Case Report: QT Prolongation and Abortive Sudden Death Observed in an 85-Year-Old Female Patient With Advanced Lung Cancer Treated With Tyrosine Kinase Inhibitor Osimertinib.

Cardiac arrest occurred in an 85-year-old female administered osimertinib for advanced lung cancer expressing epidermal growth factor receptor (EGFR) mutations. Electrocardiogram (ECG) recorded at recurrence of spontaneous circulation showed sinus rhythm associated with mild QT prolongation (QTc = 455 ms) to which silent myocardial ischemia and coadministration of itraconazole and herbal drug causing hypokalemia (2.1 mEq/L) may have contributed. Discontinuation of osimertinib, itraconazole and herbal drug, potassium supplementation and percutaneous coronary intervention alleviated QT prolongation (QTc = 432 ms). Osimertinib is the third-generation tyrosine kinase inhibitor lengthening QT interval, and careful monitoring of ECG, serum potassium and drugs coadministered during chemotherapy including osimertinib are highly required.

Association of systolic blood pressure and pulse pressure with carotid intima thickness in elderly Japanese patients.

Many studies have demonstrated that increased carotid intima-media thickness (IMT) is related to future cardiovascular events and is influenced by cardiovascular risk factors such as sex, hypertension, diabetes, and hypercholesterolemia. Although aging is a well-known risk factor for an increase in carotid IMT, few studies have investigated which factors influence carotid IMT in the very elderly. In the present study, we investigated the relationship of pulse pressure (PP), blood pressure (BP), and its variability (six consecutive visits) with carotid IMT among 240 high-risk elderly in whom risk factors were managed clinically (average age was 79 ± 5 years). In the simple correlation, mean systolic BP (SBP) had a positive correlation with IMT and max IMT (P = .012 and P = .045), as did PP (P = .018 and P = .004), but did not diastolic BP or standard deviation of BP and coefficient of variation of BP. In multiple regression analyses, mean SBP and mean PP were each determinants of both IMT and max IMT, when each parameter was added separately to the regression model. We concluded that high SBP and wide PP still have an influence on increased carotid IMT in the very elderly Japanese patients.

Serum albumin levels as an independent predictor of 4-year mortality in a community-dwelling 80-year-old population.

BACKGROUND AND AIMS: Although serum albumin levels are associated with mortality in non-institutionalized elderly people under 80 years old, as well as in the institutionalized very elderly, little is known about the relationship in community-dwelling very elderly people. We, therefore, examined the association in a Japanese population of 80-year-old community residents. METHODS: Serum albumin levels were measured in 672 (267 men, 405 women) out of 1282 80-year-old individuals. Over the following 4 years, the dates and causes of death were recorded from resident registration cards and official death certificates. RESULTS: Of the above individuals, 107 subjects died (58 men, 49 women: 27 due to cancer, 27 cardiovascular disease, and 22 pneumonia). Survival rates were compared among 4 groups (highest >or=45 g/L, higher than 43-44 g/L, lower than 41-42 g/L, lowest

Quality of life and physical fitness in an 85-year-old population.

Since little is known about the very elderly population aged 80 years and older, we evaluated the association of quality of life (QoL) in an 85-year-old population with physical fitness measurements assessed at age 80 and 85 years. Two hundred seven individuals (90 males, 117 females) aged 85 years underwent the Short Form-36 (SF-36) questionnaires for QoL assessment and physical fitness measurements (handgrip strength, leg-extensor strength, one-leg standing time, stepping rate of legs, walking speed). In 85-year-olds, significant associations were found, by multiple regression analysis or logistic regression analysis, with adjustment for various influencing factors in QoL assessed by SF-36 with physical fitness measurements examined at the age of 85 and 80 years. Physical scales and scores in SF-36, such as physical functioning (PF), limitation in role functioning for physical reasons (role physical; RP), bodily pain (BP), and the physical component score (PCS) tended to be more tightly associated with fitness measurements than mental scales and scores such as limitation in role functioning for emotional reasons (role emotional; RE), and emotional well-being (mental health; MH), and mental component score (MCS). Three scales the general health perceptions (GH), the vitality (VT), and the social functioning (SF) consisting of both physical and mental components were associated with fitness, the extent being intermediate between physical scales and mental scales. Of the several physical fitness measurements, leg-extensor strength and the walking speed of 85-year-olds, and the stepping rate of 80-year-olds were most closely associated with QoL. In a very elderly population of 85- and 80-year-olds, significant associations were found between QoL by SF-36 and physical fitness measurements, suggesting that increases in the levels of physical fitness, even in the very elderly, can contribute to improvements in QoL.

Role of Rho kinase and oxidative stress in cardiac fibrosis induced by aldosterone and salt in angiotensin type 1a receptor knockout mice.

Large clinical trials have shown that mineralocorticoid receptor (MR) antagonists improve cardiovascular or total mortality in patients with heart failure or myocardial infarction even though the patients were taking angiotensin-converting enzyme inhibitors or angiotensin II receptor (AT1R) antagonists. We previously reported that cardiac fibrosis induced by aldosterone and salt (Ald-NaCl) was exaggerated in AT1aR knockout mice (AT1aR-KOs). As the association of Rho kinase and oxidative stress was reported in Ald-NaCl-induced hypertension of rats, we investigated the effects of an MR antagonist (eplerenone) and a Rho kinase inhibitor (fasudil) on Ald-NaCl-induced cardiac fibrosis in AT1aR-KOs. AT1aR-KOs were administered aldosterone (0.15 microg/h) subcutaneously using an osmotic minipump and were provided with 1% NaCl drinking water for 4weeks. AT1aR-KOs receiving Ald-NaCl were treated with a low (30 mg/kg/day) or high (100mg/kg/day) dose of eplerenone or a fasudil (100mg/kg/day). Systolic blood pressure (SBP), left ventricular weight/body weight (LVW/BW), histological examination and cardiac gene expression were evaluated on day 28. Ald-NaCl treatment caused increases in SBP and LVW/BW in AT1aR-KOs, and eplerenone dose-dependently decreased SBP, LVW/BW and cardiac fibrosis. Fasudil decreased LVW/BW and cardiac fibrosis without affecting SBP. The expressions of connecting tissue growth factor (CTGF) and nicotinamide adenine dinucleotide phosphate (NADPH) components (p22phox, p47phox and p67phox) were increased in Ald-NaCl-treated AT1aR-KOs, and eplerenone or fasudil decreased the expression of CTGF and NADPH components. Phosphorylated ERM (a marker of the phosphorylation of Rho kinase) was increased in Ald-NaCl-treated AT1aR-KOs and was decreased by eplerenone. Nitrotyrosine and 4-hydroxy-2-nonenal, which indicate tissue damage via oxidative stress, were increased in AT1aR-KO and were apparently attenuated by eplerenone or fasudil. These results suggested that the Rho kinase pathway was activated to induce cardiac fibrosis by Ald-NaCl via MR in AT1aR-KOs. A Rho kinase inhibitor as well as eplerenone might be useful for cardiac damage by Ald-NaCl.

Does decreased diastolic blood pressure associate with increased mortality in 80-year-old Japanese?

Hypertension is one of the greatest risk factors for cardiovascular disease, but its contribution to cardiovascular mortality weakens with aging. We have previously demonstrated that at the age of 80, higher systolic blood pressure (SBP) is not correlated with increased mortality in Japan. However, we did not examine in detail whether diastolic blood pressure (DBP) independently affects mortality. In the present study, 639 participants, who were 80 years old in 1997, were enrolled. The subjects were divided by their DBP [below 70 mmHg (group 1, n = 136), from 70 mmHg to 80 mmHg (group 2, n = 200), from 80 mmHg to 90 mmHg (group 3, n = 194), over 90 mmHg (group 4, n = 109)]. During the 4-year follow-up period, 90 individuals died. Cox multivariate regression analysis revealed that group 1 showed a significantly higher mortality rate than group 4 [relative risk (RR) 2.47, confidence interval (CI) 1.07-5.70, p = 0.03)]. The relative risks of deaths from cardiovascular diseases, pneumonia, and cancer tended to be higher in group 1 than in group 4, but the difference did not reach statistical significance. These results suggest that decreased DBP is associated with higher mortality in the Japanese elderly.

Correlation between increased urinary sodium excretion and decreased left ventricular diastolic function in patients with type 2 diabetes mellitus.

BACKGROUND: Increased salt intake may induce hypertension, lead to cardiac hypertrophy, and exacerbate heart failure. When elderly patients develop heart failure, diastolic dysfunction is often observed, although the ejection fraction has decreased. Diabetes mellitus (DM) is an established risk factor for heart failure. However, little is known about the relationship between cardiac function and urinary sodium excretion (U-Na) in patients with DM. METHODS: We measured 24-hour U-Na; cardiac function was evaluated directly during coronary catheterization in type 2 DM (n = 46) or non-DM (n = 55) patients with preserved cardiac systolic function (ejection fraction > or = 60%). Cardiac diastolic and systolic function was evaluated as - dp/dt and + dp/dt, respectively. RESULTS: The average of U-Na was 166.6 +/- 61.2 mEq/24 hour (mean +/- SD). In all patients, stepwise multivariate regression analysis revealed that - dp/dt had a negative correlation with serum B-type natriuretic peptide (BNP; beta = - 0.23, P = .021) and U-Na (beta = - 0.24, P = .013). On the other hand, + dp/dt negatively correlated with BNP (beta = - 0.30, P < .001), but did not relate to U-Na. In the DM-patients, stepwise multivariate regression analysis showed that - dp/dt still had a negative correlation with U-Na (beta = - 0.33, P = .025). CONCLUSION: The results indicated that increased urinary sodium excretion is associated with an impairment of cardiac diastolic function, especially in patients with DM, suggesting that a reduction of salt intake may improve cardiac diastolic function.

Possible association of atrophic gastritis and arterial stiffness in healthy middle-aged Japanese.

AIM: Helicobacter pylori (HP) has been implicated as a risk factor for cardiovascular and atherosclerotic diseases. Arterial stiffness determined by pulse wave velocity (PWV) or the cardio-ankle vascular index (CAVI) has been shown to be higher in HP-positive subjects than in HP-negative subjects; however, this result has been observed only in young subjects. The aim of the study was to investigate the possible correlation between HP infection and PWV or CAVI in middle-aged subjects. METHODS: We measured brachial-ankle PWV (baPWV), CAVI, metabolism markers, pepsinogens (PGs) and IgG antibody to HP in 343 individuals aged either 60 or 65 year old. Atrophic gastritis (AG) was diagnosed based on the values of PGs. RESULTS: baPWV and CAVI were significantly higher in the AG-positive group than in the AG-negative group even after adjusting for possible confounding factors (baPWVc; 16.63+/-3.50 vs. 15.59+/-3.47 p=0.010, CAVIc; 8.59+/-1.20 vs. 8.27+/-1.19 p=0.022). baPWV and CAVI values tended to be higher in the HP-positive group than in the HP-negative group. High-density lipoprotein (HDL) cholesterol level and the adiponectin level were lower in the AG-positive group than in the AG-negative group. CONCLUSION: There may be an association between atrophic gastritis and atherosclerosis in middle-aged subjects.

IgA level is associated with risk for mortality in an eighty-year-old population.

BACKGROUND: Immunoglobulin levels are elevated in the older people. However, it is unknown whether these levels are related to mortality. OBJECT: To evaluate the association between immunoglobulin levels and mortality. METHODS: The study population included 697 individuals (277 males and 420 females) of 1,282 eighty-year-old individuals residing in the Fukuoka prefecture, Japan. The participants were followed for 4 years after the baseline examination. RESULTS: The hyper-IgA group, defined as a serum IgA level >400 mg/dl, had high mortality using Kaplan-Meier analysis (log rank, p=0.037). Multivariate Cox regression analyses revealed a high risk of mortality (hazard rate=1.233, 95% confidence interval 1.109-1.491, p=0.031) after adjusting for covariates. The high risk of mortality in the hyper-IgA group was significant in males, but not in females. Moreover, Kaplan-Meier analysis revealed that IgA was related to cancer mortality in males (log rank, p=0.031), but not to pneumonia or cardiovascular disease. IgM and IgG levels were not related to high risk of mortality. CONCLUSION: Serum IgA levels appear to be a predictor of mortality, especially cancer mortality in males.

Chronic kidney disease increases cardiovascular mortality in 80-year-old subjects in Japan.

Chronic kidney disease (CKD) is one of the greatest risk factors for cardiovascular disease (CVD). The contribution of CKD to CVD mortality is not well understood in very elderly patients. Our study examined whether CKD might be a risk factor for total and CVD mortality in very elderly Japanese individuals. A total of 621 participants were enrolled, all of whom were 80 years old. The subjects were divided on the basis of the presence (CKD(+) group, n=280) or absence (CKD(-) group, n=341) of CKD. CKD was defined by as an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m(2). The eGFR of the CKD(+) and CKD(-) groups was 49.7+/-8.5 and 70.9+/-9.5 mL/min/1.73 m(2), respectively. During the 4-year study period, 87 individuals died, and 25 of those deaths were due to CVD. A Cox multivariate regression analysis revealed no association between total mortality and CKD (relative risk [RR] 1.17, confidence interval [CI] 0.75-1.82, p=0.50). However, the CVD mortality was significantly increased in the CKD(+) group (RR 4.60, CI 1.69-12.52, p=0.003). CKD significantly increased the CVD mortality in subjects who were not taking antihypertensive medication (RR 5.15, CI 1.04-25.50, p=0.04). Our results suggest that CKD increases the risk of CVD mortality in very elderly individuals. It is not only important to prevent progression toward CKD in patients who do not suffer from CKD, but also critical to manage the risk factors for CVD in patients with CKD, despite their advanced age. (Hypertens Res 2008; 31: 2053-2058).

Atrophic gastritis, but not antibody to Helicobacter pylori, is associated with body mass index in a Japanese population.

BACKGROUND: The relationship between Helicobacter pylori (HP) infection and body mass index (BMI) is controversial. Several reports have indicated that eradication of HP infection induces an increase in BMI. In contrast, epidemiological case-control studies have failed to show an association between HP infection and BMI. Therefore, we investigated whether HP and atrophic gastritis (AG) were associated with BMI. METHODS: A total of 617 individuals were recruited for the measurements of BMI, serum leptin, pepsinogens (PGs) I and II, and IgG antibody to HP (HP-IgG). BMI and leptin of the subjects were compared when the subjects were stratified by HP-IgG and PGs. RESULTS: The subjects were divided into AG-positive and AG-negative groups according to PGs (AG-positive: PG I < or = 70 ng/ml and PG I/II ratio < or =3.0). BMI after adjusting for sex and age was significantly lower in the AG-positive group than in the AG-negative group (23.47 +/- 3.05 vs. 24.18 +/- 3.25, P = 0.010). When the subjects were divided into two groups according to HP-IgG, BMI tended to be lower in the HP-IgG-positive group, though the difference was not large. When the subjects were divided into four groups for different combinations of AG and HP-IgG, BMI was the lowest in the AG-positive and HP-IgG-negative group. CONCLUSIONS: BMI was associated with AG, as diagnosed by PGs, but not with HP infection status. These results mean that HP infection affects BMI via atrophic gastritis.

Association between blood pressure and mortality in 80-year-old subjects from a population-based prospective study in Japan.

Hypertension is one of the greatest risk factors for cardiovascular disease, but the contribution of high blood pressure to cardiovascular morbidity and mortality is weakened with aging. In the present study, we examined whether high blood pressure would be a risk factor for total and cardiovascular mortality in a group of very elderly Japanese. Six hundred and thirty-nine participants who were 80 years old in 1997 were enrolled. The subjects were divided into three groups on the basis of their systolic blood pressure (SBP) (below 140 mmHg [group 1, n=212], from 140 mmHg to 159 mmHg [group 2, n=217], over 160 mmHg [group 3, n=210]). During the 4-year follow-up period, 87 individuals died and 24 of these deaths were due to cardiovascular diseases. Cox multivariate regression analysis revealed that there was no association between total mortality and SBP levels (relative risk [RR] 1.71; confidence interval [CI] 0.81-3.58; group 3 compared with group 1, p=0.35). However, the subjects taking antihypertensive medication showed significantly higher mortality with increasing SBP level (RR 5.72, CI 1.03-31.6, p=0.04, group 3 compared with group 1). Furthermore, in the subjects with a cardiovascular disease such as angina or stroke, high SBP increased the total mortality (RR 13.4, CI 2.39-75.1, p=0.004, group 3 compared with group 1). The present study did not find an association between blood pressure and mortality in the very elderly. However, our results did suggest that high SBP increases the risk of mortality in patients with cardiovascular diseases and/or taking antihypertensive medication.

Relationship between chewing ability and high-level functional capacity in an 80-year-old population in Japan.

OBJECTIVES: To evaluate the association between high-level functional capacity and chewing in a middle-old community-based population. BACKGROUND: Although basic and instrumental activities of daily living are known to be associated with chewing ability in the elderly, an association between higher levels of competence and chewing ability has not been evaluated in the elderly. MATERIALS AND METHODS: The association between chewing ability using a number of different foods and high-level functional capacity by the Tokyo Metropolitan Institute of Gerontology was evaluated in 694, 80-year-old people residing in Fukuoka Prefecture, Japan. RESULTS: A significant correlation was found, using multiple regression or logistic regression analyses adjusted for various confounding factors, between the number of total chewable foods, hard foods or moderately hard foods, and total functional capacity, instrumental activity, intellectual activity or social role ability. In contrast, the number of slightly hard foods, easily chewable foods and remaining teeth were only partly related to total functional capacity and intellectual activity. CONCLUSION: High-level functional capacity including intellectual activity and social role in middle-old elderly was associated with the ability to chew hard foods than to chew easily chewable foods. Maintenance of chewing ability in elderly might result in better intellectual activity and social role.

Relationship between volatile sulfur compounds in mouth air and systemic disease.

This study examined the relationship between volatile sulfur compounds (VSCs), including hydrogen sulphide (H(2)S), methyl mercaptan (CH(3)SH) and dimethyl sulphide [(CH(3))(2)S], in mouth air of patients and a history of systemic disease. The subjects were 387 residents (174 males and 213 females) of Fukuoka Prefecture, Japan, who participated in an oral and systemic health survey for elderly persons (mean age: 61.8, s.d. 2.8 years). The VSCs were measured using a portable gas chromatograph (OralChroma). The H(2)S concentrations were significantly greater in the 132 subjects with a history of hypertension and the 41 subjects with a history of respiratory disease, including pneumonia, pulmonary emphysema and bronchitis, than in those without such a history. The CH(3)SH concentrations were significantly greater in those with a history of hypertension. The 16 subjects with a history of cerebrovascular disease, including intracerebral haemorrhage, cerebral infarction, and subarachnoid haemorrhage, and the 58 subjects with a history of liver disease, including hepatitis, alcoholic liver disease, drug-induced liver injury, fatty liver and liver cirrhosis, showed significantly greater (CH(3))(2)S concentrations (p < 0.05). These results suggest an association between the production of VSCs in mouth air and systemic diseases such as hypertension as well as respiratory, cerebrovascular and liver diseases.

Aldosterone-and-salt-induced cardiac fibrosis is independent from angiotensin II type 1a receptor signaling in mice.

Aldosterone infusion with high salt treatment induces cardiac fibrosis in rats. Aldosterone enhanced angiotensin II (Ang II) has been shown to induce proliferation and increase the expression of Ang II receptor mRNA and Ang II binding in vitro. To investigate the role of Ang II type 1a receptor (AT1aR) in aldosterone-and-salt (Ald-NaCl)-induced cardiac fibrosis, we subcutaneously infused aldosterone (0.15 microg/h) and 1% NaCl (Ald-NaCl) into AT1aR knockout mice (AT1aR-KO) or wild type mice (Wt). To examine the role of NaCl on cardiac fibrosis, we gave some of the aldosterone-treated AT1aR-KO tap water (Ald-H2O). Ald-NaCl treatment increased systolic blood pressure and induced cardiac hypertrophy in both strains, whereas there were no such changes in the mice without aldosterone. Severe cardiac fibrosis was seen in Ald-NaCl-treated AT1aR-KO and not in Ald-NaCl-treated Wt. In contrast, Ald-NaCl-treated Wt with co-administration of an active metabolite of olmesartan, the AT1aR antagonist (10 mg/kg/day) did not show cardiac fibrosis. Na+/H+ exchanger, and Na+-K+ ATPase alpha2 subunit mRNA were decreased in AT1aR-KO. Na+/Ca2) exchanger mRNA was lower in AT1aR-KO than Wt and was decreased by Ald-NaCl in both strains. Phosphorylation of epidermal growth factor receptor and extracellular signal-regulated kinase was increased by Ald-NaCl treatment in AT1aR-KO. Connective tissue growth factor (CTGF) and osteopontin mRNA were increased and accumulation of CTGF proteins was seen in the hearts of Ald-NaCl-treated AT1aR-KO. Ald-H2O-treated AT1aR-KO did not show any cardiac fibrosis. These results suggest that Ald-NaCl-induced cardiac fibrosis required both aldosterone and salt. Because cardiac fibrosis was exaggerated in Ald-NaCl-treated AT1aR-KO but was not seen in Wt treated with Ald-NaCl and olmesartan, AT1aR may not play a primary role in progression of cardiac fibrosis by Ald-NaCl, and gene disruption of AT1aR may have some implications in this model.

Physical fitness and 4-year mortality in an 80-year-old population.

BACKGROUND: Because little is known about the relationship between physical fitness and mortality among very elderly people, we evaluated this association in a Japanese population of 80-year-old community residents. METHODS: Among 1282 80-year-old residents of Fukuoka Prefecture, Japan, 697 individuals (277 men and 420 women) underwent physical fitness tests of handgrip strength, isometric leg extensor strength, isokinetic leg extensor power, stepping rate, and one-leg standing time. Four years later, the dates and causes of death among the participants during those years were analyzed based on data from resident registration cards and from official death certificates. RESULTS: During the 4-year follow-up period, 107 individuals (58 men and 49 women) died. Of these deaths, 27 were due to cardiovascular disease (CVD), 27 to cancer, 22 to pneumonia, and the rest to other causes. The relative hazard ratios (HR) for all-cause mortality, adjusted for various confounding factors, fell with increases in stepping rate, and the HR for pneumonia mortality fell with increases in leg extensor strength. In contrast, there was no association between cardiovascular or cancer mortality and physical fitness. CONCLUSIONS: A partial association was found between impaired physical fitness at the age of 80 years and increased mortality in the 4 years thereafter. Mortality due to all causes was related only to stepping rate, and mortality due to pneumonia was related to leg extensor strength. Mortality due to CVDs or cancers was not associated with physical fitness.

Association between body mass index and mortality in an 80-year-old population.

OBJECTIVES: To evaluate the association between body mass index (BMI) and all-cause mortality and cardiovascular disease (CVD) in an 80-year-old population. DESIGN: Cohort study. SETTING: Community-based. PARTICIPANTS: Six hundred ninety-seven of 1,282 (54.4%) 80-year-old candidate individuals. MEASUREMENTS: The dates and causes of all deaths were followed up for 4 years. RESULTS: The relative hazard ratios (HRs) for all-cause mortality were lower in overweight subjects (BMI > or= 25.0) than in underweight (BMI<18.5) or normal-weight (BMI 18.5-24.9) subjects. Similarly, the HRs for mortality due to CVD in overweight subjects were 78% less (HR=0.22, 95% confidence interval (CI)=0.06-0.77) than those in underweight subjects, and those in normal weight subjects were 78% less (HR=0.22, 95% CI=0.08-0.60) than those in underweight subjects. Mortality due to CVD was 4.6 times (HR 4.64, 95% CI=1.68-12.80) as high in underweight subjects as in normal-weight subjects, and mortality due to cancers was 88% lower (HR=0.12, 95% CI=0.02-0.78) in the overweight group than in the underweight group. There were no differences in mortality due to pneumonia. CONCLUSION: Overweight status was associated with longevity and underweight with short life, due to lower and higher mortality, respectively, from CVD and cancer.

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.

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.

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.