SEARCH · PubMed Health

Results for “vasoconstrictor”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources

PubMed1998

Positive inotropic, negative chronotropic, and coronary vasoconstrictor effects of acetylcholine in isolated rat hearts: role of muscarinic receptors, prostaglandins, protein kinase C, influx of extracellular ca2+, intracellular Ca2+ release, and endothelium.

The involvement of nitric oxide (NO), muscarinic receptors, prostaglandins, calcium influx via slow calcium channels, Ca2+ release from intracellular stores, protein kinase C, and endothelium in the positive inotropic, negative chronotropic, and coronary vasoconstrictor effects of acetylcholine (ACh) has been investigated in isolated rat hearts. The perfusion of hearts with ACh (10(-7), 5 x 10(-7), and 10(-6) M) produced marked decreases in heart rate and coronary flow and a marked increase in contractile force. Similar effects have been observed during the perfusion of hearts with ACh in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME), which is an inhibitor of NO synthesis. The positive inotropic, negative chronotropic, and coronary vasoconstrictor effects of ACh were abolished by muscarinic receptor blocker atropine. In hearts pretreated with cyclooxygenase inhibitor indomethacin, ACh significantly decreased heart rate but did not significantly affect coronary flow and contractile force. In the presence of calcium channel antagonist verapamil or protein kinase C inhibitor staurosporine, ACh produced a significant drop in heart rate but did not significantly affect coronary perfusion pressure and force of contraction. In the presence of the inhibitor of the release of Ca2+ from intracellular stores dantrolene sodium, ACh produced a significant increase in coronary perfusion pressure and a marked decline in heart rate, but did not significantly affect force of contraction. Furthermore, the disruption of endothelium by perfusing the hearts with saponin abolished the vasoconstrictor effect of ACh but did not alter negative chronotropic and positive inotropic effect. Our results suggest that ACh causes vasoconstrictor, negative chronotropic, and positive inotropic effects in isolated rat hearts. Cardiac effects of ACh are related to muscarinic receptor activation, and prostaglandins modulate ACh-induced vasoconstriction and positive inotropy. Our data also suggest that protein kinase C and calcium influx from extracellular source may be responsible for the vasoconstrictor and positive inotropic effect of ACh. The calcium release from intracellular stores may mediate the positive inotropic effect, and the vasoconstrictor effect of ACh depends on an intact endothelium.

Acetylcholine↗

PubMed1981

Vasoconstrictor activity in cerebrospinal fluid from patients subjected to early surgery for ruptured intracranial aneurysms.

Vasoconstrictor activity was examined in serial samples of cerebrospinal fluid (CSF) obtained from 10 patients undergoing aneurysm clipping within 48 hours after subarachnoid hemorrhage (SAH). There was no close relationship between vasoconstrictor activity in postoperative CSF samples and the patient's clinical condition or angiographic vasospasm. The identity of the vasoconstrictor substance(s) in CSF was not established, but serotonin, histamine, norepinephrine, epinephrine, acetylcholine, or angiotensin II were eliminated as prime vasoconstrictor agents inducing cerebral vasospasm. Differences in the temporal profile of the responses of isolated tissues to CSF from patients with early and late surgery suggested that differing substances were involved in the production of spasm. A correlation between CSF potassium concentrations and vasoactive substances was found, but potassium could not account for vasoconstrictor activity of CSF. A log:linear correlation between total vasoconstrictor activity and total CSF collected could not be explained. Also, because of possible differences in the identity of vasoactive substances in CSF in this study compared to earlier studies, clinical comparisons based on apparent differences in pharmacological potency of CSF were not warranted. Nevertheless, removal of subarachnoid blood by cisternal rinsing seemed to be a useful surgical adjunct.

Adult↗

PubMedDate not supplied

Vasoconstrictor responses to the alpha 2-adrenoceptor agonist UK14304 during responses to noradrenaline, phenylephrine, serotonin and vasopressin of the rat tail artery.

In the isolated perfused rat tail artery, the alpha 2-adrenoceptor agonist UK14304 alone did not exert a direct vasoconstrictor action until a concentration of at least 30 microM was reached. However, when administered during the sustained vasoconstrictor response to 1.6 microM vasopressin, UK14304 (1-100 nM) produced additional concentration-dependent increases in perfusion pressure. The vasoconstrictor response to UK14304 in the presence of vasopressin was antagonized by idazoxan (1 microM) but was not affected by prazosin (10 nM), indicating that it was due to activation of alpha 2-adrenoceptors, and it was reduced by diltiazem (10 microM) and abolished when perfusion was done with a Ca2(+)-free solution, suggesting that the effect depends on the influx of Ca2+. UK14304 (50 nM) also produced a further increase in perfusion pressure when given during sustained vasoconstrictor responses to phenylephrine (1 microM) or low concentrations (100 nM) of noradrenaline or serotonin. However, UK14304 did not produce a further increase in perfusion pressure when given during sustained vasoconstrictor responses to higher concentrations (300 nM) of noradrenaline or serotonin: the lack of an additional effect of UK14304 was not due to the primary response to noradrenaline or serotonin being maximal. The findings show that vasoconstrictor responses following activation of alpha 2-adrenoceptors may be uncovered by an increase in vascular tone produced by some agonists.

Adrenergic alpha-Agonists↗

PubMed1998

Endothelium-released adenosine triphosphate contributes to vasoconstrictor responses to periarterial nerve stimulation in isolated, perfused canine splenic arteries.

P2X-Purinoceptors and alpha1-adrenoceptors have previously been shown to be involved in double-peaked vasoconstrictor responses to periarterial electrical nerve stimulation in the isolated and perfused canine splenic artery. The present study was designed to investigate the influence of endothelium removal on vasoconstrictor responses to periarterial nerve stimulation, tyramine, noradrenaline, and adenosine triphosphate (ATP) in the isolated canine splenic artery. Intraluminal administration of saponin completely abolished the acetylcholine-induced vasodilatation and potentiated the vasoconstrictor response to KCl. Double-peaked vasoconstriction (two phases of vasoconstriction) was readily induced by periarterial electrical nerve stimulation in the canine splenic arterial preparation with or without endothelium and was consistently abolished by treatment with tetrodotoxin. Removal of endothelium slightly but significantly decreased the first-phase vasoconstrictor responses to stimulation of 1 or 10 Hz, and did not affect the second-phase. The vasoconstrictor responses to tyramine, noradrenaline, and ATP were not modified by endothelium removal. From these results, it is postulated that ATP released from endothelium, as a modulator of sympathetic nerve cotransmission, may partially contribute to the purinergic constriction component in the canine splenic artery.

Adenosine Triphosphate↗

PubMed1995

Role of thromboxane A2 in the vasoconstrictor response to endothelin-1, angiotensin II and 5-hydroxytryptamine in human placental vessels.

The possibility that the vasoconstrictor agents present in the circulation may mediate their effect on placental blood flow by stimulating local prostanoid production was investigated. Placental cotyledons obtained at term from normal pregnancies were perfused in vitro. The dose-related vasoconstrictor effects of endothelin-1 (ET-1), angiotensin II (A II) and 5-hydroxytryptamine (5 HT) were reduced by graded concentrations of the thromboxane A2 (TXA2) receptor antagonist GR32191 (10(-7)-10(-4)M), aspirin (10(-5)-10(-4)M) and indomethacin (10(-5)M). The effect of the TXA2 receptor agonist U46619 was totally abolished by GR32191 (10(-7)M) but unaffected by the prostanoid synthesis inhibitors, aspirin and indomethacin although they prevented a self-priming effect of U46619. When effluents were collected from perfused placentae, 5-10 min after administration of sub-maximal doses of ET-1 (20 pmol), A II (500 pmol) and 5 HT (15 pmol), there was a significant increase in TXB2, the stable metabolite of TXA2, indicating the vasoconstrictors had induced an increase in local prostanoid production. These findings indicate that the vasoconstrictor effects of ET-1, A II and 5 HT in the placental vascular bed are mediated, at least in part, by vasoconstrictor prostanoids including TXA2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1998

Cyclooxygenase inhibition reveals synergistic action of vasoconstrictors on mesangial cell growth.

Since endogenous vasoconstrictors promote mesangial cell growth and increase the biosynthesis of antiproliferative prostaglandins, the effects of cyclooxygenase inhibition on mesangial cell proliferation should be strongly dependent on the prevailing levels of neuroendocrine vasoconstrictors. We compared the effects of indomethacin (10(-6) M), a cyclooxygenase inhibitor, on [3H]thymidine incorporation by cultured rat mesangial cells in the presence of various combinations of angiotensin II (10(-10) M), [Arg8]vasopressin (10(-11) M), (-)-norepinephrine (10(-8) M) and endothelin-1 (10(-11) M). Indomethacin did not enhance [3H]thymidine incorporation in cells treated with each individual vasoconstrictor, or in cells treated with two-way combinations with the exception of modestly increased [3H]thymidine incorporation in cells treated with angiotensin II + (-)-norepinephrine or [Arg8]vasopressin + (-)-norepinephrine. In contrast, in cells treated with any three-way or the four-way combination, indomethacin markedly increased [3H]thymidine incorporation. Importantly, a highly significant interaction (P<0.0001) was observed for thymidine incorporation between the number of vasoconstrictors present and indomethacin treatment, thus demonstrating that cyclooxygenase inhibition reveals a synergistic action of vasoconstrictors on the DNA synthesis in mesangial cells.

Analysis of Variance↗

PubMed2002

Pregnancy-associated increase in rat systemic arteries endothelial nitric oxide production diminishes vasoconstrictor but does not enhance vasodilator responses.

Late pregnancy in rats is characterized by a decrease in arterial pressure and in isolated arterial vessels response to vasoconstrictors. In uterine arteries the pregnancy-associated attenuation of the response to vasoconstrictors has been attributed to an increase in basal and agonist-induced endothelial NO production. However, the role of NO in pregnancy-associated changes of systemic arteries reactivity to vasoactive agents remains to be fully elucidated. We examined whether pregnancy influences the reactivity of systemic arteries to vasodilator or vasoconstrictor agents through NO-dependent mechanisms. Thoracic aortic rings and mesenteric arterial bed of late pregnant rats showed refractoriness to phenylephrine-induced vasoconstriction that was abolished by NO synthase inhibition. The potency of L-NNA to enhance tension of aortic rings preconstricted with phenylephrine (10-20% of their maximal response) was significantly lower in preparations from pregnant animals. In phenylephrine-contracted aortas and mesenteric bed, the effects of the endothelium-dependent vasodilators acetylcholine, A23187 and bradykinin, were not influenced by pregnancy. Similarly, pregnancy did not affect the vasodilator responses of adenosine, isoproterenol, capsaicin, nitroprusside, forskolin, and Hoe234 in the mesenteric bed. NO synthase activity measured by determining the conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline in aorta and mesenteric arteries homogenates was not altered by pregnancy. These findings show that endothelial-dependent and -independent vasodilators action as well as NO synthase activity in systemic arteries is uninfluenced by pregnancy, whereas pregnancy-associated hyporeactivity of systemic arteries to vasoconstrictors is related to an enhanced endothelial NO production either spontaneous or elicited directly or indirectly by vasoconstrictor agents. This interpretation implies that the enhanced NO production observed in systemic arteries during late pregnancy involves cellular pathways other than the ones involved in the response to endothelium-dependent vasodilators such as acetylcholine.

Animals↗

PubMed1979

Effect of the addition of a vasoconstrictor to local anesthetic solution on operative and postoperative bleeding, analgesia and wound healing.

A clinical study of local anesthetic solutions with and without epinephrine was conducted involving 32 healthy adults requiring removal of bony impacted mandibular third molars. The time elapsing from the administration of the anesthetic solution until analgesia was obtained was significantly shorter in the vasoconstrictor group (P less than 0.001). Additional anesthetic was necessary in 44% of the patients in the control group. The blood loss in the vasoconstrictor group was significantly lower (P less than 0.001) than in the group receiving anesthetic solution without the vasoconstrictor. No statistically significant difference in operation time between the groups was found, although the profuse bleeding in the control group impeded to some extent the surgical procedure. A positive correlation coefficient between operation time and blood loss of r = 0.65 in the vasoconstrictor group (P less than 0.006) and r = 0.77 in the control group (P less than 0.001) was found. Hemorrhage occurring 24 h postoperatively was recorded in 37% of the subjects in the vasoconstrictor group, and of these 83% revealed a healing of the socket by second intention.

Adolescent↗

PubMed2000

Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.

1. Urotensin-II (U-II) and its G-protein-coupled receptor, GPR14, are expressed within mammalian cardiac and peripheral vascular tissue and, as such, may regulate mammalian cardiovascular function. The present study details the vasoconstrictor profile of this cyclic undecapeptide in different vascular tissues isolated from a diverse range of mammalian species (rats, mice, dogs, pigs, marmosets and cynomolgus monkeys). 2. The vasoconstrictor activity of human U-II was dependent upon the anatomical origin of the vessel studied and the species from which it was isolated. In the rat, constrictor responses were most pronounced in thoracic aortae and carotid arteries: -log[EC(50)]s 9.09+/-0.19 and 8.84+/-0.21, R(max)s 143+/-21 and 67+/-26% 60 mM KCl, respectively (compared, for example, to -log[EC(50)] 7.90+/-0.11 and R(max) 142+/-12% 60 mM KCl for endothelin-1 [ET-1] in thoracic aortae). Responses were, however, absent in mice aortae (-log[EC(50)] <6.50). These findings were further contrasted by the observation that U-II was a 'coronary-selective' spasmogen in the dog (-log[EC(50)] 9.46+/-0.11, R(max) 109+/-23% 60 mM KCl in LCX coronary artery), yet exhibited a broad spectrum of vasoconstrictor activity in arterial tissue from Old World monkeys (-log[EC(50)]s range from 8.96+/-0.15 to 9.92+/-0.13, R(max)s from 43+/-16 to 527+/-135% 60 mM KCl). Interestingly, significant differences in reproducibility and vasoconstrictor efficacy were seen in tissue from pigs and New World primates (vessels which responded to noradrenaline, phenylephrine, KCl or ET-1 consistently). 3. Thus, human U-II is a potent, efficacious vasoconstrictor of a variety of mammalian vascular tissues. Although significant species/anatomical variations exist, the data support the hypothesis that U-II influences the physiological regulation of mammalian cardiovascular function.

Animals↗

PubMed1998

The impact of systemic vasoconstrictors on the cerebral circulation of anesthetized patients.

UNLABELLED: BACKGROUND. The effect of vasoconstrictors on intracerebral hemodynamics in anesthetized patients is controversial. The influence of phenylephrine and norepinephrine on the cerebral circulation was investigated in isoflurane- or propofol-anesthetized patients using transcranial Doppler ultrasonography. METHODS: Forty patients were randomly assigned to have vasoconstrictor tests with norepinephrine or phenylephrine during either isoflurane or propofol anesthesia. Blood flow velocities were simultaneously measured in the middle cerebral artery and ipsilateral extracranial internal carotid artery. Baseline recordings were done during stable anesthesia in a supine position (test 0). A second series of measurements were performed after norepinephrine or phenylephrine had increased mean arterial blood pressure by about 20% (test 1). With maintained norepinephrine or phenylephrine infusion, a final series of results were obtained after the increased mean arterial blood pressure was counteracted by a slightly head-up patient position (test 2). RESULTS: Both vasoconstrictors significantly increased mean flow velocities in the middle cerebral artery (norepinephrine: 43 +/- 11 cm/s to 49 +/- 11 cm/s; phenylephrine: 43 +/- 8 cm/s to 48 +/- 9 cm/s; +/- SD) and internal carotid artery (norepinephrine: 27 +/- 7 cm/s to 31 +/- 8 cm/s; phenylephrine: 27 +/- 9 cm/s to 31 +/- 10 cm/s) in the isoflurane-but not in the propofol-anesthetized patients. In the head-up position, only small and insignificant flow velocity changes were observed in both cerebral arteries independent of the vasoconstrictor or background anesthetic. CONCLUSIONS: The results of the present study indicate that norepinephrine and phenylephrine do not directly affect intracranial hemodynamics in anesthetized patients, but rather that hemodynamic changes observed with vasoconstrictors reflect the effect of the background anesthetic agents on cerebral pressure autoregulation.

Adult↗

PubMed1993

Effects of vasoconstrictors on rabbit coronary arteries exposed to isotonic ionic and nonionic contrast media.

RATIONALE AND OBJECTIVES: Vasodilation is a well-known side effect of contrast media (CM) that is primarily explained by the hyperosmolality of the media. Few reports have dealt with the influences of chemotoxicity and ion toxicity on vessel tone. We compared the effects of solutions iso-osmolar to plasma of iohexol (nonionic monomer), ioxaglate (ionic dimer), diatrizoate (ionic monomer), and mannitol on responses to vasoconstrictors (potassium chloride [KCl], histamine, and endothelin-1). The aim of this study was to investigate if differences in chemotoxicity and ion toxicity could contribute to the changes in vessel tone seen clinically during arteriography. METHODS: Segments of rabbit coronary arteries were mounted between two L-shaped prongs in tissue baths with buffer solution or CM solutions. Their responses to increasing concentrations of a vasoconstrictor were measured. The maximal contraction of the vasoconstrictor (Emax) and the concentration of the vasoconstrictor causing half maximal contraction (EC50) were calculated. RESULTS: Iohexol caused the same changes as the nonionic solution of mannitol. The media reduced the actions of KCl, histamine, and endothelin-1 to 50% to 60% of their action in buffer. The ionic CM, ioxaglate and diatrizoate, caused a more pronounced inhibition of histamine and almost totally inhibited the action of KCl. The action of endothelin-1 was inhibited to a greater extent by iohexol and mannitol than by ioxaglate and diatrizoate. CONCLUSIONS: Different types of iso-osmolar CM interact differently with vasoconstrictors. These effects are caused by differences in chemo- and ion toxicity. These interactions might contribute to the differences in vasodilatation found clinically.

Animals↗

PubMed2003

Early multiple organ failure after recurrent endotoxemia in the presence of vasoconstrictor-masked hypovolemia.

OBJECTIVE: Critically ill patients who develop multiple organ failure during systemic inflammatory states are often predisposed to hypovolemia and vasoconstrictor therapy. Although numerous investigations have evaluated the sequelae of systemic inflammation, no data are available on the contribution of chronic vasoconstrictor-masked hypovolemia to organ dysfunction and morphology. DESIGN: Prospective, randomized laboratory investigation. SETTING: University research laboratory. SUBJECTS: Eighteen adult chronically instrumented sheep. INTERVENTIONS: The animals were randomly assigned to one of three groups. In the norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) group, mean arterial pressures of 80 mm Hg were maintained by using the alpha1-adrenergic catecholamine norfenefrine for 52 hrs during hypovolemia. Hypovolemia was induced by hemorrhage (about 23 mL x kg(-1)) until mean arterial pressures reached 40 mm Hg. Endotoxin (0.5 microg x k(-1)) was then injected after 4, 16, 28, and 40 hrs. The NMH group received norfenefrine-masked hypovolemia but no endotoxin. In the ENDO group, recurrent endotoxemia was induced during normovolemia. MEASUREMENTS AND MAIN RESULTS: Despite profound differences in fluid management, cardiovascular filling pressures were not statistically different between groups. Endotoxemia induced norfenefrine-refractory shock (p < .05 vs. the other groups) and contributed to renal dysfunction only during vasoconstrictor-masked hypovolemia. Norfenefrine-masked hypovolemia caused disseminated cardiac cell necrosis independent of endotoxemia (p < .05 vs. ENDO). CONCLUSIONS: Hypovolemia can be masked when volume status is monitored by filling pressures. In this new model of endotoxemia-associated multiple organ failure, chronic vasoconstrictor-masked hypovolemia turned systemic inflammation into a life-threatening condition with renal and cardiovascular failure. Cardiomyocyte necroses were caused by vasoconstrictor-masked hypovolemia but were unrelated to cardiovascular failure.

Adrenergic alpha-Agonists↗

PubMed2005

Vasoconstrictor hyporeactivity can be reversed by antioxidants in patients with advanced alcoholic cirrhosis of the liver and ascites.

OBJECTIVE: Hyperdynamic circulation and systemic vasodilation complicate cirrhosis of the liver and are related to vasoconstrictor hyporeactivity. We investigated whether impaired vasoconstrictor responsiveness may be overcome by antioxidants in patients with decompensated alcoholic cirrhosis. DESIGN: Controlled clinical study. SETTING: University setting. PATIENTS: Nine patients with liver cirrhosis Child-Pugh grade C and nine healthy age-matched volunteers. INTERVENTIONS: Forearm blood flow responses to intra-arterial norepinephrine, angiotensin II, and the nitric oxide synthase inhibitor N-monomethyl-l-arginine were measured by strain-gauge plethysmography and compared between groups of patients. To assess the role of oxidative stress, the antioxidant vitamin C (24 mg/min) was administered locally into the brachial artery, and forearm blood flow responses were reassessed. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of vitamin C were lower in patients with cirrhosis (p < .05). In patients with cirrhosis, the reactivity to norepinephrine and angiotensin II was markedly reduced (p < .05 vs. controls). Coadministration of vitamin C completely restored the potency of vasoconstrictors to that in controls but had no effect in healthy subjects. No changes were observed in time-control experiments in cirrhosis patients (n = 3) employing vehicle coinfusion. The response to N-monomethyl-L-arginine was comparable between groups and not affected by vitamin C. CONCLUSIONS: Oxidative stress with consumption of antioxidants seems to play an important role in the development of vasoconstrictor hyporeactivity in patients with cirrhosis. Antioxidant therapy may be a promising clinical approach to restore vasoconstrictor hyporeactivity in these patients.

Angiotensin II↗

PubMed1994

Evidence for a differential location of vasoconstrictor endothelin receptors in the vasculature.

1. There are at least two subtypes of vascular endothelin (ET) receptors. Stimulation of the ETA receptors on vascular smooth muscle cells leads to vasoconstriction, whereas activation of the ETB receptors on endothelial cells elicits vasodilatation. Several reports in the literature have suggested the presence of a vasoconstrictor non-ETA receptor on vascular smooth muscle which has pharmacological similarities to the ETB receptor. The present study was undertaken to determine the location of this ETB-like receptor within the vascular system. 2. Fourteen vascular smooth muscle preparations from six species were used to determine the effect of the ETA receptor antagonist, BQ-123, on concentration-response curves elicited by ET-1 and the ability of the ETB receptor agonist, sarafotoxin S6c, to cause contraction. The vessels fell into two categories. One group was sensitive to BQ-123 and insensitive to sarafotoxin S6c and, thus, probably contained ETA receptors. The other group, with vasoconstrictor ETB-like receptors, was insensitive to BQ-123 and sensitive to sarafotoxin S6c. 3. Vessels from cynomolgus monkeys, when studied in vitro, appeared to contain primarily ETA receptors, although the potency of BQ-123 was quite variable, suggesting the possibility of ETA receptor subtypes. In contrast, both ET-1 and sarafotoxin S6c, given as intravenous injections in conscious monkeys, produced transient, equipotent, and dose-related increases in blood pressure. The highest dose of sarafotoxin S6c (1 nmol kg-1, i.v.) also caused a marked secondary depressor response (-80 +/- 6 mmHg) that lasted approximately 10 min. The pressor responses suggest that the vasoconstrictor ETB-like receptors are present in cynomolgus monkeys. 4. The data suggest the presence of two distinct vasoconstrictor ET receptor subtypes on smooth muscle cells. The ETA receptors are primarily located on the high pressure side of the circulation. The vasoconstrictor ETB-like receptors appear to be concentrated on the low pressure side.

Animals↗

PubMed1995

Presence of vasoconstrictor 5HT1-like receptors revealed by precontraction of rabbit isolated mesenteric artery.

1. A series of 5-hydroxytryptamine (5-HT) receptor agonists including 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced little or no contraction of rabbit isolated mesenteric arteries under resting tone conditions, even at concentrations up to 10(-4) M. 2. When the same agonists were retested in mesenteric artery preparations pre-contracted with the thromboxane-mimetic, U46619, each demonstrated concentration-related vasoconstrictor activity. 5-CT and 5-HT were especially potent and effective in this model giving EC50 values of 4.3 x 10(-9) M and 1.6 x 10(-8) M respectively and maximum effects equivalent to those of KCl 80 mM. In preparations precontracted by U46619 (conditions retained throughout the rest of the study) the order of agonist potency was 5-CT > 5-HT > RU 24969 = sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) > cisapride. 3. The vasoconstrictor effects of 5-CT were competitively antagonized by methiothepin (pA2 8.20) but resistant to antagonism by a range of other 5-HT receptor antagonists, i.e. pindolol (5-HT1A/5-HT1B), propranolol (5-HT1B), spiperone (5-HT2A), ondansetron (5-HT3), ICS 205930 (5-HT3/5-HT4) and SDZ 205557 (5-HT4). 5-CT responses were slightly antagonized by a high concentration of ritanserin (5-HT2A/5-HT2C). Responses to 5-HT and sumatriptan were also antagonized by methiothepin with similar affinity (pA2/pKB values congruent to 8.0). 4. Metergoline and rauwolscine (10(-7)-10(-6) M) antagonized the effects of 5-CT in a non-competitive fashion giving pKBapp values of 7.13 (metergoline) and 6.86 (rauwolscine). 5. Vasoconstrictor responses to 5-HT were not modified in the presence of ritanserin (3 x 10-7 M) orspiperone (3 x 10-7 M) and only modestly antagonized by ketanserin (10-6 M) suggesting that 5-HT2Areceptors do not make a significant contribution in this model.6. Hence, precontraction of rabbit mesenteric arteries reveals potent vasoconstrictor effects of 5-HT and related agonists. Based on the agonist potency order and the antagonist studies performed, the receptor subtype responsible has the characteristics of a 5-HT1-like (probably 5-HTlD) receptor. This study therefore demonstrates a particularly striking example of vasoconstrictor synergy involving 5-HT1-like receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2004

Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium.

Insulin exerts both NO-dependent vasodilator and endothelin-dependent vasoconstrictor effects on skeletal muscle arterioles. The intracellular enzymes 1-phosphatidylinositol 3-kinase (PI3-kinase) and Akt have been shown to mediate the vasodilator effects of insulin, but the signaling molecules involved in the vasoconstrictor effects of insulin in these arterioles are unknown. Our objective was to identify intracellular mediators of acute vasoconstrictor effects of insulin on skeletal muscle arterioles. Rat cremaster first-order arterioles (n=40) were isolated, and vasoreactivity to insulin was studied using a pressure myograph. Insulin induced dose-dependent vasoconstriction of skeletal muscle arterioles (up to -22 +/- 3% of basal diameter; P <0.05) during PI3-kinase inhibition with wortmannin (50 nmol/l). Insulin-induced vasoconstriction was abolished by inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) with PD-98059 (40 micromol/l). In addition, inhibition of ERK1/2 without PI3-kinase inhibition uncovered insulin-mediated vasodilatation in skeletal muscle arterioles (up to 37 +/- 10% of baseline diameter; P <0.05). Effects of insulin on ERK1/2 activation in arterioles were then investigated by Western blot analysis. Insulin induced a transient 2.4-fold increase in ERK1/2 phosphorylation (maximal at approximately 15 min) in skeletal muscle arterioles (P <0.05). Removal of the arteriolar endothelium abolished insulin-induced vasoconstriction, which suggests that activation of ERK1/2 in endothelial cells is involved in acute insulin-mediated vasoconstriction. To investigate this, acute effects of insulin on ERK1/2 phosphorylation were studied in human microvascular endothelial cells. In support of the findings in skeletal muscle arterioles, insulin induced a 1.9-fold increase in ERK1/2 phosphorylation (maximal at approximately 15 min) in microvascular endothelial cells (P <0.05). We conclude that acute vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by activation of ERK1/2 in endothelium. This ERK1/2-mediated vasoconstrictor effect antagonizes insulin-induced, PI3-kinase-dependent vasodilatation in skeletal muscle arterioles. These findings provide a novel mechanism by which insulin may determine blood flow and glucose disposal in skeletal muscle.

Androstadienes↗

PubMed1990

Combined effects of autoregulation and vasoconstrictors on hindquarters vascular resistance.

Relative contributions of local autoregulatory tone and vasoconstrictor tone to skeletal muscle vascular resistance were studied in anesthetized rats during hypertension produced by vasoconstrictor infusion. Rats were instrumented with a Doppler flow probe on the sacral aorta (SA) to measure blood flow and to allow calculation of vascular resistance. An occluder was placed on the SA and used to produce stepwise reductions in local perfusion pressure. Pressure-flow curves for the hindquarters were obtained in the absence and presence of elevated mean arterial pressure (MAP) produced by infusion of angiotensin II (ANG II; 50-1,247 ng.kg-1.min-1) or phenylephrine (PE; 2.5-12.4 micrograms.kg-1.min-1). Both ANG II and PE infusion increased MAP. For example, MAP was increased by ANG II from 91 to 134 mmHg and by PE from 89 to 156 mmHg. In addition, infusions of ANG II and PE produced dose-dependent rightward shifts in the hindquarters pressure-flow relationship. To examine the effect of pressure on the dose-response relationships of ANG II or PE, local perfusion pressure was adjusted to remain constant at various pressure levels that were independent of MAP during drug infusions. This produced a series of distinct dose-response curves with each curve defined by a different pressure level and with each characterized by a different maximum change in vascular resistance. If local perfusion pressure was not held constant but was permitted to increase with MAP, a compound dose-response curve was obtained in which the combined effects of the change in local pressure (i.e., autoregulation) and vasoconstrictor dose on vascular resistance could be discerned. These data demonstrate that hindquarters blood flow autoregulation continues to occur in the presence of vasoconstrictors. Consequently, autoregulatory mechanisms may be stimulated by any increase in MAP whether associated with systemic vasoconstrictor infusion or activation of neurohumoral pressor systems. The result is an amplified rise in local vascular resistance.

Angiotensin II↗

PubMed2003

Effects of 14 days of head-down tilt bed rest on cutaneous vasoconstrictor responses in humans.

This study tested the hypothesis that head-down tilt bed rest (HDBR) reduces adrenergic and nonadrenergic cutaneous vasoconstrictor responsiveness. Additionally, an exercise countermeasure group was included to identify whether exercise during bed rest might counteract any vasoconstrictor deficits that arose during HDBR. Twenty-two subjects underwent 14 days of strict 6 degrees HDBR. Eight of these 22 subjects did not exercise during HDBR, while 14 of these subjects exercised on a supine cycle ergometer for 90 min a day at 75% of pre-bed rest heart rate maximum. To assess alpha-adrenergic vasoconstrictor responsiveness, intradermal microdialysis was used to locally administer norepinephrine (NE), while forearm skin blood flow (SkBF; laser-Doppler flowmetry) was monitored over microdialysis membranes. Nonlinear regression modeling was used to identify the effective drug concentration that caused 50% of the cutaneous vasoconstrictor response (EC(50)) and minimum values from the SkBF-NE dose-response curves. In addition, the effects of HDBR on nonadrenergic cutaneous vasoconstriction were assessed via the venoarteriolar response of the forearm and leg. HDBR did not alter EC(50) or the magnitude of cutaneous vasoconstriction to exogenous NE administration regardless of whether the subjects exercised during HDBR. Moreover, HDBR did not alter the forearm venoarteriolar response in either the control or exercise groups during HDBR. However, HDBR significantly reduced the magnitude of cutaneous vasoconstriction due to the venoarteriolar response in the leg, and this response was similarly reduced in the exercise group. These data suggest that HDBR does not alter cutaneous vasoconstrictor responses to exogenous NE administration, whereas cutaneous vasoconstriction of the leg due to the venoarteriolar response is reduced after HDBR. It remains unclear whether attenuated venoarteriolar responses in the lower limbs contribute to reduced orthostatic tolerance after bed rest and spaceflight.

Adult↗