UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In estrogen-depleted [i.e., ovariectomized (Ovx)] animals, an endothelium-derived hyperpolarizing factor (EDHF)-like mechanism may arise to, at least partially, replace endothelial nitric oxide (NO) synthase (eNOS)-derived NO in modulating cerebral arteriolar tone. Additional findings show that eNOS expression and function is restored in estrogen-treated Ovx female rats, while the nascent EDHF-like activity disappears. Because NO has been linked to repression of EDHF activity in the periphery, the current study was undertaken to examine whether the nascent EDHF role in cerebral vessels of Ovx females relates to a chronically repressed eNOS-derived NO-generating function. We compared the effects of chronic NOS inhibition with Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 mg. kg-1. day-1 for 3 wk) on EDHF-mediated pial arteriolar vasodilation in anesthetized intact, Ovx, and 17beta-estradiol-treated (0.1 mg. kg-1. day-1 ip, 1 wk) Ovx (OVE) female rats as well as in male rats that were prepared with closed cranial windows. In the chronic NOS inhibition groups, pial arteriolar responses were monitored in the absence (all groups) and presence (females only) of indomethacin (Indo; 10 mg/kg iv). Finally, the gap junction inhibitory peptide Gap 27 (300 muM) was applied to block EDHF-related vasodilation. NO donor (S-nitroso-N-acetyl-penicillamine) responses were similar in all rats studied. Acetylcholine (ACh) reactivity was virtually absent in control Ovx rats and chronically NOS-inhibited intact female, OVE, and male rats. However, a partial recovery of ACh reactivity was seen in L-NAME-treated Ovx females. In addition, in the presence of L-NAME, a normal CO2 reactivity was observed in all females, whereas a 50% reduction in CO2 reactivity was seen in males. In intact and OVE rats, both chronic and acute (NG-nitro-L-arginine suffusion) NOS inhibition, combined with Indo, depressed ADP-induced dilation by > or =50%, and subsequent application of Gap 27 had no further effect on ADP-induced vasodilation. ADP reactivity was retained in Ovx rats after combined chronic NOS inhibition and acute Indo, but was attenuated significantly by Gap 27. In males, Gap 27 had no effect on arteriolar reactivity. Taken together, our data demonstrate that in the cerebral microcirculation, NO does not have an inhibitory effect on EDHF production or action. The increased EDHF-like function in chronic estrogen-depleted animals is not due to eNOS deficiency, suggesting a more direct effect of estrogen in modulating EDHF-mediated cerebral vasodilation.
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PMID:Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction. 1286 71

Streptozotocin (STZ) is widely used for the induction of diabetes in animals by causing destruction of pancreatic beta cells. This experiment was designed to elucidate the sequential process of beta-cell destruction in rats with a single high-dose injection of STZ. At 0, 2, 5, 8 and 24 h after injection, rats were perfused with Krebs-Ringer buffer with dichlorofluorescein diacetate (DCF-DA), a marker for free radicals, and the pancreata were pathologically analyzed. Injection of STZ rapidly elicited an increase in fluorescence of DCF-DA in beta cells at 2 h after the injection. The fluorescence was diminished by carboxy-PTIO, a specific scavenger of nitric oxide (NO), but not by L-NAME, an inhibitor of NO synthase. During this process, an inducible form of NO synthase was not detected. Thereafter, upregulated expression of poly(ADP ribose) polymerase (PARP) and massive beta-cell death were detected at 5-8 h after injection. Migration of macrophages into the islet was conspicuous at 24 h, clearing up the debris of destroyed beta cells. Nicotinamide, a PARP inhibitor, significantly inhibited beta-cell death without apparent suppression of NO generation at 2 h. The current study documented serial processes of STZ-induced beta-cell death, starting with NO generation and PARP activation followed by a clearance with macrophages, where the activation of PARP plays a central role in beta-cell death.
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PMID:Nitric oxide generation and poly(ADP ribose) polymerase activation precede beta-cell death in rats with a single high-dose injection of streptozotocin. 1476 14

The purine nucleotide ATP mediates pulmonary vasodilation at birth by stimulation of P2Y purine receptors in the pulmonary circulation. The specific P2Y receptors in the pulmonary circulation and the segmental distribution of their responses remain unknown. We investigated the effects of purine nucleotides, ATP, ADP, and AMP, and pyrimidine nucleotides, UTP, UDP, and UMP, in juvenile rabbit pulmonary arteries for functional characterization of P2Y receptors. We also studied the expression of P2Y receptor subtypes in pulmonary arteries and the role of nitric oxide (NO), prostaglandins, and cytochrome P-450 metabolites in the response to ATP. In conduit size arteries, ATP, ADP, and AMP caused greater relaxation responses than UTP, UDP, and UMP. In resistance vessels, ATP and UTP caused comparable vasodilation. The response to ATP was attenuated by the P2Y antagonist cibacron blue, the NO synthase antagonist N(omega)-nitro-l-arginine methyl ester (l-NAME), and the cytochrome P-450 inhibitor 17-octadecynoic acid but not by the P2X antagonist alpha,beta-methylene ATP or the cyclooxygenase inhibitor indomethacin in conduit arteries. In the resistance vessels, l-NAME caused a more complete inhibition of the responses to ATP and UTP. Responses to AMP and UMP were NO and endothelium dependent, whereas responses to ADP and UDP were NO and endothelium independent in the conduit arteries. RT-PCR showed expression of P2Y(1), P2Y(2), and P2Y(4) receptors, but not P2Y(6) receptors, in lung parenchyma, pulmonary arteries, and pulmonary artery endothelial cells. These data suggest that distinct P2Y receptors mediate the vasodilator responses to purine and pyrimidine nucleotides in the juvenile rabbit pulmonary circulation. ATP appears to cause NO-mediated vasodilation predominantly through P2Y2 receptors on endothelium.
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PMID:P2Y purine receptor responses and expression in the pulmonary circulation of juvenile rabbits. 1496 41

1 ATP is an important vasoactive mediator, which acts via two receptor classes: P2X and P2Y. Activation of P2X receptors has traditionally been associated with the well-characterised vasoconstrictor properties of ATP. 2 In the current study, we have shown that the P2X(1 & 3) receptor ligand, alpha, beta methylene ATP, induces vasodilation of rat isolated mesenteric arteries and that P2X1 receptors are abundantly expressed in the endothelium of these vessels. 3 Second-order rat mesenteric arteries were mounted in myographs and vasomotor responses recorded. Both ATP and alpha, beta methylene ATP induced a constriction followed by a vasodilation. The dilator effects of either ATP or alpha, beta methylene ATP were slower in onset than those induced by acetylcholine. By contrast, the traditional vasodilator P2Y ligand, ADP, induced vasodilation without contraction. 4 Vasodilation induced by alpha, beta methylene ATP was endothelial dependent, but was not affected by treatment of the vessels with L-NAME plus indomethacin alone. Dilation was, however, partially inhibited by the combination of apamin plus charybdotoxin and blocked by treating vessels with all four drugs. 5 Using confocal microscopy, P2X1 receptor immunoreactivity was localised to the endothelial, smooth muscle and adventitial layers of mesenteric vessels. P2X1 protein migrated as a primary band at around 50-60 kDa in vascular tissue. 6 These results show for the first time that P2X1 receptors are expressed on the endothelium and that a selective ligand of this receptor results in vasoconstriction followed by vasodilation. These observations have important implications for our understanding of the role of purines in biological responses.
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PMID:Novel role for P2X receptor activation in endothelium-dependent vasodilation. 1546 40

The main objective of the present study was to evaluate the in vivo and in vitro effect of Arg on serum nucleotide hydrolysis. The action of Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, on the effects produced by Arg was also examined. Sixty-day-old rats were treated with a single or a triple (with an interval of 1 h between each injection) intraperitoneal injection of saline (group I), Arg (0.8 g/kg) (group II), L-NAME (2.0 mg/kg or 20 mg/kg) (group III) or Arg (0.8 g/kg) plus L-NAME (2.0 mg/kg or 20 mg/kg) (group IV) and were killed 1 h later. The present results show that a triple Arg administration decreased ATP, ADP and AMP hydrolysis. Simultaneous injection of L-NAME (20 mg/kg) prevented such effects. Arg in vitro did not alter nucleotide hydrolysis. It is suggested that in vivo Arg administration reduces nucleotide hydrolysis in rat serum, probably through nitric oxide or/and peroxynitrite formation.
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PMID:L-NAME administration prevents the inhibition of nucleotide hydrolysis by rat blood serum subjected to hyperargininemia. 1597 41

The neurotransmitters mediating relaxation of lower esophageal sphincter (LES) were studied using circular LES strips from adult pigs in organ baths. LES relaxation by sodium nitroprusside (1 nM-3 microM), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP; 1 nM-1 microM), ATP (10 microM-30 mM), and tricarbonyldichlororuthenum dimer (1 microM-1 mM) was unaffected by tetrodotoxin (1 microM) or l-N(G)-nitroarginine methyl ester (l-NAME; 100 microM). Calcitonin gene-related peptide (CGRP; 1 nM-1 microM) did not affect LES tone. ATP relaxation was blocked by 1 microM apamin and the P2Y(1) antagonist MRS 2179 (N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate; 10 microM). Apamin inhibited PACAP relaxation. VIP and PACAP relaxation was blocked by 10 U/ml alpha-chymotrypsin. L-NAME (-62.52 +/- 13.13%) and 1H-[1,2,4]oxadiazole-[4,3-alpha]quinoxalin-1-one (ODQ; 10 microM, -67.67 +/- 6.80%) similarly inhibited electrical LES relaxation, and apamin blocked non-nitrergic relaxation. Nicotine relaxation (100 microM) was inhibited by L-NAME (-60.37 +/- 10.8%) and ODQ (-41.90 +/- 7.89%), and apamin also blocked non-nitrergic relaxation. Non-nitrergic and apamin-sensitive LES relaxation by electrical stimulation or nicotine was strongly inhibited by MRS 2179, slightly inhibited by alpha-chymotrypsin and the P2X(1,2,3) receptor antagonist NF 279 (8,8 cent-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; 10 microM), and unaffected by tin protoporphyrin IX (100 microM). Porcine LES relaxation after stimulation of intrinsic inhibitory motor neurons is mediated by two main neuromuscular pathways: nitric oxide through guanylate cyclase signaling and apamin-insensitive mechanisms and by non-nitrergic apamin-sensitive neurotransmission mainly mediated by ATP, ADP, or a related purine acting on P2Y1 receptors and a minor contribution of purinergic P2X1,2,3 receptors and PACAP. Nitrergic and purinergic co-transmitters show parallel effects of similar magnitude without major interplay. Our study shows no role for CGRP and only a minor one for VIP and carbon monoxide in porcine LES relaxation.
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PMID:Pharmacologic characterization of intrinsic mechanisms controlling tone and relaxation of porcine lower esophageal sphincter. 1630 17

We tested two hypotheses: 1) that the effects of hypercholesterolemia on endothelial function in femoral arteries exceed those reported in brachial arteries and 2) that exercise (Ex) training enhances endothelium-dependent dilation and improves femoral artery blood flow (FABF) in hypercholesterolemic pigs. Adult male pigs were fed a normal fat (NF) or high-fat/cholesterol (HF) diet for 20 wk. Four weeks after the diet was initiated, pigs were Ex trained or remained sedentary (Sed) for 16 wk, thus yielding four groups: NF-Sed, NF-Ex, HF-Sed, and HF-Ex. Endothelium-dependent vasodilator responses were assessed in vivo by measuring changes in FABF after intra-arterial injections of ADP and bradykinin (BK). Endothelium-dependent and -independent relaxation was assessed in vitro by measuring relaxation responses to BK and sodium nitroprusside (SNP). FABF increased in response to ADP and BK in all groups. FABF responses to ADP and BK were not impaired by HF but were improved by Ex in HF pigs. BK- and SNP-induced relaxation of femoral artery rings was not altered by HF or Ex. To determine whether the mechanism(s) for vasorelaxation of femoral arteries was altered by HF or Ex, BK-induced relaxation was assessed in vitro in the absence or presence of N(G)-nitro-l-arginine methyl ester [l-NAME; to inhibit nitric oxide synthase (NOS)], indomethacin (Indo; to inhibit cyclooxygenase), or l-NAME + Indo. BK-induced relaxation was inhibited by l-NAME and l-NAME + Indo in all groups of femoral arteries. Ex increased the NOS-dependent component of endothelium-dependent relaxation in NF (not HF) arteries. Indo did not inhibit BK-induced relaxation. Collectively, these results indicate that hypercholesterolemia does not alter endothelial function in femoral arteries and that Ex training improves FABF responses to ADP and BK; however, the improvement cannot be attributed to enhanced endothelial function in HF femoral arteries. These data suggest that Ex-induced improvements in FABF in HF arteries are mediated by vascular adaptations in arteries/arterioles downstream from the femoral artery.
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PMID:Exercise training improves femoral artery blood flow responses to endothelium-dependent dilators in hypercholesterolemic pigs. 1639 63

Dilation of rat preglomerular microvessels (PGMV) by activation of adenosine A2A receptors (A2AR) is coupled to epoxyeicosatrienoic acid (EET) release. We have investigated the commonality of this signal transduction pathway, i.e., sequential inhibition of G(salpha), adenylyl cyclase, PKA, and Ca2+-activated K+ (KCa) channel activity, to the vasoactive responses to A2AR activation by a selective A2A agonist, CGS-21680, compared with those of 11,12-EET. Male Sprague-Dawley rats were anesthetized, and microdissected arcuate arteries (110-130 microm) were cannulated and pressurized to 80 mmHg. Vessels were superfused with Krebs solution containing NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin and preconstricted with phenylephrine. We assessed the effect of 3-aminobenzamide (10 microM), an inhibitor of mono-ADP-ribosyltranferases, on responses to 11,12-EET (3 nM) and CGS-21680 (10 microM) and found that both were inhibited by approximately 70% (P<0.05), whereas the response to SNP (10 microM) was unaffected. Furthermore, 11,12-EET (100 nM), like cholera toxin (100 ng/ml), stimulated ADP-ribose formation in homogenates of arcuate arteries compared with control. SQ-22536 (10 microM), an inhibitor of adenylyl cyclase activity, and myristolated PKI (14-22) amide (5 microM), an inhibitor of PKA, decreased activity of 11,12-EET and CGS-21680. Incubation of 11,12-EET (3 nM-3 microM) with PGMV resulted in an increase in cAMP levels (P<0.05). The responses to both 11,12-EET and CGS-21680 were significantly reduced by superfusion of iberiotoxin (100 nM), an inhibitor of KCa channel activity. Thus in rat PGMV activation of A2AR is coupled to EET release upstream of adenylyl cyclase activation and EETs stimulate mono-ADP-ribosyltransferase, resulting in Gsalpha protein activation.
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PMID:Adenosine2A receptor vasodilation of rat preglomerular microvessels is mediated by EETs that activate the cAMP/PKA pathway. 1647 79

In autonomic-blocked rats treated with NG-nitro-L-arginine methyl ester (L-NAME, 7.5 mg/kg), heart rate increased 18% and mean arterial pressure increased 48%. Thyroidectomy, along with autonomic blockade, hampered the chronotropic response but did not modify the effect on blood pressure. After 150 min of autonomic blockade, the experimental end point, total nitric oxide (NO) production by heart NO synthases (NOS) decreased 61%: from 54 to 21 nmol NO.min-1.g heart-1. Mitochondrial NOS (mtNOS) and sarcoplasmic reticulum endothelial NOS activities decreased 74% and 52%, respectively. Mitochondria isolated from whole heart showed a well-coupled oxidative phosphorylation with high respiratory control and ADP-to-O ratios, decreased mtNOS activity (55-60%), and decreased mtNOS protein expression (70%). Immunohistochemistry with anti-inducible NOS antibody linked to gold particles localized mtNOS at the inner mitochondrial membranes. Histochemical right atrial NOS (NADPH-diaphorase) decreased 55% after heart denervation. The effects of autonomic denervation on the NO system were partially prevented by thyroidectomy performed simultaneously with autonomic blockade. Western blot analysis indicated a very rapid mtNOS protein turnover (half time=120 min) with a process of protein expression that was upregulated by thyroidectomy and a degradation process that was downregulated by the autonomic nervous system. The observations suggest that NO-mediated pathways contribute to pacemaker heart activity, likely through the NO steady-state levels in the right atrium and the whole heart.
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PMID:Autonomic regulation of pacemaker activity: role of heart nitric oxide synthases. 1661 32

To analyze the cerebrovascular effects of ischemia-reperfusion, cerebrovascular reactivity to ADP was studied after inducing 60-min occlusion followed by 60-min reperfusion of the left middle cerebral artery (MCA) in anesthetized goats. In 12 goats, at the end of reperfusion, left MCA resistance was decreased by 19%, and reactive hyperemia to 5- and 10-s occlusions as well as the cerebral vasodilatation to ADP (0.03-0.3 microg) but not to sodium nitroprusside (0.3-3 microg) was decreased. In 28 animals, killed at the end of reperfusion, segments 3-mm long were obtained from the left (ischemic) and right (control) MCA, prepared for isometric tension recording, and precontracted with the thromboxane A2 analogue U46619. The relaxation to ADP (10(-8) to 10(-5) M) but not to sodium nitroprusside (10(-8) to 10(-4) M) was lower in ischemic arteries. L-NAME (inhibitor of nitric oxide synthesis, 10(-4) M), charybdotoxin (10(-7) M)+apamin (10(-6) M) (blockers of KCa), or catalase (1000 U/ml) reduced the relaxation to ADP only in control arteries. Charybdotoxin+apamin further augmented the L-NAME-induced reduction in the relaxation to ADP in control arteries. The inhibitor of cyclooxygenase meclofenamate (10(-5) M) increased the relaxation to ADP only in ischemic arteries. The superoxide dismutase mimetic tiron (10(-2) M) increased the ADP-induced relaxation only in ischemic arteries. Therefore, it is suggested that ischemia-reperfusion produces cerebrovascular endothelial dysfunction, which may be associated with decreased nitric oxide bioavailability, decreased release of an EDHF, and increased production of vasoconstrictor prostanoids. All these alterations may be related in part with an increased production of superoxide anion.
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PMID:Goat cerebrovascular reactivity to ADP after ischemia-reperfusion. Role of nitric oxide, prostanoids and reactive oxygen species. 1699 44

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