Influence of high sodium intake on urinary calcium excretion and cardiac calcium channels in spontaneously hypertensive rats.
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Animals↗
Biomedical subjects
A Rutledge
Publications and source records attributed to A Rutledge.
Binding of A 1,4-dihydropyridine calcium channel activator, (-) S Bay K 8644, to cardiac preparations.
The 1,4-dihydropyridine Ca2+ channel activator, (-) [3H]Bay K 8644, binds to cardiac membranes and polarized [5 mM K+] and depolarized [50 mM K+] cardiac cells. Binding to microsomal membranes at 25 degrees C indicates a single set of binding sites, KD = 2.9 x 10(-9) M and a site density, 337 fmoles/mg protein, not different from that measured by antagonist 1,4-dihydropyridines. Binding to neonatal rat myocytes at 37 degrees C was independent of membrane potential with a KD value of 5 x 10(-8)M and a site density, 63 fmoles/mg protein, not significantly different from that measured by PN 200 110. These results indicate that 1,4-dihydropyridine activators and antagonists label the same number of binding sites in cardiac tissue, but that activator binding to intact myocytes is voltage-independent.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Ca2+ channels in chick neural retina cells characterized by 1,4-dihydropyridine antagonists and activators.
The voltage-sensitive calcium channel in cultured chick neural retina cells was characterized by the actions of the enantiomers of Bay K 8644 and 202-791 and other 1,4-dihydropyridines. These cells showed time- and voltage-dependent Ca2+ uptake that was stimulated by K+ depolarization and blocked by the inorganic calcium channel blockers Cd2+ and Co2+. A small fraction only (15% maximum) of the uptake was inactivated by predepolarization of the cells with 80 mM K+. Ca2+ uptake was sensitive to the 1,4-dihydropyridine calcium channel antagonists and activators. (S)-Bay K 8644 and (S)-202-791 stimulated the Ca2+ uptake, and (R)-Bay K 8644 and (R)-202-791 as well as nitrendipine and PN 200-110 inhibited Ca2+ uptake stimulated by K+ depolarization or channel activators. The K+ depolarization-stimulated uptake was inhibited by 90%, but the activator-stimulated uptake was completely blocked by the 1,4-dihydropyridine antagonists. The potencies of these agents as inhibitors of Ca2+ uptake were significantly lower than the binding affinities in membrane preparations from the same cells or their binding and pharmacologic affinities in vascular smooth muscle. K+ depolarization or (S)-Bay K 8644 induced 45Ca2+ uptake was not observed in a glial cell culture. [3H]Nitrendipine and [3H]PN 200-110 bound to membrane preparations of the cells consistent with the presence of a single type of high affinity binding site.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Voltage-dependent binding of 1,4-dihydropyridine Ca2+ channel antagonists and activators in cultured neonatal rat ventricular myocytes.
Binding of 1,4-dihydropyridine Ca2+ channel ligands was characterized as a function of membrane potential using saturation, competition, and kinetic measurements in cultured neonatal rat ventricular myocytes. The 1,4-dihydropyridine antagonist [3H]PN 200-110 bound to polarized cells (5.8 mM K+) with a KD value of 3.53 X 10(-9) M and a Bmax value of 50.1 fmol/mg of protein. In depolarized cells (50 mM K+), a KD value of 6.33 X 10(-11) M was found, reflecting a 55-fold increase in affinity; Bmax did not change upon depolarization. Dissociation rates (k-1) of [3H]PN 200-110 binding were faster in polarized cells (0.53 min-1) than in depolarized cells (0.018 min-1), but association rates (k1 of 2.17 X 10(8) and 2.27 X 10(8) min-1M-1 were not different in polarized and depolarized cells. The KD values calculated from the ratio of k-1/k1 accorded well with those determined from equilibrium binding assays. The enantiomers of Bay K 8644 and 202-791 and a series of nifedipine analogs inhibited specific binding of [3H]PN 200-110 in depolarized cells. In polarized cells, the affinities of the S-enantiomers (activators) were close to those in depolarized cells; however, the affinities of R-enantiomers (antagonists) were 50- to 65-fold lower. The effects of both (S)- and (R)-Bay K 8644 on [3H]PN 200-110 binding were mediated through increased apparent KD values, without changes in Bmax and nH. In depolarized cells, l-D600 and d-D600 partially inhibited [3H]PN 200-110 binding to a maximum of 71% and 56%, respectively; in polarized cells, l-D600 (d-D600 not measured) was ineffective on [3H]PN 200-110 binding. d-(cis)-Diltiazem, but not l-(cis)-diltiazem, partially inhibited (maximum 30%) specific binding of [3H]PN 200-110 in depolarized cells, but potentiated (maximum 79%) binding in polarized cells. The potentiating effect of d-(cis)-diltiazem was mediated through an increase in affinity without change in Bmax of [3H]PN 200-110 binding. (S)-Bay K 8644 potentiated 45Ca2+ uptake into the cells, with an EC50 value of 4.26 X 10(-10) M; concentrations higher than 10(-7) M were inhibitory, producing a biphasic concentration-response relationship. (R)-Bay K 8644 inhibited 80 mM K+-stimulated 45Ca2+ uptake with an IC50 value of 2.11 X 10(-9) M. These pharmacologic values correlate well with the binding affinities.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Effect of thyroid status on beta-adrenoceptors and calcium channels in rat cardiac and vascular tissue.
To determine the influence of thyroid hormone on beta-adrenoceptors and Ca2+ channels, rats were treated with thyroxine (75 micrograms/100 g sc daily for 5 days) or propylthiouracil (0.05% in drinking water for 30 days). beta-Adrenoceptor density in ventricular tissue, measured by [125I]iodocyanopindolol binding, was significantly increased and decreased respectively, following thyroxine or propylthiouracil treatment to 124.7 +/- 7.11 fmol/mg protein and 71.98 +/- 5.37 fmol/mg protein from euthyroid (control) levels of 93.7 +/- 4.58 fmol/mg protein. Ca2+ channel density, measured by [3H]nitrendipine binding, was altered in the opposite direction; it was significantly decreased and increased to 324 +/- 24 fmol/mg protein and 691 +/- 31 fmol/mg protein from 562 +/- 35 fmol/mg protein after thyroxine or propylthiouracil treatment, respectively. No changes in affinity of either ligand were observed. Responses of isolated papillary muscles from propylthiouracil-treated animals accorded with changes seen in the binding studies. The geometric mean EC50 of isoproterenol increased from 9.5 x 10(-9) mol/l to 5.5 x 10(-8) mol/l, and the EC50 for calcium decreased from 3.16 x 10(-3) mol/l to 1.36 x 10(-3) mol/l; moreover, the responsiveness to the Ca2+ channel activator Bay K 8644 was increased. The corresponding responses in thyroxine-treated animals could not be examined because of prominent arrhythmic activity. As with papillary muscles the sensitivity of left atria to isoproterenol was decreased after treatment with propylthiouracil, with geometric mean EC50 values increasing from 3.21 x 10(-9) mol/l to 89.4 x 10(-9) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Crystal structures and pharmacologic activities of 1,4-dihydropyridine calcium channel antagonists of the isobutyl methyl 2,6-dimethyl-4-(substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nisoldipine) series.
A series of isobutyl methyl 2,6-dimethyl-4-(X-substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylates (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, 4-F, 2-CF3, 3-CF3, and 4-Cl) related to and including nisoldipine (X = 2-NO2) has been synthesized, their solid-state structures determined by X-ray analysis (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, and 4-F), and their pharmacologic activities determined, as the racemic compounds, against [3H]nitrendipine binding and K+-depolarization-induced tension responses in intestinal smooth muscle as measures of Ca2+ channel antagonist activity. Comparisons of structure are presented to previously analyzed 1,4-dihydropyridines. The degree of 1,4-dihydropyridine ring puckering is dependent on the nature and position of the phenyl ring substituent and the adopted interring conformation. Different ester substituents affect 1,4-dihydropyridine ring puckering to a small extent in most cases. Pharmacologic and radioligand binding activities for the nine compounds studied show a parallel dependence on phenyl ring substituent, but the compounds are approximately 10-fold more active in the radioligand binding assay than in the pharmacologic assay. Consistent with a previous report for the nifedipine series (Fossheim et al. J. Med. Chem. 1982, 25, 126), pharmacologic activity increases with increasing 1,4-dihydropyridine ring planarity.
Animals↗
The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations.
The activities of menthol and peppermint oil were determined in guinea-pig ileal smooth muscle, in rat and guinea-pig atrial and papillary muscle, in rat brain synaptosomes and in chick retinal neurones by pharmacological 45Ca2+ uptake and radioligand binding assays. Menthol is a major constituent of peppermint oil and is approximately twice as potent as peppermint oil as an inhibitor of K+ depolarization-induced and electrically stimulated responses in ileum and electrically stimulated atrial and papillary muscles. IC50 values in the ileal preparation ranged from 7.7 to 28.1 micrograms ml-1 and in the cardiac preparations from 10.1 to 68.5 micrograms ml-1. Similar potencies were demonstrated against K+ depolarization-induced 45Ca2+ uptake in synaptosomes and against K+ depolarization and Bay K 8644-induced uptake in chick retinal neurons. IC50 values for menthol inhibition of K+ and Bay K 8644 responses in the retinal neurons were 1.1 x 10(-4) M (17.2 micrograms ml-1) and 1.75 x 10(-4) M (26.6 micrograms ml-1), respectively, and for peppermint oil were 20.3 and 41.7 micrograms ml-1 respectively. Both menthol and peppermint oil inhibited specific [3H]nitrendipine and [3H]PN 200-110 binding to smooth and cardiac muscle and neuronal preparations with potencies comparable to, but slightly lower than, those measured in the pharmacological and 45Ca2+ uptake experiments. Binding of menthol and peppermint oil, studied at 78 micrograms ml-1, was competitive against [3H]nitrendipine in both smooth muscle and synaptosome preparations. The data indicate that both menthol and peppermint oil exert Ca2+ channel blocking properties which may underlie their use in irritable bowel syndrome. Ca2+ channel antagonism may not be the only pharmacological effect of menthol and peppermint oil contributing to intestinal smooth muscle relaxation.
Animals↗
Comparative aspects and temperature dependence of [3H]1,4-dihydropyridine Ca2+ channel antagonist and activator binding to neuronal and muscle membranes.
Binding of [3H]nitrendipine, [3H]nimodipine, and (+)[3H]PN 200-110 to microsomal preparations of guinea pig smooth and cardiac muscle and brain synaptosomes revealed high affinity interaction with KD values in the sequence, (+)PN 200-110 greater than nitrendipine greater than nimodipine. Bmax values for a particular tissue were independent of the 1,4-dihydropyridine employed in radioligand binding at 25 degrees C. The temperature dependence of [3H]nitrendipine binding in cardiac and smooth muscle microsomal preparations and brain synaptosomes was measured from 0 degrees to 37 degrees C and for skeletal muscle preparations from 0 degrees to 30 degrees C. Bmax values increased with temperature for cardiac membranes, but did not vary in other tissues. van't Hoff plots were nonlinear in all tissues, enthalpy and entropy changes becoming increasingly negative with increasing temperature. Competition binding of the activator-antagonist enantiomeric 1,4-dihydropyridine pairs of Bay k 8644 and PN 202-791 for [3H]nitrendipine in smooth muscle did not reveal significant thermodynamic differences between activator and antagonist molecules.
Animals↗
Pharmacologic and radioligand binding analysis of the actions of 1,4-dihydropyridine activator-antagonist pairs in smooth muscle.
The actions of the enantiomers of Bay K 8644 and 202-791 were studied in rat tail artery and guinea pig ileal longitudinal smooth muscle using pharmacologic and radioligand binding assays. (-)-(S)-Bay K 8644 (below 10(-7) M in rat tail artery and 3 X 10(-7) M in guinea pig ileum) and (+)-(S)-202-791 (below 10(-6) M) induced contractions and potentiated the responses to KCl depolarization in both smooth muscle preparations. In contrast, (+)-(R)-Bay K 8644 and (-)-(R)-202-791 inhibited the responses to KCl-induced depolarization. At higher concentrations, (-)-(S)-Bay K 8644 (10(-7) to 10(-6) M) and (+)-(S)-202-791 (10(-6) to 3 X 10(-5) M) in rat tail artery, and (-)-(S)-Bay K 8644 (3 X 10(-7) to 3 X 10(-6) M) in guinea pig ileal smooth muscle relaxed the tissues contracted maximally at lower concentrations of the same drug. Cross antagonism between 1,4-dihydropyridine activators was observed when (-)-(S)-Bay K 8644 (10(-7) to 10(-6) M) relaxed the maximum contraction in response to (+)-(S)-202-791. [3H]Nitrendipine bound in a tail arterial microsomal preparation to a single class of site, with KD of 3.63 X 10(-10) M and maximum binding of 552.7 fmol mg-1 protein. In both rat tail artery and guinea pig ileal smooth muscle, (-)-(S)-Bay K 8644, (+)-(R)-Bay K 8644, (+)-(S)-202-791 and (-)-(R)-202-791 inhibited specific [3H]nitrendipine binding competitively; the Kl values correlate well to the pharmacologic EC50 (for activators) or IC50 (for antagonists, measured against 80 mM KCl depolarization) values. The biphasic response to (-)-(S)-Bay K 8644 and (+)-(S)-202-791 suggests that the properties of Ca++ channel activation and antagonism may reside within a single 1,4-dihydropyridine molecule.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Calcium-dependence and antagonism of responses to alpha 1- and alpha 2-adrenoceptor agonists in vascular tissues from hypertensive and normotensive rats.
Inhibition by D600 (methoxyverapamil) of responses to an alpha 2-adrenoceptor selective agonist, B-HT 920, (6-allyl-2-amino-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d] azepin dihydrochloride), an alpha 1-adrenoceptor selective agonist, phenylephrine (PE), and a nonselective agonist, noradrenaline (NA), was studied in isolated preparations of the aortae and carotid arteries obtained from young (5-7 weeks) and old (15-17 weeks) hypertensive (SHR) and normotensive (WKY) rats. Maximum responses of WKY tissues to B-HT 920 were the most sensitive, PE-induced responses the least sensitive and maximum responses to NA were intermediate in their sensitivity to inhibition by D600. Sub-maximal responses to NA and PE were not different in their sensitivity to inhibition by D600, but were less sensitive than the responses to B-HT 20. Sub-maximal responses to PE were significantly more sensitive to D600 inhibition than were the maximal responses to this agonist. NA-induced responses of tissues from older SHR were less sensitive to inhibition by D600 when compared to responses in WKY rats. Responses to B-HT 920, in tissues suspended in calcium-free solutions, showed the largest decline compared to NA- and PE-induced responses. We conclude that responses to B-HT 920 largely utilize extracellular calcium. PE- and NA- induced responses mobilize extracellular calcium to varying degrees depending upon the concentration of the agonist employed to elicit the response.
Adrenergic alpha-Agonists↗
Absence of an effect of dietary corn oil content on plasma prolactin, progesterone, and 17 beta-estradiol in female Sprague-Dawley rats.
Enhancement of mammary tumorigenesis in rats by high-fat diets has been postulated to be due to altered hormonal status. Elevated serum prolactin and, in some cases, estrogen have been reported in rats fed diets high in corn oil or lard that increase 7,12-dimethylbenz(a)anthracene (DMBA) tumorigenesis. However, we have found no difference in plasma prolactin during the proestrus surge or at the other stages of the estrous cycle in rats fed a diet high (24%) in corn oil that augments DMBA-induced tumorigenesis or a control diet containing 5% corn oil. There was no effect of the same dietary treatment on plasma progesterone or serum estradiol in the same experiments. In addition, we found that DMBA administration did not change the blood concentration of any of the three hormones. Female Sprague-Dawley rats, bearing atrial cannulae and given a carcinogenic dose of DMBA at 8 weeks of age, were studied 2 to 5 weeks or 10 to 13 weeks after DMBA administration. Rats given only the oil vehicle for DMBA were studied at the same ages. Blood samples were taken from rats with 4-day estrous cycles at 3-hr intervals on the day of proestrus and at 6- to 12-hr intervals on the other days of the cycle. No effect of dietary corn oil content or of DMBA administration on plasma prolactin and progesterone was detected in either age group. On the afternoon of proestrus, rats were sampled more frequently to examine the hormonal patterns in detail; again, no dietary effect was detected. Serum estradiol was measured in rats that were fed the control or high-corn-oil diets, treated with DMBA or vehicle, and decapitated on one of the 4 days of the estrous cycle. There was no detectable effect of dietary corn oil content or DMBA treatment during any stage of the cycle. All three hormones showed qualitative and quantitative patterns identical to normal cycling rats at both ages studied. Our results indicate that earlier reports of an effect of dietary fat on blood prolactin and estrogen content may have been due either to diets low in essential fatty acids or to anesthesia-induced hormonal responses.
9,10-Dimethyl-1,2-benzanthracene↗
Chemical and pharmacological approaches to the definition and quantitation of calcium channels.
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Animals↗
Endometrial cancer and estrogen use. Report of a large case-control study.
Our case-control study of the relation between estrogen use and endometrial cancer involved 451 cases and 888 controls. The overall risk of endometrial carcinoma was sixfold for estrogen users as compared with nonusers; long-term users (greater than five years) had a 15-fold risk. Excess risk was present for both diethylstilberstrol and conjugated estrogens. The risk associated with cyclic use was as great as that for continuous use. Increased risk was associated with estrogen use for all histologic grades of the tumor. The risk of advanced-stage carcinoma was fourfold for estrogen users, but rhe confidence interval was wide, and this question requires further study. Finally, this investigation contradicts the speculation that the association between this cancer and estrogen use can be explained by swifter diagnosis for estrogen users, misclassification of estrogen-related hyperplasia or treatment of early symptoms of the tumor with estrogen.
Clinical Trials as Topic↗
Agreement rates between oral contraceptive users and prescribers in relation to drug use histories.
A comparison between prescriber records and patient-reported oral contraceptive histories obtained during a case-control study of thromboembolism and oral contraceptive use served as the basis for evaluating the extent of agreement between these two sources of information. Agreement between oral contraceptive user and prescriber was highest on the name of the most recently-used product (89% agreement), and dropped to 62.5% on the name of the product taken before the more recent one. For total duration of oral contraceptive use (to within one month of hospital admission), agreement (defined as differences not exceeding one month) was 36%, while 39% showed the users reporting longer duration of use, and 25% showed users reporting shorter duration. Cases showed a higher rate of agreement with prescriber records than the controls on both the name of the product and the total duration of use. Disagreement from prescriber records in the direction of reporting longer duration of use was 45% for the controls compared to 27% for the cases. These results indicate that while user information in connection with the most recently used oral contraceptive can be acceptable in studies employing the case-control research strategy, user reports about previous oral contraceptive use may be less useful.
Adolescent↗
Parenting during hospitalization.
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California↗
Hyperactivity in children: types, diagosis, drug therapy, approaches to management.
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Amphetamine↗
Dietary sodium intake: influence on calcium channels and urinary calcium excretion in spontaneously hypertensive rats.
Binding of the 1,4-dihydropyridine [3H]PN200 110 was employed as an index of cardiac Ca2+ channels in normotensive (WKY) and spontaneously hypertensive (SHR) rats during 4 weeks of normal (0.73% NaCl) and high (8% NaCl) sodium diets when the rats were between 20 and 24 weeks of age. Binding site density was not different at the beginning of the study but was increased significantly (P less than 0.01) after 1 week in the SHR on a high sodium diet; this difference was not apparent at 2, 3 or 4 weeks of the diet. During this same period, the urinary Ca2+ excretion in SHR was enhanced significantly (P less than 0.01) and the urinary calcium/sodium ratio was elevated during the high sodium intake period.
Animals↗