Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibiting effect of the calcium channel blocker nisoldipine (CAS 63675-72-9, Baymycard, Syscor) on potassium-induced contraction on bovine mesenteric veins and arteries and human peripheral veins was investigated. Nisoldipine inhibited the contraction on bovine mesenteric veins at a significantly lower concentration (1 x 10(-10) mol/l) than nifedipine and glyceryl trinitrate (GTN) (1 x 10(-7) mol/l). When the preparations were preincubated with the drugs, nisoldipine reduced the contraction, measured as area under the curve (AUC), with 47 +/- 8% (mean +/- SEM) and nifedipine with 29 +/- 13% in veins. It was necessary to use an inconsiderably higher concentration of nisoldipine to relax bovine mesenteric arteries contracted by potassium. Preincubation of these arteries with nisoldipine (1 x 10(-7) mol/l) reduced contraction measured as AUC by 46 +/- 10% and preincubation with nifedipine (1 x 10(-7) mol/l) by 77 +/- 3%. Nisoldipine also caused a marked relaxation in human saphenous veins. The introduction of nisoldipine (1 x 10(-8) mol/l) after potassium-induced contraction caused 54 +/- 8% relaxation.
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PMID:Inhibition of nisoldipine on bovine mesenteric arteries and veins and on human peripheral veins. 857 21

In the present study we investigated the effect of a selective alpha 1-adrenergic blocker (doxazosin), an angiotensin-converting enzyme (ACE) inhibitor (captopril), and a calcium channel antagonist (nifedipine) on renal function in hypertensive non-insulin-dependent diabetic patients. 30 NIDD hypertensive patients (age = 50 +/- 3 years; BMI = 30 +/- 1 kg/m2) (mean +/- SEM) were studied before and after a 12-week period of antihypertensive treatment. Ten patients were treated with doxazosin (Cardura) (2-8 mg once daily or 8 mg b.i.d.), 9 with captopril (Capoten) (25-50 mg b.i.d.), and 11 with nifedipine (Procardia-XL) (30-60 mg once daily). Blood pressure, creatinine clearance, 24-hour urinary protein excretion, fasting plasma glucose concentration and glycosylated hemoglobin were measured before and after drug treatment. Fasting plasma glucose and glycosylated hemoglobin (HbA1c) were similar in all three groups prior to the start of antihypertensive therapy and did not change significantly from baseline in any treatment groups. In the doxazosin group creatinine clearance rose from 99 +/- 8 to 122 +/- 8 ml/1.73 m2.min (p < 0.01), while 24-hour urinary protein excretion declined from 2.66 +/- 0.05 to 1.76 +/- 0.02 mg/day/ml/1.73 m2.min (p < 0.01). In diabetics treated with captopril creatinine clearance rose from 93 +/- 6 to 109 +/- 9 ml/1.73 m2.min (p < 0.05), while the 24-hour urinary protein excretion fell from 2.70 +/- 0.05 to 2.03 +/- 0.04 mg/day/ml/1.73 m2.min (p < 0.05). In patients treated with nifedipine creatinine clearance did not change (97 +/- 6 vs. 94 +/- 7 ml/1.73 m2.min), while 24-hour urinary protein excretion decreased from 2.84 +/- 0.04 to 1.95 +/- 0.03 mg/day/ml/1.73 m2.min. Systolic and diastolic blood pressure were similar in doxazosin (150 +/- 3/95 +/- 2 mm Hg), captopril (153 +/- 3/93 +/- 1), and nifedipine (155 +/- 4/93 +/- 1) groups prior to the start of antihypertensive therapy and declined to 143 +/- 3/84 +/- 3 (doxazosin), 139 +/- 3/82 +/- 3 (captopril), and 141 +/- 3/84 +/- 1 (nifedipine) mm Hg (all p < 0.01 vs. pretreatment). In summary, both doxazosin and captopril treatment were associated with significant rises in GFR, while all three antihypertensive agents caused a significant decline in proteinuria. These results indicate that alpha-adrenergic blockers, ACE inhibitors, and calcium channel antagonists can safely and effectively be used in the clinical management of non-insulin-dependent diabetic patients with hypertension.
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PMID:Effect of alpha-adrenergic blockers, ACE inhibitors, and calcium channel antagonists on renal function in hypertensive non-insulin-dependent diabetic patients. 885 95

Verapamil produces comparatively greater in vivo left ventricular (LV) depression than other calcium channel antagonists produce, possibly because of myocardial metabolic derangements in addition to L-channel antagonism. Therefore, we studied myocardial lipid and carbohydrate usage and the effect of insulin treatment during progressive verapamil toxicity. Verapamil was infused through the portal vein to simulate oral overdose. Eighteen mongrel dogs were instrumented to measure multiple hemodynamic and metabolic parameters. After 1-week recovery, dogs underwent control euglycemic insulin dose-response studies (n = 6) in the conscious state: at 1,000 mU/mm insulin infusion rate, myocardial glucose and lactate extraction increased seven- and threefold, respectively with no change in coronary artery blood flow or ventricular elasticity and end-systole (Ees). In 12 separate dogs, intraportal graded verapamil toxicity was induced in 3 h by increasing the infusion rate hourly: 0.04 -- 0.08 -- 0.1 mg/kg/mm. At the end of hour 3, myocardial extraction of free fatty acids decreased from 33 +/- 4 to 9 +/- 3% (mean +/- SEM, p < 0.05), without significant change in myocardial blood flow or arterial free fatty acid concentration. Verapamil toxicity increased arterial glucose from 3.5 +/- 0.16 to 6.1 +/- 1.1 mM; simultaneously, myocardial glucose extraction doubled, although endogenous insulin concentrations did not increase. Arterial lactate concentrations and net myocardial lactate uptake both increased (p < 0.05 vs basal blue). Ees decreased from 28 +/- 1 mm Hg/mm (basal) to 20 +/- 2 mm Hg/mm (end of hour 3, p <0.05). Animals were randomized into two treatment groups; either (a) insulin-glucose (1,000 mU/mm, n 6; arterial glucose was clamped +/- 10% with 50% dextrose), or (b) saline controls (n = 6) that received equivalent volume of saline. After 1-h insulin treatment, Ees increased to 34 + 3 mm Hg; in controls, Ees was 15 +/- 3 mm Hg/mm (p < 0.05). With insulin-glucose treatment, neither myocardial glucose nor lactate extraction increased significantly (p = 0.06 for lactate). Verapamil therefore inhibits myocardial fatty acid uptake and impedes insulin-stimulated myocardial glucose uptake; under these conditions, insulin-glucose treatment increases myocardial contractile function independent of increased sugar transport. These findings indicate that verapamil toxicity produces myocardial insulin resistance and, potentially, nutrient deprivation that may contribute to clinically relevant negative inotropy.
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PMID:Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. 885 43

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (tau-on) or from 180 to 240 ms (tau-off). The adaptation of the AVCT in the presence of verapamil (tau-on = 178 +/- 45 beats, tau-off = 125 +/- 33 beats, mean +/- SEM) was more pronounced than in the presence of digoxin (tau-on = 144 +/- 24 beats, tau-off = 98 +/- 15 beats) or diltiazem (tau-on = 70 +/- 11 beats, tau-off = 98 +/- 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of dilitiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.
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PMID:Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction. 904 Jan 11

A role for calcium channels in the regulation of surfactant secretion is suggested by the observation that endothelin-1-stimulated surfactant secretion is inhibited by calcium channel blockers. 1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid methyl ester (Bay K 8644), a dihydropyridine derivative, stimulates voltage-dependent and non-voltage-dependent calcium channels in a number of cell types. This study demonstrates that Bay K 8644 increased phosphatidylcholine (PC) secretion in isolated lung epithelial type II cells in a time- and concentration-dependent manner with an EC50 of 100 +/- 8 nM (mean +/- SEM, N = 6). The secretagogue effect of Bay K 8644 was independently decreased in the absence of external calcium, or in the presence of nifedipine, a calcium channel antagonist, or inhibitors of protein kinase C (PKC). Bay K 8644 increased intracellular calcium from 130 +/- 8 to 230 +/- 14 nM (N = 6, P < 0.05), an effect that was blocked by nifedipine. Bay K 8644 also increased the membrane-associated PKC activity in a concentration-dependent manner. In the membranes from Bay K 8644-stimulated cells, the increase in calcium-dependent PKC was greater than that in the calcium-independent PKC, suggesting preferential translocation of calcium-dependent PKC to the membranes. We suggest that both elevated calcium and activation of PKC are required for calcium agonist Bay K 8644-induced surfactant secretion in type II cells.
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PMID:Activation of protein kinase C by 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-py rid ine carboxylic acid methyl ester (Bay K 8644), a calcium channel agonist, in alveolar type II cells. 921 91

Previously, it had been demonstrated that cataract in diabetic rats can be prevented by systemical administration of the calcium channel blocker verapamil. In addition to that, 0.125% verapamil eye drops were found to significantly reduce the intraocular pressure in ocular hypertensive human subjects. The purpose of this study was to investigate the ocular penetration and elimination of verapamil after topical administration of the drug in rabbits. Two drops of a 0.125% aqueous solution of RS-verapamil hydrochloride (corresponding to a total dose of 125 microg RS-verapamil hydrochloride) were administered into the conjunctival sac. Aqueous humor and blood samples were taken at different times after administration and analysed for drug concentration by combined gas chromatography-mass spectroscopy. Following the instillation of 0.125% verapamil eye drops in a total dose of 125 microg RS-verapamil, mean (+/- SEM) aqueous humor peak levels of 1607 +/- 272 ng/ml were achieved after 20 min. Mean half-life for the elimination from the aqueous humor was 33 min. Topical application of verapamil produced very low serum peak concentrations (10.5 +/- 1.3 ng/ml). The results of our study demonstrate that topically administered verapamil readily penetrates into the anterior chamber leading to aqueous humor drug levels in the microM range without producing serum levels that are high enough to cause cardiovascular side effects.
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PMID:Ocular pharmacokinetics of verapamil in rabbits. 955 Mar 6

We compared the effects of cilnidipine and nifedipine retard on 24-h blood pressure (BP), heart rate (HR), and autonomic nerve activity in patients with essential hypertension. Cilnidipine is a novel and unique 1,4-dihydropyridine calcium antagonist that has the L-type and N-type voltage-dependent calcium channel-blocking action. Fourteen hypertensive outpatients (four men and 10 women; aged 64 +/- 2 years, mean +/- SEM) were enrolled in this study. Their ambulatory BP and electrocardiogram were monitored for 24 h at intervals of 30 min with a portable recorder after a 4-week drug-free period, after a 4-week treatment period with cilnidipine (5 or 10 mg once daily), and after a 4-week treatment period with nifedipine retard (10 or 20 mg twice daily). The order of the three periods was randomized. Autonomic nerve activity was evaluated by a power spectral analysis of HR variability, by using the high-frequency (HF) component as an index of parasympathetic nerve activity and the ratio of the low-frequency (LF) component to the HF component (LF/HF) as an index of sympathovagal balance. Cilnidipine and nifedipine retard significantly reduced the 24-h BP of these patients to similar extents (cilnidipine, -11 +/- 3/-6 +/- 1 mm Hg; nifedipine retard, -15 +/- 3/-6 +/- 2 mm Hg). Cilnidipine did not change the 24-h average HR, whereas nifedipine retard significantly increased it (+3.3 +/- 1.4 beats/min; p < 0.05). Nifedipine retard significantly increased the LF/HF ratio in the daytime and the nighttime. Such changes were limited to the daytime in the treatment period with cilnidipine. These results suggest that cilnidipine is effective as a once-daily antihypertensive agent and had less influence on autonomic nervous system and HR than did nifedipine retard.
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PMID:Comparison of 24-hour blood pressure, heart rate, and autonomic nerve activity in hypertensive patients treated with cilnidipine or nifedipine retard. 970 Sep 98

Double-blind, randomized controlled studies of longer than 1 week in duration comparing the antiproteinuric potential of long-acting dihydropyridine calcium channel blockers with that of angiotensin converting enzyme (ACE) inhibitors are lacking. Therefore, we performed such a study in patients with nondiabetic renal disease and proteinuria. After a 4-week wash-out period in which patients did not use any medication known to affect proteinuria, 21 patients were randomized in a double-blind fashion to receive either the calcium channel blocker amlodipine (Amlo, 5 to 10 mg) or the ACE-inhibitor lisinopril (Lis, 5 to 10 mg). Throughout the 16-week study period, blood pressure, creatinine clearances, and proteinuria were measured every 2 weeks. In addition, device-measured blood pressure and renal hemodynamic studies were performed at the start and end of the study. Systolic blood pressure fell in the Lis group from 163+/-7 (SEM) to 140+/-8 mm Hg (P < .01) and from 157+/-10 to 147+/-6 mm Hg in the Amlo group; diastolic blood pressure fell from 101+/-3 to 86+/-7 mm Hg in the Lis group and from 98+/-3 to 91+/-2 mm Hg in the Amlo group. Renal hemodynamics were not affected by amlodipine treatment, whereas a fall in glomerular filtration rate (GFR) was seen in lisinopril-treated patients (from 55+/-11 to 50+/-10 mL/min; P < .01). Amlodipine did not significantly affect proteinuria. Lisinopril induced a decline in the protein-creatinine ratio with a maximal effect reached after 12 to 16 weeks of therapy (from 0.39+/-0.17 to 0.26 +/-0.11 g/mmol; P < .009). In conclusion, we could not demonstrate an antiproteinuric effect of the long-acting dihydropyridine calcium channel blocker amlodipine, whereas therapy with the ACE-inhibitor lisinopril resulted in a decrease in proteinuria. Amlodipine did not affect renal hemodynamics, whereas lisinopril induced a fall in GFR.
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PMID:Comparison between the effects of amlodipine and lisinopril on proteinuria in nondiabetic renal failure: a double-blind, randomized prospective study. 975 92

Cilnidipine is a new and unique 1,4-dihydropyridine calcium antagonist that has both L-type and N-type voltage-dependent calcium channel blocking actions. We compared the effects of cilnidipine and another once-daily dihydropyridine calcium antagonist, nisoldipine, on 24-h blood pressure and heart rate in patients with essential hypertension. We enrolled 10 hypertensive outpatients [9 men and 1 woman; age, 55+/-3 yr (means+/-SEM)] in this study. Their ambulatory blood pressure and heart rate were monitored for 24 h at intervals of 30 min with a portable recorder (TM-2425) after 8 wk of treatment with cilnidipine (5 to 20 mg once daily) and after 8 wk of treatment with nisoldipine (5 to 20 mg once daily). The order of the two treatments was randomized. Blood pressure and heart rate measurements for a 24-h period were analyzed for four segments of the day: morning (06:00 to 11:30), afternoon (12:00 to 17:30), nighttime (18:00 to 23:30), and sleeping time (0:00 to 5:30). Blood pressure levels were similar during the two treatment periods for each 6-h segment of the day. Heart rate was significantly higher during treatment with nisoldipine than during treatment with cilnidipine in the morning segment [by 4.1+/-1.3 beats/min (p < 0.05)] and the afternoon segment [by 6.4+/-3.6 beats/min (p< 0.05)]. These results suggest that cilnidipine is effective as a once-daily antihypertensive agent and causes reflex tachycardia less than does nisoldipine.
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PMID:Comparison between cilnidipine and nisoldipine with respect to effects on blood pressure and heart rate in hypertensive patients. 978 7

Dihydropyridine-type calcium channel blockers (dihydropyridine CCB) adversely affect renal function in diabetes. The effects of dihydropyridine CCB on 24-h urinary protein excretion rate and GFR decline (deltaGFR) were prospectively evaluated in 117 nondiabetic patients with chronic, proteinuric nephropathies enrolled in the Ramipril Efficacy in Nephropathy study and randomized to angiotensin-converting enzyme inhibition (ACEI) or placebo plus conventional antihypertensive therapy. Sixty-three percent of patients were treated with dihydropyridine CCB. During follow-up, CCB-treated compared with no CCB patients had higher proteinuria (mean+/-SEM: 4.8+/-0.2 g/24 h versus 4.2+/-0.2 g/24 h, respectively, P = 0.015) and mean arterial BP (MAP). The difference in proteinuria was significant in the placebo group (5.1+/-0.2 g/24 h versus 4.3+/-0.3 g/24 h, P = 0.02), but not in the ACEI group (4.4+/-0.2 g/24 h versus 4.1+/-0.2 g/24 h). Of note, CCB-treated patients had significantly less proteinuria (P = 0.028) in the ACEI group compared with placebo. CCB-treated versus no CCB patients had a faster deltaGFR in the overall study population and in the placebo group, but not in the Ramipril group. Proteinuria was comparable in CCBtreated and no CCB patients for MAP < or = 100 mmHg, but was higher in CCB-treated patients for MAP >100 mmHg. Similarly, proteinuria was comparable in the placebo and in the ACEI group for MAP < or = 100 mmHg, but was higher in the placebo group for MAP >100 mmHg. In CCB- and placebo-treated patients, a linear correlation (P = 0.006 for both groups) was found between proteinuria and MAP values. MAP, proteinuria, and deltaGFR in patients given nifedipine versus those given other dihydropyridine CCB were comparable. Thus, in nondiabetic proteinuric nephropathies, dihydropyridine CCB may have an adverse effect on renal protein handling that depends on the severity of hypertension and is minimized by ACEI therapy or tight BP control. ACE inhibitors may electively limit proteinuria in patients on dihydropyridine CCB treatment and/or with uncontrolled hypertension.
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PMID:Effects of dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). 980 96


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