Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.
Exp Mol Pathol 1985 Aug
PMID:The protective effect of nitrendipine on gentamicin acute renal failure in rats. 315 93

The interactions of propranolol, nimodipine, and amiodarone with membrane lipids were examined in an effort to explain their different pharmacokinetic and pharmacodynamic properties. Propranolol and nimodipine, which bind with high affinity to plasmalemmal beta-adrenergic and calcium channel receptors, respectively, have membrane partition coefficients of approximately 1200 and 5000 and are readily washed out of membranes with which they had been equilibrated. X-ray and neutron diffraction studies showed that after partitioning into lipid membranes, both propranolol and nimodipine are located approximately 6 A from the phosphate headgroup region of the membrane bilayer, near the hydrocarbon core/water interface. Amiodarone, which blocks Na and K channels with less site specificity than propranolol and nimodipine, has a much higher partition coefficient of approximately 1,000,000, resists washout from membrane bilayers, and is located deeper in the membrane, approximately 12 A from the phosphate headgroup region of the bilayer, nearer to the terminal methyl groups of the fatty acyl chains. The shorter durations of clinical action of propranolol and nimodipine may be related to the reversibility of their interactions with the region of the bilayer exposed to the aqueous media near the hydrocarbon core/water interface, whereas the much longer duration of clinical action of amiodarone may reflect a location more deeply within the fatty acyl region of the bilayer where this hydrophobic drug interacts avidly with the hydrocarbon core of the membrane.
J Mol Cell Cardiol 1988 May
PMID:Possible molecular basis for the pharmacokinetics and pharmacodynamics of three membrane-active drugs: propranolol, nimodipine and amiodarone. 321 Feb 48

The ability of the beta-receptor antagonist propranolol to influence the response of isolated cardiac and vascular smooth muscle to several classes of calcium channel blockers was examined. For comparison, the interactions between propranolol and other classes of negative inotropic and vasorelaxant agents was also evaluated. The results of these studies demonstrate that propranolol pre-treatment significantly enhances the in vitro response to the dihydropyridine calcium channel blocker nifedipine, but not the thiazapine calcium channel blocker diltiazem. This enhancement was unrelated to the negative inotropic or vasorelaxant properties of these agents. In addition, propranolol pre-treatment of rat cortical membranes also enhanced the affinity of nifedipine for the 3H-nitrendipine binding site, but did not alter the effect of diltiazem on 3H-nitrendipine binding. These observations suggest that a direct interaction may exist between beta-receptor antagonists and dihydropyrine-type calcium channel blockers. This interaction may be an important factor in selecting drug therapy for conditions such as hypertension and angina.
J Mol Cell Cardiol 1988 Oct
PMID:Interaction between propranolol and calcium channel blockers in cardiac and vascular smooth muscle. 321

PRL synthesis by GH cells in culture has previously been shown to increase when calcium is added to cultures grown in calcium-depleted medium or when cultures are treated for 18 h or longer with the dihydropyridine calcium channel agonist BAY K8644, whereas the antagonist nimodipine inhibits PRL. The experiments described here were designed to test whether differences in PRL synthesis caused by the dihydropyridines are due to changes in PRL mRNA levels, whether structurally different classes of calcium channel blockers alter PRL production, and whether long term treatment with calcium channel agonists and antagonists alters intracellular free calcium, [Ca2+]i. PRL synthesis and PRL mRNA levels were increased similarly by BAY K8644 and decreased in parallel by the dihydropyridine antagonist nimodipine, while overall protein and RNA synthesis were not changed by either the agonist or antagonist. Two calcium channel blockers which act at different sites on L-type channels than the dihydropyridines also inhibited PRL synthesis without affecting GH; 5 microM verapamil reduced PRL by 64% and 15 microM diltiazem by 89%. Partial depolarization with 5-25 mM KCl increased PRL synthesis up to 2-fold. The intracellular free calcium ion concentration was estimated by Quin 2 and averaged 142 nM for control cultures in normal medium, and 128 and 168 nM for cultures treated 72 h with nimodipine or BAY K8644, respectively. Nimodipine totally prevented the calcium rise obtained upon depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1988 Nov
PMID:Calcium channel agonists and antagonists: effects of chronic treatment on pituitary prolactin synthesis and intracellular calcium. 322 79

A comparative study of human atrial fibers (HAF), human ventricular fibers (HVF), frog ventricle, and frog skeletal muscle demonstrated marked differences in tension development in the presence of diltiazem. There was no significant difference between the tension developed by HAF and by HVF over a range of diltiazem concentrations when the differences in resting membrane potential were corrected by increasing external K+ concentration. In human myocardium, diltiazem resulted in both a voltage and use-dependent blockade of the calcium channel. Comparison of the tension-dose response curves in human myocardium, frog ventricle and skeletal muscle showed that diltiazem was most effective at decreasing tension in frog heart, and least effective in skeletal muscle with human myocardium being intermediate. In skeletal muscle, neither tension development nor the birefringence signal related to the Ca2+ release from the sarcoplasmic reticulum was significantly altered by Diltiazem in concentrations less than 10(-6) M, but in concentrations greater than 10(-5) M both were suppressed. Diltiazem suppressed tension in human myocardium over the range of membrane potentials associated with Ca2+ channel activity, while at more positive potentials, diltiazem appeared to have little effect on the tension-voltage relations. Diltiazem had no effect upon tension development induced by acetyl strophanthidin in human myocardium or upon the Ca2+ sensitivity of chemically skinned atrial or ventricular fibers. Thus the tension-suppressant effect of diltiazem in human myocardium appears to be mediated by a combination of voltage-dependent block of the Ca2+ channel and inhibition of Ca2+ release from internal stores, and not from alterations in either Na+-Ca2+ coupled transport or Ca2+ sensitivity of the myofilaments.
J Mol Cell Cardiol 1987 May
PMID:Mechanisms of action of diltiazem in isolated human atrial and ventricular myocardium. 349 47

1. Experiments were performed to determine the mechanisms by which ethanol (EtOH) decreases the amplitude of voltage-dependent inward currents through calcium channels in Aplysia neurons. Voltage-clamp protocols used conditioning prepulses of varying amplitude, duration, and frequency, to examine the relationship between prior activity of the channel and EtOH action. Calcium and barium were used as charge carriers, allowing dissociation of effects due to inactivation of calcium channels from other perturbations resulting in the impediment of current flow through the open channel. 2. When Ba2+ was the charge carrier and channel activation was unconfounded by inactivation processes, the reduction of ICa produced by EtOH was independent of the voltage, frequency, or duration of conditioning prepulses. 3. When Ca2+ was the charge carrier, ICa was reduced as a function of conditioning prepulses, in three protocols used. EtOH enhanced this reduction, most probably because of its effects on the inactivation of ICa. Consistent with this interpretation, the time constant of decay of ICa was decreased, and recovery from inactivation was retarded by EtOH. 4. EtOH did not reduce ICa by a change in membrane surface potential, at least at low EtOH concentrations. 5. An analysis of the time course of development of ICa reduction by EtOH showed that it developed slowly, over a matter of minutes. 6. Our data indicate that EtOH does not reduce ICa by direct occlusion of the calcium channel. EtOH affects the inactivation of the calcium current, and this may occur by an action on the channel protein.
Cell Mol Neurobiol 1987 Jun
PMID:Ethanol-induced reduction of neuronal calcium currents in Aplysia: an examination of possible mechanisms. 365 15

This study was designed to examine whether diltiazem, a calcium channel-blocker, inhibits the cardiac ultrastructural alterations induced by coronary occlusion with or without reperfusion, in dogs anesthetized with pentobarbital. The left anterior descending coronary artery (LAD) was completely occluded for 60 min with or without reperfusion (induced by release of occlusion) for 20 min. Coronary occlusion increased ST segment in the ischemic area, and also produced typical ultrastructural alterations including decreased glycogen granules, destruction of mitochondria, and margination of the nuclear chromatin, especially in the subendocardium. Reperfusion of the ischemic area resulted in more severe alterations of the myocardial ultrastructure, including many myofibrillar contraction bands. Diltiazem was injected intravenously at the dose of 200 micrograms/kg (bolus injection) 20 min before LAD occlusion, and was then infused intravenously at the rate of 80 micrograms/kg/min for 10 min starting at the beginning of LAD occlusion, the total dose being 1 mg/kg. Diltiazem decreased heart rate and diastolic blood pressure, inhibited the increase in ST segment, and also inhibited the ultrastructural alterations induced by coronary occlusion, regardless of reperfusion. A bolus injection of diltiazem alone (200 micrograms/kg), however, did not inhibit markedly the ultrastructural alterations induced by coronary occlusion, regardless of reperfusion. It is concluded that the large dose of diltiazem (1 mg/kg) protects the myocardium from ischemic injury.
J Mol Cell Cardiol 1986 Apr
PMID:Protective effect of diltiazem on ultrastructural alterations induced by coronary occlusion and reperfusion in dog hearts. 371 50

The interaction of verapamil and other phenylalkylamine calcium channel blockers with the 1,4-dihydropyridine receptor was examined. Studies characterizing the interaction and relationship between calcium channel blocking potency and binding affinity were performed in rat myocardium. The 1,4-dihydropyridines, nifedipine and nitrendipine, interacted competitively. The apparent Kd and Bmax of nitrendipine were 270 +/- 140 pM and 390 +/- 76 fmol/mg protein, respectively. In contrast, the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor was not competitive. At a 3H-nitrendipine concentration of 0.12 nM, verapamil displaced only 60% of specifically bound radioactivity and progressively less as the concentration of 3H-nitrendipine increased. Kinetic data indicated that the interaction of both D600 and verapamil with the 1,4-dihydropyridine receptor was not cooperative. At infinite dilution the dissociation rate constant (k-1) was not altered in the presence of 10(-5) M D600. We examined the hypothesis that 3H-nitrendipine interacts at several sites with similar affinities and that the phenylalkylamines interact at one of these sites. Although D600 could not further displace 3H-nitrendipine in the presence of a maximally displacing concentration of nifedipine (10(-6) M), nifedipine could further displace 3H-nitrendipine in the presence of a maximally displacing concentration of D600 (10(-5) M). These results are consistent with competitive interactions at multiple sites but do not explain the diminished ability of the phenylalkylamines to displace progressively less radioactivity at increasing 3H-nitrendipine concentrations. No relationship between binding affinity and pharmacologic potency of the phenylalkylamines was found suggesting that the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor is not responsible for their calcium channel blocking effects.
J Mol Cell Cardiol 1986 Sep
PMID:The interaction of phenylalkylamine calcium channel blockers with the 1,4-dihydropyridine binding site. 378 30

We studied the effects of a calcium channel blocking agent, verapamil (V) (2 to 10 micrograms/ml), in the presence of increasing external calcium on simultaneously recorded transmembrane electrophysiological properties and mechanical function of rat myocardium. Left ventricular papillary muscles from male Fischer 344 rats were studied electrically, by standard microelectrode techniques, and mechanically in an isolated tissue bath at 30 degrees C. Control (0 micrograms/ml V + 2.4 mM Ca2+) = C, action potential duration at 50% and 75% repolarization (D50ap and D75ap) recorded from papillary muscles were short (14.1 +/- 0.75 ms; 33.3 +/- 2.7 ms) compared with recordings from papillary muscles subjected to increasing doses of verapamil (2, 4, 6, 8, or 10 micrograms/ml) + 2.4 mM Ca2+ = V, (17.3 +/- 0.77 ms; 121.4 +/- 8.9 ms: 10 micrograms/ml) (P less than 0.001). Upon augmentation of external calcium [10 micrograms/ml Verapamil + augmented Ca2+ (4.8, 7.2, or 9.6 mM] = VCa, D50ap and D75ap decreased but still remained significantly longer than control D50ap and D75ap (15.1 +/- 0.77 ms; 110.1 +/- 7.9 ms). Developed tension (Td), time to peak developed tension (TPT), time to one-half relaxation (T1/2R) and resting tension (Tr) decreased as a function of verapamil concentration. Although TPT and T1/2R returned toward C values when external calcium was increased, Tr continued to decrease while Td increased above control levels. A significant correlation was found between measured parameters of contraction and transmembrane action potential for C and VCa muscles. However, in V muscles no significant correlation was observed between these same mechanical and electrical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1985 Mar
PMID:Calcium induced reversible alterations in excitation-contraction coupling in verapamil treated rat myocardium. 383 26

We have previously reported that the negative inotropic effects of both verapamil and nifedipine on cat papillary muscles are enhanced as pH is lowered from 7.4 to 6.8 and 6.0. These studies have now been extended to compare the relative sensitization by acidosis of verapamil, nifedipine, lidoflazine, perhexilene and diltiazem. Developed tension was recorded in cat papillary muscles and the calcium concentration was adjusted over the range 2 to 10 mM. At pH 7.4, addition of all five drugs moved the dose response curve to the right with pA2 values from 4.82 (lidoflazine) to 9.94 (nifedipine). At pH 6.0, there was eight-fold sensitization by acidosis for verapamil, but four, three, and two-fold sensitization for nifedipine, lidoflazine and perhexilene. Diltiazem, however, was not sensitized by acidosis. The differential effects of acidosis on the negative inotropic properties of the five drugs may reflect their ancillary properties opposite gating of the calcium channel, local anaesthesia, intracellular calcium movement or Na+/Ca2+ exchange, but also suggest that diltiazem may have the property of inhibiting the effects of low pH on cell membranes.
J Mol Cell Cardiol 1985 Jul
PMID:The relative sensitization by acidosis of five calcium blockers in cat papillary muscles. 402 Aug 84


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