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H Hayakawa

Publications and source records attributed to H Hayakawa.

At least 55 records · Page 3Linked to original sources
PubMed1999

Metabolic fate of oxidized guanine ribonucleotides in mammalian cells.

8-Oxo-7,8-dihydroguanine- (8-oxoguanine-) containing nucleotides are generated in the cellular nucleotide pool by the action of oxygen radicals produced during normal cellular metabolism. We examined the interconversion and metabolic fate of 8-oxoguanine-containing ribonucleotides in mammalian cells. (1) 8-OxoGTP can be generated not only by direct oxidation of GTP but also by phosphorylation of 8-oxoGDP by nucleotide diphosphate kinase, and the 8-oxoGTP thus formed can serve as a substrate for RNA polymerase II to induce transcription errors. (2) MTH1 protein carrying intrinsic 8-oxo-dGTPase activity has the potential to hydrolyze 8-oxoGTP to 8-oxoGMP, thus preventing misincorporation of 8-oxoguanine into RNA. 8-OxoGMP, the degradation product, cannot be reutilized, since guanylate kinase, which has the potential to phosphorylate both GMP and dGMP, is inactive on 8-oxoGMP. (3) Ribonucleotide reductase, which catalyzes reduction of four naturally occurring ribonucleoside diphosphates, cannot convert 8-oxoguanine-containing ribonucleotide to the deoxyribonucleotide. This step appears to serve as a gatekeeper to prevent formation of mutagenic substrates for DNA synthesis from oxidized ribonucleotides.

Animals↗
PubMed1999

Molecular mechanisms of endothelin-1-induced cell-cycle progression: involvement of extracellular signal-regulated kinase, protein kinase C, and phosphatidylinositol 3-kinase at distinct points.

Although it is well established that endothelin-1 (ET-1) has not only vasoconstrictive effects but also mitogenic effects, which seem to be implicated in vascular remodeling, little is known about the molecular mechanisms by which ET-1 induces cell-cycle progression. In this study, we examined the effects of ET-1 on the cell-cycle regulatory machinery, including cyclins, cyclin-dependent kinase (cdk), and cdk inhibitors in NIH3T3 cells. ET-1 increased cyclin D1 protein (5.1+/-1.9-fold increase, 8 hours after stimulation, P<0.05), cdk4 kinase activity (2.8+/-0. 5-fold increase, 12 hours after stimulation, P<0.01), and cdk2 kinase activity (2.1+/-0.4-fold increase, 16 hours after stimulation, P<0.05) in a time- and dose-dependent manner. ET-1-induced increase in cyclin D1 protein, and cdk4 kinase activity was not significantly inhibited by an inhibitor of the mitogen-activated protein kinase kinase 1/2, PD98059, nor by the protein kinase C inhibitor calphostin C, whereas ET-1-induced upregulation of cyclin D1 protein and cdk4 kinase activity was significantly inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002. In contrast, ET-1-induced activation of cdk2 kinase was significantly inhibited by PD98059, calphostin C, and LY294002. ET-1 increased 3H-thymidine uptake in a time-dependent fashion (0 hours, 4216+/-264 cpm per well; 8 hours, 5025+/-197 cpm per well; 16 hours, 9239+/-79 cpm per well, P<0.001 versus 0 hours). ET-1-induced increase in 3H-thymidine uptake was significantly inhibited by PD98059, calphostin C, and LY294002. These results suggest that ET-1-induced cell-cycle progression is, at least in part, mediated by the extracellular signal-regulated kinase, protein kinase C, and phosphatidylinositol 3-kinase and that those pathways may be involved in the progression of the cell cycle at distinct points.

3T3 Cells↗
PubMed1999

Effects of hypertension, diabetes mellitus, and hypercholesterolemia on endothelin type B receptor-mediated nitric oxide release from rat kidney.

BACKGROUND: Although endothelin-1 is a potent vasoconstrictor peptide, stimulation of endothelin type B receptor (ETBR) causes bidirectional changes in vascular tone, ie, vasodilation and vasoconstriction. Roles of ETBR in pathological conditions are largely unknown. METHODS AND RESULTS: We studied the effect of BQ-3020, a highly selective ETBR agonist, on renal vascular resistance and nitric oxide (NO) release in the isolated, perfused kidney of rats with hypertension, diabetes mellitus, and hypercholesterolemia. Immunohistochemistry of endothelial NO synthase and ETBR was also examined. Infusion of BQ-3020 at concentrations of </=10(-10) mol/L reduced renal perfusion pressure in Dahl salt-resistant (R) rats but increased renal perfusion pressure in Dahl salt-sensitive (S) rats (10(-10) mol/L: -10.3+/-0. 6% versus 11.2+/-1.5%, R versus S; P<0.01). BQ-3020 caused a dose-dependent release of NO in both R and S rats, although the level of NO release in S rats was lower, as detected by chemiluminescence (10(-10) mol/L: 10.7+/-0.7 versus 3.1+/-0.4 fmol/min per gram of kidney, R versus S; P<0.01). Similar effects of BQ-3020 were observed in streptozotocin-induced diabetic rats and diet-induced hypercholesterolemic rats. Expression of endothelial NO synthase decreased in S rats but not in diabetic or hypercholesterolemic rats. In contrast, expression of ETBR in the endothelium was decreased in all 3 disease models compared with that in the vascular smooth muscle cell. CONCLUSIONS: These results suggest that impaired NO release in response to stimulation of ETBR is due, at least in part, to a decrease in endothelial ETBR and may play a role in vascular dysfunction usually associated with arteriosclerosis-related diseases.

Animals↗
PubMed1999

Development and clinical application of high performance liquid chromatography for the simultaneous determination of plasma levels of theophylline and its metabolites without interference from caffeine.

A high performance liquid chromatography (HPLC) method has been developed for the simultaneous determination of plasma levels of theophylline and its metabolites without interference from caffeine or caffeine metabolites. The method is simple and of practical use because it is applicable even to plasma samples from patients who take caffeine-containing beverages. The method was also reproducible with a coefficient of variation of less than 5% for each analyte. The levels of theophylline, determined by HPLC, were validated by their high correlation to the levels obtained by fluorescence polarization immunoassay. HPLC was used to determine theophylline levels in patients with bronchial asthma. The data revealed that the ratio of 1,3-dimethyluric acid, the major metabolite of theophylline, to theophylline concentration in the plasma was within a narrow range in most patients (0.055 +/- 0.01, n = 66), regardless of the method of theophylline administration or the time of blood sampling. Conversely, this ratio was as low as 0.027 +/- 0.005 in the patient with a long plasma half-life of theophylline. These results suggest that it may be possible to predict the plasma half-life of theophylline for each patient from a single blood sample. This may be useful when planning theophylline administration, especially in patients with abnormal theophylline metabolism.

Adolescent↗
PubMed1999

Expression of an mNSC1 in mammalian cells.

We have cloned a cDNA inducing a cation-permeable current (mNSC1) from pancreatic beta-cells, which shows niflumate-sensitive current in Xenopus oocytes. To elucidate the expression in mammalian cells, mNSC1 was expressed in CHO cells. The reversal potential by mNSC1 was shifted toward positive which was significantly reversed by flufenamic acid. Single-channel analysis showed a characteristic of a Ca-activated nonselective cation channel. Therefore, we may conclude that mNSC1 expresses a fenamates-sensitive cation channel, inducing membrane depolarization in a mammalian cell.

Animals↗
PubMed1999

Solid cystic tumor of the pancreas in elderly men: report of a case.

Solid cystic tumor of the pancreas is a primary pancreatic neoplasm of unknown etiology that most commonly occurs in young women and ordinarily contains hemorrhagic tissue. We report herein the unusual case of a 75-year-old man found to have a solid cystic tumor in the body and tail of the pancreas, who is the oldest such male patient to be documented in Japan. The results of laboratory data and imaging studies indicated that the patient had a nonfunctioning islet tumor or solid cystic tumor of the pancreas, and distal pancreatectomy with splenectomy was performed. The diagnosis of solid cystic tumor was confirmed based on macroscopic and histological findings of the resected pancreatic tumor. The patient is currently in good health, without any signs of tumor recurrence 1 year and 4 months after his operation. A total of 181 cases of solid cystic tumors of the pancreas reported in the Japanese literature, including our case, were reviewed to evaluate the clinical differences between patients aged 50 years or over and those younger than 50 years.

Aged↗
PubMed1999

Successful surgical treatment for implanted intraperitoneal metastases of ruptured small hepatocellular carcinoma: report of a case.

We report herein the case of a 53-year-old man with disseminated intraperitoneal metastases caused by the rupture of small hepatocellular carcinoma (HCC). He was admitted to our hospital in shock after suffering a trauma injury to the upper abdomen. Ultrasonography revealed a massive hemoperitoneum. At surgery, 4000 ml of blood was drained from the abdominal cavity and a ruptured tumor, 2 cm in diameter, was found in the right lobe of the liver. The tumor was resected with an adequate surgical margin and subsequent microscopic examination confirmed a diagnosis of moderately differentiated HCC without associated liver cirrhosis. The patient was readmitted 14 months later following the development of right lower quadrant pain. Ultrasonography and computed tomography revealed extrahepatic abdominal tumors, and abdominal angiography demonstrated four intraperitoneal tumors. At surgery, four implanted metastases adhered to the greater omentum were found and resected. No other tumors were detected. Microscopically, all four tumors were confirmed as moderately differentiated hepatocellular carcinoma. Ruptured HCC may lead to implanted intraperitoneal metastasis, but rupture of small HCC is very rare. While hepatic resection is the treatment of choice for ruptured HCC, according to our review of the literature, only a few patients have survived long-term after resection of implanted metastasis.

Adult↗
PubMed1999

Long-term treatment with antipsychotic drugs in conventional doses prolonged QTc dispersion, but did not increase ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease.

OBJECTIVE: The aim of this study was to examine the hypothesis that long-term treatment with antipsychotic drugs in conventional doses prolongs QTc dispersion and increases ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease. METHODS: We measured QTc and QTc dispersion and ventricular tachyarrhythmias in 64 patients with schizophrenia, including 59 patients who received psychiatric medications, and five patients who did not receive psychiatric medications, and 45 healthy volunteers. None of the subjects had a history of cardiac disease or showed any abnormality in chest radiograph and transthoracic echocardiographic studies. None of the subjects had electrolyte abnormality. None of the subjects were taking drugs known to influence the QT interval, other than psychiatric medications. RESULTS: QTc and QTc dispersion were significantly (P < 0.017) increased in patients who received psychiatric medications compared with patients who did not receive psychiatric medications, or with healthy volunteers [QTc: 0.442 (0.029), 0.418 (0.029), 0.417 (0.028) s, QTc dispersion: 0.054 (0.013), 0.038 (0.017), 0.038 (0.009) s]. Daily ventricular premature beats were 183 (689), 77 (23), and 86 (149), respectively. No ventricular tachycardia was observed. There were no correlation between QTc and QTc dispersion and ventricular premature beats. CONCLUSION: Long-term treatment with antipsychotic drugs in conventional doses prolonged both QTc and QTc dispersion in patients with schizophrenia, but did not increase ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease. However, despite the negative findings, ventricular tachyarrhythmias may occur as a rare side-effect of antipsychotic drugs, particularly if a patient has additional risk factors.

Adult↗
PubMed1999

Hypercholesterolemia and glomerular diseases in urinary screening of school children.

Although hypercholesterolemia frequently accompanies nephrotic syndrome, high serum total cholesterol (TC) levels are occasionally seen in children with non-nephrotic glomerular diseases. However, little is known of the significance, if any, of these elevated serum TC levels in non-nephrotic glomerular diseases. During the past 5 years, a total of 256,179 school children received yearly urinary screening at school for renal diseases and 1,702 children (0.66% of the total, although 174 children dropped out) had proteinuria and/or hematuria. Using the data obtained from the 1,528 children, we studied whether there is any association between serum TC levels and the presence of glomerular diseases. The detection rate of glomerular diseases (IgA nephropathy, membranoproliferative glomerulonephritis, focal segmental glomerular sclerosis, etc.) in the subjects with high serum TC levels (> or =200 mg/dl) was significantly higher (16 of 161, 9.94%, P<0.001) than in those with normal serum TC levels (<200 mg/dl) (10 of 1,367, 0.73%). There were no significant differences in serum albumin and blood urea nitrogen levels between the two groups. We conclude that children with chance proteinuria and/or hematuria may be at higher risk for glomerulonephritis of various types when they have unexplained hypercholesterolemia, and that measurement of serum cholesterol levels may be useful in urinary screening for renal diseases.

Adolescent↗
PubMed1999

Apolipoprotein E epsilon 4 allele and nephrotic glomerular diseases in children.

Hyperlipidemia is a well-recognized complication of the nephrotic syndrome and is a factor contributing to the progression of the initial glomerular injury and the development of glomerulosclerosis. Apolipoprotein E (apoE) is a plasma protein and apoE epsilon 4 allele is associated with higher plasma cholesterol levels. With this in mind, we studied apoE phenotypes and alleles in children with nephrotic glomerular diseases (NGD, n=29), including idiopathic nephrotic syndrome (n=16), membranoproliferative glomerulonephritis (n=7), and focal segmental glomerulosclerosis (FSGS, n=6). Children with NGD had a higher epsilon 4 allele frequency (20.7%) than controls (10.8%), and those with FSGS had both higher apoE4/3 (66.7%) and epsilon 4 allele (33.3%) frequencies than controls (20.4% and 10.8%, respectively). In IgA nephropathy (n=30, disease controls), no significant association with specific apoE was found. Further studies are needed to clarify the significance of the observed high frequencies of apoE epsilon 4 allele in children with NGD and apoE4/3 phenotype distribution in FSGS.

Adolescent↗
PubMed1999

Chronic hypersensitivity pneumonitis in Japan: a nationwide epidemiologic survey.

BACKGROUND: Pulmonary fibrosis inevitably develops in patients with chronic hypersensitivity pneumonitis (HP). OBJECTIVE: We conducted a nationwide epidemiologic study in Japan to evaluate the frequency and clinical characteristics of chronic HP. METHODS: This report is on 36 cases of chronic HP, including 10 patients with summer-type HP, 5 patients with home-related HP, 7 patients with bird fancier's lung, 5 patients with isocyanate-induced HP, 4 patients with farmer's lung, and 5 patients with other types of chronic HP. Chronic HP was further subgrouped into 2 types: one type of patients were first seen with chronic disease (9 patients), and the other type became chronic with fibrosis after repeated acute episodes (27 patients). RESULTS: The upper lung field was frequently involved in chronic HP (17%). Ground-glass opacities were observed in 57% and air space consolidation in 30% of the patients. Honeycombing was apparent in 37%. Twenty-six of 28 patients had antibodies to the presumptive antigens. Five of 8 patients with chronic HP were positive for antigen-induced lymphocyte proliferation. In 2 cases patients did not have detectable antibodies to causative antigens, although antigen-induced lymphocyte proliferation was detectable. The ratio of CD4 to CD8 in BAL lymphocytes was lowest in isocyanate-induced HP (mean 0.22) and tended to be high in farmer's lung and bird fancier's lung. Granulomas were observed in 39% and Masson bodies in 42% of specimens on histologic examination. Administration of prednisolone was effective in 58% of patients. CONCLUSIONS: The insidious form of chronic HP has probably been misdiagnosed as idiopathic pulmonary fibrosis when a good history was not taken and immunologic (especially antigen-induced lymphocyte proliferation) and BAL testing were not counted.

Aged↗
PubMed1999

Biased T cell receptor Vbeta gene expression in bronchoalveolar lavage fluid from Japanese patients with sarcoidosis.

OBJECTIVE: Sarcoidosis is believed to be one of the T cell-mediated granulomatous diseases with unknown aetiology. We attempt to search for the causative T cell clones of sarcoidosis. METHODS: We study T cell receptor beta-chain variable region (Vbeta) repertoire in peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) from patients with sarcoidosis, using semi-quantitative reverse transcriptase-polymerase chain reaction method. The expression of 22 kinds of Vbeta genes is examined in 17 patients with sarcoidosis and nine normal subjects. RESULTS: Compared with control subjects, the group with sarcoidosis exhibits significantly high expressions of the Vbeta2 (P < 0.005, Wilcoxon's test) and Vbeta6 (P = 0.005) genes in BALF. In each BALF sample, the Vbeta2 (P < 0.01, chi2 test) and Vbeta6 (P < 0.01) genes were overexpressed (> 2 SD above the mean value for each Vbeta observed in control subjects) in 11 and 10 of 17 patients with sarcoidosis, respectively. Furthermore, the amino acid sequences of Vbeta6+ complementarity determining region 3 were conserved in one of three patients. There is, however, no disposition of Vbeta gene usage in PB from patients with sarcoidosis compared with control subjects. CONCLUSIONS: The T lymphocytes with Vbeta2 and/or Vbeta6 are associated with the pathogenesis of sarcoidosis. The possibility exists that these T lymphocytes might be capable of recognizing the restricted antigens, thereby inducing oligoclonal expansion.

Adult↗
PubMed1999

Hypoxia-induced adrenomedullin production in the kidney.

BACKGROUND: Adrenomedullin (AM) is a newly discovered peptide that has a potent vasorelaxant activity. To investigate its potential roles in hypoxia-induced renal injury, we examined whether AM production in the kidney increased under hypoxic conditions. METHODS: The AM transcript levels in Madin-Darby canine kidney (MDCK) cells, rat vascular smooth muscle cells (VSMCs), and rat mesangial cells were assessed by Northern blot analyses under normoxic and hypoxic conditions. The AM peptide in culture media was measured by radioimmunoassay. The effects of hypoxia on accumulation of cAMP in VSMCs were also examined. The stability of AM transcripts under normoxic and hypoxic conditions was compared in the presence of actinomycin D. The effects of hypoxia on AM promoter activity was assessed by transient transfection assays using the AM promoter subcloned upstream of luciferase gene. RESULTS: The expression of AM transcripts increased significantly in MDCK cells, rat VSMCs, and rat mesangial cells under hypoxic conditions without changes in the stability of AM transcripts; however, the AM promoter activity under hypoxic was not elevated significantly. The accumulation of AM peptide in culture media also increased significantly under hypoxic conditions in MDCK cells (2.2 +/- 0.1 fmol/10(5) cells in normoxia vs. 3.5 +/- 0.3 fmol/10(5) cells in hypoxia, 6 hr after hypoxia induction, P < 0.001), and in rat VSMCs (5.5 +/- 0.3 fmol/10(5) cells in normoxia vs. 7.8 +/- 0.4 fmol/10(5) cells in hypoxia, 8 hr after hypoxia induction, P < 0.01). Under hypoxic conditions, cAMP levels in rat VSMCs increased significantly compared with those under normoxic conditions (13.3 +/- 1.4 pmol/well vs. 4.6 +/- 0.4 pmol/well, P < 0.01). CONCLUSIONS: Renal parenchymal cells as well as renal vessels may produce AM under hypoxic conditions.

Adrenomedullin↗
PubMed1999

Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension.

OBJECTIVES: We have previously shown that in the rat a diet high in cholesterol and deficient in vitamin E and selenium results in hypercholesterolaemia and increased lipid oxidation. We utilized this model to determine whether rats given this diet develop impaired endothelium-dependent relaxation mediated by nitric oxide (NO) in mesenteric and in renal vessels. In addition, we tested whether the impairment is due to (i) decreased endothelial NO synthase activity, (ii) increased NO inactivation and/or (iii) increased production of the endothelium-derived constricting factors thromboxane A2/prostaglandin H2 and endothelin-1. We also investigated whether endothelial dysfunction induced by dyslipidaemia increases the sensitivity for the development of hypertension in response to high dietary salt. METHODS: Male Dahl salt-sensitive (DSS) rats were divided into three groups and received a standard diet (control group), a high (4%) cholesterol diet (HChol), or a high cholesterol diet deficient in the anti-oxidants vitamin E and selenium (HChol-Def). The NaCl content of these diets was 0.5%. After 18 weeks we studied endothelium-dependent relaxation in response to acetylcholine (ACh) in aortas and in isolated perfused preparations of mesenteric arteries and kidneys. In some experiments, ifetroban, a thromboxane A2/prostaglandin H2 receptor antagonist, was added to the organ bath or the perfusion buffer. Vascular responses to endothelin-1 as well as to BQ-123, an endothelin A receptor blocker, were studied in the isolated perfused kidneys. In addition, two extra groups of rats were fed a diet high in sodium chloride (2%): one of the groups received the normal cholesterol diet whereas the other group received the diet high in cholesterol and deficient in vitamin E and selenium. RESULTS: Compared to normocholesterolemic rats, responses to ACh were significantly impaired in aortas, mesenteric arteries and kidneys of HChol-Def rats (P < 0.01). Endothelial NO synthase activity (conversion of [14C]L-arginine to [14C]L-citrulline) was similar in aortas of control, HChol and HChol-Def rats; thus suggesting that impaired endothelium-dependent relaxation in the HChol-Def rats was not due to decreased cNOS catalytic activity. Ifetroban improved the impaired endothelium-dependent relaxation in mesenteric vessels, but not in aortas and kidneys. Endothelin-1 (ET-1: 10(-13)-10(-11) mol/l) elicited NO-mediated relaxations in kidneys of control rats but not in kidneys of HChol-Def; blockade of ET-1 with BQ-123, an ET(A) receptor blocker, did not improve NO-mediated relaxation of HChol-Def. Despite impaired endothelium-dependent relaxation in renal and mesenteric vessels, HChol-Def DSS rats failed to develop hypertension (systolic blood pressure 144 +/- 1 in control and 150 +/- 2 mmHg in HChol-Def) but manifested a significant increase in sensitivity to the pressor effects of a high (2% NaCl) dietary salt content during the initial 10 weeks of the study, although the final blood pressure at 18 weeks was similar in both groups. CONCLUSION: These studies support the notion that (i) products of lipid oxidation may reduce NO bioactivity without affecting endothelial NO synthase mass or catalytic activity, (ii) the mechanisms involved in the endothelial dysfunction induced by hypercholesterolaemia and oxidized lipids may differ among vascular beds, and (iii) decreased NO bioavailability does not necessarily result in systemic hypertension, but it may enhance the sensitivity to the hypertensinogenic effect of dietary salt.

Acetylcholine↗
PubMed1999

Simple model for granular friction.

We propose a simple phenomenological model to describe the motion of a plate on granular layers pushed at a constant speed. The model contains the order parameter characterizing the transition from a solidlike state to a liquidlike state. The model reproduces the hysteresis in frictional force and the universal profile of the slip velocity, which are observed in experiment. Our model predicts that the area of hysteresis loop depends on the pushing speed.

Journal Article↗
PubMed1999

Effects of vasodilatory beta-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney.

The mechanisms for the vascular actions of vasodilatory beta-blockers remain undetermined. For some kinds of beta-blockers, the involvement of nitric oxide (NO) has been suggested. We studied the effects of vasodilatory beta-blockers on renal perfusion pressure (RPP) and NO release in the rat kidney. Infusion of bopindolol, celiprolol, and nebivolol caused a dose-dependent reduction in RPP and an increase in NO release (RPP: bopindolol 10(-6) mol/L, -23+/-2%; celiprolol 10(-4) mol/L, -27+/-2%; nebivolol 10(-5) mol/L, -35+/-3%; NO: bopindolol 10(-6) mol/L, +33+/-2; celiprolol 10(-4) mol/L, +41+/-2; nebivolol 10(-5) mol/L, +45+/-5 fmol. min-1. g kidney-1, mean+/-SEM). Metergoline (10(-6) mol/L), a 5-hydroxytryptamine (5-HT)1/2 antagonist, or NAN-190 (10(-6) mol/L), a 5-HT1A antagonist, almost completely abolished the vasorelaxation and NO release caused by bopindolol, celiprolol, and nebivolol. However, neither propranolol nor bisoprolol decreased RPP. Celiprolol and nebivolol caused vasodilation in the rat thoracic aorta, and it was markedly reduced by endothelial denudation, Nomega-nitro-L-arginine methyl ester (10(-4) mol/L), or NAN-190 (10(-6) mol/L). In deoxycorticosterone acetate-salt hypertensive rats, 4-week administration of celiprolol (50 mg. kg-1. d-1 IV) restored the responses regarding RPP and NO release to acetylcholine. These results suggest that several beta-blockers exert their vasodilatory action through the 5-HT1A receptor/NO pathway and that treatment with these beta-blockers may protect against endothelial injury in hypertension.

Adrenergic beta-Antagonists↗
PubMed1999

Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat.

We previously reported that adrenomedullin (AM), a potent vasodilator peptide discovered in pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat kidney. To further investigate whether the NO-cGMP pathway is involved in the mechanisms of AM-induced vasodilation, we examined the effects of E-4021, a cGMP-specific phosphodiesterase inhibitor, on AM-induced vasorelaxation in aortic rings and perfused kidneys isolated from Wistar rats. We also measured NO release from the kidneys using a chemiluminescence assay. AM (10(-10) to 10(-7) mol/L) relaxed the aorta precontracted with phenylephrine in a dose-dependent manner. Denudation of endothelium (E) attenuated the vasodilatory action of AM (10(-7) mol/L AM: intact (E+) -25.7+/-5.2% versus denuded (E-) -7. 8+/-0.6%, P<0.05). On the other hand, pretreatment with 10(-8) mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (-49. 0+/-7.9%, P<0.05) but not in the denuded one. E-4021 also enhanced acetylcholine (ACh)-induced vasorelaxation in the rat intact aorta (10(-7) mol/L ACh -36.6+/-8.4% versus 10(-8) mol/L E-4021+10(-7) mol/L ACh -62.7+/-3.1%, P<0.05). In perfused kidneys, AM-induced vasorelaxation was also augmented by preincubation with E-4021 (10(-9) mol/L AM -15.4+/-0.6% versus 10(-8) mol/L E-4021+10(-9) mol/L AM -23.6+/-1.2%, P<0.01). AM significantly increased NO release from rat kidneys (DeltaNO: +11.3+/-0.8 fmol. min-1. g-1 kidney at 10(-9) mol/L AM), which was not affected by E-4021. E-4021 enhanced ACh-induced vasorelaxation (10(-9) mol/L ACh -9.7+/-1.7% versus 10(-8) mol/L E-4021+10(-9) mol/L ACh -18.8+/-2.9%, P<0.01) but did not affect ACh-induced NO release from the kidneys. In the aorta and the kidney, 10(-4) mol/L of NG-nitro-L-arginine methyl ester, an NO synthase inhibitor, and 10(-5) mol/L of methylene blue, a guanylate cyclase inhibitor, reduced the vasodilatory effect of AM. These results suggest that the NO-cGMP pathway is involved in the mechanism of AM-induced vasorelaxation, at least in the rat aorta and kidney.

Adrenomedullin↗