstriction of 138 +/- 13% (-E) and 87 +/- 14% (+E); VB, of 70 +/- 14% (-E) and 23 +/- 4% (+E); and AB plasma obtained before intervention, of 49 +/- 9% (-E) and 36 +/- 8% (+E). The vasoconstrictor potency of AS plasma in endothelium-denuded vessels was related to the severity of anginal symptoms, angiographic stenosis severity, plaque volume, and plaque burden as determined by intravascular ultrasound. The AS plasma-induced vasoconstriction was largely attenuated by combined serotonin/5-hydroxytryptamine (5-HT)(2A/2C)- and 5-HT(1A/1B)-receptor blockade and eliminated by additional thromboxane A2 thromboxane-prostanoid (TP)-receptor blockade. CONCLUSIONS: Stent implantation releases, apart from and in addition to particulate debris, soluble vasoconstrictor substances that possibly contribute to impaired microvascular perfusion.

Animals↗
PubMed2004

Cerebral cortical abnormalities seen in a non-human primate model of prenatal cocaine exposure are not related to vasoconstriction.

In our previous studies [J. Comp. Neurol. 435 (2001) 263] we demonstrated that rhesus monkeys born to mothers receiving cocaine orally during the period of pregnancy when neurons destined for the cerebral neocortex were generated displayed inappropriate positioning of neocortical neurons, loss of normal neocortical lamination, and reduction in neocortical volume, density and total number of neocortical neurons. In the present paper, we examined whether these cytoarchitectural abnormalities were related to the relatively high blood levels of the cocaine metabolite, benzoylecgonine, associated with oral cocaine administration. We also evaluated the role of vasoconstriction of the uteroumbilical and fetal brain vessels in the generation of these abnormalities. For these purposes, we compared cerebral neocortical cytoarchitecture in 2-month-old monkeys from five groups of mothers: (1). a drug-naïve group, (2). a cocaine-treated group, (3). a group treated with benzoylecgonine at doses producing higher blood levels of this metabolite and stronger vasoconstriction that those in the cocaine-treated group, (4). a group treated with cocaine plus the vasodilator, isosorbide dinitrate, which counteracted the vasoconstrictive actions of cocaine, and (5). a group exposed to isosorbide dinitrate alone. All treatments were carried out from the 45 th through 102 nd day of pregnancy. We found that the general appearance of the neocortex and the position and number of neocortical neurons in the offspring of benzoylecgonine- and isosorbide dinitrate-treated mothers were indistinguishable from those in the offspring of drug-naïve mothers. In contrast, significant alterations in these parameters (similar to those seen in our previous studies) were observed in the offspring of cocaine and cocaine + isosorbide dinitrate-treated mothers. These findings suggest that it is unlikely that either benzoylecgonine or vasoconstriction are responsible for the abnormalities seen in the neocortical cytoarchitecture in our non-human primate model of prenatal cocaine exposure.

Animals↗
PubMed2005

Angiopoietin-1 increases arteriolar vasoconstriction to phenylephrine during sepsis.

Sepsis leads to a reduction in vascular tone and a loss of vasoconstriction in response to catecholamines. We propose that angiopoietin-1 (Ang-1), which is known to modulate vascular inflammation and nitric oxide (NO), could improve responsiveness to vasopressor agents during sepsis. Mesenteric arterioles (300-400 microm) from rats (n=19) were mounted in a pressurized myograph and incubated with lipopolysaccharide (LPS, 50 microg/mL) for up to 4 h to model sepsis. Vasoconstriction (mean+/-SD) to phenylephrine (10(-8)-10(-3) M) was reduced in the presence of LPS (4 h, pD2: 5.8+/-0.2 (controls, n=6), 1.4+/-2.2 (LPS, n=6); maximal constriction: 48.2+/-4.8% (controls), 2.6+/-5.8% (LPS), P<0.05). However, in the presence of Ang-1 (250 ng/mL) phenylephrine caused greater vasoconstriction compared to LPS alone (4 h, pD2: 4.5+/-2.1; maximal constriction: 12.6+/-4.0% (n=7), P<0.05). In conclusion, Ang-1 increases vasoconstriction to phenylephrine in the presence of LPS. During sepsis therefore, Ang-1 increases vascular reactivity and has the potential to increase blood pressure and decrease vasopressor requirements in vivo.

Angiopoietin-1↗
PubMed1996

Pulmonary arterial endothelial dysfunction potentiates hypercapnic vasoconstriction and alters the response to inhaled nitric oxide.

BACKGROUND: Pulmonary hypertensive crisis can be initiated by episodes of hypercapnic acidosis. Hypercapnic vasoconstriction in the newborn pulmonary arterial circulation may be modulated by endogenous production of nitric oxide (NO) by the endothelial cell and effectively treated with inhalation of NO. METHODS: Sixteen 48-hour-old piglets were randomized to receive a hypercapnic challenge after administration of either saline vehicle or the NO synthase inhibitor N-omega-nitro-L-arginine (L-NA). Pulmonary arterial pressure, flow, and radius measurements were taken at baseline, after infusion of vehicle or L-NA, during hypercapnia (inspired fraction of carbon dioxide, 0.15), and during inhalation of NO (100 ppm). Fourier analysis was used to calculate input mean impedance, reflecting distal arteriolar vasoconstriction, and characteristic impedance, reflecting proximal arterial geometry and distensibility. RESULTS: Input mean impedance was increased with L-NA administration. Animals pretreated with L-NA also underwent a much larger increase in input mean impedance with exposure to hypercapnia than untreated animals. Characteristic impedance increased in the treated animals, but not in the controls. CONCLUSIONS: In the newborn pulmonary arterial circulation, endogenous NO production by the endothelial cell modulates resting tone distally, but not proximally. In addition, lack of a functional endothelium markedly potentiates the distal vasoconstrictor response to hypercapnia and produces proximal vasoconstriction. Despite impaired endothelial function, inhaled NO remains an effective vasodilator in hypercapnic pulmonary vasoconstriction.

Administration, Inhalation↗
PubMed1997

Effects of sympathetic nerve blockade on vasoconstrictive properties of nitric oxide synthase inhibition in sheep.

OBJECTIVE: Inhibition of nitric oxide synthase causes intense vasoconstriction. This effect is thought to be dependent on sympathetic nerve activity. Thus, we investigated the vasoconstrictive effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in sheep, in which a reversible sympathetic block was established by thoracic epidural anesthesia. METHODS: Sheep (n = 11) were surgically prepared for chronic study. After at least 5 days of recovery, L-NAME was continuously administered and hemodynamics were monitored. This was done in sheep with and without sympathetic blockade in randomized order. RESULTS: The vasoconstrictive effects of L-NAME were similar in sheep with and without sympathetic blockade. CONCLUSION: The obtained results suggest that the vasoconstrictive properties of nitric oxide synthase inhibitors are independent of sympathetic tone.

Anesthesia, Epidural↗
PubMed1984

Possible role of nickel ions in the pathogenesis of ischemic coronary vasoconstriction in the dog heart.

To test the hypothesis that nickel ions released from the ischemic dog myocardium [18] play a role in the pathogenesis of ischemic coronary vasoconstriction, the present experiments on the in situ heart of the anesthetized open-chest dog were designed to analyze coronary vascular action of intravenous (i.v.) and intracoronary (i.c.) injection of exogenous NiCl2 under the influence of ischemia, arterial hypoxemia and adenosine. The experimental results showed that (1) exogenous NiCl2 induced coronary vasoconstriction by a direct action on coronary vessels in low doses (0.02 mg X kg-1 i.v. bolus injection, or 0.04 mg X min-1 X kg-1 i.c. infusion) comparable to the Ni amount released endogenously, (2) NiCl2 significantly inhibited postocclusion reactive hyperemia and coronary vasorelaxation in response to arterial hypoxemia or intracoronary infusion of adenosine, (3) NiCl2 is capable of inducing coronary vasoconstriction when the coronary arteries are dilated by low flow ischemia, arterial hypoxemia and adenosine infusion, and (4) the Ni-sensitivity of coronary arteries increases significantly under these conditions. A hypothetical model is proposed summarizing the possible positive feedback loops triggered by endogenous Ni-release, which may cause coronary vasoconstriction in the ischemic dog myocardium.

Adenosine↗
PubMed1998

Hypoxic pulmonary vasoconstriction is impaired in rats with nitrofen-induced congenital diaphragmatic hernia.

BACKGROUND: Pulmonary hypertension and persistent fetal circulation contribute to the high mortality rate associated with congenital diaphragmatic hernia (CDH). Morphological alterations of the pulmonary vasculature in infants with CDH are thought to contribute to exaggerated vasoconstrictor responses to normal vasoconstrictor stimuli. In the pulmonary circulation, hypoxia is a potent vasoconstrictor. Under pathological conditions, hypoxia-induced vasoconstriction may contribute to the development of pulmonary hypertension. METHODS: The authors have used the nitrofen-induced model of congenital diaphragmatic hernia in rats to investigate the magnitude of the hypoxic vasoconstrictor response. Congenital diaphragmatic hernias were induced in fetal rats by feeding nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) to pregnant Sprague-Dawley rats at midgestation. Hypoxia-induced vasoconstriction was measured in isolated, perfused third-generation pulmonary arterioles from normal rats and from rats with nitrofen-induced CDH. RESULTS: The hypoxic vasoconstrictor response was significantly blunted in the pulmonary arterioles of fetal rats with nitrofen-induced (2% +/- 1% vasoconstriction), as compared with the responses observed in normal fetal rats (15% +/- 3% vasoconstriction, P = .004). CONCLUSION: Blunting of the hypoxic pulmonary vasoconstrictor response may contribute to ventilation-perfusion mismatching in infants with CDH.

Animals↗
PubMed2003

Water immersion and EMLA cause similar digit skin wrinkling and vasoconstriction.

Water immersion skin wrinkling tests limb sympathetic vasoconstrictor function. We have recently shown that water immersion wrinkling is accompanied by digit vasoconstriction and postulated that vasoconstriction is the main underlying mechanism. To test this further, we applied vasoconstrictive cream (EMLA) to the distal digit and compared the degree of skin wrinkling and digit blood flow reduction with those after water immersion. In 25 healthy volunteers (6 male, 19 female; mean age, 35 yr) subjected to EMLA and water immersion, both clinical wrinkling scores and reduction in digit blood flow (mean of 2.01 and 2.29 cm/s, respectively) were nearly identical. Control using aqueous cream resulted in minimal skin wrinkling and nonsignificant reduction in digit artery flow (P = 0.170). These data further support that water immersion skin wrinkling is mediated by vasoconstriction. The EMLA cream patch test may develop into a useful screening test for hand sympathetic vasoconstrictor function.

Adult↗
PubMed1997

Endothelin-1 induces liver vasoconstriction through both ETA and ETB receptors.

BACKGROUND/AIMS: We investigated which endothelin receptors mediate the vasoconstrictive effects of endothelin-1 on liver circulation. METHODS: An isolated perfused rat liver model in recirculation was used. RESULTS: The perfusion of 10(-10) M endothelin-1 had no significant influence on the liver flow, whereas 10(-9) M endothelin-1 induced significant vasoconstriction, with flow dropping from 3.20 +/- 0.34 to 1.48 +/- 0.28 ml. min-1.g-1 liver tissue (p < 0.01 vs controls). The liver flow was interrupted following the perfusion of 10(-8) M endothelin-1. Sarafatoxin C and BQ 3020, two agonists of ETB receptor, had vasoconstrictive effects in this model. Sarafatoxin C decreased the liver flow in a dose-dependent manner, from 3.32 +/- 0.21 to 2.18 +/- 0.20, 1.60 +/- 0.09, and 1.01 +/- 0.06 ml.min-1. g-1, respectively, with 10(-9) M, 10(-8) M, and 10(-7) M. While BQ 123, an antagonist of ETA receptor, or BQ 788, an antagonist of ETB receptor, partially reversed the effect of 10(-9) M endothelin-1, the simultaneous administration of BQ 123 and BQ 788 completely reversed these effects. CONCLUSIONS: These results indicate that the vasoconstrictive effects of endothelin-1 on the liver circulation are mediated through both ETA and ETB receptors.

Animals↗
PubMed2000

Reactive pulmonary artery vasoconstriction in pulmonary consolidation evaluated by color Doppler ultrasonography.

A total of 122 patients with pulmonary consolidation on chest radiographs underwent color Doppler ultrasonography to evaluate hemodynamic change in regional pulmonary artery in pulmonary consolidation due to various causes. The diseases underlying pulmonary consolidation included 66 simple pneumonia, 37 obstructive pneumonia, 13 tumor consolidation and 6 pulmonary infarctions. Blood flow signals in consolidation were detected by color-flow mapping. The degree of reactive vasoconstriction was evaluated from analysis of the spectral waveform of the blood flow in the segmental pulmonary artery by several vessel resistance-indicating Doppler ultrasound (US) indices, including pulsativity index (PI), resistive index (RI), and acceleration time (AT). The results showed that reactive vasoconstriction was most marked in obstructive pneumonia, followed by simple pneumonia, and least in tumor consolidation (p < 0.001, Kruskal-Wallis test and p < 0.001, Dunn's test for comparison of PI, RI and AT values between different groups of pulmonary consolidation). No flow was detected in pulmonary infarction. We conclude that color Doppler US is a useful tool for evaluating reactive vasoconstriction in pulmonary consolidation. The different degrees of reactive vasoconstriction may be helpful in exploring the possible etiology of pulmonary consolidation.

Blood Flow Velocity↗
PubMed2000

Role of the postsynaptic alpha(2)-adrenergic receptor subtypes in catecholamine-induced vasoconstriction.

Catecholamines induce direct vasoconstriction mediated by postsynaptic alpha-adrenergic receptors (alpha-ARs) of both the alpha(1) and alpha(2) type. To evaluate the contribution of each alpha(2)-AR subtype (alpha(2A), alpha(2B), and alpha(2C)) to this function, we used groups of genetically engineered mice deficient for the gene to each one of these subtypes and compared their blood pressure (BP) responses to their wild-type counterparts. Blood pressure responses to a bolus of norepinephrine (NE) were assessed before and after sequential blockade of alpha(1)-ARs with prazosin and alpha(2)-ARs with yohimbine. The first NE bolus elicited a brief 32 to 44 mm Hg BP rise (p < 0.001 from baseline) in all six groups. Prazosin decreased BP by 23 to 33 mm Hg in all groups, establishing a new lower baseline. Repeat NE at that point elicited lesser but still significant (p < 0.001) brief pressor responses between 32% and 45% of the previous BP rise in five of the six groups. Only the alpha(2A)-AR gene knockouts differed, responding instead with a 20-mm Hg fall in BP, a significant change from baseline (p < 0.001) and different from the pressor response of their wild-type counterparts (p < 0.001). The addition of yohimbine produced no further BP change in the five groups, but it did produce a small 7. 5-mm Hg fall (p < 0.05) in the alpha(2A)-AR knockouts. Norepinephrine bolus during concurrent alpha(1) and alpha(2)-AR blockade produced significant (p < 0.001) hypotensive responses in all subgroups, presumably attributable to unopposed stimulation of beta(2)-vascular wall ARs. We conclude that the alpha(2)-AR-mediated vasoconstriction induced by catecholamines is attributable to the alpha(2A)-AR subtype because mice deficient in any one of the other subtypes retained the capacity for normal vasoconstrictive responses. However, the alpha(1)-ARs account for the major part (as much as 68%) of catecholamine-induced vasoconstriction.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1999

Source(s) of activator calcium for noradrenaline-induced vasoconstriction in the perfused rabbit isolated ovarian vascular bed: a role for tyrosine kinase.

The effects of Ca2+ withdrawal and agents affecting Ca2+ translocation on alpha1-adrenoceptor-mediated vasoconstrictor responses in the perfused rabbit ovarian vascular bed were studied. Noradrenaline-induced vasoconstriction was lost in a Ca(2+)-free Krebs' solution, and the rate of loss of the response was accelerated by EGTA (2 mM). Noradrenaline-induced vasoconstriction and SDZ NVI 085-induced vasoconstriction were concentration-dependently inhibited by verapamil and nifedipine. These agents were, however, more effective against KCl-induced responses. Cyclopiazonic acid, an intracellular Ca(2+) depletor, concentration-dependently inhibited noradrenaline-induced responses and abolished the response in Ca(2+)-free Krebs' solution. GF 109203X and polymyxin B, inhibitors of protein kinase C (PKC), had no significant effect on noradrenaline-induced responses. Tyrosine kinase inhibitors, genistein and erbstatin, inhibited noradrenaline-induced vasoconstriction in the perfused rabbit ovarian vascular bed. The results would suggest that both extracellular Ca2+ and intracellular Ca2+ participate in noradrenaline-induced vasoconstrictor responses in the perfused rabbit ovarian vascular bed. The results would also suggest that tyrosine kinase and not protein kinase C activation has a role in such effects.

Animals↗
PubMed1999

Alpha-adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries.

OBJECTIVES: The study aimed to evaluate the role of alpha-adrenergic mechanisms during dynamic exercise in both normal and stenotic coronary arteries. BACKGROUND: Paradoxical vasoconstriction of stenotic coronary arteries has been reported during dynamic exercise and may be due to several factors such as alpha-adrenergic drive, a decreased release of nitric oxide, platelet aggregation with release of serotonin, or a passive collapse of the vessel wall. METHODS: Twenty-six patients were studied at rest, during two levels of supine bicycle exercise and after 1.6 mg sublingual nitroglycerin. The alpha-blocker phentolamine was given to 16 patients before exercise, five of whom had also taken a beta-adrenergic-blocker the same morning. Ten patients served as controls. The cross-sectional areas of a normal and a stenotic coronary vessel were determined by biplane quantitative coronary arteriography. RESULTS: In the normal vessel segments, coronary cross-sectional area did not change after phentolamine injection, but increased in all patient groups similarly during exercise. Although coronary vasoconstriction existed in stenotic vessel segments in control patients, phentolamine-treated patients showed exercise-induced vasodilation without difference in patients with and without chronic beta-blockade. CONCLUSIONS: Exercise-induced vasoconstriction of stenotic coronary arteries is prevented by intracoronary administration of phentolamine. There was no difference in coronary vasomotion between patients receiving phentolamine alone and patients receiving phentolamine in addition to a beta-blocker. This finding suggests that exercise-induced vasoconstriction is mediated not only by endothelial dysfunction but also by alpha-adrenergic mechanisms.

Adrenergic alpha-Antagonists↗
PubMed2003

The vasoconstriction threshold is increased in obese patients during general anaesthesia.

BACKGROUND: In anaesthetized patients, body temperature decreases often, but overweight patients become less hypothermic. Obesity in itself protects body heat, and thermoregulatory reflexes may maintain normothermia in obese patients. We tested the hypothesis that even slight obesity increases the vasoconstriction threshold. METHODS: Twenty male patients aged 30-65 years scheduled for open abdominal surgery were allocated to two groups: body fat >/=25% (obese group, n = 10), or <25% (normal weight group, n = 10). Anaesthesia was maintained with 0.4% isoflurane and opioid. The thermoregulatory vasoconstriction threshold was defined by the tympanic membrane temperature at which the skin temperature gradient equalled 0 degrees C. Plasma adrenaline, noradrenaline and leptin were measured. RESULTS: Age, height, heart rate and blood pressure did not differ between the two groups of patients. In the obese group the vasoconstriction threshold was higher than that in the normal weight group: 36.0 +/- 0.1 vs. 35.5 +/- 0.2 degrees C. Consequently, after 4 h of anaesthesia, the core temperature was highest in the obese patients: 36.4 +/- 0.1 vs. 35.5 +/- 0.2 degrees C. CONCLUSIONS: These results suggest that core temperature is maintained in obese patients because their vasoconstriction threshold to a low environmental temperature is high.

Adult↗
PubMed2003

Blood pressure response to thermoregulatory vasoconstriction during isoflurane and desflurane anesthesia.

BACKGROUND: Mild perioperative hypothermia produces morbid cardiac outcomes that may result from sympathetically induced hypertension. However, volatile anesthetics produce vasodilatation that may reduce the hemodynamic response to hypothermia. We tested the hypothesis that the volatile anesthetics isoflurane and desflurane blunt the normal cold-induced hypertensive response. METHODS: We analyzed prospective data from three analogous studies: 1) 10 volunteers given desflurane (2.6 volume percentage) maintained in left-lateral position; 2) nine volunteers without anesthesia or anesthetized with various doses of desflurane; and 3) eight volunteers given various concentrations of isoflurane. Mean skin temperature was reduced to 31 C, which decreased core body temperature and triggered thermoregulatory vasoconstriction. Mean arterial pressures were determined before and after hypothermia provoked intense thermoregulatory vasoconstriction. RESULTS: The hemodynamic responses to thermoregulatory vasoconstriction were similar without anesthesia and at all concentrations of desflurane and isoflurane. On average, mean arterial pressure increased 14 (SD = 5) mmHg with and without anesthesia. CONCLUSION: We conclude that thermoregulatory vasoconstriction significantly increases arterial pressure with or without isoflurane or desflurane anesthesia.

Anesthesia, General↗
PubMed2001

Role of the extracellular signal-regulated kinase (Erk) signal transduction cascade in alpha(2) adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein.

The mechanism of alpha(2) adrenoceptor-mediated vasoconstriction is unknown, but may involve activation of voltage-sensitive calcium channels, and/or a protein tyrosine kinase. Recently the extracellular signal-regulated kinase (Erk) cascade, often an event downstream of tyrosine kinase activation, has been shown to mediate vasoconstriction to a variety of agents. The aim of this present study was to determine the involvement of the Erk signal transduction cascade in alpha(2) adrenoceptor-mediated vasoconstriction, and to confirm the involvement of activation of voltage-sensitive calcium channels, and protein tyrosine kinase. Contractions to the alpha(2) adrenoceptor agonist UK14304 in the porcine palmar lateral vein in vitro were reduced 70 - 80% by the MEK inhibitors PD98059 (10 - 50 microM) and U0126 (10 - 50 microM), indicating the involvement of the Erk signal transduction cascade. Immunoblots also demonstrated an increase in the phosphorylated (activated) form of Erk in palmar lateral vein segments after contraction with UK14304, which was inhibited by PD98059 and U0126. The calcium channel blockers nifedipine and verapamil, or removal of extracellular calcium inhibited UK14304-induced contractions and phosphorylation of Erk, demonstrating the importance of an influx of extracellular calcium. UK14304-induced contractions were inhibited by PP2 (1 - 10 microM), a selective inhibitor of Src tyrosine kinases, but not by PP3, an inactive analogue. PP2 also prevented the phosphorylation of Erk by UK14304. These data demonstrate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon activation of the Erk signal transduction cascade, which is downstream of an influx of extracellular calcium, and activation of Src tyrosine kinases.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2003

Alpha 2 adrenoceptor-mediated vasoconstriction in porcine palmar lateral vein: role of phosphatidylinositol 3-kinase and EGF receptor transactivation.

1 Alpha(2) adrenoceptors cause vasoconstriction in the porcine palmar lateral vein through a mechanism involving the ERK signal transduction cascade, calcium influx, and a Src tyrosine kinase. The aim of the present study was to determine if phosphatidylinositol 3-kinase (PI 3-kinase) and/or epidermal growth factor (EGF) receptor transactivation are also involved. 2 alpha(2) Adrenoceptor-mediated vasoconstriction and ERK2 activation in the porcine palmar lateral vein was inhibited in the presence of either the PI 3-kinase inhibitor LY294002, or the EGF receptor tyrosine kinase inhibitor AG1478 suggesting the involvement of both PI 3-kinase and EGF receptor transactivation. 3 Akt phosphorylation was increased in segments of porcine palmar lateral vein contracted with UK14304 indicating an increase in Akt activation. This is a further indication that PI 3-kinase is involved in alpha(2) adrenoceptor-mediated vasoconstriction. Akt activation was inhibited by the Src tyrosine kinase inhibitor PP2, and removal of extracellular calcium. 4 UK14304 (10 microM) stimulated an increase in intracellular calcium in segments of palmar lateral vein. This was inhibited by removal of extracellular calcium, but not by nifedipine suggesting the rise in calcium is due to influx of calcium through non-L type calcium channels. The increase in calcium was also inhibited by LY294002 indicating that PI 3-kinase is upstream of calcium influx. 5 These data indicate that alpha(2) adrenoceptor-mediated vasoconstriction in the porcine palmar lateral vein is dependent upon stimulation of PI 3-kinase, leading to an influx of calcium. This results in activation of the EGF receptor tyrosine kinase, and finally activation of ERK-MAP kinase.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2007

Selective AT1 receptor antagonism enhances sympathetically mediated vasoconstriction in man.

The vasoconstrictive action of angiotensin II (AII) is partly, sympathetically mediated and angiotensin-converting enzyme (ACE) inhibitors appear to exert a sympatholytic effect. We examine the effect of an orally administered, selective AT(1) receptor antagonist (losartan 50 mg) on sympathetically mediated vasoconstriction in healthy volunteers in an observer blind crossover study. Seven healthy, normotensive volunteers (21-32 years), were studied on two occasions at the end of each 6-week treatment period (losartan or placebo). Forearm blood flow (FABF) (ml/dl forearm/min) was measured by venous occlusion plethysmography during the application of lower body negative pressure (LBNP) (-20 cm H(2)O) and at the end of each incremental infusion of norepinephrine (60, 120, and 240 pmol/min). Comparison of blood flow changes was by repeated measures analysis of variance; P<0.05 was taken as statistically significant. Losartan did not alter blood pressure compared to placebo. It did significantly enhance LBNP-induced vasoconstriction in both the left arm compared to placebo (-36.6+/-3.4 vs -23.5+/-3.3%; P=0.017) and the right arm compared to placebo (-39.5+/-3.8 vs -21.0+/-3.6%; P=0.005). The FABF response to all doses of infused norepinephrine (60, 120, and 240 pmol/min) was also enhanced by losartan compared to placebo (-35.0+/-2.7 vs -18.2+/-6.0%; -43.6+/-4.3 vs -28.6+/-5.8%, and -53.9+/-3.2 vs -42.5+/-6.8%; P=0.057, respectively. Losartan enhances locally mediated sympathetic vasoconstriction in the forearm circulation of man, probably through its effect on circulating AII concentrations and we postulate that the adrenergic sympathetic constrictor action of AII is not mediated by the AT(1) receptor or is surmountable at this receptor.

Adult↗