Biomedical subjects

H Shimokawa

Publications and source records attributed to H Shimokawa.

At least 73 records · Page 4Linked to original sources

PubMed2000

Coronary vascular K+ATP channels contribute to the maintenance of myocardial perfusion in dogs with pacing-induced heart failure.

The functional role of coronary vascular ATP-sensitive potassium (K+ATP) channels in the regulation of coronary blood flow (CBF) has not been determined in chronic heart failure (CHF). To test the hypothesis that K+ATP channels contribute to myocardial perfusion in HF, we examined the effects of intracoronary infusion of glibenclamide, an inhibitor of K+ATP channels, on basal CBF in control and CHF dogs. CHF was produced in mongrel dogs by pacing the right ventricle for 4 weeks. Under anesthesia, CBF in the left anterior descending coronary artery, other hemodynamic and metabolic parameters, or regional myocardial blood flow were measured. Basal CBF was less in CHF dogs than in controls. Glibenclamide at the graded doses (5, 15 and 50 microg x kg(-1) x min(-1) decreased CBF in both control and CHF dogs. The percentage decrease in CBF with glibenclamide at 50 microg x kg(-1) x min(-1) was greater (p<0.01) in CHF dogs than in controls. The greater decrease in CBF with glibenclamide at 50microg x kg(-1) x min(-1) was associated with myocardial ischemia. Glibenclamide decreased myocardial blood flow in each sublayer of the myocardium in the 2 groups. These results suggest that the basal activity of coronary vascular K+ATP channels is increased in CHF dogs but not in controls. This may contribute to the maintenance of myocardial perfusion in CHF.

Adenosine Triphosphate↗

PubMed2000

Nociceptive responses and immunohistochemical changes in the rat brain under gravity stress.

It is well known that exposure to various stresses leads to pain suppression in animals. However, there is no report about the effects of gravitational alteration to serve as a kind of stress. The purpose of the present study is to clarify the effect of hypergravity (2 G) on the nociceptive responses and histochemical changes in rats. We examined the level of the threshold of withdrawal reflex against the noxious [correction of noxicious] stimulation in rats that were exposed to 2 G. Data show that the 2 G exposure elevates the nociceptive threshold. We have demonstrated for the first time that gravity change induces analgesic effects on rats in concomitant with c-fos induction in the arcuate, and paraventricular nuclei of rat hypothalamus. Gravity change acts as a kind of stress in rats.

Analgesia↗

PubMed1999

Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins.

Human MTH1 and Escherichia coli MutT proteins hydrolyze 7, 8-dihydro-8-oxo-dGTP (8-oxo-dGTP) to monophosphate, thus avoiding the incorporation of 8-oxo-7,8-dihydroguanine into nascent DNA. Although only 30 amino acid residues (23%) are identical between MTH1 and MutT, there is a highly conserved region consisting of 23 residues (MTH1, Gly(36)-Gly(58)) with 14 identical residues. A chimeric protein MTH1-Ec, in which the 23-residue sequence of MTH1 was replaced with that of MutT, retains its capability to hydrolyze 8-oxo-dGTP, thereby indicating that the 23-residue sequences of MTH1 and MutT are functionally and structurally equivalent and constitute functional modules. By saturation mutagenesis of the module in MTH1, 14 of the 23 residues proved to be essential to exert 8-oxo-dGTPase activity. For the other 9 residues (40, 42, 44, 46, 47, 49, 50, 54, and 58), positive mutants were obtained, and Arg(50) can be replaced with hydrophobic residues (Val, Leu, or Ile), with a greater stability and higher specific activity of the enzyme. Indispensabilities of Val(39), Ile(45), and Leu(53) indicate that an amphipathic property of alpha-helix I consisting of 14 residues of the module (Thr(44)-Gly(58)) is essential to maintain the stable catalytic surface for 8-oxo-dGTPase.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Endothelial vasodilator function is preserved at the spastic/inflammatory coronary lesions in pigs.

BACKGROUND: The question of whether or not endothelial vasodilator function in the spastic coronary artery is preserved is still controversial. We recently developed a porcine model in which long-term and local treatment with interleukin-1beta (IL-1beta) from the adventitial site causes coronary arteriosclerotic changes and vasospastic responses to autacoids. The aim of this study was to examine the endothelial vasodilator function in our new porcine model of the spasm both in vivo and in vitro. METHODS AND RESULTS: A segment of the porcine coronary artery was aseptically wrapped with cotton mesh that held absorbed IL-1beta-bound microbeads. Two weeks after the procedure, intracoronary administration of serotonin caused coronary vasospasm at the IL-1beta-treated site (n = 10). Coronary vasodilatation to bradykinin, substance P, or an increase in coronary blood flow was preserved at the spastic site. Vasodilator responses to 3-morpholinosydnonimine (an NO donor) and nitroglycerin also were comparable between the 2 sites. The vasoconstricting response to N(G)-monomethyl-L-arginine and the extent of the augmentation of the serotonin-induced vasoconstriction were comparable between the 2 sites. Organ chamber experiments showed that endothelium-dependent relaxations to bradykinin, the calcium ionophore A23187, and even the vasospastic agonist serotonin were preserved at the spastic site, whereas contractions to serotonin were augmented at the spastic site regardless of the presence or absence of the endothelium (n = 6). Endothelium-independent relaxations to sodium nitroprusside were also preserved at the spastic site. CONCLUSIONS: These results indicate that endothelial vasodilator function is preserved at the spastic site and that the spasm is caused primarily by smooth muscle hypercontraction in our porcine model.

Animals↗

PubMed1999

Interferon-gamma inhibits the myofibroblastic phenotype of rat palatal fibroblasts induced by transforming growth factor-beta1 in vitro.

Interferon-gamma (IFN-gamma), a multifunctional cytokine, has been noted as a potential therapeutic agent for various fibrotic disorders, including excessive scar tissue formation. We previously reported that transforming growth factor-beta1 (TGF-beta1) induced the myofibroblastic phenotype in palatal fibroblasts derived from palatal mucosa, and that such effects might have a close link to palatal scar formation. In the present study, we examined the effects of IFN-gamma on TGF-beta1-pretreated palatal fibroblasts for the purpose of clarifying the suppressive potency against myofibroblastic phenotype expression in vitro. IFN-gamma significantly altered the spindle morphology of TGF-beta1-pretreated palatal fibroblasts into the polygonal one that was similar to the non-treated palatal fibroblasts. This change was parallel with a decrease in the expression of alpha-smooth muscle actin protein, a marker for myofibroblast, as determined by immunoblot analysis. Northern blot analysis showed that IFN-gamma inhibited proalpha2(I) collagen mRNA expression that was stimulated by TGF-beta1 pretreatment for 24 h. Furthermore, IFN-gamma decreased the cell contractility enhanced by TGF-beta1 pretreatment for 24 h in a three-dimensional collagen gel culture system. These results suggest that IFN-gamma may have negative effects with regard to controlling the myofibroblastic phenotype induced by TGF-beta1 in palatal fibroblasts.

Actins↗

PubMed1999

Primary endothelial dysfunction: atherosclerosis.

The endothelium synthesizes and releases several vasodilating factors, including nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin. Under certain conditions, it also liberates vasocontracting factors. Thus, the endothelium plays an important role in regulating vascular homeostasis. Several intracellular mechanisms are involved in the synthesis of nitric oxide, including receptor-coupled G proteins, the availability of L-arginine, cofactors for endothelial nitric oxide synthase and the expression of the enzyme. Endothelial dysfunction by aging, menopause and hypercholesterolemia is involved in the development of atherosclerotic vascular lesions, and predisposes the blood vessel to several vascular disorders, such as vasospasm and thrombosis. Multiple mechanisms are apparently involved in the pathogenesis of the endothelial dysfunction in atherosclerosis. The reduced production of nitric oxide by the endothelium is caused by abnormalities in endothelial signal transduction, availability of L-arginine, cofactors for endothelial nitric oxide synthase and expression of the enzyme. Other mechanisms may also be involved in the impaired endothelium-dependent relaxations in atherosclerosis, including increased destruction of nitric oxide by superoxide anion, altered responsiveness of vascular smooth muscle, and concomitant release of vasocontracting factors. In addition to the treatment of the underlying risk factors, several pharmacological agents can improve endothelial dysfunction in atherosclerosis. Thus, the endothelium is a novel therapeutic target for the treatment of atherosclerotic cardiovascular disease.

Animals↗

PubMed1999

In situ hybridization for matrix metalloproteinase-1 and cathepsin K in rat root-resorbing tissue induced by tooth movement.

The movement of teeth during orthodontic treatment occasionally induces undesirable root resorption. Although high collagenolytic activity has been detected in resorbing tissue of deciduous teeth, the cellular origin of collagenolytic enzymes in root-resorbing tissue caused by tooth movement has not been identified. Here, rats were subject to 7 days of experimental tooth movement to induce root resorption. In situ hybridization with digoxigenin-labelled RNA probes was performed on sections of the maxillary bone to detect the mRNAs that encode matrix metalloproteinase-1 (MMP-1) and cathepsin K in root-resorbing tissue. MMP-1 mRNA was detected in fibroblastic cells, cementoblasts and osteoblasts, but not in odontoclasts nor osteoclasts. Moreover, MMP-1 mRNA was highly expressed in some cementocytes located near odontoclasts and in many osteocytes. In contrast, cathepsin K mRNA was expressed only in odontoclasts and osteoclasts. These results suggest that MMP-1 and cathepsin K are important in root resorption during tooth movement in a mode similar to bone resorption.

Animals↗

PubMed1999

Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo.

OBJECTIVE: Although studies in vitro have implicated oxygen-derived free radicals as possible mediators of inflammatory cytokine-induced cell injury, the role of the radicals in the cytokine-induced myocardial dysfunction in vivo remains unclear. The present study was designed to address this point in our novel canine model of cytokine-induced myocardial dysfunction in vivo. METHODS: Studies were performed in mongrel dogs, in which microspheres (MS, 15 microns in diameter) with and without interleukin-1 beta (IL-1 beta) were injected into the left main coronary artery (control and IL-1 beta group). Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 week. RESULTS: Immediately after the intracoronary injection of MS (10(6)/kg), LVEF equally decreased to approximately 30% in both the control and IL-1 beta group. While LVEF rapidly recovered within 2 days in the control group, it remained depressed in the IL-1 beta group until day 7 (p < 0.0001 vs. control group). Pretreatment with OPC-6535 (an inhibitor of superoxide production) before (2 mg/kg i.v.) and 1 and 2 days after IL-1 beta MS application (1 mg/kg i.v.) prevented the IL-1 beta-induced myocardial dysfunction. Superoxide production in the myocardium was significantly higher in the IL-1 beta group than in the control group at day 2 (p < 0.01), and OPC-6535 significantly suppressed the IL-1 beta-induced superoxide production (p < 0.01). An HPLC assay showed that nitrotyrosine, a marker of the formation of peroxynitrite by superoxide anion and nitric oxide, was present in the myocardium treated with IL-1 beta but not in that with control MS. OPC-6535 abolished the IL-1 beta-induced formation of myocardial nitrotyrosine. CONCLUSION: These results indicate that superoxide anion and the resultant formation of peroxynitrite may substantially be involved in the pathogenesis of the cytokine-induced myocardial dysfunction in dogs in vivo.

Analysis of Variance↗

PubMed1999

Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm.

OBJECTIVE: We recently demonstrated in our swine model of coronary artery spasm that enhanced myosin light chain (MLC) phosphorylations (both MLC mono- and diphosphorylations) play a central role in the pathogenesis of the spasm. However, the molecular mechanism for and the phosphorylation sites for the enhanced MLC phosphorylations were unknown. In the present study, we addressed these points using hydroxyfasudil, a novel inhibitor of protein kinases, which we found preferentially inhibits Rho-kinase. METHODS: The specificity of the inhibitory effects of hydroxyfasudil on Rho-kinase, MLCK, MRCK beta and PKC were examined by kinase assay in vitro. The left porcine coronary artery was chronically treated with interleukin-1 beta (IL-1 beta, 2.5 micrograms). Two weeks after the operation, coronary artery vasomotion was examined both in vivo and in vitro. MLC phosphorylations were examined by Western blot analysis and the sites for the phosphorylations by anti-phosphorylated MLC antibodies that identified the monophosphorylation site as Ser19 and diphophorylation sites as Ser19/Thr18 of MLC. RESULTS: Inhibitory effects of hydroxyfasudil was at least 100 times more potent for Rho-kinase as compared with other protein kinases tested. Intracoronary serotonin (10 micrograms/kg) caused coronary hyperconstriction at the IL-1 beta-treated site in vivo, which was dose-dependently inhibited by hydroxyfasudil (p < 0.01). The coronary segment taken from the spastic site also showed hypercontractions to serotonin in vitro, which were again dose-dependently inhibited by hydroxyfasudil (p < 0.01). Western blot analysis showed that MLC monophosphorylation was significantly greater in the spastic segment than in the control segment, while MLC diphosphorylation was noted only at the spastic segment (p < 0.01). The sites for the mono- and diphosphorylated MLC were identified as the monophosphorylated site Ser19 and diphosphorylated sites Ser19/Thr18 of MLC, respectively. Both types of MLC phosphorylations at the spastic segment were markedly inhibited by hydroxyfasudil (p < 0.01). CONCLUSION: These results indicate that hydroxyfasudil-sensitive Rho-kinase-mediated pathway appears to mediate the enhanced MLC phosphorylations (on Ser19 and Ser19/Thr18 residues) and plays a central role in the pathogenesis of coronary artery spasm.

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

PubMed1999

Expression of PDGF-beta receptor, EGF receptor, and receptor adaptor protein Shc in rat osteoblasts during spaceflight.

A number of studies have indicated that microgravity induces osteopenia and modulates functions of mammalian cells. However, the molecular mechanisms underlying these effects of microgravity are still unknown. Rat osteoblasts were cultured for 4 and 5 days during Shuttle-Spacelab flight, and fixed by guanidine isothiocyanate solution on board after treatment with 1alpha, 25 (OH)2 vitamin D3. The mRNA levels for platelet-derived growth factor (PDGF)-beta receptor, epidermal growth factor (EGF) receptor, the growth factor receptor adaptor protein Shc, and c-fos were determined using the method of quantitative reverse transcription-polymerase chain reaction. The mRNA levels for EGF receptor were not altered by microgravity. However, the mRNA levels for PDGF-beta receptor, Shc, and c-fos were decreased to 62, 55 and 25% on the 4th day of flight, and 47, 40, and 43% on the 5th day, respectively, as compared to the corresponding ground controls. Expression of the growth factor receptor and the receptor adaptor protein was modulated in rat osteoblasts during spaceflight. Data suggest that signal transduction via growth factor receptors in rat osteoblasts is impaired by microgravity. Dysfunction of osteoblasts might be involved in spaceflight-induced osteopenia.

Animals↗

PubMed1999

Long-term vascular effects of Nomega-nitro-L-arginine methyl ester are not soley mediated by inhibition of endothelial nitric oxide synthesis in the rat mesenteric artery.

Nomega-nitro-L-arginine methyl ester (L-NAME), one of the synthetic L-arginine analogues with inhibitory effects of nitric oxide (NO) synthesis, is now widely used to examine the role of NO in various organs. We and others demonstrated that long-term treatment with L-NAME causes hypertension and cardiovascular lesions (perivascular fibrosis and medial thickening), especially at microvascular levels. However, convincing evidence is still lacking that these long-term cardiovascular effects of L-NAME are solely mediated by the inhibition of the synthesis of endothelium-derived NO (EDNO). This study was thus designed to better understand the effects of long-term treatment with L-NAME with special reference to EDNO synthesis. Male Wister-Kyoto rats were orally administered L-NAME for 8 weeks. Blood pressure significantly increased at 3 days and 1 and 8 weeks of the treatment. Endothelium-dependent relaxations to acetylcholine (ACh) of the aorta were reduced 3 days after the treatment, recovered at 1 week, and again reduced at 8 weeks, whereas the relaxations of the small mesenteric artery were unaltered throughout the experimental periods. At 8 weeks, indomethacin-sensitive, endothelium-dependent contractions to ACh were noted. The relative contributions of NO and endothelium-derived hyperpolarizing factor also were unchanged. Citrulline assay demonstrated that substantial levels of constitutive NO synthase activity remained in the aorta during the experiments. The long-term treatment with L-NAME caused perivascular fibrosis and medial thickening, not only in the aorta but also in the mesenteric artery. These results suggest that mechanism(s) other than simple inhibition of EDNO synthesis is involved in the long-term cardiovascular effects of L-NAME in the rat mesenteric artery.

Animals↗

PubMed1999

Long-term treatment with eicosapentaenoic acid augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilatation in patients with coronary artery disease.

Long-term treatment with eicosapentaenoic acid (EPA) is known to improve impaired endothelium-dependent relaxations of atherosclerotic blood vessels in animals and humans. However, it remains to be determined which mechanisms are involved in this beneficial effect of EPA. In this study, we investigated our hypothesis that EPA improves both nitric oxide (NO)-mediated and non-NO-mediated endothelium-dependent vasodilatation in patients with coronary artery disease. The study included eight patients with documented coronary artery disease. The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine and substance P were examined before and after intraarterial infusion of NG-monomethyl-L-arginine (L-NMMA). Same measurements were repeated after the treatment with EPA (1,800 mg/day) for 6 weeks. The long-term treatment with EPA augmented forearm blood-flow response to both acetylcholine and substance P. Furthermore, acute administration of L-NMMA significantly inhibited the EPA-induced augmented response to acetylcholine but not that to substance P. The forearm vascular response to sodium nitroprusside was unchanged by the EPA treatment. These results indicate that long-term treatment with EPA augments both NO-dependent and non-NO-dependent endothelium-dependent forearm vasodilatation in patients with coronary artery disease. Thus the beneficial effects of EPA appear to extend to non-NO-dependent mechanism(s).

Acetylcholine↗

PubMed1999

Important role of endothelium-derived hyperpolarizing factor in shear stress--induced endothelium-dependent relaxations in the rat mesenteric artery.

Shear stress is one of the most important stimulators for the release of endothelium-derived relaxing factors. Although shear stress-induced release of nitric oxide (NO) has been extensively investigated, it remains to be elucidated whether endothelium-derived hyperpolarizing factor (EDHF) contributes to the endothelium-dependent relaxations to shear stress. This study was designed to address this point in the isolated rat mesenteric artery. Large mesenteric arteries (400-500 microm) and resistance mesenteric arteries (150-250 microm) of the rat were precontracted with phenylephrine (at 80 mm Hg of perfusion pressure), and the changes in vessel diameter in response to variable flow (0-300 microl/min) were continuously examined. The relative contributions of vasodilator prostaglandins, NO, and EDHF were analyzed by the inhibitory effects of indomethacin (10(-5) M), N(G)-nitro-L-arginine (L-NNA, 10(-4) M), and KCl (40 mM), respectively. The shear stress-induced relaxations were totally endothelium dependent in both-sized blood vessels, and the contribution of NO was more prominent in large arteries than in resistance arteries, whereas that of EDHF was noted in both-sized blood vessels. Tetrabutylammonium (a nonselective inhibitor of K channels) almost abolished, whereas the combination of charybdotoxin (an inhibitor of both large- and intermediate-conductance Ca2+ -activated K channels) and apamin (an inhibitor of small-conductance Ca2+ -activated K channels) significantly inhibited the EDHF-mediated component of the shear stress-induced relaxations. These results indicate that EDHF plays an important role in shear stress-induced endothelium-dependent relaxations, where K channels, especially calcium-activated K channels, appear to be involved.

Animals↗

PubMed1999

Pathogenic role of oxidative stress in vascular angiotensin-converting enzyme activation in long-term blockade of nitric oxide synthesis in rats.

Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) activates vascular angiotensin-converting enzyme (ACE) and causes oxidative stress. We investigated the role of oxidative stress in the pathogenesis of ACE activation in rats. Studies involved aortas of rats receiving no treatment, L-NAME, L-NAME plus L-arginine, or L-NAME plus an antioxidant drug (N-acetylcysteine, allopurinol, or ebselen) for 7 days. L-NAME significantly increased oxidative stress (O(2)(-)) and ACE activity. The increased O(2)(-) production was normalized by removal of endothelium. Immunohistochemistry showed the increased ACE activity in the endothelial layer. Treatment with antioxidant drugs did not affect the L-NAME-induced increase in systolic arterial pressure but did prevent increases in vascular O(2)(-) production and ACE activity. These results implicate oxidative stress in the pathogenesis of vascular ACE activation in rats with long-term inhibition of NO synthesis. The observed effects of antioxidant drugs on ACE activation do not appear to involve the hypertension induced by L-NAME.

Animals↗

PubMed1999

An immunocytochemical study of amelogenin proteins in the developing tooth enamel of the gar-pike, Lepisosteus oculatus (Holostei, Actinopterygii).

Previous studies have demonstrated the morphological similarity of the enamel-like layer found in the teeth of the coelacanth, lungfish and gar-pike to the enamel of tetrapods. In order to clarify the phylogenetic continuity between both structures, tooth germs of the gar-pike were immunocytochemically studied using an anti-bovine amelogenin polyclonal antibody. Intense immunoreaction was shown over the enamel-like matrix layer. Certain cell organelles associated with the secretory pathway of the ameloblasts were recognized as immunoreactive. These results indicate that the enamel-like layer of the gar-pike is a tissue homologous with the mammalian enamel because both possess a common, amelogenin-like substance.

Amelogenin↗

PubMed1999

Induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro.

PURPOSE: To investigate the response to mechanical stress of vascular endothelial growth factor (VEGF) production by cultured retinal pigment epithelial (RPE) cells. METHODS: A pulsatile stretch device was used in vitro. RPE cells of the second passage were seeded onto flexible-bottomed culture plates; then, at subconfluent culture, the plates were subjected to pulsatile stretch. Culture plates prepared in the same way but not subjected to stretch were used as controls. After stretching for 1 hour or 24 hours, conditioned medium for measurement of VEGF production by RPE cells was collected using a mouse VEGF immunoassay. To study the expression of VEGF in RPE cells, passaged-cultured RPE cells were exposed to pulsatile stretch for 0, 1, 3, or 14 hours. Total cytoplasmic RNA was then prepared from the RPE cells. Northern blot analysis was performed for VEGF, with G3PDH used as an internal control. RESULTS: The expression and secretion of VEGF in RPE cells were increased by pulsatile stretching. CONCLUSIONS: Results indicate that stretching of the RPE could result in increased production of VEGF, with associated risk for neovascularization and changes in the blood-retinal barrier.

Animals↗

PubMed1999

Space flight modulates signal transduction pathway of growth factor receptors in rat osteoblasts.

Bone metabolism is regulated by the balance of bone formation and resorption. Osteoblasts serves primarily for bone formation. Microgravity deteriorates osteoblastic function and inhibit bone formation. Growth factors regulate osteoblast function via receptors. Binding of EGF and PDGF to the receptors activates receptor tyrosine kinase and rapid association of adapter proteins Shc and Grb2, and evokes the Ras/MAP kinase cascade. Signals from various chemical and physical stimuli are transmitted to the nucleus, and induce c-fos and c-jun gene expression. However, effects of microgravity on the molecular events in osteoblasts remain unknown. The purpose of this study is to investigate the mRNA levels for PDGF-beta receptor, EGF receptor, Shc, and c-fos in rat osteoblasts during space flight.

Animals↗

PubMed1998

Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats.

It has been shown that nitric oxide (NO) may regulate angiotensin II (Ang II) receptors in vitro. To determine whether the chronic inhibition of NO synthesis upregulates cardiac Ang II receptors in a rat model, we evaluated the in vivo effect of Nomega-nitro-L-arginine methyl ester (L-NAME) on several Ang II receptors and on the expression of AT1 receptor mRNA in heart tissue. The chronic administration of L-NAME to normal rats increased the arterial blood pressure. The number of AT1 and AT2 receptors was increased, with no change in affinity, during the first week of L-NAME administration but returned to control levels after 4 weeks of treatment. The AT1 receptor mRNA was changed parallel to AT1 receptor number. Inflammatory changes (monocyte infiltration and myofibroblast formation) in perivascular areas surrounding coronary vessels and myocardial interstitial spaces were observed during the first week. The immunohistochemistry revealed that myofibroblasts expressed AT1 receptor. AT1 receptor blockade or cotreatment with L-arginine, but not cotreatment with hydralazine, prevented the L-NAME-induced increase in Ang II receptors and inflammatory changes. In conclusion, rat cardiac Ang II receptors are upregulated at an early phase of chronic inhibition of NO synthesis. This may contribute to cardiovascular inflammatory changes in an early phase and to remodeling at the later phase, which occurs after inhibition of NO synthesis.

Actins↗