Yasuaki Dohi

Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries.

In cultured endothelial cells, endothelin is produced after stimulation with angiotensin II. The effects of angiotensin II and endothelin-1 on vascular sensitivity to norepinephrine were studied in perfused rat mesenteric resistance arteries. Expression of endothelin messenger RNA (mRNA) was determined in endothelial cells obtained from the mesenteric circulation. Perfusion (5 hours) of the arteries with angiotensin II (10(-7) M) potentiated contractions in arteries with endothelium induced by norepinephrine in spontaneously hypertensive rats but not Wistar-Kyoto rats. The potentiation was inhibited by phosphoramidon and an endothelin antibody. Short-term stimulation (1 hour) with angiotensin II did not cause the potentiation. Stimulation with angiotensin I (10(-7) M; 5 hours) caused a potentiation prevented by captopril. In endothelial cells collected from the mesenteric arterial bed of spontaneously hypertensive rats, endothelin-specific mRNA was constitutively expressed, and the level of endothelin transcripts was increased by angiotensin II (10(-7) M). Threshold concentrations of exogenous endothelin-1 potentiated contractions induced by norepinephrine in arteries with and without endothelium of spontaneously hypertensive rats but not Wistar-Kyoto rats. Thus, angiotensin II stimulates the endothelial production of endothelin in situ and therapy potentiates contractions to norepinephrine in mesenteric resistance arteries of spontaneously hypertensive rats. This suggests that vascular endothelin production acts as an amplifier of the pressor effects of the renin-angiotensin system that may play an important role in hypertension.

Nifedipine controlled-release 40 mg b.i.d. in Japanese patients with essential hypertension who responded insufficiently to nifedipine controlled-release 40 mg q.d.: a phase III, randomized, double-blind and parallel-group study.

This phase III, multicenter, randomized, double-blind, parallel-group study compared the efficacy and safety of nifedipine controlled-release (CR) 40 mg twice daily (b.i.d.) and once daily (q.d.) in 325 Japanese patients with essential hypertension uncontrolled with nifedipine CR 40 mg q.d. (ClinicalTrials.gov record: NCT01287260). The primary endpoint was the change from baseline in trough seated diastolic blood pressure (DBP) after 8 weeks. Nifedipine CR 40 mg b.i.d. showed significantly greater reductions in trough seated DBP (−7.7±0.6 mm Hg vs. −3.6±0.6 mm Hg) and trough seated systolic blood pressure (BP) (−11.1±0.9 mm Hg vs. −3.7±0.9 mm Hg) after 8 weeks of treatment compared with nifedipine CR 40 mg q.d. (both P<0.0001). At week 8, BP target achievement and responder rates were higher with nifedipine CR 40 mg b.i.d. (21.5% and 42.4% vs. 10.3% and 19.5%, respectively). Adverse events considered related to the study drug were reported in 9.0 and 9.7% of patients receiving nifedipine CR 40 mg b.i.d. and q.d., respectively. The frequency of drug-related adverse events commonly reported with nifedipine CR (headache, hot flush, palpitations, peripheral edema, hypotension, dizziness, tachycardia) was low and the results were similar between the treatment groups. In conclusion, a higher dose of nifedipine CR was associated with greater efficacy and a safety profile similar to that of the currently approved dose (40 mg q.d.) in Japanese patients with essential hypertension, and it may offer a valuable treatment choice for patients who do not achieve target BP levels with standard treatment.

Angiotensin Blockade or Calcium Antagonists Improve Endothelial Dysfunction in Hypertension: Studies in Perfused Mesenteric Resistance Arteries

Summary Endothelial regulation of peripheral vascular resistance is impaired in hypertension. We studied the effects of different antihypertensive therapies on endothelial function in perfused mesenteric resistance arteries. Spontaneously hypertensive rats (SHR) aged 7 weeks were treated with either the nonpeptidic angiotensin II (AH) receptor antagonist CGP 48369, the angiotensin-converting enzyme (ACE) inhibitor benazepril HC1, or the calcium antagonist nifedipine (each 10 mg/kg/day orally, p.o.) for 8 weeks. All forms of therapy inhibited the increase in systolic blood pressure (SBP) to a comparable degree (18–23 mm Hg) and reduced but did not normalize medial hypertrophy in SHR. Changes in intraluminal vascular diameter to acetylcholine (ACh), norepinephrine (NE), and endothelin-1 (ET-1) were measured. Impaired endothelium-dependent relaxations to intraluminal ACh improved or normalized with all therapies, whereas the response to extraluminal ACh (which was unimpaired in SHR) remained unaffected. The endothelium-dependent inhibition of contractions to NE was lost in untreated SHR and improved or restored by antihypertensive therapy. In SHR, the sensitivity but not the maximal response of vascular smooth muscle (VSM) to ET-1 was paradoxically decreased. Antihypertensive therapy with CGP 48369, nifedipine, or benazepril HC1 restored or increased the sensitivity to ET-1. Thus, chronic blockade of the renin-angiotensin system or voltage-operated calcium channels reduces BP and improves endothelial dysfunction in the resistance circulation of SHR. This may contribute to normalization of peripheral vascular resistance during antihypertensive treatment and improve local blood flow to vital organs.

Increased Circulating Levels of Natriuretic Peptides Predict Future Cardiac Event in Patients with Chronic Hemodialysis

Background/Aim: Cardiovascular events are the major determinant of the prognosis in patients with chronic hemodialysis. The present study was designed to investigate whether increased plasma levels of atrial or brain natriuretic peptides (ANP or BNP) predict future cardiac events in such patients. Methods: Fifty-three patients undergoing chronic hemodialysis without clinical symptoms suggestive of cardiac disorders were enrolled and their blood was sampled for ANP and BNP measurements. Electrocardiograms demonstrated left ventricular hypertrophy in 28 patients but no other abnormal findings. We followed them up for 11.3 ± 0.2 months. The endpoint was cardiac events. Results: Cardiac events occurred in 13 patients (CE group). Both ANP and BNP levels were higher in CE group than in patients without cardiac events (ANP: 118 ± 21 vs. 56 ± 5 pg/ml, BNP: 769 ± 204 vs. 193 ± 25 pg/ml, respectively). Receiver operating characteristics curve revealed that the cut-off levels of ANP and BNP were 58 and 390 pg/ml, respectively. Using the Kaplan-Meier method, the incidence of cardiac events was significantly greater in patients with higher levels of ANP (50.0 vs. 0.0%) or BNP (72.7 vs. 11.9%) than in those with lower levels of the peptides. Conclusion: Elevated levels of ANP or BNP indicate an increased risk of cardiac events and these peptides are clinically useful to predict cardiac events in patients with hemodialysis.

Aging differentially affects direct and indirect actions of endothelin-1 in perfused mesenteric arteries of the rat

1 The effects of age on the vascular action of endothelin‐1 were studied in mesenteric resistance arteries of 4,9 and 27 month old Fischer 344 rats. 2 Third order branches (about 200 μm in diameter) of mesenteric resistance arteries were dissected free and mounted on glass cannulae in organ chambers. Changes in intraluminal diameter of the perfused and pressurized vessels were continuously measured with a video dimension analyzer. 3 Endothelin‐1 (10−14−3 × 10−8 m.) caused contractions that were augmented after removal of the endothelium. The inhibitory effects of the endothelium were greater in young than in old rats. 4 The sensitivity of vascular smooth muscle to endothelin‐1 decreased with age, while the maximal response was maintained. In contrast, the contractions to noradrenaline were unaffected by aging. 5 Threshold concentrations of endothelin‐1 potentiated the contractions evoked by low and moderate concentrations of noradrenaline (10−7−10−6m) in old, but not in young, rats. 6 Endothelium‐dependent relaxations to acetylcholine inhibited maximal contractions to endothelin‐1 and this effect decreased with age. In contrast, the relaxations to the nitric oxide donor, 3‐morpholinosydnonimine (SIN‐1; the active metabolite of molsidomine), did not differ in the three age groups. 7 Aging specifically decreases the direct contractile effects of endothelin‐1 and the inhibitory effects of the endothelium against these contractions, while the indirect (potentiating) effects of the peptide become more pronounced.

Uric Acid Levels Predict Future Development of Chronic Kidney Disease

Aims: Increased uric acid levels are associated with kidney dysfunction. We tested the hypothesis that uric acid level predicts future development of chronic kidney disease (CKD) in the general population. Methods: For this study, we enrolled 7,078 consecutive subjects with normal estimated glomerular filtration rates (eGFR; ≧60 ml/min/1.73 m2) who visited our hospital for a yearly health checkup (age: 52.8 ± 10.7 years; female: 35.8%). Subjects underwent a routine physical examination and laboratory assessment of cardiovascular disease risk factors at enrollment, and were followed up for 1,694 days (median) with the endpoint being the development of CKD (eGFR <60 ml/min/1.73 m2). The impact of uric acid and other cardiovascular risk factors at baseline on the future development of CKD were assessed. Results: During the follow-up period, 417 male (9.2%) and 151 female subjects (6.0%) developed CKD. Univariate logistic regression analysis revealed a significant association between the onset of CKD and age, male gender, body mass index, blood pressure, fasting plasma glucose, dyslipidemia and uric acid. Multiple logistic regression analysis revealed that new-onset CKD was independently correlated with the baseline uric acid level after adjustment for possible factors. Subanalysis showed similar results in subjects with normal uric acid levels (male: ≤7.0 mg/dl; female: ≤6.0 mg/dl; n = 6,223). Conclusion: Uric acid is an independent predictor of future development of CKD. Whether preventing an increase in uric acid levels reduces the incidence of CKD must be clarified by prospective follow-up studies.

Effects of atorvastatin on inflammation and oxidative stress

Treatment with inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A reductase (statins) reduces the incidence of cardiovascular events, but it is unclear whether the beneficial effects are mediated solely by their lipid-lowering properties. We therefore investigated whether atorvastatin reduces inflammation and oxidative stress independently of its lipid-lowering effects. The subjects comprised 71 hyperlipidemic patients (64 ± 9 years old, mean ± SD) who were not receiving medical treatment. Serum lipid and C-reactive protein (CRP) levels, and urine 8-isoprostane level (an index of oxidative stress) were measured before and after 4 weeks of treatment with atorvastatin at 10 mg/day. In 38 patients, these biochemical variables and carotid intima-media thickness (IMT) were also measured after 6 months of treatment with atorvastatin. Atorvastatin markedly reduced CRP (from 0.69 ± 0.36 to 0.42 ± 0.20 and 0.35 ± 0.19 mg/l, median ± median absolute deviation, P < 0.0001), 8-isoprostane (from 225 ± 99 to 178 ± 75 and 179 ± 60 ng/g creatinine, P < 0.05), and low density-lipoprotein cholesterol (LDLC; from 165 ± 21 to 106 ± 18 and 112 ± 17 mg/dl, P < 0.0001) after 4 weeks and 6 months of treatment, respectively. However, the reductions in CRP and 8-isoprostane were not correlated with those of LDLC. After 6 months of treatment, IMT was significantly decreased compared with the baseline value (from 0.94 ± 0.26 to 0.90 ± 0.20 mm, P < 0.05), but this was not correlated with the reduction in LDLC. These results suggest that atorvastatin has beneficial effects on inflammation, oxidative stress, and the lipid profile in patients with hyperlipidemia. The extra-lipid effects are not attributable to the lipid-lowering effect of the statin, suggesting that the pleiotropic effects of atorvastatin are independent of its effects on the lipid profile.

Salt sensitivity and circadian rhythm of blood pressure: the keys to connect CKD with cardiovasucular events

In healthy subjects, blood pressure (BP) drops by 10–20% during the night. Conversely, in patients with the salt-sensitive type of hypertension or chronic kidney disease, nighttime BP does not fall, resulting in an atypical pattern of circadian BP rhythm that does not dip. This pattern is referred to as the ‘non-dipper’ pattern. Loss of renal functional reserve, due to either reduced ultrafiltration capacity or enhanced tubular sodium reabsorption, induces the salt-sensitive type of hypertension. When salt intake is excessive in patients with salt-sensitive hypertension, the defect in sodium excretory capability becomes evident, resulting in elevated BP during the night. This nocturnal hypertension compensates for diminished natriuresis during the daytime and enhances pressure natriuresis during the night. Nocturnal hypertension and the non-dipper pattern of circadian BP rhythm cause cardiovascular events. When excess salt intake is loaded in patients who are in a salt-sensitive state, glomerular capillary pressure is also elevated, resulting in glomerular sclerosis and eventual renal failure. In this way, salt sensitivity and excess salt intake contribute to both cardiovascular and renal damage at the same time. We propose that salt sensitivity of BP and excess salt intake have important roles in the genesis of the cardiorenal connection. Salt sensitivity and circadian rhythm of BP are the keys to understanding the connections between cardiovascular and renal complications.

Age-Related Changes in Vascular Smooth Muscle and Endothelium

SummaryAging is associated with structural and functional changes in the blood vessel wall. In vascular smooth muscle, the effects of aging on the response mediated by β-adrenoceptors have been most intensively studied. β-Adrenoceptor-mediated relaxation decreases in most arteries, but not veins, with increasing age. In contrast, studies on contractile responses to α-adrenergic drugs are conflicting. The response to α-adrenoceptor agonists appears to be unchanged or decreased by aging.The endothelium takes part in the local regulation of vascular tone as a source of several vasoactive factors. Basal release of endothelium-derived nitric oxide decreases with age in in vitro studies. Aging is also associated with reduced endothelium-dependent relaxations in response to vasoactive substances such as acetylcholine, histamine or adenosine. The impairment of the relaxation is, in most cases, achieved by a decreased release and/or decreased production of endothelium-derived relaxing factors (endothelium-derived nitric oxide, hyperpolarising factor and prostacyclin). An increased release of endothelium-derived, cyclo-oxygenase-dependent contracting factor is also responsible for the reduced relaxation in some tissues. On the other hand, the release of endo-thelin-1 from the endothelium increases with age, while the response to the pep-tide decreases under the same conditions, especially in small resistance arteries.The alterations of vascular smooth muscle and endothelial cells occurring with age may have important clinical implications for the pathogenesis of cardiovascular disease.

Increased oxidative stress impairs endothelial modulation of contractions in arteries from spontaneously hypertensive rats

Objectives The endothelium modulates vascular contractions. We investigated the effects of oxidative stress on endothelial modulation of contractions in hypertension. Methods Changes in isometric tension of femoral arterial rings from spontaneously hypertensive (SHR) and Wistar–Kyoto (WKY) rats were recorded. Results The contractile response to norepinephrine of arteries with endothelium was greater in SHR than in WKY rats (P < 0.0001). Endothelium removal augmented the norepinephrine-induced contraction (P < 0.05). The augmentation was more pronounced in WKY than in SHR, which resulted in comparable contraction of arteries without endothelium in both strains. Nω-nitro-L-arginine methyl ester (100 μmol/l) mimicked the effect of endothelium removal. Production of nitric oxide (NO, assessed by measuring nitrite/nitrate concentrations) during the contraction was not different between SHR and WKY. Vitamin C suppressed the contraction of arteries with endothelium from SHR but not from WKY (P < 0.05). Diphenyleneiodonium and apocynin, inhibitors of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase, attenuated the contraction of arteries with endothelium from SHR (P < 0.001) but not WKY, but did not affect contractions induced by serotonin. Superoxide generated by xanthine oxidase/hypoxanthine enhanced the norepinephrine-induced contraction of arteries with endothelium from WKY (P < 0.0001), and this effect was reversed by vitamin C. Conclusions In rat femoral arteries, NO released from the endothelium modulates vascular contraction. In SHR, production of superoxide by NADH/NADPH oxidase, which may be activated by norepinephrine, is enhanced, resulting in the inactivation of NO and impairment of endothelial modulation of vascular contractions. Vascular oxidative stress may contribute to the altered circulation in hypertension by impairing endothelial modulation of vascular contractions.