Comparative Effects of an Angiotensin II Receptor Blocker (ARB)/Diuretic vs. ARB/Calcium-Channel Blocker Combination on Uncontrolled Nocturnal Hypertension Evaluated by Information and Communication Technology-Based Nocturnal Home Blood Pressure Monitoring　- The NOCTURNE Study.

BACKGROUND: Nocturnal blood pressure (BP) is an independent risk factor of cardiovascular events. The NOCTURNE study, a multicenter, randomized controlled trial (RCT) using our recently developed information and communication technology (ICT) nocturnal home BP monitoring (HBPM) device, was performed to compare the nocturnal HBP-lowering effects of differential ARB-based combination therapies in 411 Japanese patients with nocturnal hypertension (HT).Methods and Results:Patients with nocturnal BP ≥120/70 mmHg at baseline even under ARB therapy (100 mg irbesartan daily) were enrolled. The ARB/CCB combination therapy (irbesartan 100 mg+amlodipine 5 mg) achieved a significantly greater reduction in nocturnal home systolic BP (primary endpoint) than the ARB/diuretic combination (daily irbesartan 100 mg+trichlormethiazide 1 mg) (-14.4 vs. -10.5 mmHg, P<0.0001), independently of urinary sodium excretion and/or nocturnal BP dipping status. However, the change in nocturnal home systolic BP was comparable among the post-hoc subgroups with higher salt sensitivity (diabetes, chronic kidney disease, and elderly patients). CONCLUSIONS: This is the first RCT demonstrating the feasibility of clinical assessment of nocturnal BP by ICT-nocturnal HBPM. The ARB/CCB combination was shown to be superior to ARB/diuretic in patients with uncontrolled nocturnal HT independently of sodium intake, despite the similar impact of the 2 combinations in patients with higher salt sensitivity.

Comparison of Azelnidipine and Trichlormethiazide in Japanese Type 2 Diabetic Patients with Hypertension: The COAT Randomized Controlled Trial.

OBJECTIVE: This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension. METHODS: In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups. RESULTS: Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period. CONCLUSIONS: Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension. TRIAL REGISTRATION: UMIN 000006081.

Combining irbesartan and trichlormethiazide enhances blood pressure reduction via inhibition of sympathetic activity without adverse effects on metabolism in hypertensive rats with metabolic syndrome.

Sympathoexcitation and oxidative stress in the brain have pivotal roles in hypertension with metabolic syndrome (MetS). Here, we examined whether oral administration of irbesartan (IRB) and trichlormethiazide (TCM) decreases blood pressure (BP) via inhibiting sympathetic activity through anti-oxidant effects in the brain of spontaneously hypertensive rats (SHR-cp). IRB/TCM treatment decreased BP more profoundly than IRB monotherapy. Urinary norepinephrine excretion and oxidative stress in the brain were decreased in both IRB and IRB/TCM groups without any adverse effect on the metabolic profile. These findings suggest that IRB/TCM profoundly decreases BP in SHR-cp by inhibiting sympathetic activity via anti-oxidant effects in the brain.

Successful conversion from thiazide to tolvaptan in a patient with stage d heart failure and chronic kidney disease before heart transplantation.

Chronic kidney disease (CKD) is often complicated with advanced heart failure because of not only renal congestion and decreased renal perfusion but also prolonged use of diuretics at higher doses, which sometimes results in hyponatremia. Preoperative CKD is known to be associated with poor prognosis after heart transplantation (HTx). We experienced a stage D heart failure patient with CKD and hyponatremia who was switched from trichlormethiazide to tolvaptan. His hyponatremia was normalized, and his renal function was improved after conversion to tolvaptan. In patients with stage D heart failure, it may be useful to administer tolvaptan with a concomitant reduction in the dose of diuretics in order to preserve renal function and avoid hyponatremia before HTx.

A novel compound heterozygous mutation of Gitelman's syndrome in Japan, as diagnosed by an extraordinary response of the fractional excretion rate of chloride in the trichlormethiazide loading test.

Gitelman's syndrome (GS), an inherited disorder due to loss of function of ion channels and transporters such as Na-Cl co-transporter (NCCT) in distal convoluted tubules, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hyperreninemic-hyperaldosteronism. A 39-year-old man was admitted to our hospital because of muscle weakness with such intractable disorders. We performed a thiazide-loading test, which revealed a poor response of the fractional excretion rate of chloride compared to healthy subjects. Based on these data, the clinical diagnosis of GS was made. Gene-sequencing analysis revealed compound heterozygous mutations of c.539C > A and c.1844C > T in SLC12A3, which is newly reported in Japanese GS.

Adverse effect profile of trichlormethiazide: a retrospective observational study.

BACKGROUND: Trichlormethiazide, a thiazide diuretic, was introduced in 1960 and remains one of the most frequently used diuretics for treating hypertension in Japan. While numerous clinical trials have indicated important side effects of thiazides, e.g., adverse effects on electrolytes and uric acid, very few data exist on serum electrolyte levels in patients with trichlormethiazide treatment. We performed a retrospective cohort study to assess the adverse effects of trichlormethiazide, focusing on serum electrolyte and uric acid levels. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2010, to identify cohorts of new trichlormethiazide users (n = 99 for 1 mg, n = 61 for 2 mg daily dosage) and an equal number of non-users (control). We used propensity-score matching to adjust for differences between users and control for each dosage, and compared serum chemical data including serum sodium, potassium, uric acid, creatinine and urea nitrogen. The mean exposure of trichlormethiazide of 1 mg and 2 mg users was 58 days and 64 days, respectively. RESULTS: The mean age was 66 years, and 55% of trichlormethiazide users of the 1 mg dose were female. In trichlormethiazide users of the 2 mg dose, the mean age was 68 years, and 43% of users were female. There were no statistically significant differences in all covariates (age, sex, comorbid diseases, past drugs, and current antihypertensive drugs) between trichlormethiazide users and controls for both doses. In trichlormethiazide users of the 2 mg dose, the reduction of serum potassium level and the elevation of serum uric acid level were significant compared with control, whereas changes of mean serum sodium, creatinine and urea nitrogen levels were not significant. In trichlormethiazide users of the 1 mg dose, all tests showed no statistically significant change from baseline to during the exposure period in comparison with control. CONCLUSIONS: Our study showed adverse effects of decreased serum potassium and increased serum uric acid with trichlormethiazide treatment, and suggested that a lower dose of trichlormethiazide may minimize these adverse effects. These findings support the current trend in hypertension therapeutics to shift towards lower doses of thiazides.

Combination therapy of calcium channel blocker and angiotensin II receptor blocker reduces augmentation index in hypertensive patients.

INTRODUCTION: The optimal combination treatment for hypertension has not been established. We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers (ARBs) on the augmentation index (AI), as a marker of arterial stiffness and wave reflection, in hypertensive patients. METHODS: Thirty-seven patients treated with ARBs were randomly allocated to either of the 2 groups receiving an ARB plus azelnidipine (AZ group) or trichlormethiazide (TCM group). Changes in brachial blood pressure (BP), AI, high-sensitive C-reactive protein (hsCRP), and serum asymmetric dimethylarginine, as an endogenous nitric oxide synthase inhibitor, were determined. RESULTS: Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly; however, after adjustment for baseline covariates, the extent of the reduction in AI (%) in the AZ group was significantly greater than in the TCM group (between-group difference was 3.2; 95%CI: 0.2-6.3; P = 0.03). The reduction of high-sensitive C-reactive protein (mg/L) and serum asymmetric dimethylarginine (micromol/L) was significantly greater in the AZ group than in the TCM group (between-group difference was 0.18 and 0.05; 95%CI: -0.01 to 0.36 and -0.01 to 0.11; P = 0.04 and 0.02, respectively). Further, when patients were analyzed according to age younger than 60 years or older than 60 years, the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group. CONCLUSION: The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide.

Comparison of effects of low dose of spironolactone and a thiazide diuretic in patients with hypertension treated with an angiotensin-converting enzyme inhibitor or an angiotensin type 1 receptor blocker.

This study was performed to investigate the additional anti-hypertensive effects and safety of low-dose thiazide diuretic, trichlormethiazide (TCTZ), and a mineralocorticoid receptor blocker, spironolactone (SPI), as add-on therapy in 64 patients whose blood pressure (BP) at office were over 140/90 mmHg, while receiving anti-hypertensive medication including an angiotensin-converting enzyme inhibitor or angiotensin II type I receptor antagonist. After 6 months, we observed a decrease of office and home BP. Moreover, urinary albumin excretion (UAE) was reduced in SPI-treated group, but not in the TCTZ-treated group. No significant change in serum potassium, lipids, glucose, or uric acid was observed. In conclusion, low-dose thiazide diuretic or SPI provided a significant additional anti-hypertensive effect in patients in whom hypertension was not controlled by medication, and SPI-reduced UAE.

Evaluation of arterial stiffness in morning hypertension under high-dose valsartan compared to valsartan plus low-dose diuretic.

Morning hypertension has been reported to be an important risk factor for cardiovascular events, and arterial stiffness bears a relationship with cardiovascular risk. The aim of this study was to evaluate whether high-dose angiotensin II receptor blocker (ARB) treatment has a more beneficial effect on arterial stiffness than regular-dose ARB plus low-dose diuretic treatment in patients with morning hypertension. Forty-three patients, in whom the home systolic blood pressure (BP) in the morning was higher than 140 mm Hg and in the evening was lower than 135 mm Hg, despite treatment with 80 mg valsartan, were randomly assigned to receive 160 mg valsartan (V group, n=22) or 80 mg valsartan plus low-dose trichlormethiazide (1 mg) (V+D group, n=21) for 6 months. There were no differences in the patient background characteristics between the two groups. There were no significant differences in BP measured at home between the two groups. The brachial-ankle pulse wave velocity (baPWV) at the time of diagnosis of morning hypertension was similar in the two groups; however, after 6 months of treatment, a greater degree of reduction of the baPWV and a greater degree of reduction of BP in the supine position were observed in the V group compared with the V+D group. Thus, though both high-dose valsartan and valsartan plus diuretic reduced the BP to a similar degree in patients with morning hypertension, high-dose valsartan exerted a greater beneficial effect on arterial stiffness than did valsartan plus diuretic.

Targeting AMPA receptor gating processes with allosteric modulators and mutations.

Allosteric modulators and mutations that slow AMPAR desensitization have additional effects on deactivation and agonist potency. We investigated whether these are independent actions or the natural consequence of slowing desensitization. Effects of cyclothiazide (CTZ), trichlormethiazide (TCM), and CX614 were compared at wild-type GluR1 and "nondesensitizing" GluR1-L497Y mutant receptors by patch-clamp recording with ultrafast perfusion. CTZ, TCM, or L/Y mutation all essentially blocked GluR1 desensitization; however, the effects of L/Y mutation on deactivation and glutamate EC50 were three to five times greater than for modulators. CTZ and TCM further slowed desensitization of L/Y mutant receptors but paradoxically accelerated deactivation and increased agonist EC50. Results indicate that CTZ and TCM target deactivation and agonist potency independently of desensitization, most likely by modifying agonist dissociation (koff). Conversely, CX614 slowed desensitization and deactivation without affecting EC50 in both wild-type and L/Y receptors. The S750Q or combined L497Y-S750Q mutations abolished all CTZ and TCM actions without disrupting CX614 activity. Notably, the S/Q mutation also restored L/Y deactivation and EC50 to wild-type levels without restoring desensitization, further demonstrating that desensitization can be modulated independently of deactivation and EC50 by mutagenesis and possibly by allosteric modulators.

Thiazide diuretics enhance nocturnal blood pressure fall and reduce proteinuria in immunoglobulin A nephropathy treated with angiotensin II modulators.

OBJECTIVE: We examined whether thiazide diuretics could restore nocturnal blood pressure (BP) decline and reduce urinary protein excretion in patients with glomerulopathy treated with angiotensin II modulators (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers). METHODS: Twenty-five Japanese outpatients (11 men, 14 women; mean age 43 +/- 12 years) with biopsy-proven immunoglobulin (Ig)A nephropathy, preserved renal function (serum creatinine concentration

Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH.

A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.

Influence of the angiotensin II receptor antagonist losartan on diuretic-induced metabolic effects in elderly hypertensive patients: comparison with a calcium channel blocker.

OBJECTIVE: Diuretic therapy frequently induces undesirable biochemical changes and side effects. We compared metabolic effects of a low-dose diuretic (D) given in combination with an angiotensin II receptor antagonist, losartan (L), with those resulting from a diuretic given in combination with a calcium channel blocker, slow-release nifedipine (N). MATERIAL AND METHODS: Thirty-seven elderly patients with mild to moderate hypertension (mean age: 71 +/- 3 years) were treated with either L+D (n = 18) or N+D (n = 19) for 1 year. Diuretic therapy included low-dose trichlormethiazide or low-dose furosemide in numbers of patients that were similar between L+D and N+D groups. Blood pressure, serum electrolytes, uric acid, blood glucose, renal function and lipid parameters were measured at baseline, 6 months and 1 year. RESULTS: Effective blood pressure control was observed in both groups at 6 months, and with further improvement at 1 year. Serum potassium was significantly decreased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but not in the L+D group. Serum uric acid was significantly increased from baseline at 6 months (p < 0.01) and 1 year (p < 0.01) in the N+D group, but had minimally decreased at 1 year in the L+D group (p < 0.1). Blood glucose, renal function and lipid parameters did not change in either group. CONCLUSION: The combination of losartan and low-dose diuretics effectively treated hypertension in elderly patients while minimizing the metabolic consequences of diuretic therapy. Larger trials will be necessary to confirm this finding.

Characterization of the antihypertensive effect of a thiazide diuretic in angiotensin II-induced hypertension.

OBJECTIVES: The antihypertensive effect of thiazide diuretics in angiotensin II induced hypertension has never been characterized. In the current study, we sought to determine the effect of a thiazide diuretic on arterial pressure and renal fluid excretion in rats receiving a chronic intravenous infusion of angiotensin II while on fixed normal or high sodium intakes. DESIGN AND METHODS: Male rats were chronically instrumented with arterial and venous catheters for drug injection and direct daily measurements of blood pressure and heart rate. Rats were maintained on high salt intake (HS), 6 mEq/day, or on normal salt intake (NS), 2 mEq/day. Rats were randomly assigned to four groups: HS and NS with 15 day angiotensin II infusion (5 ng/min) and HS and NS without angiotensin II infusion. Trichlormethiazide (TCM), a thiazide diuretic, was orally administered, approximately 10 mg/kg per day, for the middle 5 days of angiotensin II infusion. RESULTS: Only HS rats receiving angiotensin II infusion became hypertensive. Angiotensin II infusion did not produce changes in heart rate, sodium balance or water balance. Chronic administration of TCM significantly reduced mean arterial pressure (MAP) within 24 h in HS rats receiving angiotensin II, but did not affect MAP in any other group. TCM produced a similar loss of Na+ and water in all rats. Blood volumes and plasma electrolytes did not change during the study. CONCLUSIONS: The antihypertensive effects of thiazide diuretics are not due exclusively to volume depletion. We propose that salt and water loss caused by TCM may lower MAP by impairment of salt-sensitive pressor mechanisms activated by angiotensin II.

New oral dosage form for elderly patients. III. Stability of trichlormethiazide in silk fibroin gel and various sugar solutions.

The hydrolysis of trichlormethiazide (TCM) in silk fibroin gel (SFG) prepared in various sugar solutions (such as ribose, fructose, mannose, and glucose solutions) was determined. The hydrolysis rate of TCM differed with the variety of sugars utilized in this study; that is, it decreased in the following order: ribose > fructose > mannose > glucose. To investigate the relationship between the hydrolysis rate of TCM and the physicochemical properties of the sugar molecule, the amount of unfrozen water of sugar molecules was calculated from differential scanning calorimetry (DSC). The amount of unfrozen water increased with an increase in the number of the equatorial OH groups n(e-OH) per sugar molecule that are able to hydrate favorably to the surrounding water molecules. The hydrolysis rate constant decreased with increase in n(e-OH); glucose, having a large n(e-OH) in this study could effectively stabilize TCM.

Long-term evaluation of combined antihypertensive therapy with lisinopril and a thiazide diuretic in patients with essential hypertension.

For the treatment of hypertension, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic is supported by multiple lines of evidence, because these drugs have synergistic action and are expected to cancel out each other's adverse side effects. However, the long-term outcome of this combination antihypertensive therapy is not entirely clear. In the present multicenter open trial, we investigated the long-term efficacy and safety of combined antihypertensive therapy with an ACE inhibitor, lisinopril, and a thiazide diuretic, trichlormethiazide. A total of 466 patients with essential hypertension were treated with lisinopril alone (monotherapy group, n = 360) or with a combination of lisinopril with trichlormethiazide (combination therapy group, n = 106) for 1 year. The average blood pressure was effectively lowered to below 150/90 mmHg in both the monotherapy and the combination therapy groups throughout the study period. The average maintenance dose of lisinopril was lower when combined with thiazide than when given alone (9.8 vs. 11.5 mg/day, p < 0.001). Dry cough was the major side effect of lisinopril; no severe adverse effects were observed. The incidence of cough was not significantly different between the monotherapy group (13.1%) and the combination therapy group (11.3%). The increase in serum potassium observed in the monotherapy group was reversed by the concurrent use of the thiazide diuretic in the combination therapy group. Fasting blood glucose was significantly reduced in the monotherapy group; the reduction observed in the combination therapy group was not significant. Thus, the present results provide useful information as to the effectiveness and safety of combined antihypertensive therapy with lisinopril and a thiazide in comparison with monotherapy with lisinopril.

Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide.

RESULTS: Incubation in vitro of human recombinant and erythrocyte (RBC) thiopurine methyl transferase (TPMT) with furosemide, bendroflumethiazide and trichlormethiazide demonstrated inhibition of both enzyme preparations, with IC50 values of 170 microM, 360 microM and 1 mM, respectively. Kinetic studies revealed that the inhibition was mixed or non-competitive with regard both to the thiopurine substrate 6-mercaptopurine (6-MP) and the methyl donor S-adenosyl-L-methionine. CONCLUSION: Since S-methylation is a major pathway in the metabolism of thiopurines, our data point to the possibility of a clinically significant diuretic-thiopurine interaction in patients treated simultaneously with these drugs.

Hypotensive effects of a new transdermal delivery system for clonidine (M-5041T) in spontaneously and renal hypertensive rats.

1. Antihypertensive effects of a new transdermal delivery system for clonidine (clonidine tape; M-50417) were investigated in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip renal hypertensive rats (RHR) and deoxycorticosterone acetate/salt (DOCA/Salt) hypertensive rats. 2. M-5041T (0.5-4.5 mg/kg) elicited long-lasting hypotensive effects and bradycardia in a dose-dependent manner during 24 h patching in three hypertensive models compared with oral clonidine (100 mu g/kg). 3. The most hypotensive effect of M-5041T was observed in DOCA/salt hypertensive rats. 4. Co-administration of M-5041T with either trichloromethiazide (1 mg/kg, orally) or nifedipine (3 mg/kg, orally) at each dose without hypotensive effects per se induced significant hypotension in SHR. 5. Repeated administrations of M-5041T (1.5 mg/kg per day) for a consecutive 7 days produced significant hypotensive effects at postpatching 6 h, and recovered a postpatching 24 h in SHR. 6. Repetitive M-5041T administrations displayed no tolerance on the hypotensive effects and were devoid of any withdrawal syndrome. 7. These findings suggest that M-5041T may serve as an efficiently useful antihypertensive transdermal delivery system in humans.

Antihypertensive effects of a novel calcium antagonist, semotiadil fumarate (SD-3211), alone and in combination with enalapril or trichlormethiazide in spontaneously hypertensive rats.

Semotiadil fumarate, a novel benzothiazine calcium antagonist, was given alone or in combination with either enalapril or trichlormethiazide to conscious, spontaneously hypertensive, rats daily for 2 weeks. Systolic blood pressure and heart rate were recorded 24 h before the start of the regimen and then every 2 and 24 h after the 1st, 3rd, 7th, 10th and 14th doses. When given alone, the antihypertensive effects of semotiadil (10 mg/kg, p.o.) and enalapril (5 mg/kg, p.o.) first became apparent after the 3rd dose and thereafter the effects appeared to develop daily although this effect had waned by the time of the next dose. When given in combination, however, these drugs appeared to potentiate each other and after the 7th dose, the antihypertensive effect persisted. Trichlormethiazide (30 mg/kg, p.o.) alone failed to exert any significant antihypertensive effect and in combination was not always additive to that of semotiadil. In contrast to the effect on blood pressure, the heart rate remained resistant to all these drugs. These results indicate that combined daily dosing of semotiadil, especially with enalapril, each at relatively low doses may be able to control hypertension in a continuous manner.

Protective effects of KW-3902, a novel adenosine A1-receptor antagonist, against gentamicin-induced acute renal failure in rats.

We investigated the possible renal protective effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), an adenosine A1-receptor antagonist, against gentamicin (GM)-induced acute renal failure (ARF) in rats. ARF was induced by subcutaneous injection of GM at 80 mg/kg/day for 12 days. KW-3902 (0.001-0.1 mg/kg, p.o., twice daily) attenuated the increases of serum creatinine and urea nitrogen and the decrease of creatinine clearance in rats treated with GM. In contrast, furosemide and trichlormethiazide aggravated the GM-induced nephrotoxicity. These results suggest that KW-3902 can ameliorate the GM-induced ARF and that endogenous adenosine may be involved in GM-induced ARF via the adenosine A1-receptor.