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At least 1,063 records · Page 59Linked to original sources
PubMed1992

Cardiovascular effects of a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent, YM-16151-4, in anesthetized and conscious dogs.

Cardiovascular effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in dogs. In anesthetized dogs, YM-16151-4 (0.01-1 mg/kg intravenously, i.v.) dose-dependently increased coronary blood flow (CBF) and decreased mean blood pressure (MBP), total peripheral resistance (TPR), dP/dtmax, double product, and left ventricular (LV) work without increasing heart rate (HR) and cardiac output (CO). YM-16151-4 increased vertebral blood flow as well as CBF, but had no effect on carotid, mesenteric, renal, and femoral blood flow. Coronary vasodilating activity of YM-16151-4 was also observed after intracoronary artery injection (i.a.). In anesthetized and vagotomized dogs, YM-16151-4 dose-dependently inhibited isoproterenol (0.2 micrograms/kg i.v.)-induced tachycardia and decrease in diastolic BP (DBP), with ED50 values of 0.039 and 0.52 mg/kg i.v., respectively. In conscious dogs, YM-16151-4 (0.1-1 mg/kg i.v.) produced a dose-dependent hypotensive effect with no effect on HR or PQ-interval. The hypotensive effect of YM-16151-4 (0.3 and 1 mg/kg i.v.) reached its maximum approximately 1-2 h after each dosing and lasted 6-8 h. These results suggest that YM-16151-4 actually behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and that this compound could be a novel long-acting antianginal and antihypertensive agent.

Adrenergic beta-Antagonists↗
PubMed1983

Inhibition by sulfur-containing amino acids and GABA of sympathetic neurotransmission in guinea-pig vas deferens.

Electrical stimulation produced a contraction in the isolated guinea-pig vas deferens. This response was blocked by tetrodotoxin, guanethidine and bretylium but not by atropine. The magnitude of the contractile response to electrical stimulation depended on the concentration of the external calcium. Sulfur-containing amino acids and GABA inhibited the electrically induced contraction but not that caused by noradrenaline and ATP. The order of potency for inhibition of the contraction at a concentration of 10(-4) M being GABA greater than or equal to cysteine greater than methionine greater than cysteic acid greater than taurine. The contractile response to electrical stimulation was also inhibited by EGTA, this inhibition being similar to that by cysteic acid and taurine but weaker than that by methionine, cysteine and GABA at a concentration of 10(-4) M. The inhibitory action of sulfur-containing amino acids and GABA was abolished by increasing the calcium concentration in the medium. The results suggest that sulfur-containing amino acids and GABA reduce transmitter release from the sympathetic nerve terminals by inhibiting calcium availability for the transmitter secretion process.

Adenosine Triphosphate↗
PubMed1991

Developmental aspects of bladder contractile function: sensitivity to extracellular calcium.

The urinary bladders of 1-day and 1-week-old rabbits generate higher intravesical pressures in response to bethanechol and field stimulation than bladders isolated from mature 8-week-old rabbits. Yet the density of cholinergic receptors in the rabbit bladder does not change with maturation (1 day to 8 weeks). In an effort to better understand the molecular mechanisms by which newborn rabbit bladders generate greater pressures than the bladders of adult rabbits, we studied the effect of maturation on the relationship between extracellular calcium and contraction. Our results showed quite clearly that (1) at physiologic concentrations of calcium (2.5 mumol/l), isolated bladder strips of 1-day- and 1-week-old rabbits contracted in response to bethanechol to 98% of their maximal tension as opposed to 68% for their 8-week-old counterparts, (2) the ED50 (for calcium) for the 1-day and 1-week bladders was 0.4 mmol/l whereas the ED50 for the adult bladder strips was 2.2 mmol/l, and (3) the neonatal bladders demonstrated a much greater sensitivity to diltiazem than the adult bladders. The contractile response to calcium of the neonatal bladders was significantly inhibited by 1 mumol/l diltiazem whereas the 8-week-old bladders showed no inhibition at this concentration. In a second series of experiments, the effect of extracellular calcium on concentration was correlated with the intracellular concentration of free calcium using the calcium fluoride FURA-2 and surface spectrofluorometry. These studies confirmed that the increased contractile response of the neonatal bladder strips to calcium or cholinergic agonists was associated with an increase in the maximal intracellular free calcium concentration.

Animals↗
PubMed2006

Identification of a novel regulatory mechanism for norepinephrine transporter activity by the IP3 receptor.

The norepinephrine transporter (NET) plays a crucial role in noradrenergic neurotransmission and is a target of many antidepressants and psychostimulants. Intracellular Ca2+ is reportedly involved in regulating NET activity, but the detailed mechanism is not clear. We employed a norepinephrine uptake assay using SH-SY5Y cells and found that the IP3 receptor inhibitors, 2-aminoethoxydiphenyl borate and xestospongin C, reduced the NET Vmax. These reductions were accompanied by the decreased cell surface expression of NET. Our findings suggest that intracellular Ca2+ mobilized by IP3 receptor is required for the maintenance of NET activity. This adds another pathway involving Ca2+ for the regulation of NET to other known mechanisms providing intracellular Ca2+.

Biological Transport↗
PubMed2000

Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-diones as AT(1) angiotensin II receptor antagonists.

On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.

Angiotensin II↗
PubMed2002

2-aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release.

Since its introduction to Ca2+ signaling in 1997, 2-aminoethoxydiphenyl borate (2-APB) has been used in many studies to probe for the involvement of inositol 1,4,5-trisphosphate receptors in the generation of Ca2+ signals. Due to reports of some nonspecific actions of 2-APB, and the fact that its principal antagonistic effect is on Ca2+ entry rather than Ca2+ release, this compound may not have the utility first suggested. However, 2-APB has thrown up some interesting results, particularly with respect to store-operated Ca2+ entry in nonexcitable cells. These data indicate that although it must be used with caution, 2-APB can be useful in probing certain aspects of Ca2+ signaling.

Animals↗
PubMed1975

Prevention of hereditary cardiomyopathy in the hamster by verapamil and other agents.

Verapamil, Prenylamine and, to a lesser extent, Cinnarizine were highly efficient in preventing the development or reducing the severity of heart lesions in cardiomyopathic hamster of the UM-X7.1 line. The calcium antagonistic compounds did not protect against the skeletal muscle changes already present at the time when treatment was initiated. The cardiac lesions were also significantly diminished in frequency and severity by a low calcium diet and in apparent contradiction, by parenteral administration of calcium gluconate. The relation of these electrolytes and creatine phosphokinase is not yet fully understood but suggests that a primary defect in muscles cell membranes may be responsible for hereditary cardiomyopathy in hamsters.

Animals↗
PubMed1998

Verapamil use in patients with cardiovascular disease: an overview of randomized trials.

BACKGROUND: Several reports have questioned the lack of safety data on calcium antagonists as a drug class. Because this drug class is heterogeneous, unique features of certain calcium antagonists may set them apart in terms of safety and efficacy. HYPOTHESIS: With in excess of 7,000 person-years of observation from randomized clinical trials, verapamil was selected to evaluate whether there was evidence of harm in patients with cardiovascular disease. METHODS: MEDLINE search of English-language articles, Science Citation Index, Current Contents, manual review of cited references, pharmaceutical files, and investigator correspondence was performed. Independent review of 66 articles identified 14 randomized, parallel-group studies for inclusion. Independent, duplicate assessments were made of patient outcomes and trial characteristics (including study design, treatment dosage and schedule, duration of treatment, inclusion criteria, and sample size). Standard meta-analytic techniques were employed for analysis and interpretation of results. RESULTS: Based on over 4,000 person-years of observation, patients with acute myocardial infarction (MI) treated with verapamil had a decreased risk of nonfatal reinfarction compared with placebo (relative risk 0.79; 2-sided 95% confidence interval 0.65.0.97; p = 0.024). Verapamil had no significant effect on overall mortality compared with placebo (relative risk ranged from 0.93; 2-sided 95% confidence interval 0.78, 1.10; p = 0.40 to 0.86; 2-sided 95% confidence interval 0.71, 1.04; p = 0.13) depending on rules used to include or exclude patients from the pooling process. For the combined outcome of death or reinfarction, verapamil use was associated with a decreased risk compared with placebo (relative risk 0.82; 2-sided 95% confidence interval 0.70, 0.97; p = 0.016). In patients with angina involving a wide spectrum of disease severity, data were limited to 2,900 person-years of observation, and verapamil use did not appear to be associated with an apparent effect on mortality or MI. Data available from randomized studies of verapamil in patients with hypertension were too limited to reach conclusions (50 person-years of observation, with no deaths or MIs reported). Subgroups of hypertensive patients in two of the largest post-MI studies and the largest angina study, involving over 600 patients, yielded little useful added information. CONCLUSIONS: In patients with MI, the risks of both nonfatal reinfarction and the combined outcome of death or nonfatal MI were reduced over intermediate-term follow-up among patients treated with verapamil compared with controls (p = 0.024 and p = 0.016, respectively). In patients with angina, no evidence for harm was noted, but in hypertension the data were too limited to draw conclusions. These findings support the need to distinguish among different calcium antagonist compounds and to emphasize the need for more data in patients with hypertension.

Angina Pectoris↗
PubMed1990

Block by a putative antiarrhythmic agent of a calcium-dependent potassium channel in cultured hippocampal neurons.

The actions of a new, putative antiarrhythmic drug, KC-8851 on single channel currents in hippocampal CA1 neurons have been studied. A calcium-dependent potassium current IK(Ca) was activated in the cultured neurons when a solution containing 140 mM K+ and 0.2 mM Ca2+ was applied to inside-out patches. Addition of the compound KC-8851, at concentrations between 1-50 microM, resulted in significant, dose-dependent, decreases in the mean open times of the K channel. The onward (blocking) rate constant was determined from a simple channel blockade scheme and was 5 x 10(7) M-1s-1; this rate constant was not dependent on voltage. Addition of KC-8851 to the solution bath with outside-out patches also caused significant decreases in the mean open times of the IK(Ca) channel consistent with channel blockade by the drug.

Animals↗
PubMed1992

The effect of dietary calcium supplementation on intestinal lipid metabolism.

Population studies in man and experimental animal work support the contention that dietary supplementation with calcium may prevent the development of colorectal cancer. The mechanism of action is postulated to be bile acid chelation in the small-bowed forming non-toxic calcium soap compounds but such substances have yet to be isolated and quantified. In this 2-part study faecal concentrations of acidic lipids and neutral sterols were measured in 93 Sprague-Dawley rats whose calcium intake was modulated by enriching the chow and adding calcium lactate (24 milligrams) to the drinking water. In study-1 (dietary calcium intake doubled from 0.4-0.8%) small bowel resection was used to manipulate colonic lipid concentration for comparison with control rats who had undergone transection with immediate restoration of bowel continuity at an equivalent point. Faecal concentrations of free bile acids were 53-67% less in animals receiving added calcium [1.76 +/- 1.33 vs 0.82 +/- 0.65 mg/g (transection); 2.74 +/- 3.73 vs 1.03 +/- 1.27 mg/g (small bowel resection): P less than 0.001]. In study-2 (dietary calcium intake trebled to 1.21%) faecal bile acid concentration was reduced by 32% (1.86 +/- 0.57 vs 1.27 +/- 0.34 mg/g: NS) whereas long chain fatty acid concentrations were increased by 117% (6.77 +/- 2.39 vs 14.67 +/- 4.82 mg/g: P less than 0.001) in animals receiving added calcium. Serum calcium levels remained unchanged in these animals. Calcium soaps of the bile acids were not detected in faeces and therefore contrary to popular theory these results indicate that conditions within the intestinal lumen favour calcium chelation of long chain fatty acids rather than bile acids.

Animals↗
PubMed2004

Exploring the pharmacology of the leukotriene B4 receptor BLT1, without the confounding effects of BLT2.

Most previous studies of leukotriene B4 (LTB4) pharmacology using primary leukocyte cultures and myeloid cell lines do not differentiate between leukotriene BLT1 and BLT2 receptor activation because both receptors are often expressed by these cells. Here we show that in HeLa cells expressing BLT1 but not BLT2 receptors, BLT1 receptor activation resulted in IP3 mediated calcium release from intracellular stores initially, followed by calcium influx through cell membrane channels. BLT1 calcium signalling was sensitive to the activity of protein kinase C (PKC), protein kinase A (PKA) and protein-tyrosine kinases (PTKs), as well as changes in membrane cholesterol levels and treatments that are known to disrupt normal membrane physiology and/or lipid rafts. Inhibition of MAP kinases, Rho-associated kinases, or phosphoinositol-3-kinases (PI3K) had no effect on BLT1 receptor induced calcium signalling, and the receptor was insensitive to the redox state of the extracellular compartment.

Boron Compounds↗
PubMed1983

Influence of castration of the neonatal rat on the contractile effects of barium chloride and adrenaline in isolated vas deferens: the role of calcium.

Time-response curves to maximal concentrations of barium chloride (BaCl2) (3 X 10(-2) M) and adrenaline (10(-4) M) were studied in vasa deferentia from 3-month-old rats castrated at birth. Either barium or adrenaline was left in the organ baths for 5-min periods, at intervals of about 30 min, and the corresponding isotonic contractions recorded. Two types of effects were measured: the fade response (Jurkiewicz et al., 1977) and the rate at which responses were reduced after Ca2+ withdrawal from nutrient solution. The fade response for BaCl2 was strikingly greater than that in controls. When calcium was removed from the nutrient solution, an almost complete loss of the response to BaCl2 was achieved in less than 3 min for preparations of 3-day castrates, in about 40 min for the organs of 15-day castrates, and in more than 140 min for normal preparations. Treatment with testosterone, 1 week before the experiments, abolished the fade response to BaCl2 and antagonized the loss of responsiveness observed for this substance in a calcium-deficient solution. These data suggest that the production of testosterone by the testis during the critical period of neonatal differentiation is important for the translocation of calcium ions in the isolated vas deferens of the adult rat.

Animals↗
PubMedDate not supplied

Comparison of the effects of endrallazine, hydrallazine and verapamil on human isolated arteries and veins.

1. The antagonist effects of endrallazine (BQ 22-708), hydrallazine and verapamil have been studied on the contractile responses produced by various agonists on human digital arteries and metacarpal veins obtained post mortem. 2. Endrallazine and hydrallazine antagonized the contractile responses to noradrenaline and serotonin in arteries by shifting the concentration-effect curves to the right and by reducing the maximum responses to both agonists. Neither drug had any effect on responses to BaCl2 in either tissue. 3. The same concentrations of endrallazine and hydrallazine which antagonized responses to noradrenaline and serotonin in arteries, had no effect on concentration-effect curves to those agonists in veins. 4. Hydrallazine was significantly more potent than endrallazine in reducing the maximum response to noradrenaline in arteries, and was less potent than endrallazine in reducing the maximum response to serotonin. 5. Verapamil antagonized the vasoconstrictor effect of all agonists tested in both arteries and veins. 6. It is concluded that in a similar manner to hydrallazine, endrallazine has a direct effect on human vascular smooth muscle at concentrations which are probably similar to those occurring in vivo. Both hydrallazine and endrallazine may produce selective arterio-dilatation by preventing the release of bound calcium from intracellular storage sites, an effect which is different to that of verapamil.

Arteries↗
PubMed1989

3-Amino-1-hydroxypropylidene-1,1-diphosphonate (APD): a novel enhancer of rectal cefoxitin absorption in rats.

The promoting action of the calcium chelating compound EDTA on intestinal drug absorption is supposed to be based on Ca2+ depletion, inducing widening of tight junctions. The aim of the present study was to evaluate the effects of the calcium-binding agent 3-amino-1-hydroxypropylidene-1,1-diphosphonate disodium salt (APD) on rectal cefoxitin absorption in rats. The extent of rectal cefoxitin absorption was enhanced by 0.5 to 6% w/v of APD, on rectal infusion as well as on bolus delivery, the latter regimen tending to result in lower bioavailabilities. A maximal cefoxitin bioavailability of 85 +/- 10% was achieved by infusion with 4% w/v of APD, compared with 14 +/- 12% without APD.

Animals↗
PubMed1984

The effect of the calcium antagonist verapamil on gastric acid secretion in humans.

Studies on isolated gastric glands and parietal cells suggest that calcium plays a role in the stimulus-secretion coupling of acid secretion. To determine which stimulants of human gastric secretion depend on calcium-mediated receptors, the effect of the calcium antagonist verapamil on gastric secretion was studied. Gastric secretion was stimulated by intravenous infusion of 50 micrograms/kg/h bethanechol, 10 micrograms/kg/h impromidine, 0.5 micrograms/kg/h pentagastrin, 4 mg/kg/h Ca++, or by sham feeding. Each type of stimulation was tested twice in six healthy subjects, alone and together with verapamil. Verapamil was administered as an intravenous bolus of 200 micrograms/kg followed by an infusion of 150 micrograms/kg/h. Six subjects had 2 step tests in which 4 doses of pentagastrin were administered consecutively in increasing dosage. Pentagastrin was given either alone or superimposed on a verapamil bolus followed by an intravenous infusion. Verapamil left gastric secretion stimulated by bethanechol, impromidine, or sham feeding unaffected. During Ca++ infusion verapamil caused a significant drop in volume, but not acid output. Pentagastrin-stimulated acid and volume output were significantly inhibited by intravenous verapamil, the inhibition resembling an uncompetitive pattern. Pentagastrin-stimulated gastric secretion was also inhibited by the calcium antagonist diltiazem. The results confirm earlier reports that calcium is involved in the stimulus-secretion coupling of the human gastric mucosa. Calcium appears to mediate the stimulation of acid secretion by gastrin.

Adult↗