Biomedical subjects

J Yoshikawa

Publications and source records attributed to J Yoshikawa.

At least 199 records · Page 11Linked to original sources

PubMed1997

Planimetry and transthoracic two-dimensional echocardiography in noninvasive assessment of aortic valve area in patients with valvular aortic stenosis.

OBJECTIVES: The aim of this study was to evaluate the reliability of transthoracic two-dimensional echocardiography in measuring aortic valve area (AVA) by planimetry. BACKGROUND: Planimetry of AVA using two-dimensional transesophageal echocardiographic images has been reported to be a reliable method for measuring AVA in patients with aortic stenosis. Recent advances in resolution of two-dimensional echocardiography permit direct visualization of an aortic valve orifice from the transthoracic approach more easily than before. METHODS: Forty-two adult patients with valvular aortic stenosis were examined. A parasternal short-axis view of the aortic valve was obtained with transthoracic two-dimensional echocardiography. AVA was measured directly by planimetry of the inner leaflet edges at the time of maximal opening in early systole. AVA was also measured by planimetry using transesophageal echocardiography, by the continuity equation and by cardiac catheterization (Gorlin formula). RESULTS: In 32 (76%) of the 42 study patients, AVA could be detected by using the transthoracic planimetry method. There were good correlations between results of transthoracic two-dimensional echocardiographic planimetry and the continuity equation (y = 0.90x + 0.09, r = 0.90, p < 0.001, SEE = 0.09 cm2), transesophageal echocardiographic planimetry (y = 1.05x - 0.02, r = 0.98, p < 0.001, SEE = 0.04 cm2) and the Gorlin formula (y = 1.02x + 0.05, r = 0.89, p < 0.001, SEE = 0.10 cm2). CONCLUSIONS: Transthoracic two-dimensional echocardiography provides a feasible and reliable method in measuring AVA in patients with aortic stenosis.

Adult↗

PubMed1997

Retinopathy identifies marked restriction of coronary flow reserve in patients with diabetes mellitus.

OBJECTIVES: This study sought to assess the differences in coronary flow reserve in patients with and without diabetic retinopathy. BACKGROUND: Microvascular abnormalities throughout the body and impairment of coronary flow reserve have been described in patients with diabetes mellitus. However, the relation between diabetic retinopathy and coronary microvascular disease has not been investigated. METHODS: The study included 29 patients with diabetes mellitus (18 with and 11 without diabetic retinopathy) and 15 control patients with chest pain and normal coronary arteries. Diabetic retinopathy was nonproliferative in all 18 patients with this disorder (8 had background, 10 preproliferative retinopathy). Five minutes after injection of 3 mg of isosorbide dinitrate, phasic flow velocities were recorded in the proximal segment of the angiographically normal left anterior descending coronary artery at rest and during hyperemia (0.14 mg/kg body weight per min of adenosine infused intravenously) using a 0.014-in. 15-MHz Doppler guide wire. Coronary blood flow was calculated, and coronary flow reserve was obtained from the hyperemic/baseline flow ratio. RESULTS: Coronary blood flow was significantly lower during hyperemia ([mean +/- SD] 107 +/- 23 and 116 +/- 18 vs. 136 +/- 17 ml/min, respectively) and higher at baseline (58 +/- 16 and 45 +/- 12 vs. 37 +/- 10 ml/min, respectively) in diabetic patients with and without retinopathy than in control subjects (p < 0.05 for both diabetic groups). As a result, coronary flow reserve in both groups of diabetic patients was significantly lower than in control patients (1.9 +/- 0.4 and 2.8 +/- 0.3 vs. 3.3 +/- 0.4, respectively, p < 0.01 for both diabetic groups), and its reduction was greater in patients with than without retinopathy (p < 0.01). Furthermore, in patients with diabetic retinopathy, maximal hyperemic coronary flow (102 +/- 11 vs. 114 +/- 16 ml/min, p < 0.05) and flow reserve (1.6 +/- 0.2 vs. 2.3 +/- 0.2, p < 0.01) were significantly lower in those with preproliferative than background retinopathy. CONCLUSIONS: Coronary flow reserve is significantly restricted in patients with diabetes mellitus, and its reduction is more marked in those with diabetic retinopathy, especially in advanced retinopathy. Thus, diabetic retinopathy should identify marked restriction of coronary flow reserve in patients with diabetes mellitus.

Adult↗

PubMed1997

Echocardiographic estimation of left ventricular cavity area with a newly developed automated contour tracking method.

Development of an automated contour tracking method provides detection and tracking of the endocardial boundary using the energy minimization method without tracing a region of interest. The purpose of this study was to compare the automated contour tracking method and manually drawn methods for the measurement of left ventricular cavity areas and fractional area change. Apical four-chamber view was visualized and recorded for off-line analysis in 11 patients by means of two-dimensional echocardiography. The automated contour tracking method automatically traces the endocardial border from the recorded images and calculates left ventricular cavity areas (end-diastole and end-systole) and fractional area change. In the same images selected as end-diastole and end-systole in the automated contour tracking method, left ventricular endocardial border was manually traced to calculate left ventricular cavity areas and fractional area change. Both methods were compared by linear regression analysis for the measurement of cavity areas and fractional area change. Left ventricular areas measured by the automated contour tracking method showed an excellent correlation with those by the manual method (end-diastole: r = 0.99, y = 0.83x + 2.6; standard error of the estimate = 1.5 cm2; end-systole: r = 0.99, y = 0.96x -0.8, standard error of the estimate = 1.2 cm2). The mean differences between the automated contour tracking and manual methods were -3.1 +/- 5.1 cm2 and -1.6 +/- 2.4 cm2 at end-diastole and end-systole, respectively. Fractional area change determined by the automated contour tracking method correlated well with that by the manual method (r = 0.95, y = 1.17x -6.5, standard error of the estimate = 3.4%). The mean difference between the automated contour tracking and manual methods was -0.8% +/- 7.1%. In conclusion, a newly developed automated contour tracking method correlates highly with the manual method for the estimation of left ventricular cavity areas and fractional area change in high-quality images. This suggests that this new technique may be useful in the automated quantitation of left ventricular function in patients with high-quality images with no dropout and no intercavity artifact or structure.

Echocardiography↗

PubMed1997

Anti-angiogenic compound (TNP-470) inhibits mesangial cell proliferation in vitro and in vivo.

Growth factors, especially basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) are known to play key roles in the pathogenesis of mesangial proliferative glomerulonephritis. TNP-470 (AGM-1470), a potent anti-angiogenic compound, has anti-growth factor properties and inhibits the activation of cyclin-dependent kinase (cdk) 2 and phosphorylation of RB protein. We investigated whether TNP-470 could suppress growth factor induced mesangial cell proliferation in vitro and experimental model of mesangial proliferative glomerulonephritis in vivo. TNP-470 inhibited potently PDGF- and bFGF-stimulated proliferation of rat mesangial cells in vitro (IC50 = 50 pg/ml). In anti-Thy 1.1 glomerulonephritis, high dose use of TNP-470 (20 mg/kg/day) markedly suppressed mesangial cell proliferation and mesangial matrix expansion on day 6; however, mesangiolysis remained. Low dose use of TNP-470 (10 mg/kg/day) moderately inhibited mesangial cell proliferation and mesangial matrix synthesis, and induced appropriate glomerular healing on day 14 in anti-Thy 1.1 glomerulonephritis. Thus, TNP-470 potently inhibits growth factor-induced proliferation of mesangial cells in vitro, and mesangial cell proliferation and extracellular matrix expansion in anti-Thy 1.1 glomerulonephritis in vivo. These results suggest a novel therapeutic potential of TNP-470 in mesangial proliferative glomerulonephritis.

Animals↗

PubMed1997

Enhanced gene expression of scavenger receptor in peripheral blood monocytes from patients on cuprophane haemodialysis.

BACKGROUND: Macrophage scavenger receptor (SR) is implicated in playing a key role in macrophage-derived foam cell formation by taking up a large amount of modified low-density lipoproteins (LDL). It has also been postulated that alpha 2-macroglobulin receptor/LDL receptor-related protein (alpha 2MG/LRP) is involved in the development of foam cells by taking up apo E-enriched chylomicrons and VLDL remnants, and lipoprotein lipase-triglyceride-rich lipoprotein complexes. Accumulation of these lipid-loaded monocyte/ macrophages in the subendothelial space is considered to be an early event of atherogenesis. Since atherogenesis is considered to be accelerated in dialysis patients, we attempted to investigate whether gene expression of SR and alpha 2MG/LRP are altered in peripheral blood monocytes from patients on haemodialysis with a cuprophane (Cu) or polymethylmethacrylate (PMMA) membranes. METHODS: Peripheral blood monocytes (PBM) were prepared from patients undergoing haemodialysis with a Cu membrane (n = 9), patients undergoing haemodialysis with a PMMA membrane (n = 9), and healthy controls (n = 7). In a separate experiment we examined SR gene expression in uraemic patients (n = 12) and healthy controls (n = 9). SR and alpha 2MG/LRP mRNA were semiquantitated using reverse-transcription polymerase chain reaction (RT-PCR) assay followed by Southern blotting. RESULTS: SR mRNA expression in PBM from patients on chronic haemodialysis with a Cu membrane was about twofold higher than that in PBM from patients on chronic haemodialysis with a PMMA membrane or the controls (P < 0.05). alpha 2MG/LRP mRNA expression in PBM showed no difference among these, three groups. SR gene expression in monocytes from uraemic patients was not increased compared with that in the controls. CONCLUSION: PBM from patients under Cu membrane dialysis showed higher gene expression of SR than patients under PMMA membrane dialysis, uraemic patients, or healthy controls. This increased gene expression of SR in monocytes may be associated with the pathogenesis of accelerated atherosclerosis in patients on dialysis with a Cu membrane.

Arteriosclerosis↗

PubMed1997

Effect of exercise training and detraining on gas exchange kinetics in patients with chronic obstructive pulmonary disease.

Symptom-limited incremental exercise tests are used to estimate the training effect on patients with chronic obstructive pulmonary disease (COPD). However, there is a need for objective parameters for measurement on submaximal exercise testing. The purpose of this study was to assess the usefulness of measurement of oxygen uptake (VO2) kinetics during a constant work rate exercise test of patients with COPD after exercise training. Eleven patients with COPD performed exercise tests before and after cycle ergometer training on 3 days per week for 8 weeks; they then went without training for 5 months and performed the same tests. They performed an incremental exercise test to symptom-limited maximum and a constant work rate exercise test for 6 min on a cycle ergometer. The time constant of VO2 during the onset of constant work rate exercise was significantly decreased (from 63.5 +/- 7.8 s to 53.2 +/- 8.0 s) after exercise training (P = 0.021), but was significantly increased (to 73.4 +/- 14.9 s) after 5 months without training (P = 0.001). The oxygen pulse at steady state during constant work rate exercise testing was significantly increased after exercise training but decreased 5 months later. The change in blood lactate from rest to steady state during constant work rate exercise was significantly decreased after exercise training, but increased 5 months later. Measurement of the time constant of VO2 and oxygen pulse during constant work rate exercise are useful for the objective evaluation of the training effect of patients with COPD.

Aged↗

PubMed1997

Aberrant gastric venous drainage in a focal spared area of segment IV in fatty liver: demonstration with color Doppler sonography.

PURPOSE: To clarify the correlation between aberrant gastric venous drainage and a focal spared area at the posterior edge of segment IV in fatty liver by using color Doppler ultrasound (US). MATERIALS AND METHODS: Seventeen patients with fatty liver were examined with gray-scale, color Doppler, and power Doppler US. In one patient with a focal spared area, arteriography and computed tomography (CT) were performed during injection of contrast medium into the right gastric artery. RESULTS: Focal spared areas of fatty liver at segment IV were shown in five of 17 patients. In all five patients with a focal spared area, aberrant gastric venous drainage was observed with color Doppler US. Power Doppler US depicted aberrant gastric venous drainage more clearly than color Doppler US. On the other hand, no definite aberrant gastric venous drainage was seen in the 12 patients who had no focal spared area. In one patient who underwent selective arteriography of the right gastric artery and CT arteriography, aberrant gastric venous drainage into segment IV was directly demonstrated. CONCLUSION: Focal spared areas at segment IV in fatty liver correlate strongly with aberrant gastric venous drainage. Noninvasive imaging methods such as color and power Doppler US are useful for depicting these aberrant drainage veins.

Adult↗

PubMed1997

Posterior aspect of hepatic segment IV: patterns of portal venule branching at helical CT during arterial portography.

PURPOSE: To determine the anatomy of the portal venous system in the posterior aspect of segment IV of the liver by using helical computed tomography (CT) during arterial portography (CTAP). MATERIALS AND METHODS: One hundred consecutive patients underwent CTAP. Helical CT during hepatic arteriography was performed in 20 patients. In seven patients with hepatocellular carcinoma in the posterior aspect of segment IV, the feeding arteries were also analyzed. RESULTS: A venule from the intrahepatic portal vein to segment IV was seen in all patients. Other findings included a tiny venule from the distal part of the main left portal vein (n = 36), from the proximal left main portal vein (n = 20), and from the right portal vein (n = 18). Aberrant right gastric venous drainage and/or parabiliary venous drainage directly into the posterior aspect was present in 14 patients. In two patients, a tiny accompanying artery was seen on images from CT during hepatic arteriography. In seven patients with hepatocellular carcinoma, the main feeding artery branched from the right (n = 2) or left (n = 5) hepatic artery. CONCLUSION: CTAP adequately demonstrates the tiny portal venous and arterial branches from the main right or left portal vein that distribute to the posterior aspect of segment IV. Knowledge of this vascular anatomy is clinically important.

Adult↗

PubMed1997

PAMP is a novel inhibitor of the tachykinin release in the airway of guinea pigs.

Proadrenomedullin NH2-terminal 20 peptide (PAMP), a newly identified hypotensive peptide, may play physiological roles in airway and cardiovascular controls. This study was designed to determine the mechanism responsible for the bronchoprotective effects of PAMP on capsaicin-induced bron-choconstriction in anesthetized guinea pigs. PAMP (10(-8)-10(-6) M) significantly inhibited capsaicin-induced bronchoconstriction in a dose-dependent manner. The bronchoprotective effect of PAMP (10(-6) M) was as large as that of isoproterenol (10(-7) M) and lasted > 10 min. The concentration of immunoreactive substance P (SP) in bronchoalveolar lavage fluid after administration of capsaicin (4 x 10(-6) M) was 120 +/- 10 fmol/ml. PAMP significantly inhibited the release of immunoreactive SP in a dose-dependent manner (60 +/- 6 fmol/ml for (10(-6) M PAMP, P < 0.01; 84 +/- 6 fmol/ml for 10(-7) M PAMP, P < 0.01; and 95 +/- 6 fmol/ml for 10(-8) M PAMP, P < 0.05). PAMP (10(-6) M) did not significantly affect exogenous neurokinin A (NKA) or NKA + SP-induced bronchoconstriction, whereas isoproterenol (10(-7) M) significantly inhibited exogenous tachykinin-induced bronchoconstriction. These findings suggest that the bronchoprotective effects of PAMP are mainly due to inhibition of the release of tachykinins at airway C-fiber endings.

Adrenomedullin↗

PubMed1997

Adenosine modulates endothelin-induced bronchoconstriction in guinea pig airway.

The present study was designed to determine whether endogenous and exogenous adenosine modulates endothelin (ET)-induced bronchoconstriction. Exogenous adenosine enhances ET-induced bronchoconstriction. Following pretreatment with adenosine deaminase and theophylline to eliminate or antagonize endogenous adenosine, ET-1-induced bronchoconstriction was significantly attenuated, but not that of ET-3. In conclusion, this is the first report of an enhancement of ET-induced bronchoconstriction of guinea pig airways by endogenous and exogenous adenosine. Our findings may be useful in designing specific adenosine receptor antagonists as therapeutic agents in the management of bronchial asthma.

Acetylcholine↗

PubMed1997

Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D1-like receptors.

Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine and specific D1-like agonists SKF 38,393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration and proliferation were studied. We observed that cells stimulated by PDGF-BB (5 ng/mL), showed increased migration and proliferation. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 (1 to 10 mumol/L), and this prevention was reversed by Sch 23,390 (1 to 10 mumol/l), a specific D1-like antagonist. These actions are mimicked by forskolin (1 to 10 mumol/L), a direct activator of adenylate cyclase and 8-bromo-cAMP at 0.1 to 1 mmol/L and are blocked by a specific protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H 89), but not blocked by its negative control, N-[2-(N-formyl)-p-chlorociannamylamino)ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/mL)-mediated activation of phospholipase D, protein kinase C, and mitogen activated protein kinase activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration and proliferation of VSMC, possibly through protein kinase A activation and suppression of activated phospholipase D, protein kinase C, and mitogen-activated protein kinase activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1997

Natriuretic peptide family as a novel antimigration factor of vascular smooth muscle cells.

Vascular smooth muscle cell (SMC) migration is proposed to be an important process in the initiation and/or progression of atherosclerosis. The present study examined the effects of the natriuretic peptide family (atrial, brain, and C-type natriuretic peptides; ANP, BNP, and CNP) on the migration of cultured rat SMCs, using Boyden's chamber methods. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB potently stimulated SMC migration. Rat ANP(1-28), rat BNP-45, and rat CNP-22 clearly inhibited SMC migration stimulated with FCS or PDGF-BB in a concentration-dependent manner. CNP-22 had the most potent inhibitory effect compared with other natriuretic peptides. When PDGF-BB-induced migration was separated into chemotactic and chemokinetic activities, the chemotactic component was strongly inhibited by these natriuretic peptides. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cyclic GMP. The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, and an activator of the cytosolic guanylate cyclase, sodium nitroprusside, significantly inhibited FCS- and PDGF-BB-stimulated migration in a concentration-dependent manner. These results suggest that natriuretic peptides, especially CNP-22, inhibit FCS- or PDGF-BB-stimulated SMC migration at least in part through a cyclic GMP-dependent process. Thus, the natriuretic peptide family may play a role as an antimigration factor of SMCs under certain circumstances.

Animals↗

PubMed1997

Dopamine D1-like receptor stimulation inhibits hypertrophy induced by platelet-derived growth factor in cultured rat renal vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) hypertrophy is believed to play some roles in atherosclerosis. To elucidate the role of vascular D1-like receptors in VSMC hypertrophy, the effects of dopamine and specific D1-like receptor agonists SKF 38393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC hypertrophy was studied. We observed that cells stimulated by PDGF-BB 5 ng/mL showed increased VSMC hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38393, and YM 435 1-10 mumol/L, and this prevention was reversed by Sch 23390 1 to 10 mumol/L, a specific D1-like receptor antagonist. These actions are mimicked by forskolin 1 to 10 mumol/L, a direct activator of adenylate cyclase and 8-bromo-cAMP 0.1 to 1 mmol/L, and are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(P-bromcoinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89) but not blocked by its negative control. PDGF-BB (5 ng/mL)-mediated mitogen-activated protein kinase (MAPK) activity was significantly suppressed by coincubation with D1-like receptor agonists, which were reversed by PKA inhibitor H 89. These results suggest that vascular D1-like receptor agonists inhibit hypertrophy of VSMC, possibly through PKA activation and suppression of activated MAPK activity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1997

Adrenomedullin is a potent inhibitor of angiotensin II-induced migration of human coronary artery smooth muscle cells.

The migration of coronary artery medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerotic lesions. In the current study, we examined the possible interaction of adrenomedullin, a novel vasorelaxant peptide, and angiotensin II (Ang II) on human coronary artery SMC migration using Boyden's chamber method. Ang II stimulated SMC migration in a concentration-dependent manner between 10(6) and 10(8) mol/L. This stimulation was clearly blocked by the Ang II type 1 receptor antagonist losartan but not by the type 2 receptor antagonist PD 123319. The migration stimulatory effect of Ang II was chemotactic in nature for cultured human coronary artery SMCs but was not chemokinetic. Human adrenomedullin clearly inhibited Ang II-induced migration in a concentration-dependent manner. Human adrenomedullin stimulated cAMP formation in these cells. Inhibition by adrenomedullin of Ang II-induced SMC migration was paralleled by an increase in the cellular level of cAMP. 8-Bromo-cAMP, a cAMP analogue, and forskolin, an activator of adenylate cyclase, inhibited the Ang II-induced SMC migration. These results suggest that Ang II stimulates SMC migration via type 1 receptors in human coronary artery and adrenomedullin inhibits Ang II-induced migration at least partly through a cAMP-dependent mechanism. Taken together with the finding that adrenomedullin is synthesized in and secreted from vascular endothelial cells, this peptide may play a role as a local antimigration factor in certain pathological conditions.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1997

Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells.

The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.

Cell Movement↗

PubMed1997

Mechanisms of action of troglitazone in the prevention of high glucose-induced migration and proliferation of cultured coronary smooth muscle cells.

Recent findings suggest that high glucose levels may promote atherosclerosis in coronary vascular smooth muscle cells (VSMCs). To explore the intracellular mechanisms of action by which troglitazone affects this process, we examined the effect of troglitazone on the migration and growth characteristics of cultured rabbit coronary VSMCs. Treatment with chronic high glucose medium (22.2 mmol/L) for 5 days increased VSMC migration by 92%, [3H]thymidine incorporation by 135%, and cell number by 32% compared with VSMCs treated with normal glucose (5.5 mmol/L glucose + 16.6 mmol/L mannose) medium. Trolitazone at 100 nmol/L and 1 mumol/L significantly suppressed high glucose-induced VSMC migration by 34% and 42%, respectively, the proliferative effect (as measured by cell number) by 17% and 27%, and [3H]thymidine incorporation by 45% and 60% (n = 6, P < .05). The high glucose-induced impairment of insulin-mediated [3H]deoxyglucose uptake was blocked by a protein kinase C (PKC) inhibitor (calphostin C, 1 mumol/L) and was also improved by troglitazone without any change in insulin receptor number and affinity. The high glucose-induced insulin-mediated increase in cell number and in [3H]thymidine incorporation was suppressed by troglitazone. Troglitazone (1 mumol/L) also suppressed high glucose-induced phospholipase D activation, elevation of the cytosolic NADH/NAD+ ratio (as measured by the cytosolic ratio of lactate/pyruvate), and membrane-bound PKC activation. Flow cytometric DNA histogram analysis of cell cycle stage showed that high glucose-induced increase in the percentage of cells in the S phase was suppressed by 1 mumol/L troglitazone. These findings suggest that PKC may be a link between impairment of insulin-mediated glucose uptake and the increase in migration and proliferation induced by high glucose levels and that troglitazone may be clinically useful for the treatment of high glucose-induced coronary atherosclerosis.

Animals↗

PubMed1997

Synergistic effect of nitric oxide and vasoactive intestinal peptide on bronchoprotection against histamine in anesthetized guinea pigs.

Vasoactive intestinal peptide (VIP) and nitric oxide (NO) are considered to be nonadrenergic, noncholinergic (NANC) inhibitory neurostransmitters in the airways. It seems likely that these neurotransmitters may be coreleased and act as functional antagonists against bronchoconstrictor stimuli. In the present study, we examined the synergistic effect of NO and VIP on bronchoprotection against histamine in anesthetized guinea pigs. The NO donor, S-nitroso-N-acetylpenicillamine (SNAP) significantly inhibited histamine-induced bronchoconstriction in a dose-dependent manner. VIP also inhibited histamine-induced bronchoconstriction in a dose-dependent manner, but this bronchoprotective effect was short-lived. Additionally, VIP (10(-9) M) had no significant bronchoprotective effect, but a subthreshold dose of SNAP (10(-7) M) significantly potentiated VIP (10(-9) M)-induced bronchoprotection against histamine. Moreover, SNAP (10(-7) M) significantly enhanced VIP (10(-7) M)-induced bronchoprotection for a longer period of time. On the other hand, VIP (10(-9) M) also significantly potentiated SNAP-induced bronchoprotection against histamine. In conclusion, combination therapy with NO donor and VIP receptor agonist may have important advantages in the treatment of bronchial asthma, and both NO and VIP may contribute in complementary fashion to the NANC-induced relaxant response in guinea pig airways.

Anesthesia↗

PubMed1997

Vascular dopamine-I receptors and atherosclerosis.

Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38,393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 at 1-10 mumol/l, and this prevention was reversed by Sch 23,390 (1-10 mumol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 mumol/l forskolin, a direct activator of adenylate cyclase and 8-bromocyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.

Animals↗