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T Godfraind

Publications and source records attributed to T Godfraind.

At least 145 records · Page 8Linked to original sources
PubMed1983

Actions of nifedipine on calcium fluxes and contraction in isolated rat arteries.

Experiments were performed on isolated rat aorta and superior mesenteric artery in order to study the action of nifedipine on norepinephrine and K-depolarization-evoked contractions and transmembrane calcium fluxes. Concentration-dependent contractions were obtained with norepinephrine in physiological solution and with Ca++ in K-depolarizing solution. Nifedipine caused a concentration-dependent depression of the maximum response. When aorta was depolarized by 40 mM KCI (instead of usual 100 mM KCI concentration), high concentrations of Ca++ evoked a relaxation that was also blocked by nifedipine. The action of nifedipine has been examined on Ca influx and efflux in arteries stimulated by norepinephrine and K-depolarization. Norepinephrine-evoked Ca influx, but not Ca efflux, was reduced by nifedipine. Concentration inhibitory curves for Ca influx and contraction could be superimposed. K-depolarization-dependent Ca entry and Ca efflux were blocked by nifedipine at concentrations lower than those required to antagonize norepinephrine actions. The results suggest that the action of nifedipine on artery contractility can be related to blockade of calcium entry through channels opened during depolarization or receptor-response coupling.

Animals↗
PubMed1983

Specificity of action of Ca++ entry blockers. A comparison of their actions in rat arteries and in human coronary arteries.

Among the large number of compounds which inhibit the contraction evoked by calcium in depolarized smooth muscle, calcium entry blockers are those that specifically block calcium entry during muscle activation. They affect neither Ca++ efflux nor intracellular Ca++ release. A comparative study of the diphenylpiperazines, cinnarizine and flunarizine, with the dihydropyridine, nifedipine, allows conclusions to be drawn as to their specificity of action. We have also examined the action of calcium entry blockers, considering tissue and stimulus selectivity. The inhibition of smooth muscle contraction can be quantitatively related to blockade of Ca++ influx. In rat aorta and mesenteric arteries, the potency of Ca++ entry blockers depends on the stimulus in the following order of sensitivity: K depolarization greater norepinephrine greater than PGF2 alpha. As far as flunarizine, but not nifedipine, is concerned, the activity is higher in mesenteric arteries than in aorta. This raises the possibility that calcium channels have receptor and organ specificity, a hypothesis which is supported by the observation that the order of potency of several calcium entry blockers is different in various vessels including human coronary arteries, and that the action of the blockers increases with the age of the patient.

Adult↗
PubMed1982

Dihydroouabain is an antagonist of ouabain inotropic action.

The Na+, K+-pump controls a wide variety of cellular systems and its inhibition by cardiac glycosides modifies important physiological functions and evokes several pharmacological effects (refs 1, 2 and refs therein). However, not all the actions of cardiac glycosides can be attributed to Na+, K+-pump inhibition and several observations show that, at low doses, cardiac glycosides stimulate the pump. It has been proposed that their positive inotropic effect could be the sum of two processes: the inhibition of the pump and a still unknown additional inotropic mechanism. In guinea pig heart, low doses of ouabain interact with high-affinity binding sites, which differ from the lower-affinity sites responsible for Na+, K+-pump inhibition. It has been suggested that ouabain interaction with these high-affinity sites could be responsible for the additional inotropic mechanism. The existence of two classes of ouabain-binding sites has been documented not only in guinea pig heart, but also in dog, rat and human heart. Dihydroouabain, a derivative of ouabain in which the lactone ring is saturated, is about 50-fold less potent than ouabain as an inhibitor of Na+, K+-pump and does not stimulate the pump at low doses. Its inotropic effect can be entirely accounted for by the inhibition of the pump. We have examined the pharmacological action of ouabain in the presence of dihydroouabain and report here that dihydroouabain reduces ouabain inotropic action but not Na+, K+-pump inhibition.

Animals↗
PubMed1982

Influence of 16 beta formylation on Na, K-ATPase inhibition by cardiac glycosides.

The inhibitory effect of formylated cardiac steroids (gitaloxin and its derivatives) on guinea-pig heart Na, K-ATPase was compared to that of other cardiac steroids with various hydroxy substituents. The decreasing order of potency of aglycones at equilibrium was as follows: gitaloxigenin greater than digitoxigenin greater than ouabagenin greater than digoxigenin greater than gitoxigenin greater than diginatigenin. This sequence was different to the sequence of drugs hydrophobic character. The compounds with hydroxy groups in the vicinity of the lactone ring (gitoxigenin, diginatigenin) were less potent than the hydrophilic compound ouabagenin. We propose that intramolecular bounding between 16 beta-OH and the lactone ring contributes to the relatively low potency of gitoxigenin and diginatigenin. The formylation of 16 beta-OH increased the potency of gitoxigenin by a factor of 41. The formylated compound (gitaloxigenin) was 5-fold more potent than digitoxigenin. The 3 beta-glycosylation of digoxigenin lead to pseudo-irreversible inhibitors of Na, K-ATPase. The half-time to achieve the equilibrium (for 5 mumol/l) was equal to 54 s, 90 s and 108 s respectively for digoxigenin monodigitoxoside, digoxin and desacetyllanatoside C. However, at equilibrium the three glycosides were equipotent, suggesting the existence of steric effects at the sugar site of the receptor. The sequence of potency observed for monodigitoxosides, monodigitalosides and tridigitoxosides after 60 min incubation was similar to that observed for the corresponding aglycones. These results suggest that the strongly negative inductive group 16 beta-OCHO is tightly bound to Na, K-ATPase, possibly to the same receptor site than that which is thought forming hydrogen and ionic bonds with the lactone ring. They show that the high toxicity of gitaloxin in guinea-pig heart is likely due to its high potency as Na, K-ATPase inhibitor.

Animals↗
PubMed1982

Actions of prostaglandin F2 alpha and noradrenaline on calcium exchange and contraction in rat mesenteric arteries and their sensitivity to calcium entry blockers.

1 The actions of prostaglandin F2 alpha (PGF2 alpha) and noradrenaline on contraction and 45Ca exchange have been studied in rat mesenteric arteries. 2 PGF2 alpha and noradrenaline contracted rat isolated mesenteric artery preparations to about the same extent. The PGF2 alpha-stimulated contractions, unlike those produced by noradrenaline, were completely inhibited in calcium-free physiological solution. 3 The calcium entry blocking drugs, cinnarizine and flunarizine, had little effect on the resting exchange of calcium in the arterial smooth muscle, but inhibited PGF2 alpha-stimulated contractions and 45Ca uptake to a similar extent. 4 Flunarizine was about 7 fold more potent as an inhibitor of noradrenaline- than of PGF2 alpha-mediated contraction and 45Ca uptake and this ratio was about 50 for cinnarizine. 5 EGTA (1.25 mM) produced a relaxation of noradrenaline and PGF2 alpha-induced maximal contractions. Measured over the first 2 min of EGTA contact, the rate of relaxation was much faster in noradrenaline than in PGF2 alpha-stimulated preparations. 6 Turnover of cellular calcium (influx plus efflux) during the first 2 min of noradrenaline contact was much greater than that produced by PGF2 alpha, largely due to a greater effect of noradrenaline on calcium efflux. 7 The results suggest that PGF2 alpha-but not noradrenaline-induced contractions are entirely dependent on the influx of extracellular calcium and that the agonists may stimulate calcium gating mechanisms differently.

Animals↗
PubMed1982

Selective alpha 1- and alpha 2-adrenoceptor agonist-induced contractions and 45Ca fluxes in the rat isolated aorta.

1 Contractile responses produced by the alpha 1-adrenoceptor selective agonist, phenylephrine, and the alpha 2-adrenoceptor selective agonists, oxymetazoline and clonidine, have been compared to those produced by noradrenaline (non selective) in the rat aorta. 2 The relative order of potency of the agonists was noradrenaline greater than phenylephrine greater than clonidine greater than oxymetazoline. Noradrenaline and phenylephrine produced similar maximal responses. The maximal responses produced by oxymetazoline and clonidine were about 59% and 24% respectively of those produced by noradrenaline. 3 Concentrations of agonists producing maximal contractions exhibited different response-time relationships. Responses to noradrenaline and phenylephrine were biphasic while responses induced by oxymetazoline and clonidine were monophasic. 4 In calcium-free solution, contractions stimulated by oxymetazoline and clonidine were almost abolished while those stimulated by noradrenaline and phenylephrine were reduced by about 60-70%. The calcium entry blocker, cinnarizine, almost completely inhibited responses to oxymetazoline and clonidine and reduced noradrenaline- and phenylephrine-stimulated responses by about 60%. 5 All the agonists stimulated the uptake of 45Ca into the La3+-resistant Ca2+ fraction of the artery but only noradrenaline and phenylephrine stimulated the efflux of 45Ca into calcium-free solution. The 45Ca uptake stimulated by oxymetazoline and clonidine was abolished by cinnarizine and that stimulated by noradrenaline and phenylephrine was reduced by about 85%. 6 It is concluded that clonidine and oxymetazoline stimulate contractions that are totally dependent on extracellular calcium. Noradrenaline and phenylephrine stimulate contractions that are partly dependent on extracellular calcium and partly dependent on intracellular calcium stores.

Adrenergic alpha-Agonists↗
PubMed1982

Calcium entry blockers and receptor-response coupling.

This review summarizes experiments investigating how Ca entry blockers interfere with receptor-response coupling in vascular tissue. It is shown that stimulatory agents increase smooth muscle membrane permeability to Ca by opening specific channels. The action of Ca entry blockers (namely, cinnarizine, diltiazem, flunarizine, and nifedipine) may be attributed to a specific blockade of these channels, as shown by a superimposition of dose-inhibition curves of contraction and Ca entry. Among the main characteristics of such drugs are their receptor and tissue selectivity. This is the basis for understanding that drugs having a common mechanism (Ca channel blockade) may present different pharmacological profiles and have different therapeutic indications.

Animals↗