Long term treatment with enalapril reduces plasma concentrations of macrophage colony stimulating factor in patients with coronary artery disease.
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Aged↗
Biomedical subjects
H Shimokawa
Publications and source records attributed to H Shimokawa.
Increased inactivation of nitric oxide is involved in coronary endothelial dysfunction in heart failure.
Recent evidence suggests the possibility that enhanced inactivation of endothelium-derived nitric oxide (NO) by oxygen free radical (OFR) may cause endothelial dysfunction in heart failure (HF). To test this hypothesis, we examined the effect of antioxidant therapy on endothelium-dependent vasodilation of the coronary circulation in a canine model of tachycardia-induced HF. Endothelium-dependent vasodilation was less than that in controls, and OFR formation in coronary arterial and myocardial tissues was greater in HF dogs than those in controls. The immunohistochemical staining of 4-hydroxy-2-nonenal, OFR-induced lipid peroxides was detected in coronary microvessels of HF dogs. Intracoronary infusion of the cell-permeable OFR scavenger Tiron inhibited OFR formation and improved endothelium-dependent vasodilation in HF dogs but not in controls. The NO synthesis inhibitor N(G)-monomethyl-L-arginine (L-NMMA) diminished the beneficial effect of Tiron in HF dogs. Endothelium-independent vasodilation was similar between control and HF dogs, and no change in its response was noted by Tiron or Tiron plus L-NMMA in either group. In summary, antioxidant treatment with Tiron improved coronary vascular endothelium-dependent vasodilation by increasing NO activity in tachycardia-induced HF. Thus coronary endothelial dysfunction in HF may be, at least in part, due to increased inactivation of NO by OFR.
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
Increased inactivation of nitric oxide is involved in impaired coronary flow reserve in heart failure.
Recent evidence suggests that increased inactivation of endothelium-derived nitric oxide (NO) by oxygen free radical (OFR) formation is involved in the pathogenesis of endothelial dysfunction in heart failure (HF). However, it is unclear whether increased OFR limits coronary flow reserve in HF. To test this hypothesis, we examined the effects of antioxidant therapy on coronary flow reserve in a canine model of tachycardia-induced HF. The flow reserve (percent increase in coronary blood flow) to adenosine or to 20-s ischemia was less and OFR formation (electron-spin resonance spectroscopy) in myocardial tissues was greater in HF dogs than in controls. Immunohistochemical staining of 4-hydroxy-2-nonenal, an OFR-induced lipid peroxide, was detected in coronary microvessels of HF dogs. Intracoronary infusion of a cell-permeable OFR scavenger, tiron, suppressed OFR formation and improved the vasodilating capacity to adenosine or brief ischemia in HF dogs but not in controls. A NO synthesis inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), diminished the beneficial effects of tiron in HF dogs. Vasodilation to sodium nitroprusside was similar between control and HF dogs, and no change in its response was noted with tiron or tiron + L-NMMA in either group. In summary, antioxidant treatment with tiron improved coronary flow reserve by increasing NO bioactivity in HF dogs. Thus increased OFR formation may impair coronary flow reserve in HF by reducing NO bioactivity.
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
Beneficial effects of eicosapentaenoic acid on endothelial vasodilator functions in animals and humans.
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Animals↗
Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo.
Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominant-negative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1beta, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of beta-galactosidase, into the interleukin-1beta-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRHOK: These results indicate that Rho-kinase is substantially involved in coronary constrictive remodeling and vasospastic responses, both of which can be reversed by the selective inhibition of the molecule in our porcine model in vivo.
Adenoviridae↗
Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression.
Plasminogen activator inhibitor type-1 (PAI-1) plays an integral role not only in the regulation of fibrinolytic activity but also in the pathogenesis of atherosclerosis and hypertension. We investigated the signaling pathways of angiotensin II (Ang II) leading to PAI-1 gene expression. Ang II increased the PAI-1 mRNA and protein levels in a time- and dose-dependent manner through the Ang II type 1 receptor in vascular smooth muscle cells. PAI-1 gene promoter activity measured by luciferase assay was significantly increased by Ang II. PAI-1 mRNA stability was also increased by Ang II. Ang II-induced PAI-1 mRNA upregulation was inhibited by BAPTA-AM, genistein, and AG1478, suggesting that intracellular calcium, tyrosine kinase, and epidermal growth factor receptor transactivation are involved. Furthermore, PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) kinase (MEK), almost completely suppressed Ang II-induced PAI-1 upregulation. Adenovirus-mediated overexpression of the dominant-negative form of Rho-kinase or Y27632, a Rho-kinase inhibitor, also completely prevented PAI-1 induction by Ang II without affecting Ang II-induced ERK activation. These data suggest that activation of MEK/ERK and Rho-kinase pathways plays a pivotal role in PAI-1 gene upregulation by Ang II. The Rho-kinase pathway may be a novel target to inhibit Ang II signaling, and its inhibition may be useful in the treatment of hypertension as well as atherosclerosis.
Angiotensin II↗
Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells.
Recently, it was shown that Rho-kinase plays an important role in blood pressure regulation. However, it is not known whether Rho-kinase is involved in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine that regulates monocyte recruitment and atherogenesis. Therefore, we examined the role of Rho and Rho-kinase in the angiotensin (Ang) II-induced expression of MCP-1. Ang II dose- and time-dependently enhanced the expression of MCP-1 mRNA and the protein production in vascular smooth muscle cells. CV11974, an Ang II type 1 receptor (AT(1)-R) specific antagonist inhibited the enhancement of MCP-1 expression by Ang II, suggesting that the effect of Ang II is mediated by the AT(1)-R. Botulinum C3 exotoxin, a specific inhibitor of Rho, suppressed Ang II-induced MCP-1 production. To examine the role of Rho-kinase in Ang II-induced MCP-1 expression, we used adenovirus-mediated overexpression of the dominant negative mutant of Rho-kinase (AdDNRhoK) or Y-27632, a specific inhibitor of Rho-kinase. Both AdDNRhoK and Y-27632 strongly inhibited Ang II-induced MCP-1 expression. Although inhibition of extracellular signal-regulated protein kinase (ERK) by PD 098,059 also inhibited Ang II-induced MCP-1 expression, Y-27632 did not affect Ang II-induced activation of ERK. These results indicate that Rho-kinase plays a critical role in Ang II-induced MCP-1 production independent of ERK. The Rho-Rho-kinase pathway may be a novel target for the inhibition of Ang II signaling and the treatment of atherosclerosis.
Amides↗
Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells.
The plasma level of interleukin-6 (IL-6) is elevated in patients with acute coronary syndromes and has prognostic value. Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. We examined the mechanism of thrombin-induced IL-6 expression in VSMCs. Thrombin induced IL-6 mRNA and protein expression in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK), or epidermal growth factor receptor (EGF-R) suppressed the thrombin-induced IL-6 expression. Deletion and mutation analysis of the promoter region of the IL-6 gene by using luciferase as a reporter showed that the DNA segment between -228 and -150 bp containing the cAMP response element (CRE) site played a critical role. Thrombin also induced phosphorylation of CRE binding protein (CREB) in an ERK- and a p38 MAPK-dependent manner. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced IL-6 mRNA expression. These results suggest that the CRE site and CREB play an important role in thrombin-induced IL-6 gene expression in VSMCs. Transactivation of EGF-R and activation of ERK and p38 MAPK are involved in this process. CREB may be a novel transcription factor that regulates thrombin-induced gene expression.
Animals↗
Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, so-called statins, reduce the relative risk of a major coronary event by lowering the serum cholesterol level. In addition, statins may confer beneficial effects by cholesterol-lowering independent mechanisms, which are incompletely characterized. Because angiotensin II (Ang II) plays crucial roles in the pathogenesis of cardiovascular diseases, we examined the effect of statins on the expression of the Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs). Cerivastatin and fluvastatin reduced the AT(1)-R mRNA and the AT(1)-R protein levels; however, pravastatin lacked this effect. Cerivastatin and fluvastatin suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. Coincubation of VSMCs with mevalonate or geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate reversed the cerivastatin-induced AT(1)-R downregulation. Overexpression of dominant-negative Rho A also suppressed AT(1)-R mRNA expression. Treatment with cerivastatin for 24 hours reduced the calcium response of VSMCs to Ang II. Taken together, statins downregulate AT(1)-R expression through a mevalonate-dependent, geranylgeranyl pyrophosphate-dependent, and Rho A-dependent manner and attenuate the biological function of Ang II. Downregulation of AT(1)-R may contribute to the cholesterol-independent beneficial effect of statins on the cardiovascular system.
Animals↗
Role of nitric oxide in regulation of coronary blood flow in response to increased metabolic demand in dogs with pacing-induced heart failure.
The role of endothelium-derived nitric oxide (NO) in the metabolic control of coronary blood flow (CBF) in heart failure (HF) is poorly understood, so the present study investigated the effects of inhibitors of NO synthesis on the response of CBF to changes in myocardial oxygen consumption (MVO2) in dogs with HF produced by rapid ventricular pacing and in control dogs. The CBF, MVO2, and other hemodynamic parameters were measured in anesthetized animals. Before infusion of Nomega-nitro-L-arginine methyl ester (L-NAME), the increases in CBF and MVO2 during pacing tachycardia were not significantly different between the control and HF dogs. Intracoronary infusion of L-NAME did not alter the responses of CBF or MVO2 to pacing tachycardia in the control dogs, but in the HF dogs, it reduced the CBF response to pacing tachycardia without altering the tachycardia-induced changes in MVO2. Intracoronary infusion of L-arginine reversed the effect of L-NAME. These results suggest that in HF dogs NO contributes to the regulation of CBF in response to an increased metabolic demand.
Animals↗
[Lipid-lowering drugs].
Accumulating evidences in recent major clinical studies have shown the importance of anti-hyperlipidemic treatment in preventing atherosclerotic cardiovascular diseases. Lipid-lowering drugs can be divided into HMG-CoA reductase inhibitors (statins), bile-acid sequestrants (resins), nicotinic acid, fibrates and probucol. Among them, statins had revolutionary impact on the treatment of hyperlipidemia since pravastatin, which was developed in Japan, was launched in 1989. Several lipid-lowering drugs are now under development in Japan, including pitavastatin, rosuvastatin, F-1394 (ACAT inhibitor), CS-505 (ACAT inhibitor) and NO-1886 (LPL activator). In this review, characteristics of these new lipid-lowering drugs will be discussed.
Benzamides↗
Antiischemic properties of fasudil in experimental models of vasospastic angina.
We studied the antiischemic properties of fasudil, a Rho-kinase inhibitor, in conscious rabbits with coronary vasospasm induced by vasopressin and endothelin. Pretreatment with fasudil (0.3 and 3 mg/kg) attenuated the maximum elevation of the T-wave elicited by endothelin. Pretreatment with fasudil inhibited the T-wave elevation elicited by vasopressin. Fasudil and hydroxy fasudil, an active metabolite of fasudil, relaxed the endothelin-, U-46619-, 5-hydroxytryptamine- or histamine-induced contraction in swine coronary arterial strips. Fasudil and hydroxy fasudil significantly prevented the reduction in coronary flow by vasopressin in the Langendorff perfused rat heart. Fasudil was effective in protecting the heart against vasopressin and endothelin-induced myocardial ischemic change in conscious rabbits, and this beneficial effect can be attributed to its action of ameliorating the severe contraction of arteries. The inhibition of Rho-kinase may have implications for the development of novel therapeutic strategies for vasospastic angina in patients.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Abortive secretion of an enamel matrix in the inner enamel epithelial cells during an enameloid formation in the gar-pike, Lepisosteus oculatus (Holostei, Actinopterygii).
The tooth in the gar-pike, Lepisosteus oculatus, an actinopterygian fish, is characterized by the occurrence of both enamel and enameloid, the former covering the tooth shaft and the latter, the tooth cap. Our previous research demonstrated that the enamel in this species was, as in the lungfish, immunoreactive for amelogenin, indicating its homologous nature with the mammalian tooth enamel, whereas the enameloid was completely immunonegative. The present study demonstrates that, during the early maturation stage of the enameloid formation, the inner enamel epithelial cells (IEECs) synthesize through a well-developed Golgi apparatus a fine-granular substance which is intensely immunoreactive for amelogenin. This substance was accumulated in a large saccule extended in a suprabasal zone of the cell; we were unable to find any morphological sign indicating a connection of the substance with the enameloid matrix. The abortive secretion of the enamel matrix-like substance in the IEEC during an enameloid formation was considered to be an instance of rudimental enamel formation. In the gar-pike, the synthesis of amelogenin in the IEEC has been demonstrated to occur independently from that of the enameloid matrix. The present findings demonstrate a prominent difference between the tooth enamel and enameloid.
Amelogenin↗
Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release.
In this study, we examine the role of NO located in the rostral ventrolateral medulla (RVLM) in the control of blood pressure and the activity of the sympathetic nervous system. To determine the effect of an increase in NO production in the RVLM on blood pressure in conscious rats, adenovirus vectors encoding either endothelial NO synthase (AdeNOS) or beta-galactosidase (Adbetagal) were transfected into the bilateral RVLM. The local expression of endothelial NO synthase (eNOS) protein in the RVLM was confirmed by immunohistochemical staining for the eNOS protein and by Western blot analysis. Mean arterial blood pressure (MAP) and heart rate, which were monitored using a radio-telemetry system, were significantly decreased in the AdeNOS-treated group from day 5 to day 10 after the gene transfer. Urinary norepinephrine excretion was decreased on day 7 after the gene transfer in the AdeNOS-treated group. Microinjection of either N(G)-monomethyl-L-arginine (L-NMMA) or bicuculine, a gamma-amino butyric acid (GABA) receptor antagonist, into the RVLM at day 7 after the gene transfer increased MAP to significantly greater levels in the AdeNOS-treated group. However, microinjection of kynurenic acid into the RVLM on day 7 after the gene transfer did not alter MAP levels in either group. GABA and glutamate levels in the RVLM, when measured by in vivo microdialysis, were significantly increased in the AdeNOS-treated group. These results suggest that the increase in NO production caused by the overexpression of eNOS in the bilateral RVLM decreases blood pressure, heart rate, and sympathetic nerve activity in conscious rats. Furthermore, these responses may be mediated by an increased release of GABA in the RVLM.
Adenoviridae↗
[Microgravity modulates function of osteoblast].
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Adaptor Proteins, Signal Transducing↗
[Gravity stress modulates pain sensation of rat via hypothalamus].
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Animals↗
Hypergravity and opioid-mediated pain suppression in rats.
It is known that pain suppression in animals is induced by certain environmental stimulus. However, little is known about the effects of gravitational alteration on the nociceptive responses in rats. A recent study indicated that Fos protein expression was strongly induced in the vestibular-related brainstem regions of rats that were exposed to 2 G hypergravity (Gustave Dit Duflo et al., 2000). A number of studies indicate that Fos expression is induced in the brain by various kinds of stress. We showed that either long-term exposure or short-term exposure to 2 G hypergravity elevated the nociceptive threshold in the rat skin surfaces, in concomitant with Fos induction in the hypothalamus including the arcuate nucleus and paraventricular nucleus (Kumei et al., 2000). We have examined the possible involvement of beta-endorphin, an endogenous opioid, in the hypergravity-induced analgesic effects on rats and its counteraction by naloxone, an opioid receptor antagonist.
Animals↗
[Anti-atherosclerotic effect of Ca channel antagonist].
Although anti-atherosclerotic effects of Ca channel antagonists have been shown in animal studies, clinical trials have failed to show such effects in humans. In those clinical studies, Ca channel antagonists did not retard progression or induce regression of atherosclerosis, however, they seemed to inhibit development of new atherosclerotic lesions. In this review, current knowledge of anti-atherosclerotic effects of Ca channel antagonists will be discussed with a special reference to the results of recent clinical trials.
English Abstract↗