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T Godfraind

Publications and source records attributed to T Godfraind.

At least 109 records · Page 6Linked to original sources
PubMed1987

Prolonged depolarization increases the pharmacological effect of dihydropyridines and their binding affinity for calcium channels of vascular smooth muscle.

Experiments were performed on isolated rat mesenteric arteries with the calcium-antagonistic dihydropyridine derivative PN 200-110 in order to examine how its time-dependent effect on K+-evoked contraction might be related to voltage sensitive binding. (+)-PN 200-110 is a potent blocker of the K+-contraction in mesenteric artery. Inhibition of the K+-contraction was time-dependent and dose-effect curves were shifted to the left with the duration of depolarization. The (-)-isomer of PN 200-110 was less potent than the (+)-isomer but its action was also time-dependent. (+)-[3H]PN 200-110 binding has been determined in arteries bathed in physiological or high K+-solutions. Nonspecific binding measured in the presence of 10(-6) M nifedipine was not different in polarized and in depolarized arteries but specific binding was increased markedly after 30 min of depolarization. Specific binding data were well fitted by one hyperbolic curve describing a one-to-one binding to a single class of sites. Maximum binding capacity was unchanged whereas apparent dissociation constant was significantly lower in depolarized arteries. Depolarization also shifted to the left displacement curves of (+)-[3H]PN 200-110 by (+)- and (-)-PN 200-110. These results indicate that time-dependent effect of dihydropyridines in vascular smooth muscle is related to increased affinity of depolarized arteries for those drugs, suggesting that calcium channels in vascular smooth muscle are modulated by membrane potential in a way similar to that reported for cardiac muscle.

Animals↗
PubMed1986

Evidence that mammalian lignans show endogenous digitalis-like activities.

Enterolactone, a lignan that has been identified in biological samples from man and several mammals, shares with ascorbic acid and cardiac glycosides a gamma-butyrolactone. It displaces 3H-ouabain from its binding sites on cardiac digitalis receptor and inhibits, dose dependently, the Na+, K+-ATPase activity of human and guinea-pig heart. The time dependence of this inhibition resembles that of dihydroouabain, a cardiac glycoside in which the lactone ring does not contain conjugated double bonds. The active concentrations of enterolactone as inhibitor of Na+,K+-ATPase are in the 10(-4) M range and, at those concentrations, the cross-reactivity with antidigoxin antibodies is low. Lignans may contribute to the putative digitalis-like activity found in tissues, blood and urine of several mammals including man.

4-Butyrolactone↗
PubMed1986

Inhibition of the erythrocyte Na+, K+-pump by mammalian lignans.

Several mammalian lignans, particularly enterolactone, 3-oxy-methyl enterolactone and prestegane B are able to inhibit Na+, K+-pump activity in human red cells with IC50 of about 1 mM. The inhibition of Na+, K+-pump activity by mammalian lignans have the following properties: the IC50 for ouabain remains unchanged suggesting a noncompetitive inhibition. The apparent affinity for internal Na+ and maximal rate of cation translocation are both diminished. The above inhibition of the Na+, K+-pump was obtained at doses 2-3 orders of magnitude higher than those required for ouabain. However we cannot exclude that a glycosyl- (and/or butenolide)-derivative of enterolactone could be one endogenous ouabain-like factor.

Cross Reactions↗
PubMed1986

Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta.

The effect of endothelium on the adrenolytic action of prazosin was studied in the rat isolated aorta. Prazosin showed a non-competitive type of antagonism in preparations with intact endothelium while in preparations where endothelium had been removed, prazosin at concentrations between 0.3 nM-10 nM acted as a competitive antagonist. Methylene blue, used to decrease tissue levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP), converted prazosin from a non-competitive antagonist into an apparently competitive antagonist in the presence of endothelium. Increasing tissue levels of cyclic GMP by incubation with 8-bromo-cyclic GMP converted prazosin from an apparently competitive antagonist into a non-competitive antagonist in the absence of endothelium. Analysis of concentration-response curves for noradrenaline in the presence and absence of endothelium showed that the affinity for noradrenaline was the same but the efficacy, measured by estimating the receptor reserve, was not; it was lower in the presence than in the absence of endothelium. It was concluded that the change in the mode of antagonism of prazosin after endothelium removal could be related to an alteration in the efficacy of the agonist, brought about by a change in the tissue levels of cyclic GMP.

Animals↗
PubMed1986

Selective inhibition by ethylisopropylamiloride of the positive inotropic effect evoked by low concentrations of ouabain in rat isolated ventricles.

The biphasic positive inotropic effect of ouabain has been studied in rat ventricular strips in the presence of ethylisopropylamiloride (EIPA) an inhibitor of Na+/H+ exchange. EIPA (10-20 microM) depressed dose-dependently the high affinity component of the ouabain inotropic effect, whereas it did not significantly modify the low affinity inotropic effect related to high concentrations of ouabain. At the EIPA concentrations studied, there was no observable modification of the inotropic effect of Bay K 8644 (10 nM, 0.3 microM) or of isoprenaline (10 nM, 1 microM). These results indicate that the inotropic effect of ouabain resulting from its interaction with high affinity sites is selectively sensitive to EIPA.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Calcium entry blockade and excitation contraction coupling in the cardiovascular system (with an attempt of pharmacological classification).

Calcium may be considered as the final intracellular messenger of excitation-contraction coupling. In this report the main mechanisms involved in the cellular regulation of calcium movements are reviewed. Most of the pharmacological agents actually available for therapy interfere with the processes responsible for increase in cytoplasmic activator calcium. Study of the relation between contraction and calcium movements shows that blockade of calcium entry may cause inhibition of contraction. This has allowed to illustrate some of the characteristics of calcium channels in smooth muscle. Potential-operated channels are activated by changes in membrane potential, that can be evoked by K-rich solutions. They are completely blocked by calcium antagonistic dihydropyridines and diphenylpiperazines. This blockade shows (time-)-use-dependence. They are opened by calcium agonistic dihydropyridines. Receptor-operated channels are activated by the interaction of an agonist with its receptors; they are incompletely blocked by calcium antagonistic dihydropyridines and diphenylpiperazines. Endothelium appears to modulate the response of the adjacent smooth muscle to vasoconstrictors. This may be accounted for by modulation of calcium metabolism, both at the level of membrane channels and of intracellular stores. As a consequence, endothelium modulates the action of calcium entry blockers. Study of isolated human tissues illustrates difference in drug sensitivity between cardiac and smooth muscle. Human isolated coronary arteries are sensitive to nifedipine concentrations found in the blood of patients receiving therapeutic regimen. These concentrations do not alter the contractility of the isolated human myocardium. Differences between drugs may be explained assuming that they may interact with one of the states (closed, open, inactivated) of the Ca channels. This also helps the understanding of tissue selectivity of some compounds. A pharmacological classification of calcium entry blockers may be proposed. This classification is a rationale to differentiate between the various clinical indications of drugs affecting calcium movements.

Adenosine Triphosphate↗
PubMed1985

Interaction of cardiodigin, endogenous inhibitor of Na+,K+-ATPase, with antidigoxin and antidigitoxin antibodies.

The present study was undertaken to further characterize the immunoreactivity of cardiodigin, digitalis-like factor present in mammalian tissues. Guinea-pig heart extracts purified by reverse-phase low pressure and high pressure liquid chromatographies were analysed for their cross-reactivity with antidigitoxin and antidigoxin antibodies. The putative digitalis-like factor showed an affinity about 10 times higher for antidigoxin antibodies than for antidigitoxin antibodies. EC50 ratios (digoxin/digitoxin assay) determined at two purification steps were different from those of digoxin and digitoxin. These results show that cardiodigin presents molecular determinants recognizable by antidigoxin and antidigitoxin antibodies but that it is a chemical entity different from these well known cardioactive steroids.

Animals↗
PubMed1985

Further characterization of cardiodigin, Na+, K+-ATPase inhibitor extracted from mammalian tissues.

This study was undertaken to characterize endogenous digitalis-like activity in water extract from mammalian tissues. Prepurified samples obtained from guinea-pig heart were analysed by reverse-phase HPLC using an acetonitrile gradient. The eluent was assayed for its activity as inhibitor of human heart Na+, K+-ATPase and digoxin-like immunoreactivity. Both activities were recovered in the same fraction after two successive chromatographic steps. These results provide further evidence for the presence of an endogenous digitalis-like factor, cardiodigin, in mammalian heart.

Animals↗
PubMed1985

Role of endothelium in the contractile response of rat aorta to alpha-adrenoceptor agonists.

The influence of endothelium on the response of rat isolated aorta to alpha-adrenergic agonists has been studied by comparing the response of intact and denuded preparations before and after treatment with calcium entry blockers flunarizine and nifedipine. Endothelium removal enhanced the response of the preparations, especially to alpha 2-agonists that had a weak effect in intact preparations. In the absence of endothelium, about 80% of the maximum response to clonidine was blocked by calcium entry blockers, whereas only 25% of the maximum response to noradrenaline was sensitive to them. In contrast about 40% of maximum noradrenaline-evoked contractions was sensitive to calcium entry blockers in the presence of endothelium. This may be attributed to an increase in the intracellular exchangeable calcium fraction, likely to be due to a slight depolarization of smooth muscle membrane of denuded preparations, which are highly sensitive to the calcium agonist BAY K 8644. The results indicate that a factor liberated by endothelial cells controls both calcium entry and calcium release evoked by alpha-adrenoceptor agonists in vascular smooth muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Subcellular localization of [3H]-nitrendipine binding sites in guinea-pig ileal smooth muscle.

The binding of [3H]-nitrendipine was studied in microsomal fractions isolated from guinea-pig ileal smooth muscle. Only one class of specific binding sites was detected, with a KD of 0.4 nM. For various dihydropyridine derivatives, including the stereoisomers of nimodipine and the 'Ca agonist' Bay K 8644, the potency for inhibition of [3H]-nitrendipine binding correlated well with the reported pharmacological potency in smooth muscle preparations. To establish the subcellular localization of [3H]-nitrendipine binding sites, untreated and digitonin-treated microsomal fractions were subfractionated by isopycnic density gradient centrifugation. The density distribution of [3H]-nitrendipine binding was markedly shifted by digitonin towards higher densities, as were the distributions of 5'-nucleotidase and [3H]-ouabain binding, whereas the distributions of NADPH:cytochrome c reductase and NADH:cytochrome c reductase were hardly modified by digitonin. It is concluded that most, if not all, [3H]-nitrendipine binding sites in guinea-pig ileal smooth muscle are present in the plasma membrane, in agreement with the postulated mode of action of dihydropyridines as inhibitors of plasmalemmal Ca channels.

5'-Nucleotidase↗
PubMed1985

The positive inotropic action of the nifedipine analogue, Bay K 8644, in guinea-pig and rat isolated cardiac preparations.

The inotropic effect of Bay K 8644 has been studied in rat and guinea-pig atria and ventricular strips stimulated at 1 Hz, in a medium containing CaCl2 1.8 mM. The positive inotropic effect at maximal effective concentrations of Bay K 8644 was in the following order: guinea-pig ventricle greater than rat ventricle greater than guinea-pig atria greater than greater than rat atria. In rat preparations, the tension recorded at maximum effective concentrations of Bay K 8644 was similar at three different calcium concentrations (0.7, 1.8, 3.0 mM). The amplitude of the positive inotropic effect evoked by Bay K 8644 increased when atrial and ventricular contractions were reduced by lowering the external calcium concentration. The contractile tension reached in the presence of maximum effective concentrations of Bay K 8644 (3 X 10(-7) -1 X 10(-6) M) was greater than that produced by the maximum effective concentration of external calcium (3 mM) in rat ventricles but not in rat atria. High doses of nifedipine (3 X 10(-7) -1 X 10(-6) M) depressed the contraction of rat atria more than the contraction of rat ventricles. In rat ventricles, nifedipine shifted to the right the inotropic dose-effect curve of Bay K 8644. It is concluded that the interaction between nifedipine and Bay K 8644 occurred at the same binding sites. These sites have some characteristics of the low affinity binding sites of nifedipine and other related dihydropyridines.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Effects of tabernanthine on calcium and catecholamine stimulated contractions of isolated vascular and cardiac muscle.

The Iboga alkaloid tabernanthine (80 microM) non-competitively antagonized contractions in both the rat aorta and mesenteric artery induced by cumulative additions of noradrenaline and calcium. Tabernanthine (8, 40 and 80 microM) antagonized the K+ depolarization-induced contractions of the aorta. Tabernanthine (80 microM) depressed the phasic component of contractions induced by a single maximal concentration (10 microM) of noradrenaline in Ca++ -free solution. Tabernanthine induced a negative inotropic effect in electrically stimulated myocardial tissue and a negative chronotropic effect in the perfused rat heart. Tabernanthine is a calcium entry blocker which also affects cellular calcium metabolism.

Alkaloids↗