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A Takeshita

Publications and source records attributed to A Takeshita.

At least 19 recordsLinked to original sources
PubMed1995

Chronic inhibition of endothelium-derived nitric oxide synthesis causes coronary microvascular structural changes and hyperreactivity to serotonin in pigs.

BACKGROUND: Endothelium-derived nitric oxide (NO) is believed to regulate myocardial perfusion and structural changes in the vascular wall. Our objective was to determine whether chronic inhibition of NO synthesis causes structural and functional changes in coronary arteries. METHODS AND RESULTS: Coronary vasomotor response was studied in pigs before and after chronic oral administration of the NO synthesis antagonist N omega-nitro-L-arginine methyl ester (L-NAME) 30 mg.kg-1.d-1 for 2 weeks. Chronic L-NAME treatment increased (P < .01) arterial pressure but did not alter baseline coronary blood flow (CBF), epicardial coronary diameter, or heart rate. Chronic L-NAME treatment augmented (P < .01) the decrease in CBF in response to intracoronary serotonin (30 micrograms/kg) from 5 +/- 14% to 40 +/- 5% but did not alter the CBF response to prostaglandin F2 alpha. The serotonin-induced decrease in CBF after acute L-NAME administration was still less before (1.3 +/- 0.4%) than after chronic L-NAME treatment (51 +/- 6%). Chronic L-NAME treatment attenuated the increase in CBF with bradykinin (100 ng/kg) but did not alter the CBF response to nitroglycerin (10 micrograms/kg). Compared with intact pigs without L-NAME treatment, L-NAME-treated pigs had significant thickening of the media in the microvessels (diameter, < 300 microns) but not in the large epicardial vessels. Chronic intracoronary infusion of L-NAME at 3 mg.kg-1.d-1 for 2 weeks, which did not produce arterial hypertension, caused similar microvascular medial thickening. CONCLUSIONS: These results indicate that chronic administration of L-NAME caused coronary microvascular structural changes and hyperreactivity to serotonin in pigs in vivo, suggesting an important role of defective NO synthesis in coronary microvascular disorders.

Animals↗
PubMed1995

Glibenclamide, a selective inhibitor of ATP-sensitive K+ channels, attenuates metabolic coronary vasodilatation induced by pacing tachycardia in dogs.

BACKGROUND: We previously reported that glibenclamide (a selective inhibitor of ATP-sensitive K+ channels [K+ATP channels]) inhibited metabolic coronary vasodilatation induced by beta 1-adrenoceptor stimulation. However, the role of K+ATP channels in metabolic coronary vasodilatation induced by tachycardia is still unknown. This study aimed to determine whether glibenclamide attenuates metabolic coronary vasodilatation induced by pacing-induced tachycardia. METHODS AND RESULTS: In anesthetized dogs, increasing heart rate from 103 +/- 1 to 160 beats per minute with atrial pacing increased coronary blood flow without altering arterial pressure and left ventricular pressure. Intracoronary infusion of glibenclamide at 1.5 and 5.0 micrograms.kg-1.min-1 did not alter basal coronary blood flow but significantly attenuated (P < .01) the tachycardia-induced coronary vasodilatation without altering the tachycardia-induced increase in myocardial oxygen consumption (MVO2). In conscious dogs, intracoronary glibenclamide at 5.0 micrograms.kg-1.min-1 attenuated (P < .05) coronary vasodilatation induced by ventricular pacing from 85 +/- 6 to 150 beats per minute. Glibenclamide markedly attenuated coronary vasodilation evoked with the K+ATP channel opener pinacidil. CONCLUSIONS: These data indicate that blockade of coronary vascular K+ATP channels with glibenclamide inhibited metabolic coronary vasodilatation induced by pacing tachycardia in dogs, suggesting that K+ATP channels are involved in the mechanism mediating metabolic coronary vasodilatation associated with pacing tachycardia.

Adenosine Triphosphate↗
PubMed1995

Bradykinin-induced vasodilation is impaired at the atherosclerotic site but is preserved at the spastic site of human coronary arteries in vivo.

BACKGROUND: Bradykinin causes endothelium-dependent vasodilation of isolated human coronary arteries in vitro. However, the effect of bradykinin on vasomotion of human coronary arteries in vivo has not been studied. The aim of this study was to examine whether bradykinin-induced vasodilation is altered at the atherosclerotic or spastic site of human coronary arteries in vivo. METHODS AND RESULTS: The effect of bradykinin on vasomotion of epicardial coronary arteries was evaluated in 8 patients with normal coronary arteries (control group), 14 patients with organic coronary stenosis (coronary artery disease [CAD] group), and 8 patients with vasospastic angina (VSA group). Changes in the diameter of epicardial coronary artery were assessed by quantitative coronary arteriography. Intracoronary administration of bradykinin at graded doses (60, 200, and 600 ng) dilated epicardial coronary arteries without altering arterial pressure or heart rate in all patients of either group. In the control group, vasomotor responses of the site where acetylcholine caused dilation were compared with the responses of the site where acetylcholine caused constriction. The magnitudes of bradykinin-induced dilation at the site with acetylcholine-induced dilation (mean +/- SD: 6 +/- 6%, 11 +/- 9%, and 15 +/- 9%) were comparable to that (3 +/- 6%, 8 +/- 8%, and 13 +/- 9%) at the site with acetylcholine-induced constriction. In the CAD group, vasomotor responses of the stenotic site (% diameter stenosis, 15% to 50%) and nonstenotic site were examined. The bradykinin-induced dilation at the stenotic site (0 +/- 4%, 3 +/- 8%, and 5 +/- 9%) was significantly less (P < .01) than at the nonstenotic site (3 +/- 4%, 8 +/- 6%, and 16 +/- 11%) and in the control group. Coronary vasodilation with nitrate at the stenotic site (20 +/- 11%) was comparable to that at the nonstenotic site (22 +/- 16%) and in the control group (21 +/- 10%). In the VSA group, vasomotor responses of the site with acetylcholine-induced spasm and the site without spasm were examined. The bradykinin-induced vasodilation at the spastic site (5 +/- 5%, 16 +/- 15%, and 33 +/- 17%) was comparable to that at the nonspastic site (4 +/- 8%, 12 +/- 14%, and 21 +/- 9%). Nitrate-induced dilation was comparable at the spastic site (51 +/- 19%) and the nonspastic site (32 +/- 13%). The ratio of bradykinin-induced vasodilation to nitrate-induced vasodilation at the spastic site was comparable to the control group. CONCLUSIONS: These results suggest that bradykinin causes vasodilation of human epicardial coronary arteries in vivo and that bradykinin-induced endothelium-dependent vasodilation is impaired at the stenotic site but is preserved at the angiographically normal site where endothelium-dependent vasodilation by acetylcholine is impaired and at the spastic site.

Acetylcholine↗
PubMed1995

TGF-beta induces expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 via transcriptional factor AP-1 induced by protein kinase in osteoblastic cells.

In this work, we demonstrate the signal-transducing mechanism of TGF-beta 1 for gene expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 (MCP-1) in clonal osteoblastic MC3T3-E1 cells. TGF-beta 1-induced JE/MCP-1 gene expression in the cells was inhibited markedly by H-7 (1-(5-isoguinolinesulfonyl)-2-O-methylpiperazine-dihydrochloride) and staurosporine, potent inhibitors of protein kinase. TGF-beta 1-induced expression of both early proto-oncogenes c-fos and c-jun in the cells was also inhibited by H-7 and staurosporine. Antisense oligonucleotides to c-fos and c-jun genes inhibited significantly the cytokine-induced JE/MCP-1 gene expression. Curcumin, a specific inhibitor of c-jun/AP-1, inhibited the cytokine-induced c-jun gene expression in a dose-dependent manner, though the c-fos gene expression was not affected. TGF-beta 1 stimulated transcriptionally the JE/MCP-1 gene expression, and this stimulation was inhibited significantly by curcumin. Curcumin-induced inhibition of the JE/MCP-1 gene product was also evidenced by both an assay involving immunoprecipitation with antiserum specific for JE/MCP-1 and an assay for monocyte chemotaxis. Curcumin markedly inhibited AP-1 binding activity to 12-tetradecanoyl phorbol-13-acetate-responsive element (TRE) in the cytokine-treated cells. Furthermore, H-7 and staurosporine also inhibited the binding activity to TRE in the cells treated by the cytokine. These results demonstrate that TGF-beta 1 induces expression of monocyte chemoattractant JE/MCP-1 via the transcriptional factor AP-1 induced by protein kinase in the osteoblastic cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Thyrotropin binding specificity for the thyrotropin receptor.

Recently, highly purified bovine thyrotropin (bTSH) of pituitary origin, as well as recombinant human (h) TSH free of lutropin (LH) contamination, has been reported to activate the LH/choriogonadotropin receptor (LH/CGR). These data challenge the concept of TSH specificity for its own receptor. We, therefore, re-evaluated these data using, as targets, the recombinant hTSH and rat LH/CGRs stably expressed in Chinese hamster ovary (CHO) cells. Partially purified bTSH (2 IU/mg protein) and, to a lesser degree, highly purified bTSH (30 IU/mg protein) increased intracellular cAMP levels in CHO-LH/CGR cells (an EC50 of 0.2 and > 20 mIU/ml, respectively). In contrast, recombinant hTSH (up to 1 IU/ml) did not. All three TSH preparations increased cAMP levels to the same extent in CHO-TSHR cells (an EC50 of 0.3 mIU/ml). Furthermore, we observed only nonspecific, low affinity TSH binding for CHO-LH/CGR cells and also for CHO cells transfected with the expression vector alone (a Kd of 100 nM), although both high and low affinity TSH binding was demonstrated in CHOT-SHR cells (a Kd of 0.3 and 100 nM, respectively). These data indicate that even highly purified bTSH of pituitary origin contains significant amounts of LH, and that TSH itself does not appear to activate the LH/CGR.

Animals↗
PubMed1995

Temporal variability in wall motion abnormality with stress-induced myocardial ischemia assessed by quantitative exercise echocardiography: difference between reversible and persistent myocardial ischemia.

Echocardiography was performed before and after treadmill tests in 30 patients to determine whether there is temporal variability in left ventricular wall motion abnormality with exercise-induced ischemia. The extent of wall motion was assessed by calculating systolic shortening in endocardial motion by two methods: (1) comparison between end diastole and end systole (ED-ES) and (2) frame-by-frame analysis throughout systole (integration). The extent of myocardial ischemia was assessed by stress thallium 201 emission tomography. Sensitivity of echocardiography for diagnosis of ischemia was 62% by ED-ES, but it increased to 83% by the integration method. Twenty-one percent of the ischemic area showed wall motion abnormality solely in the middle of systolic phase but not at end systole, and this occurred more at the reversible ischemic area (31%) than at the persistent ischemic area (19%). In conclusion, analysis throughout systole is important in detecting a reversible ischemic area.

Aged↗
PubMed1995

Detection of angina-provoking coronary stenosis by resting iodine 123 metaiodobenzylguanidine scintigraphy in patients with unstable angina pectoris.

Resting iodine 123-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy was performed in 19 patients with unstable angina to determine if it can detect myocardial ischemia and identify the angina-provoking coronary artery. Visual assessment of 123I-MIBG single-photon-emission computed tomograms was related to coronary vessel stenoses revealed by arteriography at each vascular territory. Fourteen (74%) of 19 patients had regional 123I-MIBG-identified defects at areas with preserved thallium-201 perfusion. 123I-MIBG defects were highly positive at areas supplied by angina-provoking coronary arteries. The sensitivity and specificity of 123I-MIBG defects for identifying the angina-provoking coronary vessel were 71% and 78%, respectively. The interval between the most recent angina attack and imaging was shorter and the angina occurred more commonly after admission in patients with 123I-MIBG defects than in those without defects. These data suggest that repetitive myocardial ischemia impairs regional 123I-MIBG uptake and that this impairment persists for several days after perfusion has been restored. Thus resting 123I-MIBG scintigraphy is a useful noninvasive method to detect coronary stenoses provoking repetitive ischemia in patients with unstable angina in its acute phase.

3-Iodobenzylguanidine↗
PubMed1995

Monocyte-related cytokines in acute myocardial infarction.

To elucidate the role of monocytes in the cytokine system in acute myocardial infarction (AMI), we examined the time courses of plasma concentrations and generation capacities of monocyte-related cytokines in 17 consecutive patients with uncomplicated AMI (from day 1 to 28) and in 10 control subjects. The concentrations of monocyte-related cytokines were measured by enzyme immunoassay with horseradish peroxidase. Cytokine generation capacity was evaluated by cytokine concentrations in the culture solution 24 hours after incubation of 0.5 ml whole blood with 5 micrograms lipopolysaccharide. Two distinct patterns of increases in the cytokine concentrations were noted: transient (plasma interleukin [IL]-6) and sustained (plasma macrophage colony-stimulating factor and generation capacities of IL-1 alpha, IL-6, granulocyte colony-stimulating factor, and tumor necrosis factor alpha). There was no significant increase in the concentrations of other cytokines. These results indicate that the concentrations of the monocyte-related cytokines dynamically change during the course of AMI, suggesting that they may contribute to the inflammatory and subsequent proliferative responses in AMI.

Adult↗
PubMed1995

Inhibitory effects of aspirin on coronary hyperreactivity to autacoids after arterial balloon injury in miniature pigs.

We examined the effects of aspirin on coronary hyperreactivity to autacoids after arterial balloon injury in miniature pigs. Coronary vasoconstriction induced by histamine and serotonin were examined angiographically before, 1 h, 1 week, and 1 month after balloon injury in 29 hypercholesterolemic miniature pigs. The animals were divided into three groups: group A, no treatment (n = 16); group B, pretreated with aspirin 50 mg/day for 2 days before injury (n = 7); and group C, treated with aspirin 50 mg/day for 2 days before and 5 days after injury (7 days in all) (n = 6). In group A, coronary vasoconstriction induced by autacoids was significantly greater at the injured than at the noninjured site at all times examined (p < 0.01). Hyperconstriction induced by the autacoids 1 h after injury were significantly less in groups B and C than in group A (p < 0.01). Hyperconstriction induced by autacoids 1 week after injury were significantly less in group B than in group A (p < 0.01) and were significantly less in group C than in group A (p < 0.01) or group B (p < 0.05). Treatment with aspirin for 2 or 7 days had no effect on the constrictive responses at the injured site 1 month after injury or on those at the noninjured site at all times examined. These results suggest that platelet-vessel wall interaction may play an important role in coronary hyperconstrictive responses to autacoids 1 h and 1 week after injury.

Angiography↗
PubMed1995

V2 receptor-mediated vasodilation in healthy humans.

Arginine vasopressin (AVP) causes biphasic changes in vascular resistance in human forearms: vasoconstriction at lower doses and vasodilation at higher doses. Vasoconstriction is mediated by the V1 receptor, but the mechanism of AVP-induced vasodilation remains unclear. To determine if the AVP-induced vasodilation in human forearm vessels is mediated by the V2 receptor, we examined the effects of OPC-31260 (a novel vasopressin V2 receptor antagonist) on AVP-induced vasodilation. The brachial artery was cannulated for drug infusions and direct measurement of arterial blood pressure (BP). We measured forearm blood flow (FBF) by a strain-gauge plethysmograph and calculated forearm vascular resistance (FVR). AVP was infused intraarterially (i.a.) at doses of 0.1, 0.2, 0.5, 1.0, and 2.0 ng/kg/min (n = 8). The lower dose of AVP (0.1 ng/kg/min) increased, whereas the higher doses of AVP (> or = 0.5 ng/kg/min) decreased, FVR (p < 0.01). Infusion of nitroglycerin (NTG) i.v. doses of 1.7, 3.3, and 10.0 ng/kg/min decreased FVR dose dependently (p < 0.01). OPC-31260 (1.0 micrograms/kg/min) infused i.a. did not alter arterial BP, baseline FVR, or heart rate (HR). OPC-31260 did not affect AVP-induced vasoconstriction but blocked AVP-induced vasodilation completely. OPC-31260 did not affect NTG-induced vasodilation. These results suggest that AVP-induced vasodilation is mediated by the V2 receptor in human forearm resistance vessels.

Adult↗
PubMed1995

New flow cytometric method for detection of minimally expressed multidrug resistance P-glycoprotein on normal and acute leukemia cells using biotinylated MRK16 and streptavidin-RED670 conjugate.

To evaluate the expression of multidrug resistance (MDR) on normal and leukemia cells, we examined P-glycoprotein (P-gp) by a newly devised flow cytometric method, utilizing a biotinylated monoclonal antibody (mAb) against P-gp (MRK16), a streptavidin-RED670 conjugate (SA-RED670) and appropriate emission filters. The combination of biotinylated MRK16 (b-MRK16) and SA-RED670 resulted in higher sensitivity as compared with standard methods such as the use of streptavidin-phycoerythrin (SA-PE) conjugate. The sensitivity was examined in K562, K562/ADR, NOMO-1, NOMO-1/ADR and HL60 cells, and compared with the data obtained from reverse transcription polymerase chain reaction (RT-PCR) of mdr-1 gene. P-gp positivity on flow cytometry was 10.4%, 99.9%, 1.4%, 90.4% and 0%, respectively. Mdr-1 mRNA was well expressed in K562/ADR and NOMO-1/ADR cells, but not in NOMO-1 and HL60 cells. In K562 cells, mdr-1 was found after 40 cycles of PCR, but not 25 cycles. These data are well correlated with those from the flow cytometry. We then studied the P-gp expression on normal peripheral blood cells and acute leukemia cells. P-gp was little expressed on peripheral lymphocytes, monocytes and granulocytes. It was also little expressed on blast cells from 5 patients with acute promyelocytic leukemia (AML) and 5 acute lymphocytic leukemia (ALL) expressed P-gp at diagnosis, ranging from 8.5% to 34.5% (16.9 +/- 11.8%) and from 2.3% to 45.6% (24.0 +/- 17.8%), respectively. All 9 relapsed or refractory cases expressed P-gp, ranging from 21.1% to 99.8% (52.2 +/- 29.9%). Significant differences were found in APL, CD34-positive and relapse and refractory cases (P = 0.0006, 0.0007 and 0.0088, respectively). These results indicate that this flow cytometric analysis is useful for the evaluation of clinical MDR status and can identify a group of patients with resistant leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Dual regulation of L-type Ca2+ channels by serotonin 2 receptor stimulation in vascular smooth muscle cells.

The purpose of the present study was to investigate regulation of voltage-dependent Ca2+ channels by serotonin in rat aortic smooth muscle cells in primary culture. L- and T-type Ca2+ currents (ICa) were recorded using the whole cell voltage-clamp method. Without pretreatment, in 25 of 30 cells examined, 10 microM serotonin decreased L-type ICa to various extents (-14 to -72%). However, in the remaining five cells, serotonin increased L-type ICa 21 +/- 4%. Thus, in 30 cells, serotonin decreased L-type ICa an average of 22 +/- 5%. In the presence of intracellular heparin (100 micrograms/ml), a blocker of inositol 1,4,5-trisphosphate binding to its receptor, serotonin increased L-type ICa in all cells 29 +/- 3% (n = 6). When stored Ca2+ was depleted by pretreatment either with 20 microM ryanodine and 20 mM caffeine or with 100 nM A-23187, serotonin also increased L-type ICa in all cells 30 +/- 5 (n = 4) or 37 +/- 5% (n = 12), respectively. In the presence of heparin, the serotonin-induced increase of L-type ICa was prevented by 100 nM staurosporine (2 +/- 3%; n = 6, P < 0.01). The serotonin-induced decrease of L-type ICa was significantly augmented by 100 nM staurosporine (-43 +/- 10%; n = 5). Phorbol 12,13-dibutylate (PDBu; 1 microM) increased L-type ICa 29 +/- 3% (n = 6), and serotonin did not further increase L-type ICa after its potentiation by PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of L-arginine analogues on vasomotion of isolated porcine coronary arteries.

L-Arginine analogues have been widely used to examine the role of endothelium-derived nitric oxide (NO) in vascular responses; however, the effects of the agents on coronary vasomotion are not fully understood. In this study, we examined the effects of the analogues on vasomotion of isolated porcine coronary arteries. Strips of the porcine coronary artery were suspended for isometric tension recording in Krebs-Henseleit solution. L-Arginine analogues, N omega-nitro-L-arginine methyl ester (L-NAME, 10(-9)-10(-3) M), NG-monomethyl-L-arginine (L-NMMA, 10(-9)-10(-3) M), and NG-nitro-L-arginine (L-NNA, 10(-9)-10(-3) M), caused dose-dependent contractions, which were greater in strips with than in those without endothelium. Those endothelium-dependent contractions were almost abolished by indomethacin (10(-5) M) and FeCl2 (10(-3) M). The latter reduces prostaglandin H2 to 12-heptadecatrienoic acid, which has no vasoconstrictor effect. These results indicate that the L-arginine analogues cause endothelium-dependent contractions that are mediated by prostaglandin endoperoxides and suggest that they have properties other than simple inhibition of NO synthesis in porcine coronary arteries.

Animals↗
PubMed1995

Quantitative analysis of repeat adenovirus-mediated gene transfer into injured canine femoral arteries.

We quantitatively evaluated the effectiveness of a repeat administration of a recombinant adenoviral vector expressing bacterial Escherichia coli lacZ into the same arterial site of a relatively large animal, the dog. The replication-defective adenoviral vector was introduced percutaneously into balloon-injured femoral arteries through a double-balloon catheter. After a single dose of adenoviral vector, up to 90% of surface (73 +/- 16%, n = 7) and smooth muscle cells in multiple layers of the media showed transgene expression as evaluated by 5-bromo-4-chloro-3-indoyl beta-D-galactopyranoside histostaining without extralocal expression, as assessed by polymerase chain reaction. High-level expression (measured as beta-galactosidase activity) peaked 7 days after transfer and was transient, although it was retained for a month. Second does of the same adenovirus to the same arterial site were given 1, 2, 5, or 8 weeks after the first administration. At 1 week the second dose significantly enhanced lacZ expression. At 2, 5, or 8 weeks the second dose reinduced lacZ expression at 25% to 30% of the full expression. lacZ expression was also detected in preimmuned dogs, although the expression levels correlated inversely to the titer of neutralizing antibodies in their serum. These results demonstrate that arterial gene expression can be enhanced by a second administration of the same adenovirus after a short interval and that a repeat dose after a long interval partially but significantly reinduces gene expression despite the presence of an immune response. These data may provide an additional scientific foundation for the use of adenovirus-mediated arterial gene transfer in future clinical practice.

Adenoviridae↗
PubMed1995

Impaired endothelium-dependent vasodilation of large epicardial and resistance coronary arteries in patients with essential hypertension. Different responses to acetylcholine and substance P.

Hypertensive patients have impaired endothelium-dependent coronary vasodilation evoked with acetylcholine. The aim of this study was to examine whether the impaired endothelium-dependent dilation of coronary arteries is related to a specific abnormality of the muscarinic receptor that mediates the effects of acetylcholine. Responses of the large epicardial and resistance coronary arteries were assessed in seven hypertensive patients (mean arterial pressure, 106 +/- 14 mm Hg) and seven control subjects (83 +/- 6 mm Hg, P < .01) during cardiac catheterization. To assess coronary endothelial function, we infused acetylcholine and substance P (endothelium-dependent agents that act on different receptors) and papaverine and nitrate (direct vascular smooth muscle dilators) into the left anterior descending coronary artery and determined coronary artery diameter by arteriography and coronary blood flow with an intracoronary Doppler catheter technique. In control subjects, 3 micrograms/min acetylcholine increased (P < .05) and 30 micrograms/min acetylcholine decreased (P < .05) arterial diameter, and in hypertensive patients, 1, 3, 10, and 30 micrograms/min acetylcholine decreased arterial diameter in a dose-dependent manner. Substance P at 3, 10, and 30 ng/min caused comparable increases in diameter in both groups. Increases in coronary blood flow with both acetylcholine and substance P were significantly (P < .01) blunted in hypertensive patients compared with control subjects. No significant differences were noted between the groups in the responses of large epicardial coronary artery diameter and coronary blood flow to papaverine and nitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats.

The aim of the present study was to investigate the effects of long-term blockade of nitric oxide synthesis with the L-arginine analogue N omega-nitro-L-arginine methyl ester (L-NAME) for 8 weeks on coronary vascular and myocardial structural changes. Four groups of Wistar-Kyoto rats were studied: those with no treatment, those treated with L-NAME 1 g/L (3.7 mmol/L in drinking water), those treated with L-NAME 0.1 g/L (0.37 mmol/L in drinking water), and those treated with L-NAME 1.0 g/L and hydralazine 120 mg/L (0.6 mmol/L in drinking water). After 8 weeks, the heart was excised, and the degrees of structural changes in coronary arteries (wall-to-lumen ratio and perivascular fibrosis), myocardial fibrosis, and myocyte size were quantified by an image analyzer. Chronic inhibition of nitric oxide synthesis increased arterial pressure compared with control animals. Chronic inhibition of nitric oxide synthesis caused significant microvascular remodeling (increased wall-to-lumen ratio and perivascular fibrosis). Cardiac hypertrophy was also observed after chronic inhibition of nitric oxide synthesis. Coadministration of hydralazine prevented arterial hypertension but did not affect microvascular remodeling and cardiac hypertrophy induced by the chronic inhibition of nitric oxide synthesis. In addition, chronic inhibition of nitric oxide synthesis caused scattered lesions of myocardial fibrosis, which was significantly attenuated by cotreatment with hydralazine. These results suggest that long-term blockade of nitric oxide synthesis caused coronary microvascular remodeling and cardiac hypertrophy in rats in vivo by a mechanism other than arterial hypertension. In contrast, arterial hypertension contributed to the development of myocardial fibrosis induced by long-term blockade of nitric oxide synthesis.

Animals↗
PubMed1995

Tyrosine kinase inhibitor suppresses coronary arteriosclerotic changes and vasospastic responses induced by chronic treatment with interleukin-1 beta in pigs in vivo.

We recently demonstrated that chronic treatment with IL-1 beta induces coronary arteriosclerotic changes and vasospastic responses to autacoids in pigs in vivo and that those responses are importantly mediated by PDGF. The receptors for PDGF and other major growth factors are known to have tyrosine kinase activity. We therefore investigated the effects of a selective tyrosine kinase inhibitor, ST 638, on those responses induced by IL-1 beta in our swine model. Intimal thickening and coronary vasospastic responses to serotonin and histamine were induced at the site of the coronary artery where IL-1 beta was chronically and locally applied. These responses were significantly suppressed in a dose-dependent manner by cotreatment with ST 638. In addition, ST 494, which is an inactive form of ST 638, did not inhibit those responses. The treatment with ST 638 alone did not affect the coronary vasoconstricting responses to the autacoids. Immunoblotting using an antibody to phosphotyrosines confirmed the inhibitory effects of ST 638 on the tyrosine phosphorylations induced by IL-1 beta. These results thus suggest that tyrosine kinase activation may play an important role in mediating the effects of IL-1 beta, while also suggesting that ST 638 has an inhibitory effect on the arteriosclerotic changes and vasospastic responses to autacoids in our swine model in vivo.

Animals↗