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PubMed2006

Effects of hsp90 binding inhibitors on sGC-mediated vascular relaxation.

Vascular soluble guanylate cyclase (sGC) exists in multimeric complexes with endothelial nitric oxide (NO) synthase (eNOS) and heat shock protein 90 (hsp90). Whereas disruption of hsp90-eNOS complexes clearly attenuates eNOS-dependent vascular relaxation, the contribution of sGC-hsp90 complexes to eNOS- or NO donor-dependent relaxations remains unclear. Isolated rat thoracic aortic rings were preincubated with structurally diverse hsp90 binding inhibitors, radicicol (RA) or geldanamycin (GA), or vehicle for 0.5, 1, or 15 h. Preconstricted vessels were exposed to ACh, 8-bromo-cGMP (8-BrcGMP), forskolin, or one of three NO donors: nitroglycerin (NTG), sodium nitroprusside, or spermine NONOate (SNN). Both RA and GA inhibited endothelium-dependent relaxations dose dependently. Indomethacin or the antioxidant tiron did not affect the inhibition of ACh-induced relaxations by GA. Long-term (15 h) exposure to RA inhibited all NO donor-induced relaxations; however, GA inhibited SNN-induced relaxation only. The effects of GA and RA appeared to be selective because 15-h treatment with either agent did not affect forskolin-induced relaxations and only slightly decreased 8-BrcGMP-induced relaxations. Similarly to their effects on NO-donor-induced relaxation, 15-h exposure to RA, but not to GA, decreased hsp90-bound sGC protein expression and NTG-stimulated cGMP formation in aortic rings, whereas RA more than GA reduced SNN-stimulated cGMP formation. We conclude that RA, much more so than GA, selectively inhibits sGC-dependent relaxations of aortic rings by reducing sGC expression, disrupting sGC-hsp90 complex formation and decreasing cGMP formation. These studies suggest that hsp90 regulates both eNOS- and sGC-dependent relaxations.

Animals↗
PubMed1993

Dependence of endothelium-mediated relaxation on oxygen and metabolism in porcine coronary arteries.

Hypoxia has major effects on endothelium-dependent relaxation. To further understand the underlying mechanism(s), we investigated the O2 dependence of the endothelium-dependent relaxations elicited by ionophore A-23187 or agonists substance P (SP) or thrombin (TB) in porcine coronary arteries. A-23187 elicits an endothelium-dependent relaxation of KCl- or U-46619-induced contractures that can be described in terms of a rapid and slow phase. The duration of the relaxation was dose dependent. SP (10 nM) and TB (0.1 U/ml) also elicited endothelium-dependent relaxations that were rapid but transient. Hypoxic conditions (95% N2-5% CO2 instead of 95% O2-5% CO2; PO2 < 1%) abolished the A-23187 rapid phase and the SP and TB transient relaxation but not the A-23187 slow phase. Threshold PO2 for the rapid phase was approximately 35 mmHg. Pretreatment with cyanide (5 mM), to inhibit respiration, or 2-deoxy-D-glucose, to inhibit glycolysis, had little effect. Similarly, propranolol (10 microM) or indomethacin (10 microM) had no effect on the relaxation to A-23187, TB, or SP. In contrast, both NO synthesis inhibitors and ouabain blunted all endothelium-dependent relaxations studied. Our results suggest that the rapid relaxations to A-23187, SP, and TB are sensitive to O2 but not mitochondrial respiration. The slow sustained relaxation induced by A-23187, however, is characterized by a sensitivity to O2 that is distinct from that of the rapid phase, yet is dependent on an intact endothelium and is affected by NO synthesis inhibitors. Thus the endothelium-dependent relaxation to A-23187 is probably mediated by NO, but its sensitivity to O2 suggests that two distinct mechanisms may be involved.

Animals↗
PubMed2000

Endoplasmic reticulum contribution to the relaxant effect of cGMP- and cAMP-elevating agents in feline aorta.

The contribution of endoplasmic reticulum (ER) and phosphorylation of phospholamban (PLB) to the relaxant effect of cGMP- and cAMP-elevating agents was studied in feline aorta. Sodium nitroprusside (NP, 100 microM) completely relaxed contracture induced by 10 microM norepinephrine. This NP-induced relaxation was partially prevented by tetraethylammonium, suggesting that a fraction of NP-induced relaxation was mediated by activation of K(+) channels. In the absence and presence of tetraethylammonium, the relaxant effect of NP was associated with a significant increase in Ser(16) phosphorylation of PLB immunodetected by phosphorylation site-specific antibodies. The relaxant effect of NP on aortic strips precontracted with 80 mM KCl was significantly reduced by 1 microM thapsigargin. This decrease, which represents the ER contribution to the relaxant effect of NP, reached 23 +/- 9% at 100 microM NP and was closely associated with a dose-dependent increase in Ser(16) phosphorylation (128 +/- 49% over control at 100 microM NP). Effects of NP were associated with a significant increase in activity of protein kinase G and were mimicked by 8-bromo-cGMP. Forskolin produced a dose-dependent relaxant effect on KCl-induced contracture, which reached 64 +/- 8% at 50 microM and was associated with an increase in phosphorylation of Ser(16) residue of PLB (88 +/- 18% over control). Thapsigargin reduced this relaxant effect by 38 +/- 9%. 8-Bromo-cAMP mimicked effects of forskolin. The ER-mediated relaxant effect and the increase in Ser(16) phosphorylation produced by forskolin were partially blocked by the protein kinase A inhibitor H-89 (5 microM). The results indicate that ER partially contributes to the relaxant effect of NP and forskolin in feline aorta. This effect may be mediated by the associated increase in Ser(16) phosphorylation of PLB.

Adrenergic beta-Agonists↗
PubMed1998

Relaxant effects of sodium nitroprusside and NONOates in rabbit basilar artery.

Abstract NONOates are a new class of NO donors that have proven useful for studying the effects of spontaneous and chemically predictable NO release in biologic systems. In order to assess their potential as vasodilatatory drugs in the cerebrovascular bed we have compared the relaxant effects of the classical nitrovasodilator sodium nitroprusside (SNP) and three NONOates, diethylamine/NO complex (DEA/NO), spermine/NO complex (SPER/NO), and diethylenetriamine/NO complex (DETA/NO) in isolated rabbit basilar arteries precontracted with UTP. The 4 NO donors induced full relaxation of the UTP-induced tone, with the following order of potency: SNP > DEA/NO > SPER/NO > DETA/NO. Relaxations induced by SNP and DETA/NO were not modified in rubbed (endothelium denuded) arteries in which acetylcholine-relaxations were almost abolished. On the other hand, relaxations to SNP and SPER/NO were more potent and effective in histamine-precontracted arteries than in KCl-precontracted arteries. Methylene blue significantly inhibited SPER/NO-induced relaxations in both KCl- and histamine-precontracted arteries while SNP-induced relaxations were only slightly inhibited by methylene blue in KCl-precontracted arteries. This study shows that the NO donors SNP, DEA/NO, SPER/NO and DETA/NO have quantitatively different relaxant effects in rabbit basilar arteries according to their rate of NO release. Relaxations are not mediated by endothelial factors, and are inhibited by arterial depolarization. Finally, cGMP formation is involved in relaxation induced by NONOates and much less in SNP-induced relaxation.

Acetylcholine↗
PubMed1991

Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light.

The characteristics of carbon monoxide (CO)-induced, endothelium-independent relaxation of rabbit aorta were compared with those of nitric oxide (NO)-induced and light-induced relaxation and endothelium-dependent relaxation mediated by endothelium-dependent relaxing factor (EDRF). CO was less than one thousandth as potent as NO as a relaxant. Various findings, including an increase in cyclic GMP associated with CO-induced relaxation, led to the conclusion that CO - like NO, EDRF and light - produces relaxation as a result of its stimulation of guanylate cyclase. LY 83583, which generates superoxide, was a potent, fast-acting inhibitor of acetylcholine-induced endothelium-dependent relaxation and NO-induced relaxation, and a fairly potent, moderately fast-acting inhibitor of photorelaxation, but only a very weak inhibitor of CO-induced relaxation. The ability of LY 83583 as well as hemoglobin to inhibit photorelaxation is consistent with the hypothesis that on radiation a photo-induced relaxing factor is formed which can stimulate guanylate cyclase and which can be inactivated by superoxide and by hemoglobin.

Aminoquinolines↗
PubMed1995

Relaxation of the aorta during hypoxia is impaired in chronically hypertensive rats.

We investigated mechanisms by which hypoxia produces relaxation of the aorta and tested the hypothesis that these mechanisms are altered during chronic hypertension. Tension of thoracic aortae from normotensive Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) was measured in an organ bath under control conditions and at two levels of hypoxia. In WKY rats, mild and severe hypoxia produced relaxation of the aortae (precontracted with phenylephrine) by 33 +/- 4% and 82 +/- 3%, respectively (mean +/- SEM). Removal of endothelium or administration of NG-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide synthase, abolished relaxation of the aortae in response to mild hypoxia but did not affect relaxation during severe hypoxia. Glibenclamide (10(-6) mol/L), an inhibitor of potassium channels, attenuated relaxation of the aortae during mild and severe hypoxia by 49 +/- 16% and 74 +/- 4%, respectively. In SHRSP, mild hypoxia produced little relaxation of the aortae (3 +/- 4%, P < .05 compared with WKY). Indomethacin did not increase relaxation to mild hypoxia in SHRSP, which suggests that a cyclooxygenase-derived contracting factor does not contribute to impaired relaxation. Severe hypoxia relaxed the aortae by 86 +/- 4% in SHRSP, and glibenclamide inhibited this response by 60 +/- 9%. These findings suggest that relaxation of the aorta in response to mild hypoxia in WKY rats is mediated primarily by endothelium-derived relaxing factor, and the response to mild hypoxia is markedly impaired in SHRSP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Endothelial-dependent relaxation induced by leukotrienes C4, D4, and E4 in isolated canine arteries.

Leukotriene D4 has been shown to possess the capacity to relax canine superior mesenteric and renal arterial rings in an endothelial-dependent manner. The present study was designed to determine if the remaining peptidoleukotrienes, leukotrienes C4 and E4, share this property. In addition, influences of atropine and of inhibitors of cyclooxygenase and lipoxygenase activities on relaxation produced by leukotriene D4 and acetylcholine were determined to characterize further leukotriene D4-induced relaxation and to compare these properties with those of acetylcholine. Vasomotor tone was measured with isometric force transducers. Following induction of tone with norepinephrine, leukotriene C4 and acetylcholine produced concentration-dependent relaxation of renal and superior mesenteric arterial rings in which the endothelium was intact. Only minimal decreases in tone were produced in response to leukotriene E4. Neither acetylcholine nor leukotriene C4 altered tone after endothelium had been intentionally disrupted. Nitroglycerin relaxed rings both before and after rubbing the endothelium. These results demonstrate that, similar to leukotriene D4, leukotriene C4 possesses the capacity to produce endothelial-dependent relaxation in canine renal and superior mesenteric arteries. Relaxation of the superior mesenteric artery produced in response to acetylcholine, but not leukotriene D4, was inhibited in presence of atropine. Incubation of the rings with meclofenamate had no effect on relaxation induced by either acetylcholine or leukotriene D4. Thus, it appears that endothelial-dependent relaxation induced by leukotriene D4 is neither dependent on muscarinic receptor activation nor related to generation of cyclooxygenase metabolites of arachidonic acid. In contrast, 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid attenuated relaxation in response to leukotriene D4 and acetylcholine, suggesting that lipoxygenase-derived products may participate in leukotriene D4-induced as well as acetylcholine-induced relaxation.

Animals↗
PubMed1989

Release of different relaxing factors by cultured porcine endothelial cells.

Experiments were performed to determine the effect of ouabain on the release of relaxing factor(s) from cultured endothelial cells, and its action on the effect of the relaxing factor(s) on arterial smooth muscle. A column of porcine aortic endothelial cells grown on microcarrier beads in suspension culture was perfused with modified Krebs-Ringer bicarbonate solution. The release of relaxing factor(s) by the endothelial cells was detected under bioassay conditions by measuring the relaxing activity of the perfusate overflowing a ring of canine coronary artery (without endothelium) contracted with prostaglandin F2 alpha. Incubation of the endothelial cells with ouabain did not affect the relaxation of the bioassay ring under basal conditions or upon stimulation of the endothelial cells with ADP but impaired the relaxation induced by bradykinin or the calcium ionophore A23187. Incubation of the bioassay ring with ouabain reduced the relaxation under basal conditions as well as the relaxation induced by ADP but did not affect the relaxation observed upon stimulation with bradykinin and A23187 and the endothelium-independent relaxations induced by nitric oxide. These experiments suggest that cultured porcine aortic endothelial cells release two endothelium-derived relaxing factors; one is released under basal conditions and upon stimulation with adenosine diphosphate and the other (which presumably is nitric oxide) upon stimulation with bradykinin and the calcium ionophore A23187.

Adenosine Diphosphate↗
PubMed1991

Inhibition of coronary artery superoxide dismutase attenuates endothelium-dependent and -independent nitrovasodilator relaxation.

Isolated bovine coronary arteries were treated with 10 mM diethyldithiocarbamate (DETCA) for 30 minutes to deplete the cytosolic ZnCu form of superoxide dismutase (SOD). This treatment completely inhibited the endothelium- and cGMP-dependent relaxation to acetylcholine (mediated via the endothelium-derived relaxing factor, which is thought to be nitric oxide) without significantly inhibiting endothelium-dependent relaxation to arachidonic acid (mediated by prostaglandins). DETCA treatment of endothelial cells cultured from the coronary arteries inhibited bradykinin-elicited release of endothelium-derived relaxing factor, which was detected by bioassay on an isolated rabbit aorta in the presence of extracellular SOD. DETCA also inhibited cGMP-associated relaxations to nitric oxide and to vasodilators thought to function via the generation of this mediator (nitroglycerin and nitroprusside), but cAMP-associated relaxations to isoproterenol and papaverine were not altered. The inhibitory effects of DETCA against the relaxation to nitroprusside and nitroglycerin were attenuated by severe hypoxia. DETCA treatment of isolated coronary arterial smooth muscle or cultured endothelial cells produced an increase of chemiluminescence elicited in the presence of lucigenin, a detector of superoxide anion generation. The addition of SOD markedly attenuated the effects of DETCA treatment on arterial relaxation and chemiluminescence. Therefore, control of cellular superoxide anion levels by endogenous SOD appears needed for the release of endothelium-derived relaxing factor and relaxation of vascular smooth muscle to nitrovasodilators mediated via cGMP in the bovine coronary artery, but SOD is not critical for other endothelium-dependent or cAMP-associated relaxant mechanisms.

Acetylcholine↗
PubMed1993

Flow-induced relaxation of the rabbit middle cerebral artery is composed of both endothelium-dependent and -independent components.

BACKGROUND AND PURPOSE: The flow-induced relaxation of a branch of the rabbit middle cerebral artery was examined to determine if an endothelial-independent as well as -dependent component occurs in pial as well as systemic small arteries and the possible role of products of the cyclooxygenase and the L-arginine nitric oxide synthase pathways. METHODS: Intraluminal flow was achieved by the infusion of a tissue bath solution into isometrically mounted rabbit pial arteries in a resistance artery myograph through a small pipette. RESULTS: Intraluminal flow caused relaxation of the artery segment precontracted with 10 microM histamine. Treatment of endothelium-intact vessels with the nitric oxide synthase inhibitors NG-nitro-L-arginine (L-NNA) (100 microM) or NG-nitro-L-arginine methyl ester (L-NAME) (0.3 mM) significantly reduced the relaxation at flow rates of 5-30 microliters/min. This effect was partially reversed by 1 mM L-arginine. These inhibitors had no effect on the flow-induced relaxation of endothelium-denuded vessels. L-NNA did not influence the relaxation to 1 and 3 microM papaverine. Exposure to 10 microM aspirin, 10 microM indomethacin, or 300 nM tetrodotoxin had no effect on the flow-induced relaxation of either endothelium-intact or -denuded vessels (n = 6). Flow-induced relaxation was attenuated, but not abolished, by removal of the cerebrovascular endothelium. This reduction was not statistically significant. CONCLUSIONS: These results show that intraluminal flow caused relaxation of a branch of the rabbit middle cerebral artery, in part through a mechanism sensitive to inhibitors of nitric oxide synthase, most likely the generation of nitric oxide from the vascular endothelium. The major component of the relaxant response is independent of the endothelium and of nitric oxide synthesis through an L-NNA- or L-NAME-sensitive mechanism. The relaxation does not involve cyclooxygenase products nor neurogenic mediators. These results suggest that pial arteries, like those of the rabbit ear, exhibit a novel mechanism for the flow-induced relaxation of agonist-induced tone that is intrinsic to the tissues of the vascular wall subjacent to the endothelium.

Animals↗
PubMed1997

Postnatal changes in mechanisms mediating acetylcholine-induced relaxation in piglet femoral arteries.

We studied the nitric oxide-cGMP pathway in endothelium-dependent relaxation in femoral arterial rings from piglets at different postnatal ages. Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined in phenylephrine-precontracted rings from newborn (10-22-h) and 7 d (7-10-d)-old piglets. Relaxant responses were investigated in endothelium-denuded rings and endothelium-intact controls, and in endothelium-intact rings incubated with the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine acetate (L-NMMA), indomethacin, or the superoxide anion generator 6-anilinoquinoline-5,8-quinone (LY83583). Arterial rings from both age groups relaxed to a similar degree in response to ACh. Relaxation in rings from newborn piglets was insensitive to NOS inhibition by L-NMMA, whereas in artery rings from 7-d-old piglets, the relaxant response was significantly inhibited by L-NMMA. Incubation with LY83583 gave an inhibition of ACh-induced relaxation very similar to that of L-NMMA. Incubation with indomethacin had no significant effect on ACh-induced relaxation in either age group. Artery rings from both age groups relaxed 100% to SNP; the 7-d-old group was more sensitive than the newborn. NOS inhibition potentiated SNP-induced relaxation in both groups, but the potentiating effect was of greater magnitude in the newborn. Our results indicate a difference in the mechanism(s) underlying ACh-induced relaxation in the femoral artery from newborn and 7-d-old piglets, with an intact relaxant response in rings from the newborn despite NOS inhibition. The SNP results indicate a down-regulated soluble guanylate cyclase in the newborn, possibly related to a difference in basal NO release between the two age groups.

Aging↗
PubMed1999

Possible involvement of Ca2+ entry and its pharmacological characteristics responsible for endothelium-dependent, NO-mediated relaxation induced by thapsigargin in guinea-pig aorta.

Thapsigargin, a specific inhibitor of Ca(2+)-pump Ca(2+)-ATPase in the sarcoplasmic/endoplasmic reticulum (SR/ER), produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features of thapsigargin-induced endothelium-dependent relaxation were functionally characterized in the isolated guinea-pig aorta especially focusing on the Ca2+ mobilization mechanisms in endothelial cells. Thapsigargin-induced endothelium-dependent vascular relaxation was markedly suppressed by N(G)-nitro-L-arginine (L-NNA) and calmidazolium, suggesting that the vascular relaxation to thapsigargin is largely attributable to endothelium-derived nitric oxide (NO) produced as a result of the activation of Ca2+, calmodulin-dependent NO synthase (NOS). Removal of Ca2+ from the external solution abolished the endothelium-dependent relaxation of guinea-pig aorta in response to thapsigargin. Thapsigargin-induced endothelium-dependent relaxation was inhibited more strongly compared with the endothelium-independent relaxation to an NO donor, SIN-1 (3-(4-morpholinyl)-sydnonimine), when the artery preparation was preconstricted with a high concentration (80 mM) of KCl instead of agonistic stimulation. Endothelium-dependent relaxation induced by thapsigargin was not affected by diltiazem, a blocker of L-type voltage-gated Ca2+ channels. SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H-imidazole) and Ni2+, both of which block capacitative Ca(2+) entry, did not show any appreciable inhibitory effects on the endothelium-dependent relaxation to thapsigargin. These findings suggest that in guinea-pig aorta, endothelium-dependent NO-mediated relaxation induced by thapsigargin is preceded by the increase in the cytosolic free Ca2+ concentrations ([Ca2+]cyt) following the depletion of stored Ca2+ in thapsigargin-sensitive store sites in endothelial cells. Although the increase in [Ca2+]cyt responsible for the activation of endothelium NOS leading to thapsigargin-induced vascular relaxation may be ascribed to the capacitative Ca2+ entry from extracellular space, the Ca2+ entry mechanism stimulated with thapsigargin is deficient in sensitivity to SK&F96365 and Ni2+ in the endothelium of guinea-pig aorta.

Animals↗
PubMed2001

Psychophysiological effects of relaxation training in children.

OBJECTIVES: This study compares the effects of progressive muscle relaxation and an imagery-based relaxation training on childrens' physiological and subjective responses in a randomized controlled trial. DESIGN: Sixty-four children aged 9 to 13 years were randomly allocated to either one of three experimental conditions: progressive muscle relaxation, imagery-based relaxation or a control condition (neutral story). There were five training sessions in each condition. METHOD: Heart rate (HR), skin conductance level (SCL), and skin temperature (ST) were measured continuously during a 5-minute baseline period, an 8-minute relaxation training period, and a 5-minute follow-up in each session. In addition, subjective ratings of mood and physical well-being were collected intermittently. RESULTS AND CONCLUSIONS: A physiological pattern indicating relaxation was most clearly associated with the imagery-based relaxation approach (decreases in HR and SCL), although ST remained unchanged. In contrast, progressive muscle relaxation led to an increase in HR during the training. The neutral story condition showed a similar trend as the imagery-based relaxation approach (although not reaching statistical significance). Furthermore, children's ratings of positive mood and physical wellbeing increased during baseline and training periods, but there were no differences between training conditions. The results indicate psychophysiological effects of relaxation instructions which, however, are not specific for systematic relaxation training.

Clinical Trial↗
PubMed2002

Nitric oxide (NO) primarily accounts for endothelium-dependent component of beta-adrenoceptor-activated smooth muscle relaxation of mouse aorta in response to isoprenaline.

Isoprenaline is known to produce vascular relaxation through activation of beta-adrenoceptors. In recent years, beta-adrenoceptor-activated vascular relaxation has been the focus of pharmacological study in terms of both the receptor subtypes and the intracellular signaling mechanisms which trigger smooth muscle mechanical functions. In addition, the possible contribution of the endothelium to beta-adrenoceptor-activated relaxation of vascular beds has provoked considerable discussion, with consensus still to be established. In the present study, we examined the effects of isoprenaline on isolated mouse aortic smooth muscles to determine whether the presence of the endothelium plays a substantial role in the relaxation it produces. A possible role for nitric oxide (NO) as a primary endothelium-derived factor released in response to isoprenaline was also elucidated pharmaco-mechanically. In isolated thoracic and abdominal aortae pre-contracted with phenylephrine (3 x 10(-7)-10(-6) M), isoprenaline elicited relaxation in a concentration-dependent fashion (10(-9)-10(-5) M). In endothelium-denuded preparations, isoprenaline-elicited relaxation was reduced to 40-50% of the response obtained in endothelium-intact preparations. In the preparations treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) M; an NO synthase inhibitor) or 1H-[1,2,4]-oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10(-5) M; a soluble guanylyl cyclase inhibitor), isoprenaline-elicited relaxation was attenuated almost to the same degree as the response in endothelium-denuded preparations. The degree of endothelium-dependency in isoprenaline-elicited relaxation was largely diminished when treated with propranolol (3 x 10(-6) M). The present findings indicate that isoprenaline substantially relaxes the mouse aorta with both endothelium-dependent and -independent mechanisms. The endothelium-dependent component seems to correspond to about 50% of the isoprenaline-elicited relaxation, and is almost entirely due to endothelium-derived NO. Activation of propranolol (3 x 10(-6) M)-inhibitable beta-adrenoceptors seems to be primarily responsible for the NO-mediated endothelium-dependent pathway in isoprenaline-elicited relaxant response of mouse aorta.

Adrenergic beta-Agonists↗
PubMed1985

Reproducibility of T1 and T2 relaxation times calculated from routine MR imaging sequences: phantom study.

Measurement of T1 and T2 relaxation times has been sought as one fundamental way to characterize tissue. Relaxation times can be calculated from routine spin-echo (SE) imaging sequences using two distinct repetition times (TRs), each with two SE samplings of signal intensity. Previous reports have quantified relaxation times without discussing the variation in their measurements. By imaging a phantom containing different samples with known T1 and T2 relaxation times on three separate occasions, the variation in relaxation time measurements inherent in different routine imaging sequences was studied. For the present study a more complete and accurate equation was used to calculate T1 values. The variation in T1 and T2 relaxation times for samples with relaxation times similar to solid tissue was 2%-4%. The amount of variability in calculated relaxation times was found to be dependent on the magnitude of the relaxation times themselves. However, the mean values were independent of the imaging sequences used to calculate the relaxation times. No significant differences were seen between left-to-right or section-to-section position within the same study or between studies performed on different occasions. The variability in the calculated T1 was dependent on the pair of TR sequences used to calculate T1. Samples with long T1 and T2 relaxation times, similar to many body fluids, had much larger variability. A computer simulation of measurement error was created to explain these results. This study indicates that properly performed routine imaging studies do yield reproducible T1 and T2 measurements.

Computers↗
PubMed1989

Pharmacological studies on relaxation of spastic primate cerebral arteries in subarachnoid hemorrhage.

Chronic cerebral vasospasm was induced in 16 monkeys by direct placement of a clot of autologous blood over the arteries of the circle of Willis on the right side. The middle cerebral arteries (MCA's) on the clot side all showed angiographic vasospasm, which was maximal 7 days after subarachnoid hemorrhage. Animals were sacrificed at this time and vascular responses to acetylcholine (ACh), histamine, and the calcium ionophore A23187 were studied in MCA rings from the clot (spastic) side and the non-clot (control) side. In control preparations with an intact endothelium, which had been precontracted by prostaglandin F2 alpha (PGF2 alpha), histamine and A23187 produced significant relaxation. The same concentrations of histamine and A23187 did not relax vascular tissues in which the endothelium had been mechanically removed. Acetylcholine did not produce a significant endothelium-dependent relaxation of primate MCA rings, but did relax rings of primate common carotid artery. Pretreatment with chlorpheniramine (an H1-receptor antagonist) prevented histamine-induced relaxation; however, cimetidine (an H2-receptor antagonist) had no inhibitory action. It thus seems that histamine mediates relaxation of intact MCA's mostly by an H1-receptor-mediated release of endothelium-derived relaxing factor (EDRF). Relaxations induced by histamine and A23187 in MCA's from the clot side were substantially reduced. Moreover, the small component of ACh-induced relaxation was also abolished. Endothelium-independent relaxation induced by glyceryl trinitrate (GTN) occurred in arteries from both the control and the clot sides. Constrictions induced by KC1 and PGF2 alpha were reduced on the clot side of the MCA's. These results suggest that subarachnoid hemorrhage influences both the generation of EDRF and the constriction of affected arteries. The small contraction which was elicited in spastic arteries was fully relaxed by GTN.

Acetylcholine↗
PubMedDate not supplied

[Alteration in relaxation of atypical beta-adrenergic but not beta-3 receptors in arterial hypertension in the rat].

The aim of this study was to investigate the involvement of beta 3-adrenoceptors (beta 3-AR) in hypertension. Aortic rings were isolated from 12 weeks old WKY (Wistar-Kyoto) and SHR (spontaneously hypertensive rat) rats. Rings were placed in organ baths and constricted with phenylephrine. Then, cumulative concentration-relaxation curves to the beta 3-AR agonists were constructed. In both strains, SR58611, a preferential beta 3-agonist, produced similar concentration-dependent relaxation. CGP 12177 (CGP), (a partial beta 3-AR and atypical beta-AR agonist with beta 1-/beta 2-AR antagonistic properties) produced similar relaxation in WKY (pD2 = 5.10 +/- 0.06; Emax = 54 +/- 2%; n = 6) and in SHR (pD2 = 4.98 +/- 0.02; Emax = 58 +/- 4%; n = 6). In WKY, relaxant response to CGP was not modified by nadolol (10 microM) or L-748.337 (3 microM) suggesting an atypical beta-AR activation. By contrast, in SHR, the effect of CGP was strongly decreased by 3 microM L-748.337 (Emax = 27.8 +/- 5.4%; n = 7; p < 0.05 vs CGP alone), suggesting a possible participation of beta 3-AR in CGP-induced relaxation. In order to investigate the role of endothelium in CGP-induced relaxation, experiments were performed in denuded aortic rings. In WKY, CGP-induced relaxation was not modified by endothelium removal, by contrast, this was greatly inhibited in SHR (Emax = 18.3 +/- 1.9%; n = 9; p < 0.05 vs CGP in intact aortic rings). Endothelium-independent relaxation to CGP was resistant to nadolol or L-748.337 treatment which seems to rule out the involvement of beta 1, beta 2 and beta 3-AR. Endothelium-independent relaxation to CGP was significantly reduced by SQ 22536 or MDL 12330A, non-selective adenylyl cyclase inhibitors, indicating a role of cAMP-dependent pathway in CGP response. By contrast, the relaxant effect to CGP was not modified by SQ 22536 in SHR. In conclusion, these results show that [1] functional response to beta 3-AR stimulation was not altered in hypertension [2]. CGP activated an atypical beta-AR distinct from beta 1, beta 2 and beta 3-AR, partly through cAMP-dependent pathway. Impaired atypical beta-AR relaxation to CGP in SHR could contribute to the pathogenesis of the hypertension.

Animals↗
PubMedDate not supplied

[Impairment of atypical beta-adrenergic-mediated relaxation in spontaneously hypertensive rats before and during the development of arterial hypertension].

The aims of this study was to characterize the functional response of atypical beta-adrenoceptors (beta-AR) in rat aorta and to investigate whether this relaxation was altered before and during the development of hypertension. Aortic rings from 4 or 12 weeks old Wistar Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were placed in organ baths and constricted with phenylephrine. Then, cumulative concentration-relaxation curves to the beta-AR agonists were constructed. In intact aortic rings from 12 weeks old WKY rats, CGP 12,177 (CGP) and cyanopindolol (partial beta 3-AR agonists and atypical beta-AR agonists with beta 1/beta 2-AR antagonist properties) produced concentration-dependent relaxation (pD2 = 5.09 +/- 0.03; Emax = 60.4 +/- 2.5%; n = 9; pD2 = 6.17 +/- 0.05; Emax = 95.9 +/- 1%; n = 5 respectively). The endothelium removal did not modify this relaxation. In 12 weeks old WKY rats, the endothelium-independent relaxation to CGP was not modified in the presence of nadolol (beta 1/beta 2-AR antagonist) or L-748 337 (beta 3-AR antagonist) excluding the participation of beta 1, beta 2 et beta 3-AR in this effect. By contrast, this relaxation was significantly inhibited by CGP 20712A or bupranolol, atypical beta-AR antagonists at high concentrations. In 12 weeks old SHR, endothelium-independent relaxation to CGP or cyanopindolol was greatly inhibited. In order to sought out whether impairment of atypical beta-AR-mediated relaxation was due to hypertension, experiments were performed in 4 weeks old SHR. At this age, CGP-induced relaxation was greatly inhibited compared to that obtained in age-matched WKY rats. In 12 weeks old SHR pretreated with pertussis toxin (10 micrograms/kg i.p./3 days), the relaxant effect to CGP was partly restored. We conclude that the atypical beta-AR were functionally expressed in aortic vascular smooth muscle cells of rat aorta. In 4 or 12 weeks old SHR rats, atypical beta-AR-mediated relaxation was impaired, suggesting that this dysfunction occurs before the establishment of hypertension. Gi proteins may be one of the factors that contributes to this impairment.

Adrenergic beta-Agonists↗