Organization of the human prostacyclin synthase gene and association analysis of a novel CA repeat in essential hypertension.
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Animals↗
Biomedical subjects
K Kanmatsuse
Publications and source records attributed to K Kanmatsuse.
Effect of dibutyryl cyclic AMP on plasma renin activity in normal men and patients with primary aldosteronism.
Dibutyryl cyclic AMP (DBcAMP) directly stimulates the release of renin from the juxtaglomerular (JG) cells in vitro. We investigated the effect of DBcAMP on plasma renin activity (PRA) in 6 normal men and in 8 patients with primary aldosteronism (PA). A 20-min infusion of 0.33 mg/kg/min of DBcAMP significantly increased PRA in normal men, but had little effect on PRA in patients with PA. Infusion of DBcAMP significantly reduced the blood pressure and the levels of serum sodium and potassium in normal men and the patients with PA. Infusion of DBcAMP significantly increased urine volume in normal men, but not in patients with PA. Urinary excretion of sodium increased in both groups after the infusion of DBcAMP. Thus, DBcAMP did not stimulate renin release in patients with PA, suggesting that the chronic excess production of aldosterone suppresses the release of renin from JG cells.
Adult↗
A prospective, randomized, double-blind multicenter trial of a single bolus injection of the novel modified t-PA E6010 in the treatment of acute myocardial infarction: comparison with native t-PA. E6010 Study Group.
OBJECTIVES: This prospective, randomized, double-blind multicenter trial evaluated the efficacy and safety of a single bolus injection of the novel modified tissue-type plasminogen activator (t-PA) E6010 in the treatment of acute myocardial infarction compared with that of native t-PA. BACKGROUND: E6010 is a novel modified t-PA with a prolonged half-life (t1/2 alpha > or = 23 min) compared with native t-PA (t1/2 alpha = 4 min). E6010 can be administered in patients as a single intravenous bolus injection, and early recanalization can be expected. METHODS: The efficacy of E6010 was compared with that of native t-PA in 199 patients with acute myocardial infarction who were treated within 6 h of onset in a prospective, randomized, double-blind multicenter trial. Patients were given either 0.22 mg/kg body weight of E6010 intravenously over 2 min or native t-PA (tisokinase) 28.8 mg or 14.4 million IU (10% of the total dose over 1 to 2 min, the remainder infused over 60 min). RESULTS: The primary end point was the recanalization rate of the infarct-related coronary artery at 60 min after the start of treatment. Time to reperfusion was shorter in the E6010 group than in the native t-PA group. Thrombolysis in Myocardial Infarction flow grade 2 or 3 recanalization at 15, 30, 45 and 60 min after administration was observed in 37%, 62%, 74% and 79% (95% confidence interval [CI] 70% to 87%) of the E6010-treated patients and in 14%, 32%, 50% and 65% (95% CI 55% to 74%) of native t-PA-treated patients, respectively (p = 0.032 at 60 min). CONCLUSIONS: The present study indicates that, compared with native t-PA, a single bolus injection of E6010 over 2 min produces a higher rate of early recanalization of the infarct-related coronary artery without fatal bleeding complications.
Aged↗
Role of long-form PDGF A-chain in the growth of vascular smooth muscle cells from spontaneously hypertensive rats.
Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit exaggerated growth relative to cells from normotensive Wistar-Kyoto (WKY) rats. Platelet-derived growth factor (PDGF) A-chain has been implicated in the exaggerated growth of VSMC from SHR. Two isoforms of PDGF A-chain mRNA that either include (long form) or exclude (short form) exon 6 are produced as a result of alternative splicing. The expression of the long-form PDGF A-chain at the mRNA level and its role in the growth of VSMC from SHR have now been investigated with the use of an antisense oligodeoxynucleotide (ODN) complementary to exon 6 of the PDGF A-chain gene. Reverse transcription-polymerase chain reaction (RT-PCR) analysis with primers encompassing exon 6 of PDGF A-chain mRNA revealed bands corresponding to both long- and short-form PDGF A-chain transcripts in quiescent VSMC from both SHR and WKY rats, with the long-form mRNA more abundant in VSMC from SHR than in cells from WKY rats. Expression of the long-form of PDGF A-chain mRNA was enhanced with angiotensin II and transforming growth factor-beta1 in VSMC from SHR, but not in cells from WKY rats. The antisense ODN significantly inhibited DNA synthesis by VSMC from SHR, but not by cells from WKY rats, in the absence or presence of serum. In addition, the antisense ODN significantly inhibited serum induced proliferation of VSMC from SHR, but not those from WKY rats. The antisense ODN abolished expression of the long-form PDGF A-chain mRNA in VSMC, suggesting that its inhibitory effects on the growth of VSMC from SHR are mediated by depletion of the long-form transcripts. These results indicate that the long-form of PDGF A-chain contributes to the exaggerated growth of VSMC from SHR.
Animals↗
The relationship of hyperinsulinemic state to left ventricular hypertrophy, microalbuminuria, and physical fitness in borderline and mild hypertension.
The relationship of the hyperinsulinemic state to left ventricular hypertrophy, left ventricular geometric patterns, microalbuminuria, and physical fitness were studied in 52 middle-aged unmedicated men with borderline and mild hypertension. Left ventricular mass index and relative wall thickness were assessed by echocardiography. Physical fitness was determined by symptom-limited maximal treadmill stress testings. The urinary concentration of microalbumin and C-peptide was measured in 24-h urine samples by radioimmunoassey. The 24-h urinary C-peptide excretion rate was correlated with left ventricular mass index (r = 0.46), relative wall thickness (r = 0.41), treadmill time (r = -0.35), normalized treadmill time (r = -0.52), systolic blood pressure at peak exercise (r = 0.29), and 24-h urinary microalbumin excretion (r = 0.48). Stepwise multiple regression analysis identified the left ventricular mass index, the 24-h urinary albumin excretion, and the normalized treadmill time as variables in the equation for the 24-h urinary C-peptide excretion. Thus, the hyperinsulinemic state is related to left ventricular hypertrophy, microalbuminuria, and impaired physical fitness in patients with borderline and mild hypertension.
Adult↗
Sequences of exon 6 and the adjacent intron boundaries of the rat platelet-derived growth factor A-chain gene: implications for alternative splicing.
Platelet-derived growth factor (PDGF) is a potent stimulator of vascular smooth muscle cell growth. Two isoforms of PDGF A-chain mRNA that either include (long form) or exclude (short form) exon 6 are produced as a result of alternative splicing in mouse, rabbit, and human. The short form of PDGF A-chain is expressed in both resting and activated cells, while the long form is present predominantly in activated cells. Reverse transcription-polymerase chain reaction analysis with primers encompassing exon 6 revealed the presence of both long- and short-form PDGF A-chain transcripts in rat vascular smooth muscle cells. The nucleotide sequences of exon 6 and its intron boundaries were determined from rat vascular smooth muscle cell cDNA and rat leukocyte genomic DNA. Translation of the long form of PDGF A-chain mRNA was shown to terminate in the 70-base pair exon 6. Conserved sequences that may contribute to the regulation of alternative RNA splicing were identified in intron 5.
Alternative Splicing↗
Antisense oligodeoxynucleotide complementary to platelet-derived growth factor A-chain messenger RNA inhibits the arterial proliferation in spontaneously hypertensive rats without altering their blood pressures.
OBJECTIVE: To evaluate the effects of the antisense oligodeoxynucleotide (ODN) to platelet-derived growth factor (PDGF) A-chain messenger RNA (mRNA) on the growth of cardiovascular organs in hypertension. DESIGN: 15-Mer antisense ODN complementary to the initiation codon region of rat PDGF-A chain mRNA and non-sense ODN of identical proportion but with a random order of bases relative to that of antisense ODN were synthesized with a DNA synthesizer. METHODS: We examined the effects of the antisense ODN on the growth of vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats, and on the expression of PDGF A-chain mRNA by reverse transcription and polymerase chain reaction and PDGF A-chain protein by Western blot analysis in vitro. We evaluated the distribution of 32P-labeled antisense ODN and examined the effects of the antisense ODN on the growth of cardiovascular organs in vivo. RESULTS: The antisense ODN reduced the basal DNA synthesis of VSMC from SHR significantly, but did not do so in cells from Wistar-Kyoto rats. Mutations in the antisense ODN sequence reduced the ODN-induced inhibition of DNA synthesis. Addition of serum or transforming growth factor-beta 1 increased the DNA synthesis in the SHR-derived VSMC that was inhibited by the antisense ODN. The antisense ODN inhibited the production of PDGF A-chain protein, but not of the PDGF A-chain mRNA. The injection of 32P-antisense ODN in vivo led to a greater accumulation of radioactivity in the aorta than in other organs. Infusion of antisense ODN for 28 days did not alter the systolic blood pressure appreciably in rats of either strain. However, in SHR, it reduced markedly the elevated DNA content, [3H]-thymidine uptake, and incorporation of [3H]-thymidine into aortic DNA, and suppressed the production of aortic PDGF A-chain protein. These results indicated that the PDGF A-chain is involved in the exaggerated growth of VSMC from SHR by which inhibition of the translation of PDGF A-chain mRNA to the protein with antisense ODN occurs in vitro, and that antisense ODN to PDGF A-chain suppresses the exaggerated arterial proliferation in SHR without altering the high blood pressure in vivo. CONCLUSION: These results imply that inhibition of the final responsible growth factor PDGF A-chain by antisense ODN can suppress the arterial proliferation in hypertension without altering the blood pressure, suggesting that the arterial proliferation in hypertension is independent of the high blood pressure in part, and that antisense therapy could be feasible for treating hypertension.
Animals↗
Association analysis of CA repeat polymorphism of the endothelial nitric oxide synthase gene with essential hypertension in Japanese.
The nitric oxide synthase (NOS) gene is thought to be associated with essential hypertension (EH), because NO is implicated in endothelium-mediated vasodilation. We investigated the possible association between the alleles of simple tandem repeat DNA polymorphism of the endothelial constitutive NOS (cNOS) gene and EH in Japanese subjects. In all, 100 patients with EH and 123 subjects with normal blood pressure were studied. Polymerase chain reaction was used to amplify the CA repeat site in the endothelial cNOS gene and alleles based on the CA repeat number were determined. The allele frequencies in the hypertensive group and normotensive group were then compared. Twenty-three alleles were identified in this study of Japanese subjects. The overall distributions of allele frequencies in the two groups were not significantly different. However, comparing the allele frequencies in the EH group without left ventricular hypertrophy (LVH) and the normotensive group, the overall distributions were significantly different (p = 0.019). The 33-repeat allele was found more frequently in the EH group without LVH than in the normotensive group (p = 0.000047, Odds ratio = 3.71). In conclusion, the 33-repeat allele of the endothelial cNOS gene is associated with EH without LVH, and may be a genetic marker of EH in Japanese subjects.
Age of Onset↗
Association analysis of TG repeat polymorphism of the neuronal nitric oxide synthase gene with essential hypertension.
The nitric oxide synthase (NOS) gene is thought to be involved in essential hypertension because nitric oxide is implicated in endothelium-mediated or nitroxidergic neuron-mediated vasodilation. Using simple tandem repeat DNA polymorphism of the neuronal constitutive NOS (nNOS) gene, we carried out an association study in patients with essential hypertension. One hundred and thirty-one patients with essential hypertension and 147 subjects with normal blood pressure were studied. Polymerase chain reaction was applied to amplify the TG repeat site in the nNOS gene, and alleles based on the TG repeat number were determined. Eight alleles were identified in this study of Japanese subjects. Overall distributions of allele frequencies in the two groups were not significantly different. Thus, the genes detected by examination of this microsatellite polymorphism in the nNOS gene are not associated with essential hypertension.
DNA↗
Influence of dialysis membranes on interleukin-1 beta and interleukin-1 receptor antagonist production by peripheral blood mononuclear cells.
We investigated the production of interleukin (IL)-1 beta and IL-1 receptor antagonist (Ra) by peripheral blood mononuclear cell (PBMC) in vitro during hemodialysis of 7 dialysis patients using 4 differential dialysis membranes (regenerated cellulose [RC], polyamide [PA], polysulfone [PS] and AN-69). Blood sampling was performed before dialysis (0 min), 15 min after starting dialysis, and after dialysis (240 min) during the last session of each treatment. The cellular content of fresh cells and the production of IL-1 beta and IL-1Ra with and without lipopolysaccharide (LPS) stimulation of the cells were evaluated and measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-1 beta with LPS stimulation using RC, PA, and PS membranes was significantly reduced at 15 min and was not changed at 240 min as compared with the level at 0 min. On the other hand, the level of IL-1 beta with LPS stimulation using an AN-69 membrane at 15 and 240 min was not significantly different from that at 0 min. Neither initial cellular content nor spontaneous production of IL-1 beta were detected at 0, 15, or 240 min in any of the membranes. The spontaneous production of IL-1Ra at 15 and 240 min was not significantly different from that at 0 min in any of the membranes. The cellular content of IL-1Ra using the RC membrane was significantly lower at 15 min and did not differ at 240 min from the level at 0 min. The cellular content of IL-1Ra using PA, PS, and AN-69 membranes was not significantly different at 15 and 240 min from that at 0 min. However, the IL-1Ra level with LPS stimulation using RC and PA membranes was significantly reduced from that at 0 min, but the level using PS and AN-69 membranes was not different from that at 0 min. Because IL-1 beta and IL-1Ra levels 15 min after starting dialysis using bioincompatible dialysis membranes were reduced from the levels at 0 min, the findings suggest that measurement of cytokines' during dialysis treatment at an early stage is a useful marker for evaluating the biocompatibility of a dialysis membrane.
Acrylic Resins↗
Chronic effects of long-term acetate-free biofiltration on the production of interleukin-1beta and interleukin-1 receptor antagonist by peripheral blood mononuclear cells.
The production of interleukin-1beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1Ra) by peripheral blood mononuclear cells (PBMC) was examined in patients on long-term acetate-free biofiltration (AFB). Five stable patients on AFB were switched to bicarbonate hemodialysis (BCD) for a 2-week period using the same AN69 membrane dialyzer. IL-1beta and IL-1Ra production was measured by ELISA before and after dialysis in the last session of both treatments. Cytokine production by unstimulated PBMC did not differ significantly before and after both AFB and BCD. However, the spontaneous IL-1Ra/IL-1beta production ratio in AFB was significantly higher than that in BCD. These findings indicate that AFB may have more beneficial effects on cytokine production by PBMC compared to BCD.
Acetates↗
Increased production of interleukin-1beta and interleukin-1 receptor antagonist by peripheral blood mononuclear cells in undialyzed chronic renal failure.
We investigated the cell content and production of IL-1beta and IL-1 receptor antagonist (Ra) by unstimulated and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) obtained from 15 undialyzed patients with chronic renal failure (CRF; estimated GFR <10 ml/min), 15 patients on chronic hemodialysis (HD) and 15 healthy controls. These cytokines were measured by ELISA. The cell content of IL-1beta in freshly obtained PBMC was not detectable in any group. In contrast, that of IL-1Ra in CRF (1,807 +/- 370 pg/ml, p < 0.05) as well as in HD (1,791 +/- 151 pg/ml, p < 0.001) was significantly higher than that of the controls (907 +/- 156 pg/ml). In unstimulated cultured PBMC, spontaneous production of IL-1beta in CRF (66 +/- 13 pg/ml, p < 0.05) and in HD (81 +/- 29 pg/ml, p < 0.05) was significantly higher than that of the controls (26 +/- 3 pg/ml). In contrast, comparison of spontaneous production of IL-1Ra in the three groups was not significantly different. In LPS-stimulated PBMC, IL-1beta production in CRF (10,896 +/- 1,359 pg/ml, p < 0.01)and in HD(11,441 +/- 1,400 pg/ml, p < 0.01) was significantly higher than that of the controls (6,117 +/- 572 pg/ml). However, IL-1Ra production by LPS-stimulated PBMC in the three groups was not significantly different. Moreover, the spontaneous IL-1Ra/IL-1beta production ratio in CRF (140 +/- 16, p < 0.01) and in HD (142 +/- 19, p < 0.01) was significantly lower than that of the controls (294 +/- 41). The present study demonstrates that cytokine production by PBMC in undialyzed CRF patients as well as in hemodialyzed patients is heightened and may induce impaired function of the immunological system before CRF patients are introduced to dialysis.
Adult↗
Interleukin 10 and interleukin 13 synergize to inhibit vascular permeability factor release by peripheral blood mononuclear cells from patients with lipoid nephrosis.
It has been proposed that a vascular permeability factor (VPF) is involved in the pathogenesis of lipoid nephrosis (LN). There is now increasing evidence that interleukin 10 (IL-10) and interleukin 13 (IL-13) have regulatory effects on cytokine production by activated macrophages. These results prompted us to study the effects of recombinant human IL-10 and IL-13 on VPF secretion in LN. In the present study, we demonstrate that the regulatory cytokines IL-10 and IL-13 are potent inhibitors of the VPF activity of activated peripheral blood mononuclear cells. Each cytokine was found to suppress VPF secretion in a dose-dependent fashion. More importantly, the combination of the cytokines was found to give a potent synergistic suppression of VPF by concanavalin A activated peripheral blood mononuclear cells from patients with LN. When both anti-IL-10 and anti-IL-13 antibodies were added together to the peripheral blood mononuclear cells, a further increase of concanavalin A enhanced secretion of VPF occurred. These data establish IL-10 and IL-13 as potent inhibitors of VPF activity and suggest their utility in controlling deleterious VPF-mediated responses such as occur in LN patients with nephrotic syndrome.
Adolescent↗
Magnetic resonance imaging in diagnosis of right coronary arteriovenous fistula--a case report.
We describe a patient with a right coronary arteriovenous fistula in whom magnetic resonance imaging (MRI) was useful in establishing the diagnosis. In a 36-year-old woman, T1 spin echo MRI demonstrated a massively dilated coronary arteriovenous fistula connecting the right coronary artery to the right atrium. The cine field echo technique showed a continuous shunt flow within the fistula as documented by the flow void throughout the cardiac cycle. These findings were confirmed by cardiac catheterization. We conclude that MRI is useful not only in detecting a coronary arteriovenous fistula but also in identifying its origin and the drainage site.
Adult↗
Relationship between preinfarction angina and time interval to reperfusion with thrombolytic therapy in acute myocardial infarction.
This study was conducted in an attempt to clarify whether preinfarction angina has an ischemic preconditioning effect. The subjects of this study were Killip class I patients who had suffered a first acute myocardial infarction (MI) as a result of total occlusion of the proximal left anterior descending coronary artery without development of collateral vessels and multivessel coronary artery disease. All subjects achieved successful reperfusion [thrombolysis in myocardial infarction (TIMI) flow grade 3] through intracoronary thrombolysis with single-chain urokinase-type plasminogen activator (SCU-PA). Subsequently, they received the same drug therapy and remained free of reocclusion. The patients were divided into those who experienced a new onset of prodromal angina within 24 h before the onset of acute MI [PA(+) group] and those who had a sudden onset of acute MI without the preceding angina [PA(-) group]. They were further divided according to the time interval from the onset of acute MI to reperfusion (within 1 h, 1-2 h, 2-3 h, 3-4 h, and 4-7 h). In addition, the left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVI), and the amount of creatine kinase (CK) released (sigma CK) were compared in these 2 groups at reperfusion time. The results of this study showed that sigma CK was significantly lower in the PA(+) group than in the PA(-) group (1,850 mIU vs 3,583 mIU) when reperfusion was induced within 1 h after the onset of acute MI. When reperfusion was induced 1-2 h after the onset of acute MI, sigma CK tended to be lower in the PA(+) group than in the PA(-) group (3,677 mIU vs 5,261 mIU). Once the time to reperfusion exceeded 2 h, there was no significant difference in sigma CK between these 2 groups. On the other hand, there were no significant differences in LVEF and LVEDVI between these 2 groups at any reperfusion time. In conclusion, preinfarction angina had a preconditioning effect (reduction in sigma CK), but this effect was lost once the time interval from the onset of acute MI to reperfusion exceeded 2 h.
Adult↗
Effects of long-term antihypertensive therapy on physical fitness of men with mild hypertension.
This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical fitness in men with mild hypertension. All subjects underwent symptom-limited treadmill stress testing and routine echocardiographic studies. Twenty-two subjects who had either a causal diastolic blood pressure of more than 105 mmHg or a left ventricular mass index (LVMI) of 125 g/m2 or more during follow-up were assigned to receive medical therapy. The other 31 men who did not meet either criterion were continuously followed-up without medication. Among the 22 treated men, the age-adjusted treadmill time (normalized treadmill time, TMTn) significantly decreased before the initiation of medication, while 31 untreated men showed no change in TMTn throughout the study. The 22 treated subjects were subsequently divided into two groups; 13 were given nifedipine and 9 were given acebutolol. All treated subjects were followed-up for more than 3 years. After treatment, the two groups showed similar reductions in blood pressure and LVMI, but a different outcome for TMTn: TMTn increased from 104 +/- 8% to 115 +/- 16% in subjects given nifedipine (p < 0.05) and decreased from 106 +/- 12% to 99 +/- 10% (p < 0.01) in those given acebutolol. Thus, the physical fitness of subjects who required medication significantly deteriorated without medication; their physical fitness improved after treatment with a calcium-channel antagonist and deteriorated after treatment with a beta-blocker.
Acebutolol↗
Catheter ablation of canine ventricular myocardium. The use of repetitive short time constant capacitive shocks to increase lesion volume.
Arching and barotrauma, seen with high energy DC catheter ablation, are responsible for diffuse cardiac damage and coronary sinus rupture. In six anesthetized dogs, we investigated the effects of an increasing number of short time-constant capacitive shocks on the volume of myocardial damage. Each dog received capacitive shocks of 2 J/kg at 3 sites in the left ventricle. One shock was delivered in 2 dogs, 2 shocks were delivered in 2 dogs and 3 shocks were delivered in 2 dogs. Shock delivery was not accompanied by hemodynamic collapse, sustained ventricular tachycardia or ventricular fibrillation. The dogs were sacrificed at 60 minutes. Mean (SEM) lesion volumes were 195 (39) mm3, 480 (41) mm3, and 595 (110) mm3, respectively. Despite variability in individual volume of damage, there was a significant increase in lesion volume with an increasing number of shocks. There was no evidence of perforation or tamponade. Increasing myocardial damage can be produced using repetitive capacitive shocks. Delivery of 2 shocks produces clinically useful lesions without the adverse effects associated with single high energy shocks. Repetitive capacitive shocks offer a method of increasing lesion volume without increasing energy and thereby without compromising safety.
Animals↗
[The role of nitric oxide in two-kidney, one-clip renovascular hypertensive rats].
The relationship between blood pressure(BP) and nitric oxide(NO) in two-kidney, one-clip renovascular hypertensive rats (2K1C) was investigated. Although urinary NO2- + NO3-(NOx) excretion (UNOX V) increased 2 weeks after surgery (2W-2K1C), UNOX V decreased 4 weeks after surgery (4W-2K1C) compared with that of the control. UNOX V levels were restored 2 weeks after unclipping (U2K1C). BP and UNOX V did not change in 2K1C after treatment with L-arginine (Arg-2K1C). Aorta from 4W-2K1C and Arg-2K1C showed significantly decreased relaxation responses to acetylcholine(Ach), but Ach-induced relaxation of aorta in U2K1C returned to control-level responses. De-endothelialized aorta from 4W-2K1C, Arg-2K1C, and U2K1C had significantly decreased relaxation responses to lipopolysaccharide. These data suggest that: (1) transient increase of NO synthesis is accompanied by elevation of BP, but long-term elevation of BP decreases NO synthesis in endothelium and smooth muscle cells: (2) L-arginine supplement has no effect on the development of hypertension and on NO production by endothelium and smooth muscle cells in 2K1C.
Acetylcholine↗