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PubMed1999

Ketamine preserves and propofol potentiates hypoxic pulmonary vasoconstriction compared with the conscious state in chronically instrumented dogs.

BACKGROUND: The authors tested the hypothesis that ketamine and propofol anesthesia would alter the magnitude of hypoxic pulmonary vasoconstriction compared with the conscious state. In addition, they assessed the extent to which cyclooxygenase pathway inhibition and adenosine triphosphate-sensitive potassium channel inhibition modulate hypoxic pulmonary vasoconstriction in the conscious state, and whether these pathways are altered during propofol anesthesia. METHODS: Twenty conditioned, male mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow relationship. Pressure-flow plots were measured during normoxia and hypoxia (systemic arterial PO2 reduced to about 60 and about 50 mm Hg) on separate days in the conscious state, during ketamine anesthesia, and during propofol anesthesia. The effects of indomethacin and glibenclamide on the magnitude of hypoxic pulmonary vasoconstriction were also assessed in the conscious and propofol-anesthetized states. RESULTS: Neither ketamine nor propofol had an effect on the baseline pressure-flow relationship during normoxia compared with the conscious state. Hypoxia resulted in stimulus-dependent pulmonary vasoconstriction (P<0.01) in the conscious state. Compared with the conscious state, the magnitude of hypoxic pulmonary vasoconstriction was preserved during ketamine but was potentiated (P<0.01) during propofol anesthesia. Indomethacin enhanced (P<0.01) hypoxic pulmonary vasoconstriction in both the conscious and propofol-anesthetized states. In contrast, glibenclamide only enhanced (P<0.01) hypoxic pulmonary vasoconstriction in the conscious state and had no effect during propofol anesthesia. CONCLUSION: Hypoxic pulmonary vasoconstriction is preserved during ketamine anesthesia but is potentiated during propofol anesthesia. The potentiated response during propofol anesthesia appears to be caused by inhibition of adenosine triphosphate-sensitive potassium channel-mediated pulmonary vasodilation.

Anesthetics, Dissociative↗
PubMed1988

Postsynaptic alpha 1- and alpha 2-adrenergic mechanisms in coronary vasoconstriction.

This study examined the relative importance of postsynaptic alpha 1- and alpha 2-adrenoceptors in mediating coronary vasoconstriction in open chest dogs in which the left circumflex coronary artery was cannulated and perfused at a constant rate. The cervical vagus nerves and central connections of the stellate ganglia were transected, and beta-adrenergic blockade was produced with propranolol. Coronary vasoconstriction occurred in response to intraarterial administration of both the alpha 1-agonist phenylephrine and the alpha 2-agonist BHT 933. The response to phenylephrine was partially blocked with prazosin and nearly completely eliminated by yohimbine. The response to BHT 933 was resistant to prazosin, but almost completely blocked by yohimbine. Coronary vasoconstriction produced by norepinephrine was resistant to prazosin, but was blunted by alpha 2-adrenergic blockade with yohimbine or idazoxan. Prazosin produced some blunting of coronary vasoconstriction in response to small doses of epinephrine, while yohimbine markedly attenuated epinephrine-induced vasoconstriction at all doses used. Measurements of regional myocardial blood flow with radioactive microspheres demonstrated no transmural redistribution of perfusion during vasoconstriction produced by either alpha 1- or alpha 2 stimulation. Thus, although stimulation of both alpha 1- and alpha 2-adrenoceptors is capable of causing coronary vasoconstriction, vasoconstriction in response to norepinephrine and epinephrine is mediated principally by postsynaptic alpha 2-adrenoceptors.

Animals↗
PubMed1997

Autacoids mediate coronary vasoconstriction induced by nitric oxide synthesis inhibition.

Inhibition of nitric oxide (NO) synthesis results in coronary vasoconstriction. Using a Langendorff rat heart preparation, we tested the hypothesis that this vasoconstriction is caused by the unopposed effect of the autacoids prostaglandin H2 (PGH2) or thromboxane A2 (TxA2) or both through a mechanism that involves oxygen free radicals. The vasoconstriction induced by NO synthesis inhibition was studied with two different NO synthase inhibitors, N(omega)-nitro-L-arginine methyl ester (L-NAME) and N(omega)-monomethyl-L-arginine (L-NMMA). We found that the decrease in coronary flow (CF) induced by L-NAME (from 19.3 +/- 0.9 to 13.2 +/- 0.9 ml/min; p < 0.001) and L-NMMA (from 20.1 +/- 0.4 to 15.0 +/- 0.3 ml/min; p < 0.001) was completely blocked by the cyclooxygenase inhibitor indomethacin. A different cyclooxygenase inhibitor (ibuprofen), a PGH2/TxA2-receptor antagonist (SQ29548), and a TxA2 synthase inhibitor (CGS 13080) also completely abolished the vasoconstrictor effect of L-NAME, suggesting that this vasoconstriction is mediated by TxA2. Two different scavengers of superoxide radical anions (O2-), the enzyme superoxide dismutase (SOD) and a cell-permeable SOD mimic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), also blocked the vasoconstriction induced by NO synthesis inhibition. In contrast, catalase, which inactivates hydrogen peroxide (H2O2), failed to do so, indicating that O2- is needed for the vasoconstrictor effect of L-NAME, whereas H2O2 is not. To determine whether O2- acts on the conversion of PGH2 to TxA2 or at the receptor or postreceptor level, we studied whether the vasoconstriction induced by exogenous PGH2 or the TxA2 receptor agonist U46619 is blocked by scavengers of O2-. CF decreased by 50% with PGH2 (from 21 +/- 2.1 to 10.6 +/- 5.8 ml/min; p < 0.01), and this decrease was abolished by SOD and Tempol but not catalase. However, SOD had no effect on the vasoconstriction induced by U46619, which decreased CF by 45% (from 17.3 +/- 2.5 to 9.5 +/- 1.8 ml/min; p < 0.01). In addition, PGH2 increased the release of TxB2 (the stable metabolite of TxA2) in the coronary effluent (from 5.1 +/- 1.2 to 136.1 +/- 11.8 pg/ml/min). The release of TxB2 was significantly lower in hearts treated with SOD (76.8 +/- 14.2 pg/ml/min) and CGS (65.7 +/- 13.9 pg/ml/min). We conclude that the coronary vasoconstriction induced by inhibition of NO synthesis is the result of the unopposed effect of the autacoid TxA2 through activation of its receptor, and that O2- is necessary for conversion of PGH2 to TxA2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2002

Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation.

Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.

Adrenergic alpha-Antagonists↗
PubMed2007

Selective protein kinase C inhibition attenuates pulmonary artery cytokine expression without affecting hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction may be an adaptive response to shunt blood to well-oxygenated areas of the lung, but hypoxia-induced inflammatory cytokine production leads to acute lung injury. We have previously shown that protein kinase C (PKC) mediates both hypoxic pulmonary vasoconstriction and inflammatory cytokine expression from the pulmonary artery; however, the effect of specific PKC isoform inhibition is currently unknown. We hypothesized that inhibition of classical PKC (cPKC) isoforms would attenuate hypoxic pulmonary vasoconstriction and downregulate hypoxia-induced pulmonary artery cytokine expression. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n = 6 per group) during hypoxia (95% N2/5% CO2) in the presence of the nonspecific PKC inhibitor bisindolylmaleimide (1 micromol/L), the cPKC inhibitor Gö 6976 (1 - 10 micromol/L), or vehicle (dimethyl sulfoxide, 0.001%). After 60 min of hypoxia, pulmonary artery rings were analyzed for tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta messenger RNA via reverse transcriptase-polymerase chain reaction. Nonspecific PKC inhibition (bisindolylmaleimide) significantly attenuated hypoxic pulmonary vasoconstriction (44.59 +/- 10.52% vs. 87.06 +/- 10.91% vehicle; P < 0.001) and downregulated hypoxia-induced expression of pulmonary artery TNF-alpha. Specific cPKC inhibition (Gö 6976) attenuated pulmonary artery TNF-alpha expression but had no effect on hypoxic pulmonary vasoconstriction. These data are indicative of the following: (1) nonspecific PKC inhibition attenuates both hypoxic pulmonary vasoconstriction and pulmonary artery TNF-alpha expression, (2) cPKC inhibition downregulates hypoxia-induced pulmonary artery TNF-alpha expression but has no effect on hypoxic pulmonary vasoconstriction, and (3) hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery cytokine expression are independent processes.

Animals↗
PubMed2005

Alpha-2B adrenoceptor polymorphism and peripheral vasoconstriction.

OBJECTIVES: Alpha-2B adrenoceptors (AR) mediate vasoconstriction in the mice. A human alpha-2B AR deletion (D) variant has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction upon alpha-2 AR activation. This study tested the hypothesis that alpha-2 AR activation will induce enhanced vasoconstriction in carriers of the alpha-2B AR DD genotype, compared to carriers of the II or the DI genotypes. METHODS: We administered 1 microg/kg dexmedetomidine (an alpha-2 agonist) intravenously to 80 surgical patients in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmission through a finger (LTF) and of hemodynamic variables. RESULTS: Dexmedetomidine increased LTF (vasoconstriction), induced an initial increase in systolic blood pressure and decreased heart rate in all genotype groups (P<0.0001 for all). Three min after the start of dexmedetomidine infusion, the increase in LTF was more pronounced (P=0.014) in the DD group compared to the DI and II groups. There were no significant differences in LTF values between the groups at the end of or 5 min after dexmedetomidine infusion. There were no differences in systolic blood pressure or heart rate values between the groups during or after the dexmedetomidine infusion. CONCLUSIONS: The results of this study confirm that the alpha-2 agonist dexmedetomidine induced marked peripheral vasoconstriction. Subjects with the alpha 2B DD genotype had an enhanced vasoconstrictive response at the beginning of dexmedetomidine infusion. However, this enhanced vasoconstrictive response was not sustained throughout or after the 15-min dexmedetomidine infusion.

Adrenergic alpha-2 Receptor Agonists↗
PubMedDate not supplied

Coronary and aortic vasoconstriction by cathinone, the active constituent of khat.

1. The psychostimulant constituent of khat leaves, S-(-)-cathinone, was examined for vascular activity on the coronary vasculature of guinea-pig-isolated perfused hearts and aortic ring preparations. 2. Cathinone caused coronary vasoconstriction, negative inotropy and negative chronotropy in isolated hearts. The major metabolite of cathinone after its ingestion, 1R.2S-(-)-norephedrine (norephedrine), also caused coronary vasoconstriction comparable with that by cathinone. Norephedrine, however, had no effect on force or rate of cardiac contractions. 3. Cocaine (10 microm) potentiated the coronary vasoconstriction and positive inotropy by noradrenaline indicating inhibition of neuronal uptake. The vasoconstriction and negative inotropy by cathinone, however, were not affected, indicating that its action was not via release of noradrenaline from sympathetic neurones. 4. The alpha(1)-adrenoceptor antagonist, prazosin, blocked the vasoconstriction by noradrenaline, but not that produced by cathinone in the presence of cocaine. This indicates that the coronary vasoconstriction by cathinone was not due to an action on alpha(1)-adrenoceptors either directly or indirectly through noradrenaline release. 5. Three repeated doses of cathinone displayed the same coronary vasoconstrictor responses, indicating a lack of tachyphylaxis and therefore confirming that the response was unlikely to be due to indirect sympathomimetic activity through release of noradrenaline. 6. In guinea-pig aortic rings, the order of vasoconstrictor activity was: noradrenaline > norephedrine > cathinone, with each causing approximately equivalent maximum responses. The time to reach plateau contractions was shortest for noradrenaline (5.1 +/- 0.5 min), then norephedrine (9.3 +/- 1.5 min) and cathinone the longest (25.4 +/- 3.2 min, 335 microm dose). 7 These results indicate that cathinone has vasoconstrictor activity which is not due to indirect or direct sympathomimetic activity. The precise mechanism for this vasoconstriction remains to be determined. The coronary vasoconstriction may explain the increased incidence of myocardial infarction in khat chewers, which may arise from coronary vasospasm.

Alkaloids↗
PubMed1995

Inhibition of sympathetic vasoconstriction in pigs in vivo by the neuropeptide Y-Y1 receptor antagonist BIBP 3226.

1. Recently, a potent non-peptide antagonist of neuropeptide Y (NPY)-Y1 receptors has been developed. In this study, the selectivity of this compound, BIBP 3226, as a functional Y1 receptor antagonist, and the possible role of endogenous NPY in sympathetic vasoconstriction in different vascular beds have been investigated in anaesthetized pigs. 2. BIBP 3226 specifically displaced [125I]-NPY binding with an IC50 value of 7 nM in membranes of pig renal arteries, which also were responsive to a Y1 receptor agonist, but had only minor effects in the pig spleen (IC50 55 microM), where instead [125I]-NPY binding was markedly inhibited by a Y2 receptor agonist. IC50 values in the same nM range for BIBP 3226 were also observed in rat and bovine cortex and dog spleen. 3. In anaesthetized control pigs in vivo BIBP 3226 (1 and 3 mg kg-1) markedly inhibited the vasoconstrictor effects of the Y1 receptor agonist [Leu31, Pro34] NPY(1-36), without influencing the responses to the Y2 receptor agonist N-acetyl [Leu28, Leu31] NPY(24-36), or to noradrenaline, phenylephrine, alpha,beta-methylene adenosine triphosphate or angiotensin II. 4. High frequency stimulation of the sympathetic trunk in control pigs caused a biphasic vasoconstrictor response in nasal mucosa, hind limb and skin: there was an immediate, peak response, followed by a long-lasting vasoconstriction. BIBP 3226 (1 and 3 mg kg-1) reduced the second phase by about 50% but had no effect on the peak response. In the spleen, kidney and mesenteric circulation (which lack the protracted response) BIBP 3226 was likewise without effect on the maximal vasoconstriction, and did not influence noradrenaline overflow from spleen and kidney. 5. The corresponding S-enantiomer BIBP 3435 had only marginal influence on [125I]-NPY binding (microM range) and did not inhibit the vasoconstrictor effects of any of the agonists used, including the Y1 receptor peptide agonist. Furthermore, BIBP 3435 did not affect the response to sympathetic nerve stimulation. Both BIBP 3435 and BIBP 3226 caused a slight transient decrease in mean arterial blood pressure (by about 5 and 15 mmHg at 1 mg kg-1 and 3 mg kg-1, respectively), accompanied by splenic and mesenteric vasodilatation, suggesting that this effect was unrelated to Y1 receptor blockade. 6. The peptide YY (PYY)- and NPY-evoked vasoconstriction in the kidney of reserpine-treated pigs was markedly reduced (by 95%) by BIBP 3226 while the vasoconstrictor effect in the spleen was attenuated by only 20%. BIBP 3226 did not influence stimulation-evoked NPY release. The vasoconstrictor response in reserpine-treated pigs to single impulse stimulation, which is observed only in nasal mucosa and hind limb, was unchanged regarding maximal amplitude and the integrated effect was only moderately reduced (by about 25%) in the presence of BIBP 3226 (1 mg kg-1). BIBP 3226 (1 mg kg-1) markedly reduced (by 55-70%) the long-lasting vascular response (total integrated blood flow reduction) evoked by sympathetic nerve stimulation at high frequency (40 impulses at 20 Hz) in spleen, kidney, nasal mucosa and hind limb. Furthermore, the maximal amplitude of the vasoconstriction was reduced mainly in the kidney (by 60%) and also in the spleen (by 40%). 7. It is concluded that BIBP 3226 can act as a selective Y1 receptor antagonist in the pig. Endogenous NPY via Y1 receptor activation may play a role in evoking the long-lasting vasoconstriction seen in nasal mucosa, hind limb and skin after high frequency stimulation of sympathetic nerves in control pigs. Furthermore, NPY via Y1 receptor mechanisms seems to be of major importance for the long-lasting component of the reserpine resistant sympathetic vasoconstriction in many vascular beds, and for the maximal vasoconstrictor response in the kidney. Circulating NPY and PYY induce splenic vasoconstriction via Y2-receptors in contrast to neuronally released NPY which mainly activates Y1 receptors.

Animals↗
PubMed1997

Possible role of T-type Ca2+ channels in L-NNA vasoconstriction of hypertensive rat lungs.

Acute inhibition of endothelium-derived nitric oxide (NO) synthesis by L-arginine analogs such as N omega-nitro-L-arginine (L-NNA) has little effect on basal vascular tone in normal rat lungs but elicits marked vasoconstriction in hypertensive lungs. The NO-suppressible vasoconstriction is dependent on extracellular Ca2+ but is not mediated by L-type Ca2+ channels. This study tested whether the response was mediated by Ca2+ influx through receptor-operated channels, reverse Na+/Ca2+ exchange, or low-threshold voltage-gated (T-type) Ca2+ channels. We first examined whether SKF-96365, a blocker of receptor-operated Ca2+ channels, inhibited L-NNA-induced vasoconstriction in salt solution-perfused hypertensive lungs isolated from chronically hypoxic male rats (exposed to hypobaria of 410 mmHg for 3-5 wk). Whereas 50 microM SKF-96365 inhibited pressor responses to angiotensin II and acute hypoxia, it did not reduce vasoconstriction in response to 100 microM L-NNA. We next examined effects of pretreatment with Na+/Ca2+ exchange blockers and observed that L-NNA vasoconstriction was reduced by both 100 microM amiloride and 50 microM ethylisopropyl amiloride (EIPA). The third experiment showed that each of two different blockers of T-type Ca2+ channels, 10 microM Ro-40-5967 and 300 microM nordihydroguariaretic acid, inhibited L-NNA vasoconstriction and that the combination of EIPA and Ro-40-5967 did not cause more inhibition than did Ro-40-5967 alone. These results suggest that, whereas receptor-operated Ca2+ channels are not significantly involved in the mechanism of NO-suppressible vasoconstriction in hypertensive rat lungs, Ca2+ influx through reverse Na+/Ca2+ exchange and/or T-type Ca2+ channels may play a role. Because both amiloride and EIPA also inhibit T-type Ca2+ channels, we speculate that Ca2+ influx through these channels rather than through reverse Na+/Ca2+ exchange is an important mediator of the vasoconstriction.

Animals↗
PubMed1989

Endothelium-dependent arterial vasoconstriction after balloon angioplasty.

To determine whether balloon angioplasty can provoke arterial vasoconstriction independent of platelet aggregation and neurogenic input, we studied the spontaneous vasomotor effects of balloon dilatation in isolated, perfused whole-vessel segments of rabbit aorta and pig carotid artery. Freshly dissected rabbit thoracic aortas were mounted in a muscle bath-perfusion chamber, perfused with physiologic saline solution at 70 mm Hg, and allowed to equilibrate. The proximal or distal half of the aortas were dilated with either a "large" (5 mm, 31-51% stretch beyond relaxed diameter) or a "small" (4 mm, 5-16% stretch) balloon angioplasty catheter with the other half of the vessel serving as the control. A similar series of experiments were performed in pig carotid arteries using "large" (6 or 8 mm, 48-90% stretch) balloon catheters. The spontaneous vasomotor effects of balloon angioplasty were examined with long-axis, high-frequency ultrasonic imaging combined with computerized edge detection image processing to measure changes in segmental internal vessel diameters. Additional experiments were carried out in rabbit aortas to determine the roles of the endothelium, extracellular calcium, indomethacin, ibuprofen, and calcium-channel blockade in modulating angioplasty-induced vasoconstriction. Significant arterial vasoconstriction was observed in the balloon angioplasty segments after dilatation with 5-mm balloons but not with 4-mm balloons. After dilatation with 5-mm balloons, the angioplasty segments' cross-sectional areas decreased by an average of 31% versus 4% for the nondilated (control) segments (p less than 0.0001). Similar postangioplasty vasoconstriction was observed in the pig carotid arteries (decrease in minimal vessel cross-sectional area of 41% [angioplasty segment] versus 2% [control segment]) (p less than 0.005). This angioplasty-induced vasoconstriction was prevented by endothelial denudation before angioplasty, removal of extracellular calcium, and pretreatment with indomethacin or ibuprofen. The vasoconstriction was only partially inhibited by calcium channel blockade with verapamil. These findings demonstrate that stretch-pressure-induced arterial vasoconstriction may occur after balloon angioplasty, independent of platelet aggregation and neurogenic input. This angioplasty-induced vasoconstriction appears to be mediated by an endothelially derived cyclooxygenase product(s).

Angioplasty, Balloon↗
PubMed1989

Adenosine produces pulmonary vasoconstriction in sheep. Evidence for thromboxane A2/prostaglandin endoperoxide-receptor activation.

Adenosine, an intermediate product in the metabolism of ATP, is thought to produce vasodilation in all vascular beds with the exception of the kidney. Due to its theoretical potential as a pulmonary vasodilator, we studied the hemodynamic effects of adenosine in the pulmonary vasculature of chronically instrumented awake sheep. Adenosine produced significant pulmonary vasoconstriction instead of the expected vasodilatation. Bolus injections of adenosine into the superior vena cava produced a dose-dependent increase in pulmonary artery pressure that was entirely due to an increase in vascular resistance, since cardiac output decreased slightly. This effect is produced via activation of specific cell surface adenosine receptors, since it was blocked by the adenosine-receptor antagonists theophylline and dipropylsulfophenylxanthine. The cell type involved in adenosine-induced pulmonary vasoconstriction appears to be located within the lung, since vasoconstriction was blunted when adenosine was infused into the left atrium, distal to the lung. However, adenosine does not directly vasoconstrict the pulmonary vasculature, because its effect could be completely abolished by cyclooxygenase inhibition with either indomethacin or ibuprofen and by a thromboxane A2/prostaglandin endoperoxide-receptor antagonist (SQ 29,548). Adenosine-induced vasoconstriction was also greatly reduced after inhibition of thromboxane synthesis. Thus, adenosine produced pulmonary vasoconstriction through generation of a thromboxane/endoperoxide product. Whether endogenous adenosine is involved in the generation of pulmonary vasoconstriction seen in pathophysiological states remains to be determined. To our knowledge, this is the first clear evidence for adenosine-induced vasoconstriction outside the kidney and for an interaction between adenosine and eicosanoid mechanisms.

Adenosine↗
PubMed1979

Mechanism of postarrhythmic renal vasoconstriction in the anesthetized dog.

The mechanism of postarrhythmic renal vasoconstriction was studied in 28 dogs anesthetized with pentobarbital sodium (30 mg/kg i.v.). Rapid atrial or ventricular pacing or induction of atrial fibrilation were used to produce at least 20% prompt decrease in cardiac output and mean arterial blood pressure. Return to control cardiac output and blood pressure occurred within 3 minutes after cessation of the arrhythmia, but renal blood flow remained significantly decreased (26%) with gradual recovery by 17.7 +/- 6.6 min. Infusion of phentolamine (0.25 mg/min) into the renal artery, intravenous hexamethonium (l mg/kg), adrenal demedullation, or cooling the cervical vagi prevented postarrhythmic renal vasoconstriction. In contrast, renal denervation, intravenous bretylium (10 mg/kg), intravenous atropine (0.5 mg/kg) or intrarenal SQ 20881 (0.20 mg/min) has no effect on postarrhythmic renal vasoconstriction. Intravenous propranolol (0.5 mg/kg) intensified postarrhythmic renal vasoconstriction. These data suggested that the postarrhythmic renal vasoconstrictive response required intact vagi and was due to alpha adrenergic stimulation by adrenal catecholamines. However, femoral arterial catecholamine levels were not elevated above control during postarrhythmic renal vasoconstriction. We therefore sought local vascular pathways by which catecholamines might reach the kidneys. An adrenorenal vascular network was found in each dog. Collection of catecholamines from these vessels during postarrhythmic renal vasoconstriction in six dogs revealed catecholamine concentrations threefold higher than simultaneously collected femoral arterial catecholamines levels. Because ligation of these vessels abolished postarrhythmic renal vasoconstriction in each dog, we conclude that postarrhythmic renal vasconstriction is due to adrenal catecholamines reaching the kidneys through an adreno-renal vascular network and that the response requires intact vagi.

Adrenal Glands↗
PubMed1984

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive O2 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate O2-metabolite-induced pulmonary vasoconstriction. We found that O2 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27 +/- 4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels of thromboxane B2 (the stable metabolite of thromboxane A2) compared with only twofold increases in 6-keto-PGF1a (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4 +/- 1.5 mmHg). Furthermore, imidazole, a thromboxane synthetase inhibitor, also decreased O2-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in O2-metabolite-induced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree of vasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to O2 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.

Animals↗
PubMed1997

Quantitative angiographic analysis of PTCA-induced coronary vasoconstriction in single-vessel coronary artery disease.

Quantitative coronary angiography was applied to investigate the degree and extent of coronary vasoconstriction following percutaneous transluminal coronary angioplasty (PTCA) in single-vessel disease of segments distal to the PTCA site (n = 46) and of control segments in nonmanipulated vessels (n = 33) before PTCA, 15 minutes after PTCA, and again 10 minutes after 10 mg sublingual isosonbide dinitrate (ISDN) in 46 patients receiving neither nitrates nor calcium channel blockers prior to PTCA. Furthermore, the degree of coronary vasoconstriction was compared with ergonovine-induced vasoconstriction (n = 8) as well as in patients with and without restenosis during follow-up angiography 4 months later. PTCA induced a moderate, but significant, vasoconstriction in both distal and control segments, with a reduction in coronary diameter from 2.34 +/- 0.58 to 2.26 +/- 0.55 mm (P = 0.011) and from 2.70 +/- 0.62 to 2.60 +/- 0.65 mm (P = 0.004), respectively. No correlation between the degree of vasoconstriction on the one side and lesion severity and PTCA-induced mechanical stretch, judged by the sum of the products of inflation pressure and time, on the other side was found. Vasoconstriction was within the limits achievable with the potent vasoconstrictor ergonovine and did not differ in patients with or without restenosis. ISDN led to a significant vasodilatation in all segments. In conclusion, coronary vasoconstriction following PTCA is present in the coronary tree in a rather diffuse way. It is not associated with stenosis severity or PTCA-induced mechanical stretch, suggesting a complex underlying mechanism. ISDN-reversible vasoconstriction was within the limits achievable with ergonovine and did not differ with regard to restenosis.

Administration, Sublingual↗
PubMed1993

Mechanism of pindolol-induced vasoconstriction in isolated and perfused dog coronary arteries.

The mechanism of pindolol-induced vasoconstriction in isolated and perfused dog coronary arteries was studied. Single injections of pindolol (1-100 micrograms), propranolol (1-30 micrograms), and 5-hydroxytryptamine (5-HT, 0.001-1 microgram) produced a dose-related vasoconstriction in dog coronary arteries which were dilated by acetylcholine. l-Pindolol constricted coronary arteries, but d-pindolol did not. The responses to pindolol and propranolol were not affected by any of the following compounds (100 micrograms): bunazosin (a selective alpha 1-adrenergic antagonist), DG 5128 (a selective alpha 2-adrenergic antagonist), atropine (a muscarinic antagonist), chlorpheniramine (a selective H1-antagonist), cimetidine (a selective H2-antagonist), and ketanserin (a selective 5-HT2 antagonist). Methysergide (10 micrograms, a 5-HT1 and 5-HT2 antagonist) significantly reduced pindolol- and propranolol-induced vasoconstrictions, although it did not reduce norepinephrine-induced vasoconstriction in the presence of 5 microM propranolol. Methysergide (10 micrograms) and ketanserin (100 micrograms) significantly suppressed 5-HT-induced vasoconstriction. Diltiazem (100 micrograms, a calcium antagonist) and the incubation in Ca(2+)-free solution containing 1 mM EGTA for 1 hr significantly reduced the vasoconstrictions induced by pindolol and propranolol. The Ca(2+)-free solution containing 1 mM EGTA abolished the vasoconstriction induced by 5-HT in the presence of 1 microM ketanserine. In a solution containing 20 mM KCl, the vasoconstrictions caused by pindolol and propranolol were enhanced in dog coronary arteries. These results indicate that the direct contractile effects of pindolol on dog coronary arteries are mediated, at least partly, through 5-HT1-like receptors, but not through alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed2000

Cytochrome P450 omega/omega-1 hydroxylase-derived eicosanoids contribute to endothelin(A) and endothelin(B) receptor-mediated vasoconstriction to endothelin-1 in the rat preglomerular arteriole.

The preglomerular arteriole of the rat was used to evaluate the contribution of cytochrome P450-derived eicosanoids to the vasoconstrictor effect of endothelin (ET)-1 and to determine the receptors mediating the response. ET-1 (4 x 10(-11) to 2 x 10(-9) M) produced dose-dependent reductions in the intraluminal diameter of the renal arteriole ranging from 25 +/- 8 to 142 +/- 16 micrometer. BMS182874 [(5-dimethylamino)-N-(3, 4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; 3 microM], an ET(A) receptor antagonist, or BQ788 (N-cis-2, 6-dimethyl-piperidino-carbonyl-L-gamma-methylleucyl-D-1-methoxy carbonyl-tryptophanyl-D-norleucine; 1 microM), an ET(B) receptor antagonist, attenuated ET-1 vasoconstriction by 59 +/- 4 and 50 +/- 10%, respectively. The combined administration of both ET receptor antagonists increased inhibition of ET-1 vasoconstriction to 75 +/- 4%. 17-Octadecynoic acid (17-ODYA, 2 microM) or 12, 12-dibromododec-enoic acid (2 microM), inhibitors of 20-hydroxyeicosatetraenoic acid (20-HETE) production, attenuated ET-1-induced vasoconstriction by 50 +/- 6 and 40 +/- 3%, respectively, as did indomethacin (10 microM), an inhibitor of cyclooxygenase. Miconazole (2 microM), the epoxygenase inhibitor, was without effect. 20-HETE (10(-8) and 2 x 10(-8) M) elicited a dose-related vasoconstriction that was inhibited by 10 microM, but not 5 microM, indomethacin. The inhibition by 17-ODYA of ET-1 vasoconstriction was not greater when combined with BMS182874 or BQ788. Moreover, vasoconstriction induced by ET-3, an ET(B)-selective agonist, was inhibited by 17-ODYA. These data indicate that both ET(A) and ET(B) receptors mediate ET-1 vasoconstriction and that 20-HETE production linked to both receptors makes a major contribution to ET-1-induced renal arteriolar vasoconstriction in the rat.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2000

[Experimental study of mechanism and measures of prevention and treatment of hypothermal vasoconstriction].

OBJECTIVE: To investigate the mechanism and to explore the measures of prevention and treatment of hypothermal vasoconstriction. METHODS: By the techniques of endothelial cell culture and scanning electron microscopy, and vasomotor functional test of isolated vascular vessels, the relation of hypothermal vasoconstriction and the release of endothelium-derived contractile and vasodilative factors were observed. RESULTS: Hypothermia obviously induced vasoconstriction of isolated vascular vessels, whether endothelium was intact or removed, the lower the temperature, the higher the vascular tension. Removal of endothelium could decrease the effect of vasoconstriction by hypothermia. The conditioned medium of bovine aortic endothelial cell could induce significantly vasoconstriction of isolated rat common neck arterial ring in hypothermia. It indicated that the bovine aortic endothelial cells secreted contractile factors into the medium. Reheating to 37 degrees C or vasodilator or reheating plus vasodilator did not obviously influence the hypothermia-induced vasoconstriction within 2 hours. When reheating to 50 degrees C, vascular tension was decreased, but only changed in range of 28% to 42%. CONCLUSION: Hypothermia vasoconstriction is relative to vasoconstrictor factors secreted by endothelium. Reheating to 37 degrees C or vasodilator does not antagonize the constriction of vascular vessels. Reheating to 50 degrees C only partially eliminates the constrict effect of blood vessels, so the prevention of hypothermia vasoconstriction should be emphasized.

Animals↗
PubMed1991

Spontaneous and pharmacologically-induced vasoconstrictive responses of rat aortic rings are attenuated by balloon angioplasty.

The effects of arterial dilatation with differently sized PTCA catheters on prestretch-induced, receptor-induced and voltage-induced vasoconstriction was investigated. Rat aortic rings were kept incubated in HEPES buffer for 0,3,6, and 12 hours before mounting in the experimental set-up for contraction measurements. Balloon dilation (BD) was applied prior to incubation or directly before measurement following a period of incubation. Isometric force was measured after applying a prestretch to the vascular rings. The ring then contracted spontaneously or, if not, was brought to contraction by norepinephrine (NE, 50 microM) or potassium ions (K+, 30 mM). Prestretch-induced vasoconstriction reached maximum values after 6 hours of incubation. NE-induced vasoconstriction was maximal at 6 hours of incubation and K(+)-induced vasoconstriction kept rising up to 12 hours of incubation. The addition of enoximone resulted in vasodilatation (ED50 = 0.1 microM) of prestretch-induced vasoconstriction, but was less potent (ED50 = 168 microM) if added to NE-induced or K(+)-induced vasoconstricted rings. BD applied before the incubation period reduced prestretch-induced, receptor-induced and voltage-induced contractions (the effectivity decreasing in that order) and did not elicit vasospastic activity. BD applied after the incubation period and immediately before the contraction measurements prevented the occurrence of prestretch-induced spontaneous contractions, caused a nonsignificant (p = 0.08) decrease of NE-induced vasoconstriction, and had no effect on K(+)-induced vasoconstriction. It is concluded that this model to study spontaneous and induced vasoactivity elucidates the consequences of the application of balloon dilatation in nonatherosclerotic vascular rings.

Angioplasty, Balloon↗