Biomedical subjects

Shuntaro Kagiyama

Publications and source records attributed to Shuntaro Kagiyama.

10 recordsLinked to original sources

PubMed2006

Transient precordial ST elevation by a spasm of the conus artery during right coronary angiography.

During coronary angiography of right coronary artery (RCA), a catheter wedged into a conus artery, and a remarkable coved-type ST elevation was seen in precordial lead through V1-3. LCA angiography did not show any abnormal findings, but we recognized a slow contrast flow in a conus artery by RCA angiography. The patient was free from chest pain, and a ST elevation was improved. The slow flow of a conus artery was recovered within five minutes. Precordial ST elevation may be caused by a catheter-induced spasm of a conus artery.

Aged↗

PubMed2005

Chronic administration of olmesartan attenuates the exaggerated pressor response to glutamate in the rostral ventrolateral medulla of SHR.

It has been shown that the pressor responses to microinjection of L-glutamate in the rostral ventrolateral medulla (RVLM) are augmented in spontaneously hypertensive rats (SHR), and that these augmented responses are not altered by chronic conventional antihypertensive treatment. The aim of the present study was to determine the effect of chronic oral treatment with a new angiotensin II type 1 (AT(1)) receptor antagonist, RNH-6270 (the active form of olmesartan medoxomil), on cardiovascular responses to excitatory amino acids in the RVLM of SHR. SHR (12 weeks old) were treated with RNH-6270 (30 mg/kg/day) or vehicle for 4 weeks. At 16 weeks of age, L-glutamate (2 nmol), N-methyl-D-aspartate (NMDA; an ionotropic glutamate receptor agonist (20 pmol)), or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD; a metabotropic glutamate receptor agonist (1 nmol)) was microinjected into the RVLM of rats. The pressor responses to microinjection of L-glutamate or NMDA in the RNH-6270-treated SHR (+28.3 +/- 1.0 and +48.3 +/- 2.5 mm Hg, respectively) were significantly smaller than those in untreated SHR (+45.7 +/- 2.2 and +69.4 +/- 7.0 mm Hg, respectively, P < 0.05 each); however, they were still greater than those in the Wistar-Kyoto rats (+21.7 +/- 1.0 and +28.6 +/- 3.3 mm Hg, respectively, P < 0.05 each). In contrast, the augmented pressor responses to microinjection of (1S,3R)-ACPD in SHR were not affected by the RNH-6270 treatment. These results demonstrated that chronic oral treatment with RNH-6270, an AT(1) receptor antagonist, partly normalizes the pressor responses to L-glutamate or NMDA, but not (1S,3R)-ACPD, in the RVLM of SHR, suggesting that endogenous angiotensin II may be involved in the exaggerated pressor response to l-glutamate, probably through its ionotropic glutamate receptors.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

Central and peripheral cardiovascular actions of apelin in conscious rats.

APJ was cloned as an orphan G protein-coupled receptor and shares a close identity with angiotensin II type 1 receptor (AT1R). Apelin is a peptide that has recently been identified as an endogenous ligand of the APJ. Apelin and APJ mRNA are expressed in peripheral tissue and the central nervous system. However, little is known about the effects of apelin in cardiovascular regulation. To examine the central and peripheral role of apelin, we injected the active fragment of apelin [(Pyr1)apelin-13] intracerebroventricularly (ICV, 5 and 20 nmol, n=6) or intravenously (IV, 20 and 50 nmol, n=4 or 5) in conscious rats. ICV injection of (Pyr1)apelin-13 dose-dependently increased mean arterial pressure (MAP) and heart rate (HR) (19+/-3 mm Hg and 162+/-26 bpm at 20 nmol). Pretreatment with ICV injection of the AT1R antagonist (CV-11974, 20 nmol) did not alter the apelin-induced increase in MAP and HR. IV injection of (Pyr1)apelin-13 also dose-dependently increased MAP and HR (13+/-2 mm Hg and 103+/-18 bpm at 50 nmol); however, the peripheral effects of apelin were relatively weak compared to its central effects. Expression of c-fos in the paraventricular nucleus (PVN) of hypothalamus was increased in the rat that received ICV injection of (Pyr1)apelin-13 but not in the rat that received IV injection of (Pyr1)apelin-13. These results suggest that apelin plays a role in both central and peripheral cardiovascular regulation in conscious rats, and that the cardiovascular effects of apelin are not mediated by the AT1R.

Animals↗

PubMed2004

Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats.

Ghrelin is an orexigenic peptide originally isolated from the stomach. Intracerebroventricular administration of ghrelin has been shown to elicit decreases in arterial pressure and renal sympathetic nerve activity in conscious rabbits. The aim of the present study was to determine the role of ghrelin in the brain stem in cardiovascular responses in rats. Unilateral microinjection of ghrelin into the nucleus of the solitary tract significantly decreased the mean arterial pressure and heart rate (-17.3+/-0.8 mm Hg and -13.6+/-3.5 bpm by 20 pmol). The microinjection of ghrelin into the nucleus of the solitary tract also suppressed the renal sympathetic nerve activity (-29.5+/-3.4%; P<0.0001). Pretreatment with intravenous injection of pentolinium (5 mg/kg), a ganglion-blocking agent, eliminated these cardiovascular responses induced by the microinjection of ghrelin (20 pmol) into the nucleus of the solitary tract; however, pretreatment with intravenous injection of atropine sulfate (0.1 mg/kg), an antagonist of muscarinic acetylcholine receptors, failed to prevent them. In contrast, unilateral microinjection of ghrelin into the area postrema, rostral, and caudal ventrolateral medulla caused no significant changes in the mean arterial pressure and heart rate. On the other hand, immunohistochemical study revealed that the receptor for ghrelin, the growth hormone secretagogue receptor, was expressed in the neuronal cells of the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, but not in the cells of the area postrema. These results suggest that ghrelin acts at the nucleus of the solitary tract to suppress sympathetic activity and to decrease arterial pressure in rats.

Animals↗

PubMed2003

Expression of angiotensin type 1 and 2 receptors in brain after transient middle cerebral artery occlusion in rats.

Angiotensin II (Ang II) type 2 receptors (AT2Rs) have been associated with apoptosis. We hypothesized that AT2Rs are increased in stroke and may contribute effects of stroke to the brain. To test this, we have examined the expression of Ang II type 1 receptor (AT1R), AT2R and Ang II levels in the brain 24 h after transient middle cerebral artery occlusion (MCAO). The densities of AT1R and AT2R were measured by quantitative autoradiography (n=6). The levels of Ang II were measured by radioimmunoassay (RIA) (n=6) and by immunohistochemistry (n=3). AT1R levels on autoradiography showed a significant decrease (0.87+/-0.06 to 1.39+/-0.07 fmol/mg, p<0.01) in the ventral cortex of the stroke side compared to the cortices of non-stroke (NS) rats (n=4). There was no significant difference on ATIR in the contralateral verbal cortex of the stroke rats compared to NS control. In contrast, levels of AT2R in the ventral cortex of both the stroke and the contralateral sides were significantly increased (0.77+/-0.06, p<0.05 and 0.91+/-0.05, p<0.01 compared to 0.60+/-0.03 fmol/mg tissue, respectively). RIA showed that Ang II in the ventral cortex of both the stroke and the contralateral sides were significantly increased (241.63+/-47.72, p<0.01 and 165.51+/-42.59, p<0.05 compared to 76.80+/-4.10 pg/g tissue, respectively). Also, Ang II in the hypothalamus was significantly increased (179.50+/-17.49 to 118.50+/-6.65 pg/g tissue, p<0.05). Immunohistochemistry confirmed the increase of Ang II. These results demonstrate that brain Ang II and AT2Rs are increased whereas AT1Rs are decreased after transient MCAO in rats. We conclude that in stroke, Ang II and AT2R are activated and may contribute neural effects to brain ischemia.

Angiotensin II↗

PubMed2002

Antisense to epidermal growth factor receptor prevents the development of left ventricular hypertrophy.

We previously demonstrated that left ventricular hypertrophy (LVH) induced by angiotensin II infusion requires epidermal growth factor receptor (EGFR) activation to mediate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. To test whether the EGFR-mediated MAPK/ERK activation plays an important role in development and maintenance of LVH in spontaneously hypertensive rats (SHR), we investigated the effects of antisense oligodeoxynucleotide to EGFR (EGFR-AS) on LVH and blood pressure in young and adult SHR. EGFR-AS, sense oligonucleotide to EGFR (EGFR-S; 1.5 mg/kg), or vehicle control (5% dextrose) with liposome was injected once a week for 2 months in 5- or 13-week-old SHR. The effect of EGFR-AS on the expression of EGFR and phosphorylated ERK in the heart were examined by Western blots. After treatment, EGFR-AS significantly (P<0.05) decreased left ventricular weight/body weight and blood pressure in young SHR compared with EGFR-S or control-treated rats. In adult SHR, EGFR-AS did not affect left ventricular weight/body weight and blood pressure. EGFR and phosphorylated ERK significantly declined from 5 to 20 weeks (P<0.05). EGFR-AS, but not EGFR-S, significantly (P<0.05) decreased the expression of EGFR and phosphorylated ERK in young SHR, but had no significant effect in adult SHR. These results suggests that EGFR-mediated ERK activation is critically important for LVH in young SHR. This may be related to the high levels of EGFR and phosphorylated ERK in young SHR, suggesting a critical role of the EGFR-activated ERK pathway in cardiovascular development but not in the maintenance of established LVH in adult SHR.

Animals↗

PubMed2002

Angiotensin II-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense.

BACKGROUND: Angiotensin II (Ang II) is a vasoconstrictor but also a growth factor. However, the Ang II type 1 receptor does not have a tyrosine kinase domain that mediates the cellular signals for mitosis. We have shown that Ang II acts via "trans"-activation of the epidermal growth factor receptor (EGFR) to induce activation of tyrosine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in vascular smooth muscle cells (VSMCs). To examine whether EGFR is involved in the development of left ventricular hypertrophy (LVH), we inhibited EGFR with a specific antisense oligodeoxynucleotide to attenuate the Ang II-induced cardiovascular hypertrophic effects. METHODS AND RESULTS: The antisense oligodeoxynucleotide to EGFR (EGFR-AS) was designed and tested on Ang II-induced ERK activation in cultured VSMCs. We also investigated the effects of EGFR-AS on LVH and blood pressure (BP) in Ang II-infused hypertensive rats. In VSMCs, EGFR-AS (2.5 micromol/L) reduced EGFR expression and inhibited the Ang II-induced phosphorylation of ERK. In rats, Ang II (150 ng/h for 14 days) increased BP compared with controls (184+/-6 mm Hg versus 122+/-3 mm Hg; n=7; P<0.01). Continuous intravenous infusion of EGFR-AS (2 mg/kg) decreased BP (169+/-8 mm Hg; n=8; P<0.05). Ang II infusion increased the left ventricular/body weight (LV/BW) ratio compared with control rats (2.75+/-0.08 versus 2.33+/-0.07; P<0.01). EGFR-AS, but not EGFR-sense, normalized the LV/BW in Ang II-infused rats (2.32+/-0.06; P<0.01) and attenuated Ang II-enhanced EGFR expression and ERK phosphorylation. CONCLUSION: Ang II requires EGFR to mediate ERK activation in VSMCs and the heart. EGFR plays a critical role in the LVH induced by Ang II.

Angiotensin II↗

PubMed2002

Vigilant vectors: adeno-associated virus with a biosensor to switch on amplified therapeutic genes in specific tissues in life-threatening diseases.

There are many life-threatening and chronic diseases in which physiological signals could be used to switch on therapeutic protective genes. We are developing a gene therapy approach in which a systemically injected "vigilant vector" waits for these signals and switches on genes to protect specific tissues with high amplification. The concept of a vigilant vector requires four components. The first component is a safe and stable vector that can be administered by systemic injection and express transgenes in a particular organ or tissue. The adeno-associated virus vector is safe and stable for this purpose. The second component is a reversible gene switch which is a biosensor that can detect certain physiological signals. We are developing a hypoxia switch, based on the oxygen-dependent degradation domain of hypoxia-inducible factor. The third component is a tissue-specific promoter, and we have used the myosin light-chain-2V promoter for specific expression in the heart. The fourth component is an amplification system. For this we have developed a double-plasmid/vector system based on the yeast GAL4 and human transcriptional activator p65 to produce a transactivating fusion protein that binds to a GAL4 activation sequence in an activating plasmid that then expresses high levels of cardioprotective genes.

Acute Disease↗

PubMed2002

Vigilant vector: heart-specific promoter in an adeno-associated virus vector for cardioprotection.

Repeated bouts of ischemia in the heart lead to fibrosis and eventually to heart failure. Although certain genes, such as SOD or hemoxygenase and antisense to AT(1)R, ACE, and (beta(1)-AR can provide short-term protection of the heart from ischemia, there is no known mechanism for constantly responding to repeated incidences of ischemia. We hypothesized that a "vigilant vector," designed to be expressed specifically in the heart and switch on therapeutic genes only during hypoxia, would provide cardioprotection. To attain cardiac specificity, we inserted an MLC2v promoter into an adeno-associated virus (AAV) designed to deliver AS to AT(1)R and gfp. In in vitro experiments in cardiomyocytes (H9C2 cells), the MLC2v-AAV-gfp drove gene expression in all cells at levels comparable to a cytomegalovirus (CMV) promoter. In in vivo experiments, the rAAV-MLC2v-gfp was injected intravenously into mice or rats. Green fluorescence protein (GFP) DNA was located in kidney, heart (right and left ventricle), lung, adrenal and spleen. GFP mRNA, however, was expressed only in the heart and absent in other tissues. To switch on the rAAV transgene during ischemia, we inserted a hypoxia response element (HRE). This upregulates transcription when O(2) levels are low. Thus, there are 4 components to the vigilant vector; a gene switch (HRE), a heart-specific promoter (MLC2v), a therapeutic gene (AS-AT(1)R) and a reporter gene (gfp). To silence or lower basal level of expression while retaining specificity, we have reduced the length of the MLC2v promoter from 3 kb to 1775 bp or 281 bp. The truncated promoter is equally effective in heart specific expression. Preliminary studies with the rAAV-HRE-gfp in vitro show an increased expression in 1% O(2) in 4 to 6 hours. By adding additional hypoxia-inducible factor (HIFalpha) (5 microg), the MLC2v-gfp expression is increased by 4-fold in 1% O(2). Further amplification of the gene to 400-fold in 1% O(2) can be achieved with a double plasmid. The construct may serve as a prototype "vigilant vector" to switch on therapeutic genes in specific tissue with physiological signals.

Angiotensin Receptor Antagonists↗

PubMed2002

Angiotensin II as a pro-inflammatory mediator.

Angiotensin II (Ang II), the most important component of the renin-angiotensin system, is usually associated with hypertension and renal failure. Through its pro-inflammatory actions, it also plays an important role in each step of the development of atherosclerotic plaques and plaque rupture. Ang II stimulates the expression of nuclear factor-kappaB (NFkappaB), a transcription factor which regulates gene expression of inflammatory cytokines such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Ang II type 1 receptors (AT1) and angiotensin converting enzyme (ACE) are dramatically increased in atherosclerotic plaques, particularly in monocytes at the fibrous cap. Thus, in multiple ways, Ang II is a critical factor in atherosclerotic plaque formation, inflammation and plaque stability. ACE inhibitors and AT1R inhibitors could therefore be appropriate therapeutic agents in the treatment of atherosclerosis.

Angiotensin II↗