dihydropyridines and Hypertension--Renal

The calcium (Ca2+) channel antagonists (CCA) are used successfully in the treatment of hypertension and angina pectoris. Their mode of action is to decrease Ca2+ entry in the vascular smooth muscle cells. Their molecular targets are voltage activated Ca2+ channels (VACC), especially the L-type (VACC-L). This review examines the role of the VACC-L and of the T-type (VACC-T) in vascular physiology and hypertension. The molecular mechanisms at the base of the vascular selectivity of CCA are presented with, in filigree, the concern of trying to understand the effect of recently developed molecules. In particular, we will examine the ideas having recently emerged concerning the mode of action of last generation dihydropyridines (DHPs) stripped of some of the undesirable effects of prototypes AC considered as highly specific of the VACC-L. These properties could result, in particular, from their effects on the VACC-T, which could occur in addition to those classically observed on the VACC-L.

Topics: Animal Experimentation; Animals; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cells, Cultured; Dihydropyridines; Electrophysiology; Humans; Hypertension; Hypertension, Renal; Kidney Glomerulus; Mice; Muscle Cells; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Rats; Vasoconstriction

Calcium channel antagonists have a well-established role in the management of cardiovascular diseases. L-type calcium channels in vascular cells are a key therapeutic target in hypertension and are the preferred molecular target of the initial calcium channel antagonists. However, third-generation dihydropyridine (DHP) calcium channel antagonists, including manidipine, nilvadipine, benidipine and efonidipine, appear to have effects in addition to blockade of the L-type calcium channel. Voltage-gated calcium channels are widely expressed throughout the cardiovascular system. They constitute the main route for calcium entry, essential for the maintenance of contraction. Cardiac and vascular cells predominantly express L-type calcium channels. More recently, T-type channels have been discovered, and there is emerging evidence of their significance in the regulation of arterial resistance. A lack of functional expression of L-type channels in renal efferent arterioles may be consistent with an important role of T-type channels in the regulation of efferent arteriolar tone. Although the exact role of T-type calcium channels in vascular beds remains to be determined, they could be associated with gene-activated cell replication and growth during pathology. The three major classes of calcium channel antagonists are chemically distinct, and exhibit different functional effects depending on their biophysical, conformation-dependent interactions with the L-type calcium channel. The DHPs are more potent vasodilators, and generally have less cardiodepressant activity than representatives of other classes of calcium channel antagonist such as diltiazem (a phenylalkylamine) and verapamil (a benzothiazepine). In contrast to older calcium channel antagonists, the newer DHPs, manidipine, nilvadipine, benidipine and efonidipine, dilate not only afferent but also efferent renal arterioles, a potentially beneficial effect that may improve glomerular hypertension and provide renoprotection. The underlying mechanisms for the heterogenous effects of calcium channel antagonists in the renal microvasculature are unclear. A credible hypothesis suggests a contribution of T-type calcium channels to efferent arteriolar tone, and that manidipine, nilvadipine and efonidipine inhibit both L and T-type channels. However, other mechanisms, including an effect on neuronal P/Q-type calcium channels (recently detected in arterioles), the microheterogeneity of vascular beds, and other types o

Topics: Animals; Antihypertensive Agents; Arteries; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, P-Type; Calcium Channels, T-Type; Cardiovascular Diseases; Dihydropyridines; Humans; Hypertension, Renal; Ion Channel Gating; Kidney Glomerulus; Muscle Contraction; Muscle, Smooth, Vascular; Nitrobenzenes; Piperazines; Renal Circulation

Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Complications; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Hypertension, Renal; Kidney; Nitrobenzenes; Piperazines; Proteinuria; Randomized Controlled Trials as Topic; Renal Circulation

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Hypertension, Renal; Indoles; Losartan; Nephrosclerosis

Numerous studies suggest that the dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) have differential antiproteinuric effects. Proteinuria reduction is a correlate of the progression of renal disease. In an earlier systematic review, calcium antagonists were shown as effective antihypertensive drugs, but there was uncertainty about their renal benefits in patients with proteinuria and renal insufficiency.. A systematic review was conducted to assess the differential effects of DCAs and NDCAs on proteinuria in hypertensive adults with proteinuria, with or without diabetes, and to determine whether these differential effects translate into altered progression of nephropathy. Studies included in the review had to be randomized clinical trials with at least 6 months of treatment, include a DCA or NDCA treatment arm, have one or more renal end points, and have been initiated after 1986. Summary data were extracted from 28 studies entered into two identical but separate databases, which were compared and evaluated by independent reviewers. The effects of each drug class on blood pressure (N= 1338) and proteinuria (N= 510) were assessed.. After adjusting for sample size, study length, and baseline value, there were no statistically significant differences in the ability of either class of calcium antagonist to decrease blood pressure. The mean change in proteinuria was +2% for DCAs and -30% for NDCAs (95% CI, 10% to 54%, P= 0.01). Consistently greater reductions in proteinuria were associated with the use of NDCAs compared with DCAs, despite no significant differences in blood pressure reduction or presence of diabetes.. This analysis supports (1) similar efficacy between subclasses of calcium antagonists to lower blood pressure, and (2) greater reductions in proteinuria by NDCAs compared to DCAs in the presence or absence of diabetes. Based on these findings, NDCAs, alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), are suggested as preferred agents to lower blood pressure in hypertensive patients with nephropathy associated with proteinuria.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension, Renal; Proteinuria

Calcium channel blockers are used in the treatment of hypertension because of their ability to decrease peripheral vascular resistance. Recent research has suggested that these drugs also preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease, and in renal transplant recipients with or without cyclosporin therapy. In general, studies in animal models of hypertension and in hypertensive humans have demonstrated reduction in renal vascular resistance, and preservation or enhancement of renal plasma flow and glomerular filtration rate. In addition, calcium channel blockers appear to have a positive effect on renal addition, calcium channel blockers appear to have a positive effect on renal haemodynamic function in the setting of diabetes mellitus; prospective trials have also demonstrated reductions in urinary protein excretion in these patients. Current evidence suggests that calcium channel blockers are well-suited for the treatment of patients with hypertensive disease even in the presence of renal impairment, a clinical scenario common in the elderly population.

Topics: Aging; Animals; Calcium Channel Blockers; Clinical Trials as Topic; Cyclosporine; Diabetic Nephropathies; Dihydropyridines; Diltiazem; Disease Models, Animal; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Transplantation; Rats; Rats, Inbred SHR; Verapamil

This study assessed the urinary albumin/creatinine ratio (ACR) and uric acid metabolism in 70 hypertensive patients with chronic kidney disease in whom urinary ACR had remained ≥30 mg/g under the treatment of the L-type calcium channel blocker amlodipine. Three months after switching to the N/L-type calcium channel blocker cilnidipine, blood pressure (BP) did not change; however, urinary ACR significantly decreased with cilnidipine. Serum uric acid levels showed no significant change. In cases where uric acid production had been high (urinary uric acid/creatinine ratio ≥0.5), the urinary uric acid/creatinine ratio decreased significantly after cilnidipine treatment, suggesting that cilnidipine can suppress excessive uric acid formation. These results suggest that switching from amlodipine to cilnidipine results in a significant reduction in urinary ACR as well as significant reduction in uric acid production. Thus, cilnidipine is more useful than amlodipine in improving albuminuria and uric acid metabolism in hypertensive patients with chronic kidney disease.

Topics: Aged; Aged, 80 and over; Albuminuria; Amlodipine; Blood Pressure; Calcium Channel Blockers; Creatinine; Cross-Over Studies; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Drug Substitution; Female; Humans; Hypertension, Renal; Japan; Kidney Failure, Chronic; Male; Middle Aged; Nephrosclerosis; Uric Acid

We conducted a multicenter, randomized, open-label, ascending dose study to investigate the efficacy and safety of combination therapy using the calcium channel blocker azelnidipine and angiotensin-converting enzyme (ACE) inhibitor temocapril in hypertensive diabetics. Patients received monotherapy with 8 mg azelnidipine (group A, n=112) or 2 mg temocapril (group T, n=111) for 4 weeks. If the target blood pressure (<130/80 mmHg) was not achieved, doses were doubled. If it was still not achieved, both drugs were coadministered at week 8, and, if needed, another antihypertensive drug was added after week 16. The treatment period was 52 weeks. Blood pressure was decreased significantly beginning at week 8 (p<0.0001 in both groups), and the systolic and diastolic blood pressure at the end of the treatment period was 128.2+/-11.1/76.4+/-8.1 mmHg. Overall, 53.8% (113/210) of patients achieved the target blood pressure by the end of the study. The effect during the monotherapy period (through week 8) was greater in group A than in group T (systolic, p=0.0475; diastolic, p=0.0001). Laboratory tests showed significant decreases in the urine albumin:creatinine ratio (p=0.0006), high-sensitivity C-reactive protein concentration (p=0.0073), and urine 8-isoprostane concentration (p=0.0215) at the end of the treatment period, as compared with baseline values. No adverse events caused safety problems. In conclusion, combination therapy using azelnidipine and temocapril is an effective treatment for hypertensive diabetics.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Azetidinecarboxylic Acid; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension, Renal; Kidney Function Tests; Lipids; Male; Middle Aged; Thiazepines; Treatment Outcome

Recent studies have shown that metabolic syndrome is associated with an increased risk for chronic kidney disease. We recently found that the prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than that in patients with essential hypertension but without metabolic syndrome. We therefore assessed the effects of benidipine, a long-acting calcium channel blocker, on the sodium sensitivity of blood pressure and renal hemodymamics in 5 patients with metabolic syndrome. Glomerular hemodynamics were assessed using pressure-natriuresis curves, which were constructed by plotting the urinary excretion of sodium as a function of the mean arterial pressure, which was calculated as the mean of 48 values based on 24-h monitoring, during the intake of low (3 g NaCl daily) and relatively high (10 g NaCl daily) sodium diets. Under the relatively high sodium diet condition, benidipine significantly lowered systolic and diastolic blood pressure. The pressure-natriuresis curve was steeper after the administration of benidipine. Benidipine lowered glomerular capillary hydraulic pressure (P(GC)) levels (from 54.4+/-7.5 to 47.0+/-7.0 mmHg, p=0.0152) and reduced both the resistance of the afferent arterioles (from 10,338+/-2,618 to 9,026+/-2,627 dyn.s/cm5, p=0.047) and the resistance of the efferent arterioles (from 4,649+/-2,039 to 2,419+/-2,081 dyn.s/cm(5), p=0.003). The urinary albumin excretion rate also decreased after the administration of benidipine. These findings indicated that benidipine may be effective for reducing the risk of developing chronic kidney disease in patients with metabolic syndrome.

Topics: Albuminuria; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension, Renal; Kidney Glomerulus; Male; Metabolic Syndrome; Middle Aged; Renal Circulation; Treatment Outcome

Cilnidipine, a dual L-/N-type calcium channel blocker, dilates both efferent and afferent arterioles and is renoprotective. Our multi-center, open-labeled, and randomized trial compared the antiproteinuric effect of cilnidipine with that of amlodipine in hypertensive patients with kidney disease. A group of 339 patients, already receiving renin-angiotensin system inhibitor treatment, were randomly assigned to cilnidipine or amlodipine. The primary endpoint was a decrease in the urinary protein to creatinine ratio. After 1-year of treatment, systolic and diastolic blood pressures were significantly reduced in both groups which did not differ between them. The urinary protein to creatinine ratio significantly decreased in the cilnidipine compared to the amlodipine group. Cilnidipine exerted a greater antiproteinuric effect than amlodipine even in the subgroup whose blood pressure fell below the target level. This study suggests that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients when coupled with a renin-angiotensin system inhibitor.

Topics: Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Creatinine; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension, Renal; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Renin-Angiotensin System; Treatment Outcome

Unlike other dihydropyridine calcium channel blockers (CCBs), cilnidipine has been reported to exert an N-type calcium-channel-blocking activity and to reduce sympathetic hyperactivity. This study compared cilnidipine and amlodipine with respect to their effects on renal function and proteinuria. Twenty-eight proteinuric hypertensive outpatients (13 men and 15 women, aged 62+/-2 years) who had been maintained on CCBs for more than 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients). CCBs were increased in dosage or other drugs were added until blood pressure decreased below 140/90 mmHg, but no inhibitors of the renin-angiotensin (RA) system were added or changed in dosage. Before and at 6 and 12 months after randomization, the concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum beta2-microglobulin were determined. The amlodipine group showed a significant increase in proteinuria, while the increase was suppressed in the cilnidipine group. The rate of increase in proteinuria at 12 months was 87% (95% confidence interval (CI) -10 to 184) of the baseline value with amlodipine and 4% (95% CI -69 to 77) of baseline with cilnidipine, a significant intergroup difference (p<0.05). The mean blood pressure remained in the 96-99 mmHg range until 12 months after randomization, showing no significant difference between the two groups. The cilnidipine group showed an increase in serum Cr levels (baseline vs. 12 months, 1.36+/-0.20 vs. 1.50+/-0.23 mg/dl, p<0.01). Overall, an inverse correlation existed between the changes in Cr and proteinuria (r= -0.477, p<0.01). These results suggest that cilnidipine results in a greater suppression of the increase in proteinuria and greater reduction in glomerular filtration rate than amlodipine, and that these effects are similar between cilnidipine and RA inhibitors. However, additional large-cohort and longer-term studies will be needed to clarify whether cilnidipine is superior to other CCBs in maintaining renal function.

Topics: Aged; Amlodipine; Calcium Channel Blockers; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Female; Humans; Hypertension, Renal; Logistic Models; Male; Middle Aged; Proteinuria; Treatment Outcome

To investigate whether calcium antagonists are nephroprotective in hypertensive cyclosporine-treated renal allograft recipients.. We studied 50 hypertensive and 17 normotensive renal transplants (eight females, nine males; 14-54 years, mean age 38.8 +/- 3.5 years). Hypertensive patients were randomized to be treated with (+Ca; 11 females, 13 males; 20-65 years, mean age 43.1 +/- 3 years) or without (-Ca; 15 females, 11 males; 25-60 years, mean age 41.3 +/- 2.5 years) a calcium antagonist (nitrendipine or nifedipine). Additional antihypertensives were given stepwise according to a standardized protocol: beta1-adrenoceptor blocker, diuretic alpha1-adrenoceptor blocker or vasodilator. Data were analysed at 0, 1, 2 and 3 years on an intention-to-treat basis.. Hypertensive patients had a higher body mass index at 0/3 years (23.7 +/- 0.6/25.1 +/- 0.6 kg/m2) than normotensive patients (22.2 +/- 0.6/22.1 +/- 0.7 kg/m2). During the study, blood pressure in normotensive transplants was always slightly, but not significantly, lower than that of transplants with treated hypertension. There was no difference between the groups (+Ca) and (-Ca). Cr51-ethylenediaminetetracetic acid (EDTA) clearance (0/2 years) was 58 +/- 4/57 +/- 6 ml/min in normotensives, 52 +/- 4/47 +/- 4 ml/min in hypertensives (+Ca) and 47 +/- 4/49 +/- 6 ml/min in hypertensives (-Ca). Proteinuria (0/3 years) was 0.16 +/- 0.04/0.15 +/- 0.02 g/24 h in normotensive, 0.26 +/- 0.08/0.23 +/- 0.05 g/24 h in hypertensives (+Ca) and 0.26 +/- 0.07/0.22 +/- 0.05 g/24 h in hypertensives (-Ca).. Post-transplant hypertension is associated with higher body mass index and poor renal function. No difference in the course of Cr51-EDTA clearance, serum creatinine, proteinuria or blood pressure was observed between groups treated with or without calcium antagonists. Calcium antagonists and conventional antihypertensive treatment have the same nephroprotective effect in hypertensive renal transplants, when treatment is started 3 months after transplantation.

Topics: Adult; Aged; Blood Pressure; Body Mass Index; Calcium Channel Blockers; Cyclosporine; Dihydropyridines; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Proteinuria

The effect of the calcium channel blocker azelnidipine on the redox status of a murine hypertension model was analyzed and imaged using in vivo low frequency electron paramagnetic resonance (EPR). A murine two kidney-one clip (2K1C) hypertension model was produced by a clipping of the right renal artery. The resulting hypertensive mice were treated with low-dose azelnidipine (1 mg/kg/d), with high-dose azelnidipine (3 mg/kg/d) or without azelnidipine (HT group). An EPR system equipped with a loop-gap resonator and an imaging system was employed. Redox status was evaluated as organ reducing activity measured by means of the decay rate (half-lives) of the spin probe 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (Carbamoyl-PROXYL). Four weeks after clipping the mice demonstrated hypertension as expected. After the additional 2 weeks of azelnidipine treatments, the Carbamoyl-PROXYL half-lives of the Low and High azelnidipine groups measured in the upper abdominal area were significantly shorter than those of the HT group, suggesting improvements in the reducing activity. The blood pressures of the three groups showed no significant differences at this time, and there was no correlation between the renal reducing activity and either blood pressure or serum creatinine values. EPR imaging studies revealed that the improvement in abdominal reducing activity was mainly recognized in the kidney but not in the liver. These results indicate that azelnidipine ameliorates renal redox status through an improvement in reducing activity independent of blood pressure control.

Topics: Animals; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Hypertension, Renal; Kidney; Male; Mice; Mice, Inbred ICR; Oxidation-Reduction; Oxidative Stress

We have known that endothelial nitric-oxide synthase (eNOS) and oxidative stress may play a key role in cardiac performance in failing rat hearts. However, the interactions between eNOS or oxidative stress and bradykinin (BK) under treatment of calcium channel blockers (CCBs) remain unknown. To elucidate the mechanism underlying the cardioprotective effect of long-acting dihydropyridine CCBs, we evaluated the effect of benidipine on the BK-eNOS and NAD(P)H oxidase pathway in Dahl salt-sensitive (DS) rats with heart failure.. 11-week-old DS rats were treated with one of the following drug combinations for 7 weeks until the onset of the failing stage: vehicle, BK B2 receptor antagonist (FR172357 (FR)) alone, hydralazine, benidipine, and benidipine plus FR. The left ventricular end-systolic pressure-volume relationship (ESPVR) (contractility: Ees) was evaluated using a conductance catheter.. Downregulated Ees and per cent of fractional shortening (%FS) assessed by echocardiography and eNOS expression in the failing stage were both significantly increased by using benidipine; this result was not found, however, when using FR alone or hydralazine or benidipine plus FR. Upregulated expression of NAD(P)H oxidase p22phox and p47phox and lectin-like oxidized low-density lipoprotein receptor-1, and downregulated superoxide dismutase-1 (SOD-1) were significantly ameliorated by benidipine, but not by FR alone or by hydralazine or benidipine plus FR. Benidipine effectively inhibited vascular lesion formation and suppressed atrial natriuretic peptide (ANP) and transforming growth factor-beta1 (TGF-beta1), but this was not the case when using FR alone or hydralazine or benidipine plus FR.. These results suggest that benidipine may be useful for cardioprotective agents in preventing the cardiac dysfunction and remodeling associated with the BK-eNOS and oxidative stress pathway.

Topics: Animals; Atrial Natriuretic Factor; Cardiotonic Agents; Collagen Type I; Dihydropyridines; Gene Expression; Heart Failure; Hypertension, Renal; Intercellular Adhesion Molecule-1; Myosin Heavy Chains; NADPH Oxidases; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Inbred Dahl; Scavenger Receptors, Class E; Superoxide Dismutase; Superoxide Dismutase-1; Transcription Factor RelA; Transforming Growth Factor beta1; Vascular Cell Adhesion Molecule-1; Vasodilator Agents; Ventricular Function; Ventricular Remodeling

The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress progressive renal disease in a variety of experimental models, but the characteristic effects of N-type calcium channel blocking action on renal injury have not been examined in detail. Therefore, we investigated the beneficial effects of cilnidipine on renal injury in Dahl salt-sensitive (Dahl S) rats fed a high-sucrose diet (HSD), which mimics metabolic syndrome, and compared them with the effects of an L-type CCB, amlodipine.. Male Dahl S rats were divided into groups with similar blood pressure at 8 weeks of age and fed an HSD. They received vehicle, cilnidipine or amlodipine for 27 weeks. At 35 weeks of age, urine and blood samples were collected for physiological analysis, and the kidneys were removed for histopathological evaluation.. Cilnidipine reduced albuminuria, glomerular hypertrophy, glomerular expression of ICAM-1, ED-1-positive cell infiltration and interstitial fibrosis compared with vehicle-treated rats. In contrast, amlodipine had no effect on these parameters. Urinary norepinephrine excretion, renal expression of renin mRNA and renal tissue levels of angiotensin II were increased only in the amlodipine-treated group.. Cilnidipine provided superior protection against renal damage compared with amlodipine in Dahl S rats given an HSD. The different effects between these two drugs may be partly explained by their different actions on the renal sympathetic nerve activity and the renin-angiotensin system through the N-type calcium channel blocking action.

Topics: Amlodipine; Animals; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dietary Sucrose; Dihydropyridines; Disease Models, Animal; Hypertension, Renal; Kidney Diseases; Male; Metabolic Syndrome; Rats; Rats, Inbred Dahl; Treatment Outcome

We examined the effects of the angiotensin II type 1 receptor blocker candesartan, the calcium channel blockers benidipine and amlodipine, hydralazine, and the combination of candesartan and benidipine or amlodipine on blood pressure and renal function in Dahl salt-sensitive (DS) hypertensive rats. Male DS rats (5 weeks of age) were fed a high-salt (8% NaCl) diet, resulting in hypertension accompanied by glomerular sclerosis and an increased urinary albumin excretion. Drugs were orally administered from 2 to 6 weeks after the start of the feeding. Although candesartan (1 or 10 mg/kg) had little effect on the blood pressure, benidipine (4 mg/kg), amlodipine (4 mg/kg) and hydralazine (5 mg/kg) had similar hypotensive effects. Benidipine, but not amlodipine, hydralazine, or candesartan, significantly inhibited the increase in the albuminuria and glomerular sclerosis. The combination of candesartan (1 mg/kg) and benidipine (4 mg/kg) lowered the levels of blood pressure and albuminuria more effectively than the combination of candesartan (1 mg/kg) and amlodipine (4 mg/kg). These results indicate that benidipine is effective in preventing the impairment of renal function in DS hypertensive rats, and suggest that additional benefits can be expected by combination therapy with benidipine and an angiotensin II type 1 receptor blocker.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Dihydropyridines; Drug Therapy, Combination; Hypertension, Renal; Kidney; Male; Rats; Rats, Inbred Dahl; Tetrazoles

Efonidipine, a calcium antagonist, has been reported to dilate not only afferent but also efferent arterioles, thereby reducing glomerular hydrostatic pressure. We investigated the effect of chronic treatment with efonidipine or lisinopril on the afferent and efferent arteriolar diameters by the vascular cast technique. Four-week-old spontaneously hypertensive rats (SHR) were divided into three groups: untreated, efonidipine (25 mg/kg/day)-treated, and lisinopril (3 mg/kg/day)-treated. At 22 weeks of age, the renal vasculatures were fixed at the maximally dilated condition. The morphometrical measurements showed that the treatments with efonidipine and lisinopril caused structural alteration of the vasculature, resulting in significantly greater efferent arteriolar diameters than in untreated SHR. In addition, lisinopril-treated rats had wider afferent lumina. The renoprotective effect of efonidipine and lisinopril might be partly due to the structurally larger efferent arteriolar lumen.

Topics: Animals; Arterioles; Blood Pressure; Body Weight; Calcium Channel Blockers; Corrosion Casting; Dihydropyridines; Hypertension, Renal; Kidney Glomerulus; Male; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Renal Circulation

Through the use of microanatomic techniques, we investigated the effects of treatment with some dihydropyridine-type calcium antagonists (CAs) (ie, lercanidipine, manidipine, and nicardipine) and with the nondihydropyridine-type vasodilator hydralazine on hypertension-dependent glomerular injury and on the morphology of afferent and efferent arterioles in spontaneously hypertensive rats (SHR). Fourteen-week-old male SHR and age-matched normotensive Wistar-Kyoto rats were left untreated (control groups). Four additional groups of 14-week-old SHR were treated for 12 weeks with daily oral doses of 2.5 mg/kg lercanidipine, 5 mg/kg manidipine, 3 mg/kg nicardipine, or 10 mg/kg hydralazine. These treatments decreased systolic blood pressure values to a similar extent in SHR. Signs of glomerular injury, as characterized by glomerulosclerosis, hypertrophy, and an increased number of mesangial cells, were observed in control SHR. The treatment with CAs improved glomerular morphology and decreased the number of mesangial cells. Lercanidipine and manidipine were more effective than nicardipine in countering glomerular injury. In the SHR, both afferent and efferent arterioles revealed luminal narrowing, accompanied by increased wall thickness in efferent arterioles. The dihydropyridine-type derivatives that were tested decreased the luminal narrowing of afferent arterioles. Lercanidipine and manidipine countered the luminal narrowing of efferent arterioles. Hydralazine had no effect on hypertension-dependent glomerular injury or vascular changes. The present data indicate that lercanidipine and manidipine vasodilate afferent and efferent arterioles in SHR. A vasodilatory activity on efferent arteriole, which is not induced by the majority of CAs, may represent an useful property in the treatment of hypertension complicated by renal disease.

Topics: Albuminuria; Animals; Arterioles; Calcium; Calcium Channel Blockers; Dihydropyridines; Hydralazine; Hypertension, Renal; Juxtaglomerular Apparatus; Male; Nicardipine; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Vasodilator Agents

The pharmacologic characterization of FR172516, a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent, was studied and compared with amlodipine in receptor-binding assay and in vivo studies. In the binding assay, Ki values of FR172516 for calcium channel and beta-receptor were 29.3 nM and 44.1 nM, respectively. In the in vivo studies with pithed rats, FR172516 shifted the dose-response curves of isoproterenol in heart rate to the right, suggesting that this compound has a antiadrenoceptor effect in vivo. The hypotensive effect of FR172516, which could be mainly attributed to its calcium channel-blocking action, was compared with that of amlodipine in normotensive Wistar rats (NTRs), spontaneously hypertensive rats (SHRs), and renal hypertensive dogs (RHDs). FR172516 showed more potent hypotensive action than amlodipine when administered intravenously to NTRs, and apparent bradycardia was seen only with FR172516. In SHRs, FR172516 showed a long-lasting hypotensive action and dose-dependently decreased heart rate, whereas amlodipine scarcely affected heart rate. In RHDs, oral administration of FR172516 once daily for 5 days decreased blood pressure without reflex tachycardia or an increase of plasma renin activity. On the other hand, amlodipine, in the dose at which hypotensive effects equipotent to those of FR172516 were observed, produced apparent reflex tachycardia and concomitant increase of plasma renin. These results indicate that FR172516 has a potent long-lasting antihypertensive effect without activating sympathetic tone by calcium channel-blocking and beta-adrenoceptor-blocking actions.

Topics: Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Arteries; Calcium Channel Blockers; Dihydropyridines; Dogs; Hypertension, Renal; Male; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Swine; Time Factors; Vasoconstriction

1. Long-term effects of manidipine hydrochloride (MAN), a calcium channel blocker, were examined in three groups of spontaneously hypertensive rats (SHR). Group 1 was given uninephrectomy (UNX) and MAN treatment, group 2 was given UNX and was not treated with MAN and group 3 was given neither UNX nor MAN treatment. 2. At week 15 after UNX, inulin clearance in group 1 rats decreased compared with rats in groups 2 and 3, but remained at the same level at week 40, when the level in group 2 rats declined below that in rats in groups 1 and 3. 3. Glomerular and tubulointerstitial lesions did not differ at week 15 after UNX among the three groups, whereas at week 40 both were advanced in the order of groups 2, 1 and 3. 4. Proteinuria did not differ between rats in groups 1 and 2 over the experimental period. 5. At week 15, the kidney weights of group 1 rats were greater than those of group 2 rats, indicating more prominent tubular hypertrophy in the former group. This was confirmed by morphometry of the proximal tubuli. In contrast, the glomerular volumes of rats in groups 1 and 2 were enlarged compared with that of rats in group 3, with no difference between the former two groups. 6. The findings suggest that MAN exerts renoprotective effects in SHR, both with regard to function and morphology. An effect on glomerular haemodynamics was considered to more likely be the mechanism underlying the renoprotective effect of MAN rather than that of a lowering of systemic blood pressure. 7. Augmented tubular hypertrophy after MAN treatment was an unexpected finding of the present study and the biological significance of this finding remains to be explored.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Hypertension, Renal; Inulin; Kidney; Kidney Cortex; Kidney Glomerulus; Kidney Tubules, Proximal; Male; Nitrobenzenes; Piperazines; Proteinuria; Rats; Rats, Inbred SHR

The antihypertensive effects of oral or intravenous administration of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj), one kidney-one clip renal hypertensive rats (RHR), deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DHR) and two kidney-one clip renal hypertensive dogs (RHD). AE0047 (1, 3, 10 mg/kg, p.o.) caused a dose-related reduction of systolic blood pressure (SBP) with low reflex tachycardia in SHR/crj and RHR. The effect reached its maximum at 2-4 hr after administration and was sustained for a long time. In DHR, AE0047 (0.3, 1, 3 mg/kg, p.o.) similarly showed the antihypertensive effects at 2-7 hr with no significant changes in heart rates (HR). The doses (ED30) of AE0047 required to decrease SBP by 30% were 2.6, 3.4 and 0.68 mg/kg in SHR/crj, RHR and DHR, respectively. In RHD, and AE0047 capsule (GJ-0956: 4, 8, 16, 32 mg/body, p.o.) produced dose-dependent and long lasting effects with a transient and slight increase in HR. Furthermore, the intravenous administration of AE0047 (10, 30, 100 micrograms/kg) produced the antihypertensive action slowly, reached a plateau 10 min later and then maintained for many hours. In contrast, nitrendipine (3-100 mg/kg, p.o., 3-30 micrograms/kg, i.v.) and nicardipine (1-30 mg/kg, p.o., 3-30 micrograms/kg, i.v.) exhibited a similar potency to AE0047, but these maximal effects were produced at 1-2 hr and 0.5-1 min in the case of oral and intravenous administration, respectively, with a rapid recovery in the above hypertensive rats. These results indicate that AE0047 exhibits an antihypertensive effect with a slow onset and long-lasting profile.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Dogs; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Hypertension, Renal; Injections, Intravenous; Nicardipine; Nitrendipine; Rats; Rats, Inbred SHR

The antihypertensive effects of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj) and two kidney-one clip renal hypertensive dogs (RHD). AE0047, which was orally administered at the dose of 0.3, 1 or 3 mg/kg once daily for 8 consecutive weeks to SHR/crj, exhibited a dose-related decrease in systolic blood pressure. The antihypertensive action was reinforced during the drug treatment at 0.3 and 1 mg/kg. At each dose, the trough-to-peak (T/P) ratio was above 0.50 two weeks later. Although the reflex tachycardia was observed at 1 or 3 mg/kg on the 1st day, it gradually weakened within 8 weeks. Long-term treatment with AE0047 led to the regression of left ventricular hypertrophy. Furthermore, AE0047 had no influences on lipid and glucose metabolism. In RHD, and AE0047 capsule (GJ-0956) containing 2 or 8 mg of the drug was administered for 2 weeks. GJ-0956 produced no reduction in blood pressure at 2 mg, but enhanced the antihypertensive effect starting at 8 mg. The T/P ratios were 0.52 and 0.67 for the systolic and diastolic pressure, respectively, on the 14th day. These results indicate that AE0047 may be expected to exhibit beneficial effects for the clinical treatment of hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Male; Rats; Rats, Inbred SHR

The contributions of hypertension and diabetes to microvascular dysfunction in the kidney and eye were investigated. Two indices of microvascular dysfunction, urinary albumin excretion rate (AER) and albumin vascular clearance (AVC) in the eye, were studied in control and streptozocin diabetic Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).. Studies were performed on four groups of untreated rats--nondiabetic and diabetic WKY and nondiabetic and diabetic SHR--and on three groups of diabetic SHR treated with a converting enzyme inhibitor (perindopril), a calcium-channel blocker (lacidipine), or triple therapy (hydrochlorothiazide, reserpine, and hydralazine). In all rats, AER and AVC were measured at 16 weeks.. There was a progressive increase in both parameters in the order WKY, diabetic WKY, SHR, and diabetic SHR. When compared with nondiabetic WKY, diabetic SHR showed an approximately 30-fold increase in AER and an approximately threefold increase in AVC. Treatment of diabetic SHR with perindopril or triple therapy normalized AER compared to an equihypotensive dose of lacidipine, which had no effect. By contrast, the three antihypertensive regimens showed a different order of efficacy in preventing increases in ocular AVC. In diabetic SHR, the increase in retinal AVC was prevented largely by lacidipine, whereas the other two antihypertensive regimens showed lesser effects [AVC expressed as percentage nondiabetic WKY: untreated diabetic SHR 278% +/- 47%, lacidipine 93% +/- 10% (P < 0.001), triple therapy 132% +/- 37% (P < 0.05), and perindopril 167% +/- 9% (P < 0.05)]. Lacidipine also prevented the increase in AVC of the anterior and posterior uvea. By contrast, increases in AVC observed in the diabetic SHR were not prevented by perindopril in the posterior uvea or by triple therapy in the anterior uvea. Thus, hypertension and diabetes increased ocular AVC and AER, and effective antihypertensive therapy substantially prevented changes in both parameters. However, despite equivalent levels of blood pressure control for each regimen, discordant effects were noted on AVC and AER. Perindopril was associated with significantly lower AER than lacidipine, whereas lacidipine was more potent in preventing increases in ocular AVC.. Results of this study suggest that different antihypertensive regimens in the diabetic rat may exert organ-specific effects on the retina and kidney despite equivalent effects on systemic blood pressure. These data also raise the possibility that retinal microvascular dysfunction in diabetes is ameliorated more readily by calcium-channel blockade than by converting-enzyme inhibition, whereas the reverse applies to renal microvascular dysfunction, as reflected by albuminuria.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dihydropyridines; Drug Therapy, Combination; Hydralazine; Hydrochlorothiazide; Hypertension, Renal; Indoles; Kidney; Male; Organ Specificity; Perindopril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reserpine; Retina; Serum Albumin

The antihypertensive action of lercanidipine (CAS 132866-11-6, Rec 15/2375), a new 1,4-dihydropyridine (1,4-DHP) calcium entry blocker (CEB), was examined in spontaneously hypertensive rats (SHR) and renal hypertensive dogs after acute and repeated administration, in comparison to several reference 1,4-DHPs. In acute experiments in SHR, lercanidipine reduced diastolic blood pressure showing a potency similar to felodipine and 2-3 fold higher than those of nicardipine and nitrendipine, after both intravenous and oral administration. Analysis of the area under the curves of percent reduction of diastolic blood pressure exerted for 3 and 8 h after intravenous and oral administrations, respectively, showed that the duration of the antihypertensive effect of lercanidipine was longer than that of the reference dihydropyridines. After repeated administrations to SHR no tachyphylaxis was observed, as indicated by the marked and persistent decrease in systolic blood pressure elicited by lercanidipine, given orally once a day for 21 days. Moreover, starting from the first week of treatment, the daily basal values of systolic blood pressure of the rats treated with lercanidipine were significantly lower than those of the placebo-treated group. In renal hypertensive dogs, after acute oral administration, lercanidipine was as potent as nitrendipine. After repeated administration, the action of lercanidipine was longer lasting than that of nicardipine and no decrease in the antihypertensive effects was observed. The in vivo studies show that lercanidipine has a potent and long-lasting antihypertensive profile, suggesting that this compound may be used for once-a-day treatment.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Catheterization; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Injections, Intravenous; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Interest in cardiovascular protection by calcium channel antagonists has grown over the past decade. We investigated the prevention of cardiac remodeling and renal injury by the long-acting calcium channel antagonist benidipine using 12 week-old Dahl salt-sensitive (Dahl S) rats fed a high-salt (4% NaCl) diet. Six-week benidipine treatment (10 mg/kg chow) decreased systolic blood pressure by 22% in Dahl S rats. This blood pressure reduction was associated with decreases in cardiac mass and weight of the aortic wall. Collagen content in the left ventricle tended to decline with benidipine treatment. In addition, glomerular filtration rate increased by 33% and arterial and glomerular lesions improved morphologically with this treatment. Regression of cardiac mass and collagen content in the left ventricle was due mainly to blood pressure reduction; however, collagen content in the low-pressure right ventricle was not only related to systemic blood pressure but to the severity of renal lesions. These data suggest that the calcium channel antagonist benidipine attenuates cardiac and renal injury in hypertensive Dahl S rats, and that part of the cardiac hypertrophy is due to a non-hemodynamic mechanism that might be responsible for, or be a consequence of, the lesions in the kidney.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Hemodynamics; Hypertension, Renal; Kidney; Myocardium; Rats; Rats, Inbred Strains; Sodium, Dietary

1. We investigated the effects of short- and long-term administration of efonidipine hydrochloride (NZ-105), 1,4-dihydropyridine derivative, in conscious spontaneously hypertensive rats (SHR). 2. Oral administration of NZ-105 for 12 weeks caused diuretic and natriuretic effects, which were not attenuated during the experimental period. 3. In the short-term experiment for investigating the mechanism of the diuretic effect, intravenous injection of NZ-105 (0.03 mg/kg of body weight) significantly increased the urine volume (UV), renal plasma flow (RPF) and glomerular filtration rate (GFR). The increment rate of UV and RPF was 105.4 +/- 17.8% and 111.7 +/- 72.8%, respectively, which were larger than the increment rate of GFR (38.5 +/- 14.0%). 4. The diuretic or natriuretic effect of NZ-105 was suggested to be due to both the inhibition of sodium reabsorption and, at least in part, the increase of GFR.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Administration Schedule; Hypertension, Renal; Kidney; Male; Nitrophenols; Organophosphorus Compounds; Potassium; Rats; Rats, Inbred SHR; Renal Circulation; Sodium

Antihypertensive effects of repeated oral administration of cilnidipine in 2K1C renal hypertensive dogs were compared with those of nicardipine. On the first day, oral administration of cilnidipine (3 mg/kg) or nicardipine (3 mg/kg) markedly lowered both systolic and diastolic blood pressure 1 hr after administration. The hypotensive effects of cilnidipine were longer compared with those of nicardipine. Both drugs elevated the heart rate and plasma renin activity. On the 8th and 15th days, similar responses were obtained by repeated administrations of cilnidipine and nicardipine. After withdrawal of these drugs, no rebound phenomena in blood pressure were observed. The changes in mean blood pressure were correlated with plasma cilnidipine or nicardipine concentrations that were obtained at each time of blood pressure measurement (r = -0.598; P < 0.001 and r = -0.594; P < 0.001, respectively). These results suggest that stable and long-acting antihypertensive effects of cilnidipine for 15 consecutive days in renal hypertensive dogs are related to the change in plasma drug concentrations.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Dogs; Hypertension, Renal; Male; Renin

The incidence of renal parenchymal hypertension is highest in patients with secondary hypertension. It is important to prevent the progression of renal dysfunction by appropriate treatment, especially by means of antihypertensive drugs. Calcium channel blockers are considered to have the advantage as antihypertensive drugs of maintaining the renal blood flow, even though the perfusion pressure may be decreased. However, these drugs can involve the risk of deteriorating the glomerular function due to hyperfiltration. To investigate whether calcium channel blockers can prevent the deterioration of renal function in renal parenchymal hypertensive patients, we administered manidipine hydrochloride (20 mg, once a day, 24 weeks) to 16 outpatients and evaluated its effects on blood pressure and renal function. The following results were obtained. (1) The systolic and diastolic pressure decreased from 2 and 4 weeks after administration, respectively. A stable antihypertensive effect appeared thereafter and no change was observed in the pulse rate. (2) The renal vascular resistance tended to decrease slightly. The glomerular filtration rate and renal blood flow did not change in spite of the decreased perfusion pressure. (3) No changes were seen in urinary protein, endocrine factors and cardiac function. (4) In some of the cases with decreased GFR (< 70ml/min), the drug could not prevent deterioration of the renal function and did not produce an antihypertensive effect.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney; Male; Middle Aged; Nitrobenzenes; Piperazines; Renal Circulation; Vascular Resistance

Hypotensive and antihypertensive effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) in Wistar Kyoto rat (WKY), spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and DOCA-salt hypertensive rat (DOCA-HR) were compared with those of other representative calcium antagonists. The minimal effective hypotensive dose of S-312-d in WKY was 3 mg/kg p.o. and those in SHR, SHRSP, and DOCA-HR were 1 mg/kg p.o. in gum arabic suspension. The minimal antihypertensive dose of S-312-d in polyethylene glycol solution was 0.3 mg/kg p.o. in SHRSP. The antihypertensive effects of S-312-d was the most potent and long-lasting compared with the calcium antagonists, nifedipine, nicardipine, nimodipine, nilvadipine, and flunarizine. In conscious two-kidney Goldblatt-type hypertensive dogs, a significant antihypertensive effect and concomitant increases of heart rate with S-312-d at 1 mg/kg lasted for 4 to 6 h after oral administration. Determination of the plasma concentration of S-312-d by HPLC showed that more than 4.3 ng/ml of S-312-d is required for a significant antihypertensive effect. Subcutaneous administration of atenolol at 20 mg/kg 30 min before S-312-d significantly inhibited the tachycardia with S-312-d at 1 mg/kg p.o. but not its antihypertensive effect. S-312-d is considered useful for the treatment of essential hypertension and related organ disorders.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Desoxycorticosterone; Dihydropyridines; Dogs; Female; Heart Rate; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Renin

The acute antihypertensive effects of 3-pyridine carboxylic acid 5-[(cyclo-propylamino)carbonyl]-1,4-dihydro-2,6-dimethyl-4-(2-nitroph eny l) octyl ester (NP-252, CAS 132031-81-3) administered orally to conscious spontaneously hypertensive rats (SHRs) and renal hypertensive rats (RHRs) were evaluated using the impedance plethysmographical technique as a modified tail cuff method, and compared with those of nifedipine (NF). In the fitness test of this indirect method, the average value of blood pressure (BP) measured in 7 conscious SHRs was 201 +/- 6.9 mmHg. This value showed good correlation with that (201 +/- 8.8 mmHg) of systolic BP measured by the direct method in the same animals. In the comparative study of antihypertensive activities of the compounds on both models of hypertension using this method, NP-252 and NF dose-dependently lowered BP having a different peak time and restoration after dosing. Therefore, the antihypertensive activities were compared using a 20% effective dose (ED20) for producing hypotension, and the ED20 values of NP-252 and NF were 2.55 and 2.00 mg/kg in SHRs, and 1.25 and 0.67 mg/kg in RHRs, respectively. Moreover, the duration of actions of the compounds were evaluated by the simulated duration time (SDT) which was calculated from the peak time of BP-fall and the pharmacological half life time for the maximum BP-fall and the SDT values of NP-252 and NF were 1.85-4.70 and 0.90-0.75 h in SHRs, and 3.30-12.80 and 0.57-6.90 h in RHRs, respectively. Also, the BP-falls by the compounds were accompanied by an increase in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Half-Life; Heart Rate; Hypertension; Hypertension, Renal; Male; Nifedipine; Rats; Rats, Inbred SHR; Rats, Wistar

Antihypertensive effects of a novel calcium antagonist, MPC-1304, (+-)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5- pyridine-dicarboxylate and its active metabolites were investigated in experimental hypertensive rats and dogs and compared with those of other dihydropyridine derivatives (nifedipine, nisoldipine, nicardipine, and nitrendipine). MPC-1304 had a dose-related antihypertensive effect with a slight increase in heart rate (HR) in rats. The antihypertensive effects of MPC-1304 were more potent than those of other dihydropyridines, and its active metabolites had antihypertensive effects comparable to those of other dihydropyridines. The hypotensive effects of MPC-1304 were stronger in hypertensive rats than in normotensive rats. During repeated oral administration of MPC-1304 to spontaneously hypertensive rats (SHR, once daily for 4 weeks, 0.3-3 mg/kg), dose-response curves of the antihypertensive effect did not change and body weight gain was equal to that of the vehicle-treated group. When given orally to conscious renal hypertensive dogs, MPC-1304 0.1-0.3 mg/kg had a potency and duration of antihypertensive action comparable to that of nitrendipine (1-3 mg/kg). MPC-1304 increased coronary blood flow (CBF) and aortic blood flow (ABF) in conscious normotensive dogs. In conclusion, MPC-1304 and its active metabolites have potent antihypertensive effects and cause slight tachycardia, and they may be useful in treating hypertension.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Coronary Circulation; Dihydropyridines; Dogs; Heart Rate; Hypertension; Hypertension, Renal; Nicardipine; Nifedipine; Nisoldipine; Nitrendipine; Rats; Rats, Inbred SHR; Rats, Wistar

The antihypertensive effect of TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate hydrochloride, CAS 96515-74-1), a new calcium antagonist, was investigated in normotensive dogs (NTD) and renal hypertensive dogs (RHD). By oral administration, the antihypertensive activity of TC-81 (ED20% was 0.09 mg/kg p.o.) was about 18 times more potent in conscious RHD in comparison with nicardipine (ED20% was 1.65 mg/kg p.o.). Duration of the antihypertensive effect of TC-81 was about 2 times longer than that of nicardipine, and the response was elicited more slowly than that of nicardipine at equipotent dose. Similar results were observed more clearly by intravenous injection, but the potency of TC-81 was only 3 times higher than that of nicardipine in anesthetized dogs. Tolerance of the antihypertensive effect of TC-81 in daily dosing for 2 weeks and the rebound phenomena after discontinuance of the treatment were not observed in RHD. TC-81 at a concentration of 10(10)-3 x 10(-9) mol/l inhibited the KCl- or norepinephrine-induced contraction of isolated dog femoral artery. From these observations, TC-81 can be characterized as having a strong, long-lasting, and slow-onset antihypertensive activity, especially by oral administration. Therefore, this new calcium antagonist may be useful for long-term antihypertensive therapy.

Topics: Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dogs; Female; Femoral Artery; Heart Rate; Hypertension, Renal; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nicardipine; Norepinephrine; Potassium Chloride

Topics: Calcium Channel Blockers; Cyclosporine; Dihydropyridines; Drug Interactions; Humans; Hypertension, Renal; Isradipine; Kidney Transplantation

CS-905, (+-)-3-(1-diphenylmethylazetidin-3-yl)5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxy lat e, is a novel dihydropyridine calcium blocker. Both CS-905 and nicardipine, when administered orally, produced a dose-dependent fall of blood pressure in conscious perinephritic hypertensive dogs. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in the heart rate and plasma renin activity (PRA). The lack of both tachycardia and increase of PRA is probably mostly due to the slow onset of antihypertensive action following CS-905.

Topics: Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Azetines; Calcium Channel Blockers; Dihydropyridines; Dogs; Dose-Response Relationship, Drug; Hypertension, Renal; Juxtaglomerular Apparatus; Male; Nephrectomy; Nicardipine; Renin; Renin-Angiotensin System

CS-905 is a novel dihydropyridine calcium blocker. A single oral administration of CS-905 or nicardipine at doses of 0.3-3.0 mg/kg produced a dose-dependent reduction of blood pressure in conscious SHR. CS-905, when administered orally in conscious SHR, was more than 3 times as potent as nicardipine. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in heart rate. An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration. This difference may be attributed to the first pass effect, which was associated with nicardipine but not with CS-905. The blood pressure lowering effects of CS-905 was most potent in DOCA-salt hypertensive rats, followed by SHR, RHR and normotensive rats, in this order. CS-905 is expected to be an antihypertensive agent that is effective on a once a day regimen in clinical settings.

Topics: Anesthesia; Animals; Antihypertensive Agents; Aorta; Azetidinecarboxylic Acid; Azetines; Blood Pressure; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Heart Rate; Hypertension; Hypertension, Renal; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred Strains

MDL 72567 (2,6 dimethyl,3 methoxycarbonyl,4-(2-nitrophenyl), 5-(2-furoyl)1,4 dihydropyridine) was a potent antagonist of Ca2+-induced contractions in K+-depolarized taenia preparations from the guinea pig caecum (pA2 8.8 +/- 0.1). MDL 72567 was a potent displacer of [3H]nitrendipine binding from rat cortical membrane preparations (Ki 3.99 nM), indicating an effect at the dihydropyridine binding site, which is consistent with the finding that the inhibitory effects of MDL 72567 in smooth muscle were prevented by the dihydropyridine Ca2+ channel activator Bay K 8644. MDL 72567 slowed spontaneously beating rat atria preparations to a greater extent than did nifedipine, however, for a given negative inotropic effect. Furthermore, in pithed rat preparations infused with angiotensin II to elevate blood pressure, the hypotensive effects of MDL 72567 (3 nmol/kg-3 mumol/kg, intravenously, i.v.) were accompanied by bradycardia, whereas nifedipine, PY 108-068, and nicardipine lowered blood pressure without affecting heart rate. When compared with nifedipine, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure, in anesthetized beagles and in conscious renal hypertensive dogs. In anesthetized dogs, MDL 72567 increased cardiac contractility at all hypotensive doses tested (30-3,000 nmol/kg, i.v.), whereas nifedipine caused profound myocardial depression at higher doses (1,000-3,000 nmol/kg, i.v.) even though the compounds had equivalent vasodilator effects. Thus, although MDL 72567 appears to cause a direct myocardial slowing that can partially offset reflex tachycardia, the compound has negligible negative inotropic effects and may therefore be useful in angina pectoris or even in congestive heart failure.

Topics: Animals; Bradycardia; Calcium Channel Blockers; Calcium Channels; Decerebrate State; Dihydropyridines; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Guinea Pigs; Hypertension, Renal; Male; Nicotinic Acids; Nifedipine; Nitrendipine; Rats; Rats, Inbred Strains; Receptors, Nicotinic; Vasodilation

Isolated perfused kidneys from prehypertensive Dahl salt-sensitive (DS) rats demonstrated marginally increased glomerular responsiveness when nitrendipine or verapamil was superimposed upon norepinephrine vasoconstriction. This was manifested by a greater increase in the glomerular filtration rate of DS rat kidneys, as compared to kidneys from Dahl salt-resistant (DR) rats. This glomerular response to nitrendipine by isolated kidneys was not affected by the development of salt-induced hypertension in DS rats, but was eliminated by antecedent salt loading in DR rats. In further experiments designed to assess more directly the reactivity of renal vascular calcium channels in DS and DR rats, the calcium channel agonist BAY-K-8644 and its pure agonist isomer elicited greater increases in renal vascular resistance in kidneys from prehypertensive DS rats than in kidneys from similarly prepared DR rats. Renal vascular reactivity to both BAY-K-8644 and its agonist isomer were greatly magnified following salt-induced DS rat hypertension. These results suggest that a genetically conferred abnormality of calcium channel function may contribute to the renal functional characteristics of the DS rat kidney.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Hypertension, Renal; In Vitro Techniques; Ion Channels; Kidney; Male; Nitrendipine; Perfusion; Pyridines; Rats; Rats, Inbred Strains; Renal Circulation; Sodium Chloride; Verapamil

B 844-39 is a new dihydropyridine calcium antagonist with a long-lasting antihypertensive action. Preliminary tests in chronically instrumented normotensive dogs revealed that B 844-39 (0.3 mg/kg p.o.) caused a marked decrease in blood pressure which was accompanied by a counterregulatory increase in heart rate. Both effects outlasted the 6-h observation period. There was no sign of cardiac depression in left ventricular positive dP/dtmax or sonomicrometrically evaluated subendocardial systolic shortening. B 844-39 was also tested in renal hypertensive dogs over a period of 12 days to investigate its potential in the long-term treatment of hypertension. A dosage of 0.3 mg/kg given orally twice a day led to a marked and persistent decrease in blood pressure, which was accompanied by a positive chronotropic effect and increases in plasma renin activity and angiotensin II. This initial counterregulatory response was blunted within several days of chronic treatment. After completion of the 12-day treatment period, the blood pressure reduction persisted for greater than 14 days. B 844-39 induced a marked and persistent reduction in blood pressure in hypertensive dogs, even with prolongation of the dosing interval to 24 h. The hypotensive effect of this drug was more pronounced in hypertensive than in normotensive animals.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dogs; Female; Hypertension, Renal; Male; Renin

Topics: Animals; Calcium Channel Blockers; Desoxycorticosterone; Dihydropyridines; Heart Rate; Hypertension; Hypertension, Renal; Male; Nifedipine; Rats; Rats, Inbred SHR

The hypotensive and cardiovascular effects of a newly synthetized dihydropyridine derivative, methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8411) were investigated in rats, guinea pigs, and rabbits, in comparison with nifedipine, nicardipine, and diltiazem. In conscious hypertensive rats, FRC-8411 (0.3-3 mg/kg p.o.) was found to be an orally effective antihypertensive agent and its effect lasted for more than 7 h. This effect was gradual and yet much more potent and longer than those of other reference drugs. An accompanied tachycardia was observed after oral administration of FRC-8411 and other dihydropyridine derivatives. In anesthetized rats, FRC-8411 (3-30 micrograms/kg i.v.) also showed a gradual, potent and long-lasting hypotension with a tachycardia. FRC-8411 (up to 3 mg/kg i.v.) had no effect on the PQ interval of the ECG in anesthetized rats. In isolated guinea pig atria, FRC-8411 (10(-9) - 3 X 10(-8) mol/l) showed a negative chronotropic effect, but a higher dose of the drug was needed for induction of the negative inotropic effect. In K+-depolarized rabbit aorta and guinea pig taenia coli, FRC-8411 (3 X 10(-9) - 3 X 10(-7) and 10(-7) - 3 X 10(-7) mol/l) showed a dose-dependent inhibition of the calcium-induced contraction, and its pA2 value was 8.4 and 7.1, respectively. FRC-8411 had a much higher sensitivity to the aorta than the taenia coli, though it was less potent than nifedipine and nicardipine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anesthesia, General; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Guinea Pigs; Heart; Heart Rate; Hemodynamics; Hypertension, Renal; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Myocardial Contraction; Nifedipine; Rabbits; Rats; Rats, Inbred Strains

Methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2 -yl)-1,4-dihydropyridine-3-carboxylate (DHP-218) is a new vasodilatory calcium antagonist with pronounced and long-lasting antihypertensive effects. It produced a significant decrease in blood pressure at doses more than 1 mg/kg in normotensive rats, 0.1 mg/kg in spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)-salt hypertensive rats and 0.3 mg/kg in renal hypertensive rats. In SHR, the antihypertensive effect of DHP-218 was approximately 7 times more potent than nifedipine. The antihypertensive effect of DHP-218 appeared very slowly and persisted even after it was injected i.v. No tolerance to the antihypertensive effects of DHP-218 was observed for 5 weeks at daily doses of 0.3 and 1 mg/kg. The antihypertensive effects of DHP-218 in cats and dogs with normal blood pressure was more than 10 and 30 times more potent than those of nifedipine, respectively. At an equivalent antihypertensive dose, the effect of DHP-218 persisted longer than that of nifedipine in all the animal species used.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cats; Dihydropyridines; Dogs; Electrocardiography; Female; Heart Rate; Hypertension, Renal; Male; Nifedipine; Organophosphorus Compounds; Plethysmography; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Species Specificity