Hisahiro Yu

Hypertensive rats produced by in vivo introduction of the human renin gene.

We established an efficient and nontoxic in vivo gene transfer method mediated by the Sendai virus (hemagglutinating virus of Japan [HVJ]), liposomes, and nuclear protein. In this study, to produce a hypertensive model rat that is dependent on human renin, the human renin gene was introduced into adult rat liver by our efficient in vivo gene transfer method using HVJ and liposomes (HVJ-liposomes). The rats treated with HVJ-liposomes containing the human renin gene showed a significant elevation of blood pressure for 6 days compared with control rats, which received injections of HVJ-liposomes without the human renin gene. On day 5 after the transfer, human active renin as well as angiotensin II were found in the plasma of rats in which the human renin gene was introduced. Moreover, the blood pressure of these rats was significantly correlated with the plasma levels of human active renin and angiotensin II. To confirm that the elevated blood pressure was due to the expression of the human renin gene, we administered a newly developed specific human renin inhibitor, FK 906. The elevated blood pressure was normalized by the intravenous administration of this drug. These data indicate that this hypertensive rat was produced by the in vivo transfer of the human renin gene into rat liver and that the expressed human renin cleaved rat substrate (angiotensinogen). This hypertensive rat produced by in vivo gene transfer should be useful in further studies on hypertension.

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis

BACKGROUND Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken. METHODS ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2 ) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls. RESULTS There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis. CONCLUSIONS The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

Incidence and time course of left ventricular dilation in the early convalescent stage of reperfused anterior wall acute myocardial infarction

The incidence and early process of left ventricular (LV) dilation in 52 patients with reperfused anterior wall acute myocardial infarction (AMI) were assessed. All patients achieved coronary reflow within 24 hours of the onset and had a patent infarct-related artery in the convalescent stage. Left ventriculography was performed at pre-reflow and 25 days (mean) later to determine LV end-diastolic volume (ml) with the area/length method. Short-axis echo images at the midpapillary muscle level were recorded at days 1, 7, 14, and 28 of the AMI. With use of the papillary muscles as the internal landmarkers, the LV wall was divided into the anterior and posterior segments, and length and thickness of each segment were determined. Among 52 patients, 10 (19%) had a > or = 20% increase in end-diastolic volume in the convalescent stage. Echocardiographic studies demonstrated that there were no significant changes in lengths and thicknesses of the anterior and posterior segments during follow-up study relative to his or her baseline value in 42 patients without LV dilation. In the patients with LV dilation, however, the anterior segment exhibited a mean increase of 25% in its length with a mean decrease of 21% in its thickness at day 7 relative to their baseline values, but no progressive expansion was observed after day 7. A mean increase of 7% in the posterior segment length without reduction in its thickness first became evident at day 28.(ABSTRACT TRUNCATED AT 250 WORDS)

Links between hypertension and myocardial infarction.

The mechanisms through which hypertension contributes to the occurrence of myocardial infarction should be discussed from two points of view: (1) common risk factors for the two diseases, such as genetic risk, insulin resistance, sympathetic hyperactivity, and vasoactive substances such as angiotensin K, and (2) linking factors that are induced by hypertension and contribute to the development of atherosclerosis and myocardial infarction, such as atherosclerosis and left ventricular hypertrophy. Mechanical stress on blood vessels because of high blood pressure is an especially important factor in endothelial dysfunction, the progression of atherosclerosis, and plaque rupture. This article concentrates on these factors from the perspective of their relationship with the renin-angiotensin system, because recent multicenter trials have demonstrated that angiotensin-converting enzyme inhibitors are effective for preventing recurrence of myocardial infarction.

EFFECT OF AN ANTIHYPERTENSIVE DRUG ON BRAIN ANGIOTENSIN II LEVELS IN RENAL AND SPONTANEOUSLY HYPERTENSIVE RATS

1. Although numerous studies suggest that brain angiotensin (AII) may play an important role in the regulation of blood pressure, it is still unclear what factors may influence brain All. In this study, we hypothesized that brain AII is influenced by circulating factors. To investigate the role of blood pressure and plasma All in brain AII level, we studied the effect of an antihypertensive drug on brain AII in two‐kidney, one‐clip (2K1C) and spontaneously hypertensive (SHR) rats.

Oral Glucose Loading Modulates Plasma β-Amyloid Level in Alzheimer’s Disease Patients: Potential Diagnostic Method for Alzheimer’s Disease

Background: Although plasma β-amyloid (Aβ) has been suggested to be a noninvasive diagnostic biomarker for Alzheimer’s disease (AD), its significance and validity have been inconclusive. Thus, it is quite important to establish a novel diagnostic method related to plasma Aβ. Methods: As our previous animal studies demonstrated a relation of glucose with plasma Aβ, we examined the effect of glucose loading on plasma Aβ levels in AD patients. After fasting, an oral glucose load was administered to AD patients and non-AD dementia patients, and subsequently, blood glucose, plasma insulin, and plasma Aβ levels were measured. Results: The plasma levels of baseline blood glucose, plasma insulin, and plasma Aβ were not different between the two groups. However, immediately after glucose loading, a significant increase in plasma Aβ40 and Aβ42 levels was observed in AD patients, whereas a mild decrease in plasma Aβ40 and Aβ42 levels was detected in non-AD dementia patients. Conclusion: The present study clearly demonstrated a different response in plasma Aβ40 and Aβ42 levels after glucose loading between AD and non-AD dementia patients, which is consistent with our previous animal studies. These findings suggest a novel diagnostic tool for AD using the elevation of plasma Aβ level after glucose loading, although further studies are necessary.

Effect of kihito extract granules on cognitive function in patients with Alzheimer's-type dementia

Background:  It has been recently suggested that Japanese herbal (kampo) medicines, such as kami‐untan‐to, may improve cognitive function in elderly subjects with Alzheimers disease. Polygalae radix is thought to be a useful component of kami‐untan‐to because it enhances the activity of choline acetyltransferase in cultured neuronal cells. The purpose of the present study was to investigate the safety and usefulness of kihito extract granules, a commercially available Japanese herbal medicine that contains P. radix, for elderly patients with senile dementia.

Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.

Although recent studies suggest that several antihypertensive drugs could reduce the risk of bone fracture, it is still unclear how these drugs act on bone remodeling, especially in elderly women with severe osteoporosis with disuse syndrome. In the present study, we investigated the effects of a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) on bone metabolism in elderly bedridden women with hypertension and disuse syndrome.

Differential Regulation of Brain Angiotensin II in Genetically Hypertensive and Normotensive Rats after Nephrectomy

To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.

Renal effects of an angiotensin II antagonist in stroke-prone spontaneously hypertensive rat.

We evaluated the renal effects of the new angiotensin II type 1 (AT ) receptor antagonist, HR 720, in the stroke-prone spontaneously hypertensive rat. Rats were treated with either vehicle, HR 720, MK-954 (a selective AT1 receptor antagonist) or enalapril for 6 weeks. Blood pressure was decreased to a similar extent by HR 720, MK-954 and enalapril (203 +/- 4, 202 +/- 5 and 190 +/- 4 vs. 247 +/- 4 mm Hg for control). Urinary protein secretion was also decreased (5.2 +/- 0.3, 5.3 +/- 0.2 and 5.5 +/- 0.6 vs. 25.2 +/- 4.6 mg/100g/24h). The glomerular hypertensive change was improved in each drug-treated group (2.0 +/- 0.2, 3.3 +/- 0.3 and 1.6 +/- 0.1 vs. 17.6 +/- 1.5%; p < 0.0001). These results show that, in addition to its antihypertensive effect, HR 720 has a beneficial effect on renal function.