Masashi Watanabe

Evaluation of changes in sympathetic nerve activity and heart rate in essential hypertensive patients induced by amlodipine and nifedipine

Objective To compare the effects of amlodipine and nifedipine on heart rate and parameters of sympathetic nerve activity during the acute and chronic treatment periods in order to elucidate their influence on cardiovascular outcome. Design A randomized and single-blind study. Methods We performed 24 h ambulatory electrocardiography and blood pressure monitoring of 45 essential hypertensive inpatients. Plasma and urinary catecholamine levels were measured during the control (pretreatment) period, on the first day (acute period) and after 4 weeks (chronic period) of administration of amlodipine and of short-acting nifedipine or its slow-releasing formulation. The low-frequency and high-frequency power spectral densities and low-frequency: high-frequency ratio were obtained by heart rate power spectral analysis. Results Blood pressure was significantly and similarly reduced by administrations of amlodipine, short-acting nifedipine and slow-releasing nifedipine during the chronic period. The total QRS count per 24 h, which remained constant during the chronic period of administration of slow-releasing nifedipine and was increased by administration of nifedipine, was decreased by 2.8% by administration of amlodipine. Administration of amlodipine decreased the plasma and urinary norepinephrine levels during the chronic period, whereas the levels were significantly increased by administration of short-acting nifedipine and not changed by administration of slow-release nifedipine. Although low-frequency: high-frequency ratio was increased significantly by administration of short-acting nifedipine and slightly by administration of slow-releasing nifedipine, administration of amlodipine reduced it during the acute and chronic periods. Conclusions Administration of amlodipine did not induce an increase in sympathetic nerve activity in essential hypertensive patients during the chronic period, suggesting that beneficial effects on essential hypertension can be expected after its long-term administration. Administration of slow-releasing nifedipine induces milder reflex sympathetic activation than does that of short-acting nifedipine.

L-NG-monomethyl arginine inhibits the vasodilating effects of low dose of endothelin-3 on rat mesenteric arteries

We have reported that low doses of endothelin-3 (ET-3) elicited continuous vasodilation of rat mesenteric arteries, which is possibly related to endothelium-derived relaxing factor (EDRF). In order to clarify whether or not the vasodilating effects of ET-3 are associated with EDRF, we examined the effects of L-NG-monomethyl arginine (L-NMMA), an analog of L-arginine, on low-dose ET-3 induced vasodilation of rat mesente-Hc arteries. Infusion of 50 microM L-NMMA inhibited the vasodilation induced by 10(-13) M ET-3 and rather elicited an increase in perfusion pressure, which itself was decreased by infusion of 150 microM L-arginine. In the presence of 50 microM L-NMMA, 10(-13) M ET-3 did not elicit any vasodilation of the mesenteric arteries preconstricted with NE, in which 150 microM L-arginine, but not D-arginine, caused considerable vasodilation. These data suggest that the vasodilating effects of low doses of ET-3 are associated with EDRF as an endothelium-derived nitric oxide.

The release of the substrate for xanthine oxidase in hypertensive patients was suppressed by angiotensin converting enzyme inhibitors and alpha1-blockers.

Objective Hyperuricemia is associated with the vascular injury of hypertension, and purine oxidation may play a pivotal role in this association, but the pathophysiology is not fully understood. We tested the hypothesis that in hypertensive patients, the excess amount of the purine metabolite, hypoxanthine, derived from skeletal muscles, would be oxidized by xanthine oxidase, leading to myogenic hyperuricemia as well as to impaired vascular resistance caused by oxygen radicals. Methods We investigated the production of hypoxanthione, the precursor of uric acid and substrate for xanthine oxidase, in hypertensive patients and found that skeletal muscles produced hypoxanthine in excess. We used the semi-ischemic forearm test to examine the release of hypoxanthine (ΔHX), ammonium (ΔAmm) and lactate (ΔLAC) from skeletal muscles in essential hypertensive patients before (UHT:n = 88) and after treatment with antihypertensive agents (THT:n = 37) in comparison to normotensive subjects (NT:n = 14). Results ΔHX, as well as ΔAmm and ΔLAC, were significantly higher in UHT and THT (P < 0.01) than in NT. This release of ΔHX from exercising skeletal muscles correlated significantly with the elevation of lactate in NT, UHT and THT (y = 0.209 + 0.031 x;R2 = 0.222, n = 139:P < 0.01). Administration of doxazosin (n = 4), bevantolol (n = 5) and alacepil (n = 8) for 1 month significantly suppressed the ratio of percentage changes in ΔHX by − 38.4 ± 55.3%, − 51.3 ± 47.3% and − 76.3 ± 52.2%, respectively (P < 0.05) but losartan (n = 3), atenolol (n = 7) and manidipine (n = 10) did not reduce the ratio of changes; on the contrary, they increased it in ΔHX by +188.2 ± 331%, +96.2 ± 192.2% and +42.6 ± 137.3%, respectively. The elevation of ΔHX after exercise correlated significantly with the serum concentration of uric acid at rest in untreated hypertensive patients (y = 0.194 − 0.255x;R2 = 0.185, n = 30:P < 0.05). The prevalence of reduction of both ΔHX and serum uric acid was significantly higher in the patients treated with alacepril, bevantolol and doxazosin (67%:P < 0.02) than in the patients treated with losartan, atenolol and manidipine (12%). Conclusions It is concluded that the skeletal muscles of hypertensive patients released ΔHX in excess by activation of muscle-type adenosine monophosphate (AMP) deaminase, depending on the degree of hypoxia. The modification of ΔHX by angiotensin-converting enzyme inhibitors and α1-blockers influenced the level of serum uric acid, suggesting that the skeletal muscles may be an important source of uric acid as well as of the substrate of xanthine oxidase in hypertension.

Effects of intravenous administration of a calcium antagonist on prostaglandins and thromboxane in plasma and urine in humans

The effects of a calcium antagonist [Nicardipine hydrochloride (NH)] on the prostaglandin [prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha)] and thromboxane B2 levels in the blood and urine were examined in 6 patients with essential hypertension following intravenous infusion of NH for 120 minutes. At the same time, the plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma and urinary electrolyte levels were also determined. During NH administration, the blood pressure was significantly decreased (p less than 0.05) with an increased pulse rate (p less than 0.05). PRA was significantly increased after NH loading (p less than 0.05) but PAC showed no change. The plasma PGE2 and 6-keto-PGF1 alpha levels tended to increase slightly, while the blood thromboxane B2 level showed a decreasing tendency. The 6-keto-PGF1 alpha to thromboxane B2 ratio was significantly increased after NH loading as compared to the preloading ratio (p less than 0.05), and then returned to the preloading value at about 30 minutes after discontinuation of NH loading. The urinary excretions of PGE2, 6-keto-PGF1 alpha and thromboxane B2, PGE2 and 6-keto-PGF1 alpha tended to decrease after NH loading. In particular, the decrease in PGE2 was statistically significant (p less than 0.05). No change occurred in the urinary excretion of thromboxane B2. The above findings indicate that NH increased the plasma 6-keto-PGF1 alpha to thromboxane B2 ratio but decreased the urinary excretion of prostaglandins. In addition, the possible involvement of an enhanced 6-keto-PGF1 alpha/thromboxane B2 ratio in part of the hypotensive mechanism of NH is suggested.

Enhancement effect of carteolol on the clonidine-induced vasodilation of rat mesenteric arteries

It has demonstrated that carteolol can increase the endothelium-dependent vasodilation induced by alpha-2 adrenergic agonist. In order to evaluate the effect of carteolol, and to clarify the mechanism, we examined the effects of 10 microM carteolol on the vasodilation induced by increasing doses (10(-7)-10(-4) M) of clonidine in perfused rat mesenteric arteries preconstricted with 100 microM phenylephrine. Clonidine elicited a dose-dependent vasodilation of the mesenteric arteries preconstricted with phenylephrine. Carteolol enhanced the vasodilation induced by higher doses (10(-5) and 10(-4) M) of clonidine, although carteolol itself exerted no direct vasodilating effect. On the other hand, 10 microM propranolol or 10 microM metoprolol did not augment the clonidine-induced vasodilation. In the presence of 100 microM NG-monomethyl L-arginine (LNMMA), an analogue of L-arginine, the enhancement of the clonidine-induced vasodilation by carteolol was abolished. This inhibition by LNMMA was restored with 300 microM L-arginine, but not with 300 microM D-arginine. These results suggest that carteolol enhances the clonidine-induced vasodilation by an endothelial-related mechanism mediated by the release of endothelium-derived nitric oxide in resistance vessels.

A comparative study on the effectiveness of losartan/hydrochlorothiazide and telmisartan/hydrochlorothiazide in patients with hypertension

Abstract Purpose: Long-term effects of a low-dose hydrochlorothiazide (HCTZ) with losartan (LOS) on uric acid (UA) metabolism as well as glucose metabolism have been studied in hypertensive patients in comparison with those of a low-dose HCTZ with telmisartan (TEL). Method: Fifty-nine hypertensive patients were allocated to a combination therapy with either losartan (50u2009mg/day)/HCTZ (12.5u2009mg/day) (LOSu2009+u2009HCTZ group: nu2009=u200937) or telmisartan (40u2009mg/day)/HCTZ (12.5u2009mg/day) (TELu2009+u2009HCTZ group: nu2009=u200922), respectively. Before and 1 year after the treatment, blood pressure and biochemical parameters of blood and urine were evaluated. Results: Both systolic and diastolic blood pressures significantly decreased in two groups, without any statistical differences among them. LOSu2009+u2009HCTZ caused no changes in the serum UA level or the ratio of UA clearance to creatinine clearance (CUA/Ccr), whereas TELu2009+u2009HCTZ significantly increased the serum UA level and reduced CUA/Ccr. LOSu2009+u2009HCTZ did not influence CUA/Ccr in patients with their serum UA below 5.4u2009mg/dl, while LOSu2009+u2009HCTZ significantly increased CUA/Ccr in patients with their serum UA above 5.5u2009mg/dl. TELu2009+u2009HCTZ significantly reduced CUA/Ccr in patients with their serum UA below and above 5.4u2009mg/dl to increase serum UA level significantly. Neither combination therapies caused any changes in fasting plasma glucose, HbA1c and HOMA-R. In patients with their serum UA level above 5.4u2009mg/dl, TELu2009+u2009HCTZ increased HOMA-R, whereas LOSu2009+u2009HCTZ did not. Conclusions: LOSu2009+u2009HCTZ did not influence UA metabolism as well as glucose metabolism, likely because of inhibitory action of losartan on URAT1, although TELu2009+u2009HCTZ were accompanied with impairment of the UA metabolism and glucose metabolism.

Effect of elastase on blood pressure and urinary excretions of prostaglandins and catecholamines in the spontaneously hypertensive rat (SHR)

The effects of elastase on blood pressure (B.P.) and the urinary excretions of prostaglandins (PGs) and catecholamines in the spontaneously hypertensive rat (SHR) were investigated. Male SHRs (n = 20), castrated at 4 weeks of age, were divided into 2 groups. Elastase was then dissolved in saline (5 mg/ml) and injected subcutaneously (10 mg/kg of body weight) into the SHRs of one of the 2 groups (n = 10) at 5 to 13 weeks of age, and the same dose of saline only was injected subcutaneously into the SHRs of the other group (n = 10) as a control during the same period. B.P. was measured by the tail-cuff method every 2 weeks. Urine sampling and measurement of body weight (B.Wt.) were also performed every 2 weeks. The B.P. in the elastase-administered group (184.1 +/- 3.3 mmHg) was found to be significantly lower (p less than 0.02) than that of the control group (198.0. +/- 4.3) at 9 weeks of age. A significant difference (p less than 0.01) in B.P. between the control group (204.0 +/- 4.5) and the elastase-administered group (187.3 +/- 2.7) was also observed at 13 weeks of age. The urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in the control group (5.1 +/- 0.4 ng/day/100 g B.Wt.) at 11 weeks of age was significantly lower (p less than 0.05) than that of the elastase-administered group (10.4 +/- 1.3).(ABSTRACT TRUNCATED AT 250 WORDS)