Hiroyuki Takase

Effects of Chronic ETA-Receptor Blockade in Angiotensin II-Induced Hypertension

Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252, on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35 +/- 5 mm Hg; tail-cuff method) compared with placebo (P < .05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase (P < .05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group (P < .05 versus placebo) and improved by concomitant chronic LU135252 treatment (P < .05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine (r = -.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment (P < .05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 (P < .05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 (P < .05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.

L-NAME Hypertension Alters Endothelial and Smooth Muscle Function in Rat Aorta: Prevention by Trandolapril and Verapamil

Nitric oxide is an important regulator of vascular function and blood pressure. Chronic administration of nitric oxide inhibitors provides a new model of hypertension with pronounced target organ damage. We investigated the effects of oral treatment with N omega-nitro-L-arginine methyl ester (L-NAME) for 6 weeks on vascular reactivity of the aorta in Wistar-Kyoto rats. Certain rats received verapamil or trandolapril in addition to L-NAME. Systolic blood pressure increased in the L-NAME group (by approximately or equal to 80 mm Hg systolic) but not in controls or rats treated with verapamil or trandolapril. Isometric tension changes of aortic rings were recorded. Endothelium-dependent relaxations to acetylcholine were reduced in the L-NAME group (58 +/- 6% versus 104 +/- 1% in placebo, P < .05) but were normalized by treatment with verapamil or trandolapril. In contrast, endothelium-independent relaxations to sodium nitroprusside were not significantly reduced in L-NAME hypertension but were slightly enhanced by trandolapril therapy (P < .05) in the L-NAME group only. In quiescent rings, acetylcholine caused endothelium-dependent contractions in particular after in vitro incubation with L-NAME. These contractions tended to be enhanced in L-NAME hypertension (23 +/- 4% versus 14 +/- 3% in the placebo group; P = NS) and were significantly reduced after treatment with verapamil or trandolapril (P < .05). Concentrations to norepinephrine and angiotensin I and II were unaffected by L-NAME hypertension, whereas those to endothelin-1 were reduced (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Therapy Prevents Endothelial Dysfunction in Chronic Nitric Oxide Deficiency: Effect of Verapamil and Trandolapril

The objective of this study was to examine the effects of long-term antihypertensive therapy on blood pressure and vascular responses of resistance arteries during prolonged inhibition of nitric oxide synthesis. Four groups of 6-week-old Wistar-Kyoto rats were treated with either placebo as controls or N omega-nitro-L-arginine methyl ester (L-NAME) alone or in combination with verapamil or with trandolapril. Drugs were given orally for 6 weeks or short-term in vitro to vessels obtained from untreated rats. Endothelium-dependent and -independent relaxations as well as contractions were studied in isolated perfused mesenteric and renal arteries with an arteriograph. Kidney nitric oxide synthase activity was also evaluated. Verapamil and trandolapril prevented the increase in systolic blood pressure and the blunted acetylcholine-induced relaxations that occurred with L-NAME treatment without improving the nitric oxide synthase activity. Both antihypertensive regimens also normalized sensitivity to sodium nitroprusside, which was enhanced by L-NAME. In contrast, short-term in vitro preincubation with verapamil or trandolaprilat in the presence of L-NAME did not improve the impaired relaxations to acetylcholine. Long-term but not short-term therapy with a calcium antagonist or angiotensin-converting enzyme inhibitor improved the blunted endothelium-dependent relaxations in nitric oxide-deficient hypertension. These findings strongly suggest that the role of other vasodilator systems, which normally do not regulate vascular tone, is enhanced with long-term but not short-term treatment with these drugs. These observations emphasize the potential importance of these treatments in the management of hypertension in which nitric oxide production is diminished.

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.

Blood Pressure and Vascular Effects of Endothelin Blockade in Chronic Nitric Oxide–Deficient Hypertension

Because nitric oxide inhibits the synthesis and vasoconstrictor effect of endothelin-1, the effect of endothelin-1 may be enhanced under conditions of chronic inhibition of nitric oxide synthesis. We studied the effect of chronic therapy with bosentan, a combined endothelin-A/endothelin-B receptor antagonist, on blood pressure and vascular function and structure of small arteries as well as on the reactivity of the aorta in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Six-week-old Wistar-Kyoto rats were randomly treated for 6 weeks with placebo (control), L-NAME (70 mg/kg per day), or L-NAME plus bosentan (100 mg/kg per day). The treatments were stopped 2 to 3 days before the in vitro experiments so that only the long-term effects of the drugs could be observed. L-NAME increased systolic blood pressure: bosentan did not prevent this effect although the initial blood pressure rise was delayed (P=NS versus L-NAME group). Bosentan administration did not modify the structural alteration of the resistance vessels induced by L-NAME, nor did it improve endothelium-dependent relaxation of resistance vessels or the aorta. However, bosentan therapy markedly increased endothelium-dependent contraction to acetylcholine, which was slightly enhanced by L-NAME. In contrast, bosentan inhibited aortic endothelium-dependent contractions when applied acutely in vitro. This observation, together with the increased maximal vasoconstriction to the thromboxane A2 receptor agonist U46619 after 2 weeks of bosentan administration, suggests that bosentan also interacts with the receptors mediating endothelium-dependent contractions. In conclusion, our experiments suggest a minor role of endothelin in chronic L-NAME-induced hypertension as well as in the concomitant alterations of vascular structure.

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.

Structure and Function of the Rat Basilar Artery During Chronic Nitric Oxide Synthase Inhibition

BACKGROUND AND PURPOSE Nitric oxide is an important regulator of vascular tone and may also be implicated in the modulation of vascular growth and structure. This study presents the effects of chronic nitric oxide inhibition, with or without antihypertensive treatment, on the structure and function of the basilar artery in rats. METHODS Rats were treated for 6 weeks with N omega-nitro-L-arginine methyl ester (50 mg/kg per day) alone or in combination with verapamil (100 mg/kg per day) or with trandolapril (1 mg/kg per day). Untreated rats served as controls. The structure and reactivity of perfused and pressurized basilar arteries were analyzed in vitro using a video dimension analyzer. RESULTS Systolic arterial pressure increased only in the nitro-arginine-treated group, as did the media-to-lumen ratio of the basilar artery. This structural alteration, which was prevented by verapamil and trandolapril, was mainly due to remodeling and not to growth. Chronic inhibition of the L-arginine pathway increased the response of the basilar artery to serotonin, while the opposite was found for endothelin. Verapamil and trandolapril prevented these functional alterations that seemed related to the changes in the vascular structure. CONCLUSIONS The remodeling and functional alterations of the basilar artery seem to depend mainly on the elevation of arterial pressure with little contribution of the L-arginine pathway. Furthermore, nitric oxide does not seem to be implicated in the modulation of normal cerebral vascular growth in vivo. However, hypertension-induced changes in vascular reactivity and structure could alter cerebral blood flow and eventually contribute to the development of stroke in this model of hypertension.

Brachial-ankle pulse wave velocity predicts increase in blood pressure and onset of hypertension.

BACKGROUND The present study was designed to test the hypothesis that brachial-ankle pulse wave velocity (baPWV) predicts longitudinal increases in blood pressure (BP) and new onset of hypertension in individuals with normal BP. METHODS baPWV was measured using a semiautomated device in 2,496 participants (27-84 years) without hypertension who visited our hospital for a yearly health check-up. They were followed up for 4 years with the endpoint being development of hypertension. RESULTS During the follow-up period (median, 733 days; actual follow-up, 5,215 person-years), hypertension developed in 698 participants (133.8/1,000 person-years). Kaplan-Meier analysis revealed that risk for hypertension was increased across the tertiles of baseline baPWV. The hazard ratio (first tertile as reference) was 2.02 (95% confidence interval (CI) 1.55-2.64) and 3.49 (95% CI 2.66-4.57) in the second and third tertiles, respectively, after adjustment for possible risk factors. Multivariate Cox proportional hazard regression analysis adjusted for known risk factors, where baPWV was used as a continuous variable, also indicated that the baseline value of baPWV independently predicted new onset of hypertension (P < 0.001). Furthermore, baseline baPWV was significantly associated with a longitudinal increase in BP after adjustment for known risk factors in multiple regression analysis (P < 0.001). CONCLUSION This study provides the first evidence that baPWV is an independent predictor of longitudinal increases in BP as well as of new onset of hypertension.

Vascular protective effects of ACE inhibitors and calcium antagonists: theoretical basis for a combination therapy in hypertension and other cardiovascular diseases.

SummaryHypertension is an important cardiovascular risk factor. High blood pressure per se is not a disease but a hemodynamic alteration associated with vascular disease. Two classes of drugs are especially effective in lowering blood pressure and preventing cardiovascular complications, angiotensin converting enzyme (ACE) inhibitors and calcium antagonists. The hemdynamic effects of ACE inhibitors and calcium antagonists are complementary. While ACE inhibitors inhibit the renin-angiotensin system and reduce sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Certain calcium antagonists, such as verapamil, lower heart rate. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are also complementary. While ACE inhibitors inhibit activation of angiotensin I into angiotensin II and prevent the breakdown of bradykinin (which stimulates nitric oxide and prostacyclin formation), calcium antagonists inhibit the effects of vasoconstrictor hormones such as angiotensin II at the level of vascular smooth muscle by reducing calcium inflow and facilitating the vasodilator effects of nitric oxide. Calcium antagonists reduce smooth muscle cell proliferation and atherosclerosis. In hypertensive animals, verapamil and trandolapril normalize endothelial dysfunction. In large angiographic trials, nifedipine and nicardipine reduced the development of new atherosclerotic plaques. After myocardial infarction, verapamil reduces mortality and cardiac events in patients without heart failure. In contrast, ACE inhibitors are effective after myocardial infarction in patients with impaired left ventricular function. Urinary albumin excretion rate decreases during ACE inhibitor therapy or with a calcium antagonist such as verapamil; combination of the two drugs has an additive effect. In resistance arteries, hypertension is associated with an increased media/lumen ratio. ACE inhibitors, but not beta-blockers, markedly improve these structural changes. In summary, ACE inhibitors and calcium antagonists have a complementary profile, both in their hemodynamic and local vascular action. Hence, combination therapy with these two classes of drugs appears particularly useful in patients with hypertension, not only to lower blood pressure, but hopefully to achieve improved cardiovascular protection.