Is the combination between beta-blockers and calcium antagonists appropriate in the management of angina pectoris?
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Adrenergic beta-Antagonists↗
Biomedical subjects
T Godfraind
Publications and source records attributed to T Godfraind.
Role of Na-H exchange in the inotropic action of Bay K 8644 and of ouabain in guinea-pig isolated atria.
1. The inotropic effects of two concentrations of ouabain and of Bay K 8644 have been studied in isolated left atria of the guinea-pig in physiological solutions at pH lowered from 7.4 to 6.0 and in the presence of ethylisopropylamiloride (EIPA) an inhibitor of Na+/H+ exchange. The low concentration of ouabain (300 nM) was chosen to saturate the high affinity binding sites (it occupied about 7% of the low affinity sites). The high concentration of ouabain saturated both high and low binding sites. Bay K 8644 evoked a positive inotropic effect of a magnitude similar to ouabain (300 nM). 2. When comparing the positive inotropic effects of equi-effective concentrations of ouabain (300 nM) and of Bay K 8644 (100 nM), it was observed that extracellular acidification specifically depressed the inotropic effect of ouabain 300 nM; the positive inotropic effect of the high concentration of ouabain (3 microM) was barely affected by extracellular acidification. 3. EIPA 10 microM depressed the positive inotropic effect of ouabain 300 nM, but did not affect the peak response to Bay K 8644. The depressant action of EIPA on the positive inotropic effect of ouabain was concentration-dependent and was much more obvious on the effect of ouabain 300 nm than on ouabain 3 microM. 4. An increase in diastolic tension was evoked by 3 microM but not by 300 nM ouabain. This increase in tone was reduced dose-dependently by EIPA (10-30 microM). It was also significantly reduced when the extracellular pH was equal to 6.4 or 6.0. 5. Ouabain (300 nM) evoked a gain in tissue Na and an equivalent loss in tissue K. Acidification of the extracellular pH down to pH 6.0 evoked a pH-dependent reduction of Na gain but left K loss unaltered. EIPA 10, 20 and 30 microM evoked a significant reduction of Na gain without significantly affecting K loss. 6. Ouabain (3 microM) evoked a large gain in tissue Na and an equivalent loss of K. Tissue Ca content was also increased. Acidification of the extracellular pH from pH 7.4 to pH 6.9 evoked a significant reduction of Na and Ca gain; changes in tissue K were not significant. Acidification down to pH 6.0 increased reduction of Na and Ca gain, but not that of K loss which nevertheless became statistically significant. 7. These results show that tissue Na gain observed after inhibition of the sodium pump by ouabain may be related to activation of Na-H exchange. They also indicate that blockade of Na-H exchange selectively reduced the inotropic effect of ouabain in guinea-pig atria resulting from interaction of the glycoside with high affinity binding sites. This confirms previous observations in rat heart.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Cerebrovascular effect of calcium antagonists.
Activity of calcium antagonists was assessed in microvessels (internal diameter 5-50 microns) isolated from rat brain. High KCl solution induced an increase of the lanthanum-resistant 45Ca influx and a marked reduction in microvessel diameter. Both responses to depolarization were inhibited by the calcium antagonists nimodipine and flunarizine. Binding studies with 3H(+)PN200-110 used as a specific ligand of Ca channels revealed the existence of voltage-dependent, stereoselective binding sites for dihydropyridine calcium antagonists.
Animals↗
Modulation of the action of calcium antagonists in arteries.
This paper is a review of the experimental evidence showing that specific binding sites for dihydropyridine Ca antagonists are involved in inhibition of stimulus-dependent Ca entry into arterial cells and thereby in inhibition of the contractile response. The apparent affinity of the dihydropyridine binding site is related to the proportion of a high- and a low-affinity state which is regulated by membrane potential but could also be dependent upon other factors such as G proteins. Among Ca antagonists, a subgroup of agents exhibiting voltage dependence may be identified. Their apparent pharmacological potency is highly dependent on resting membrane potential and on the duration of the depolarizing stimulus.
Animals↗
[Postnatal maturation of excitation-contraction coupling of the heart].
We have studied the post-natal maturation of excitation-contraction coupling in rat ventricle by means of pharmacological agents that selectively modulate either Ca entry via voltage-dependent sarcolemmal channels (dihydropyridines) or Ca release from sarcoplasmic reticulum (ryanodine). We have investigated the effects of those agents on cardiac contractility, and we have used them as radioligands to examine the properties of their receptors. Our results show that, after birth, dihydropyridine receptors (i.e. voltage-dependent Ca channels) redistribute to transverse tubules, in close proximity of terminal cisternae of sarcoplasmic reticulum. This redistribution favors the mechanism whereby, in adult ventricle, extracellular Ca entry triggers Ca release from sarcoplasmic reticulum.
Animals↗
Calcium antagonists and vasoconstrictor effects in intracerebral microarterioles.
The purpose of this work was to study the contractile activity of intracerebral microarterioles and their sensitivity to the calcium antagonist nimodipine. Potassium depolarization evoked contraction and rhythmic activity that was blocked by nimodipine (IC50 0.08 nM). High concentrations of noradrenaline and prostaglandin F2 alpha were needed to elicit a contractile response. Intracerebral microarterioles were very sensitive to endothelin (ED50, 0.2 nM). The contractions evoked by concentrations of endothelin lower than or equal to ED50 were relaxed by nimodipine, which also blocked the amplified response to potassium chloride depolarization occurring with subthreshold concentrations of endothelin. We discuss these observations in relation to brain ischemia.
Animals↗
Inhibition by amlodipine of activity evoked in isolated human coronary arteries by endothelin, prostaglandin F2 alpha and depolarization.
Amlodipine, a dihydropyridine calcium antagonist has been examined on the rhythmic activity of isolated human coronary arteries. Amlodipine inhibited both the spontaneous rhythmic activity and the rhythmic activity evoked by prostaglandin F2 alpha and endothelin in isolated human coronary arteries. It also inhibited the contraction evoked by potassium depolarization. The action of amlodipine was characterized by slow onset and voltage dependency.
Amlodipine↗
The protective action of R56865 against ouabain-induced intoxication in rat heart isolated atria and ventricles.
The action of R56865 has been examined on the contractile effects produced by ouabain concentrations interacting with high (3 microM) and low (300 microM) affinity digitalis receptors on electrically stimulated ventricular strips isolated from rat. R56865 1 microM reduced the increase in resting tension produced by ouabain 300 microM and left unalterated the inotropic effect evoked by ouabain 3 and 300 microM that was reduced by higher concentrations (3 and 6 microM) of R56865. The action of R56865 was also studied on ouabain-induced intoxication in electrically stimulated and spontaneously beating atria of rat. On electrically stimulated (3 Hz) whole atria, R56865 0.3 microM reduced the maximal increase in resting tension produced by ouabain 300 microM and delayed the time to onset of the ouabain-induced arrhythmias but did not affect ouabain's inotropic effect. Higher concentrations of R56865 were required to reduce the inotropic effect of ouabain. The protective action of R56865 against ouabain-induced intoxication was most pronounced on spontaneously beating atria where it reduced spontaneous rate of beats. Experiments in electrically driven left atria indicated that only a part of the protective effect of R56865 could be related to its bradycardic action. The effect of R56865 was also examined on ouabain-induced inhibition of sodium pump in human red blood cells. R56865 6 microM did not modify the inhibition produced by ouabain (from 0.3 to 10 nM), this indicates that the protective action of R56865 against ouabain-induced intoxication is not due to an interaction with the inhibitory effect of ouabain on sodium pump.
Animals↗
Spontaneous rhythmic contractions of human saphenous veins isolated from old subjects are sensitive to cyclooxygenase inhibitors.
Spontaneous rhythmic contractions were observed in some preparations of human isolated saphenous veins from old (greater than 60 years) subjects. These contractions were insensitive to adrenergic and histaminergic blockers, but were abolished by the cyclooxygenase inhibitors, aspirin and indomethacin, indicating the participation of endogenous eicosanoids.
Adult↗
Pharmacological properties of voltage-dependent calcium channels in functional microvessels isolated from rat brain.
Voltage-operated calcium channels were studied in rat intracerebral microvessels. The contractile reactivity to KCl-depolarization was assessed by the measurement of internal diameter of superfused microvessels. Dihydropyridine receptor sites associated with calcium channels were identified and characterized using 3H(+)PN 200-110 [isopropyl-4-(2,1,3-benzodiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5- -methoxycarbonyl-pyridine-3-carboxylate]. Depolarization induced by high-KCl solution produced a marked reduction of the internal diameter of cerebral microvessels which was associated with the appearance of rhythmic activity. The vessel contraction was reversible and abolished by nimodipine. Binding studies with 3H(+)PN 200-110 revealed the existence of a single class of specific, stereoselective and voltage-dependent binding sites which bound (+)PN 200-110 with a KD of 88 +/- 6.6 pmol l-1 at 37 degrees C in microvessels incubated in NaCl medium. When microvessels were incubated in KCl-medium, the apparent KD value was reduced to 35 +/- 2 pmol l-1. Bmax was not significantly changed. The effect of KCl was not related to concomitant changes in the Na concentration. The potency of various dihydropyridine derivatives in inhibiting 3H(+)PN 200-110 binding was in agreement with their pharmacological potency in smooth muscle preparations. The effect of PN 200-110 and of nimodipine was stereoselective. Ki values of PN 200-110 and of nimodipine were increased in depolarized preparations, while nifedipine's potency was unchanged. Verapamil was only a partial inhibitor of 3H(+)PN 200-110 binding. The effect of diltiazem was stereoselective: the (+)-cis isomer enhanced the binding and the (-)-cis isomer of diltiazem poorly inhibited the binding of PN 200-110. Results showed that isolated cerebral microvessels possess functional voltage-operated calcium channels, which contain potential-modulated receptors for dihydropyridine calcium entry blockers with characteristics similar to those described in other tissues.
Animals↗
Increasing complexity revealed in regulation of Ca2+ antagonist receptor.
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Animals↗
Effect of endothelin-1 on calcium channel gating by agonists in vascular smooth muscle.
Rat isolated aorta was more sensitive to the contractile effect of endothelin-1 (ET-1) when the endothelium was removed. ET-1 was more potent on mesenteric resistance arteries than on aorta. A threshold concentration of ET-1 (100 pM) enhanced the contractile responses of aortic rings to Bay K 8644 and clonidine, especially in the absence of endothelium. Potentiation of clonidine-evoked contraction was accompanied by an enhancement of 45Ca influx and was abolished by nifedipine. These actions of ET-1 (100 pM) could not be attributed to a decrease in membrane potential or in cAMP levels. ET-1 (100 pM) decreased cGMP in intact aortic rings, which could contribute to its actions in the presence of endothelium. Removal of endothelium reduced cGMP levels and these were not further decreased by ET-1. Since ET-1 exerted a pronounced potentiating effect in the absence of endothelium, it is likely that ET-1 modulates calcium channels by an additional mechanism, unrelated to cyclic nucleotides.
Animals↗
Effects of cicletanine on histamine-induced contractions of isolated rabbit mesenteric arteries.
The antagonism by cicletanine of contractile responses to histamine has been examined in vitro on ring preparations of rabbit mesenteric arteries. Cicletanine (10(-8)-10(-6) M) caused a parallel rightward shift of histamine concentration response curve, with a pA2 value of 7.48 (slope = 0.89 +/- 0.19, not significantly different from unity). Histamine-induced contractions were nifedipine-sensitive and associated with cicletanine-sensitive increased 45Ca uptake. Endothelium removal resulted in enhanced contractile responses to histamine, but did not significantly modify cicletanine-induced antagonism: KB (dissociation constant) values for cicletanine antagonism in the presence or absence of endothelium were: 3.7 (+/- 0.1) X 10(-8) M and 3.6 (+/- 0.3) X 10(-8) M, respectively. Cicletanine (greater than 10(-4) M) also significantly attenuated 10 mM caffeine-induced contractions in rings exposed to Ca-free 100 mM K+ depolarizing medium. The results suggest that cicletanine-induced antagonisms of histamine H1 receptor-mediated contractions of rabbit mesenteric arteries is associated with interference with calcium entry as well as at high concentrations, release from intracellular stores.
Animals↗
Histamine receptors in the smooth muscle of human internal mammary artery and saphenous vein.
The effects of histamine were characterized and compared in the vascular smooth muscle of two human isolated blood vessels, the human internal mammary artery (HIMA) and the human saphenous vein (HSV). Segments of these vessels were obtained during aortocoronary bypass surgery and their intimal surface was rubbed in order to eliminate any possible influence of the endothelium. Histamine contracted both types of vessels in a concentration-dependent manner and this effect was antagonized by the H1 receptor antagonists mepyramine and cicletanine. In the case of HIMA only this antagonism was found to be competitive (pA2 values of 9.3 and 7.7 for mepyramine and cicletanine, respectively). Histamine-induced contractions were not significantly affected by phentolamine (0.3 microM). In HSV, but not HIMA, indomethacin (5 microM) significantly depressed histamine-induced contractions (by about 30%). In the presence of the H2 receptor antagonist cimetidine (10 microM), concentration-response curves of histamine-induced contractions were significantly shifted to the left in both HIMA and HSV, suggesting the presence of H2 receptors mediating relaxation. HIMA and HSV precontracted by noradrenaline could be partially and concentration dependently relaxed by histamine, only in the presence of a H1 receptor antagonist. This relaxation was inhibited by cimetidine. The results show that in de-endothelialized HIMA and HSV histamine induced mainly contraction which is sensitive to the H1 receptor antagonists. Only in HIMA, nevertheless, was competitive antagonism established. In addition, histamine-induced relaxation, antagonized by cimetidine, could be demonstrated in both precontracted vessels, indicating the presence of H2 receptors.
Diuretics↗
Comparative pharmacology of cardiac and vascular tissues in heart failure.
The purpose of this paper is to review various factors of the control of cardiac contractility and of vascular tone that may be altered in heart failure and that are targets for pharmacotherapeutic interventions. This paper is divided into three main sections: pathophysiological aspects of heart failure, differences in the regulation of cardiac contraction and of vascular tone, and pharmacological principles in the management of heart failure.
Adrenergic beta-Agonists↗
Tissue specificity of dihydropyridine-type calcium antagonists in human isolated tissues.
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Animals↗
Modulatory role of the vascular endothelium in the contractility of human isolated internal mammary artery.
1. Endothelium-dependent relaxant responses and modulation of contractile responses were investigated in human isolated internal mammary artery (HIMA), a vessel widely used for coronary bypass surgery. 2. Acetylcholine and ionophore A23187 (both 10 nM-1 microM) elicited concentration-dependent relaxations of precontracted HIMA. These relaxations were abolished after rubbing of the endothelium, they were inhibited by methylene blue and were insensitive to indomethacin. 3. Histamine at concentrations lower than 10 microM elicited an endothelium-dependent, methylene blue-sensitive relaxation of precontracted HIMA. This effect of histamine was inhibited by the H1-receptor antagonist mepyramine. Bradykinin, noradrenaline and alpha 2-adrenoceptor agonists (in the presence of prazosin) did not relax unrubbed HIMA in which acetylcholine or A23187 were shown to be efficient. 4. Tissue levels of guanosine-3':5'-monophosphate (cyclic GMP) were found to be significantly higher in unrubbed HIMA rings than in matched rubbed rings. 5. Methylene blue evoked a slow contraction in resting HIMA, and this contraction was significantly greater in unrubbed than in rubbed preparations. Also, methylene blue enhanced the contractile response of HIMA to noradrenaline and this potentiating effect was significantly greater in unrubbed than in rubbed preparations. Indomethacin induced a slow contraction, of similar magnitude in unrubbed and rubbed HIMA rings. 6. In resting HIMA, the concentration-effect curve of noradrenaline-induced contraction was significantly shifted to the left after rubbing of the endothelium, without change in the maximal responses. In unrubbed rings the EC50 value of noradrenaline was about 2 fold that in rubbed rings. 7. Histamine also contracted resting HIMA in a concentration-dependent manner and in addition, it triggered rhythmic activity. This rhythmic activity was more prominent in unrubbed preparations and could be partially inhibited by indomethacin. The concentration-effect curve of histamine-induced contractions was displaced to the left after rubbing the endothelium, without changes in the maximal responses. The EC50 value of histamine in unrubbed rings was 4 to 9 fold that found in rubbed rings, depending on the level of tension taken into account for the concentration-effect curve during rhythmic contractions. 8. In the presence of nifedipine (3 microM), noradrenaline-induced contractions were not significantly altered, whereas histamine-induced contractions were found to be inhibited by about 70%. 9. It is concluded that in HIMA, both spontaneous and stimulated endothelium-dependent relaxing factor (EDRF) release may occur, and that basal EDRF can itself be responsible for the modulatory effect of endothelium on contractile responses.
Acetylcholine↗
The modulatory role of vascular endothelium in the interaction of agonists and antagonists with alpha-adrenoceptors in the rat aorta.
1. We have examined the effect of endothelium on the antagonistic action of prazosin, doxazosin, yohimbine and phentolamine against phenylephrine, clonidine and noradrenaline. 2. The action of prazosin against phenylephrine was similar to that earlier reported against noradrenaline, acting as a non-competitive antagonist in the presence of endothelium and as a competitive antagonist in the absence of endothelium. Prazosin also acted as a non-competitive antagonist against clonidine in the absence of endothelium. 3. Doxazosin behaved in a similar way to prazosin against noradrenaline, phenylephrine and clonidine acting as a non-competitive antagonist in the presence of endothelium and as competitive antagonist after removal of endothelium. In contrast, yohimbine and phentolamine acted as competitive antagonists both in the presence and in the absence of endothelium. 4. Analysis of the concentration-response curves for noradrenaline, phenylephrine and clonidine in the presence and in the absence of endothelium showed that the affinity for all three agonists was the same but not the efficacy and the receptor reserve, both of which were lower in the presence than in the absence of endothelium. 5. The rank order of agonist potency in the absence of endothelium was noradrenaline greater than phenylephrine greater than clonidine. The rank order of antagonist potency was prazosin greater than or equal to doxazosin greater than phentolamine greater than yohimbine. 6. The results show that vascular endothelium modulates the contractile response to alpha-adrenoceptor agonists and also modifies the action of the antagonists prazosin and doxazosin but not that of yohimbine and phentolamine. This effect of endothelium was related to a change in agonist efficacy and receptor reserve. These results also suggest that the alpha-adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the alpha 1-subtype.
Adrenergic alpha-Agonists↗