Increasing complexity revealed in regulation of Ca2+ antagonist receptor.
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Animals↗
Biomedical subjects
T Godfraind
Publications and source records attributed to T Godfraind.
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↗
Selective modulation by membrane potential of the interaction of some calcium entry blockers with calcium channels in rat mesenteric artery.
1. The effects of flunarizine, (+)-PN 200-110 and nifedipine on [3H]-(+)-PN 200-110 specific binding were investigated in intact rat mesenteric arteries bathed in physiological solution or in KCl-depolarizing solution, and in a membrane fraction from rat mesenteric arteries. 2. Unlabelled dihydropyridines, (+)-PN 200-110 and nifedipine, inhibited [3H]-(+)-PN 200-110 specific binding concentration-dependently in polarized as well as in depolarized intact arteries. The Ki value of (+)-PN 200-110 was decreased in arteries bathed in KCl-depolarizing solution compared to arteries bathed in physiological solution, while the Ki value of nifedipine was not significantly changed. Ki values measured in depolarized arteries were close to the IC50 values (concentrations inhibiting by 50% the KCl-contraction of rat mesenteric artery). 3. Flunarizine (10(-6) M) was unable to displace the specific binding of [3H]-(+)-PN 200-110 in intact arteries bathed in physiological solution. At 10(-7) M-10(-6) M, it inhibited the binding in depolarized arteries, suggesting that prolonged depolarization is required for the interaction of flunarizine with the dihydropyridine receptor. 4. In a membrane fraction isolated from rat mesenteric arteries, (+)-PN 200-110, nifedipine and flunarizine were all able to displace completely the specific binding of [3H]-(+)-PN 200-110. Displacement curves were parallel and Hill coefficients were close to unity. Ki values were close to the values obtained in depolarized intact arteries. 5. These results revealed a good correlation between the data obtained from binding tests and from pharmacological studies for dihydropyridine calcium entry blocking drugs, taking into account the time-dependence associated with their action on KCl-contraction compared to their binding properties. There was an important discrepancy between the concentrations of flunarizine active in binding studies and those active in pharmacological studies, which could be accounted for by the existence of multiple binding sites for calcium entry blockers in calcium channels.
Animals↗
Calcium channels in smooth muscle.
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3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Pharmacologic relevance of dihydropyridine binding sites in membranes from rat aorta: kinetic and equilibrium studies.
The kinetic features of the interaction of dihydropyridines with rat aortic smooth muscle were investigated in parallel mechanical and binding studies. The inhibitory action of (+)-PN200-110 and nisoldipine on contractions evoked by potassium chloride depolarization was characterized by a pronounced time dependency, in which the inhibition increased slowly after depolarization to attain a steady-state value, while with (-)-PN200-110 and (+)-Bay K8644 the inhibition was almost instantaneous. To explain these observations, specific binding sites for dihydropyridines were studied in membranes isolated from rat aorta, using [3H](+)-PN200-110 as a radioligand. We found that the time course of the development of inhibition of potassium chloride-evoked contractions by various concentrations of (+)-PN200-110 paralleled the time course of [3H](+)-PN200-110 binding to isolated membranes and that the level of inhibition was predictable from the level of occupation of these binding sites. These results indicate that depolarization increases the affinity of calcium channels for dihydropyridines in vascular smooth muscle and that the time course of the inhibitory effect on contraction is determined by the time course of association with the high-affinity state of the channel.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Pharmacological basis of the classification of calcium antagonists.
In this brief account of Ca antagonists, I have attempted to illustrate similarities and differences among selective Ca antagonists. Four typical pharmacological profiles may be recognized by taking into account studies at molecular, cellular and tissular levels. This gives a rational basis for understanding that all calcium antagonists do not show identical therapeutic actions.
Animals↗
Antihistaminic properties of cicletanine in human isolated coronary arteries.
Cicletanine was tested as an antagonist of the various actions of histamine in coronary artery rings isolated from old (mostly atherosclerotic) and young (non-atherosclerotic) patients. Histamine mainly induced concentration-dependent contractions in arteries from old patients. Cicletanine antagonized this effect with a pA2 value of 6.9 (slope factor of 0.94), revealing in some cases a relaxant effect of histamine. In addition, cicletanine increased the threshold concentration of histamine required to trigger spastic, indomethacin-sensitive rhythmic contractions in (some) rings of the oldest patient. At variance with what occurred in coronary rings from old patients, the predominant effect of histamine in rings from young patients was relaxation. This relaxation remained unaltered by cicletanine (1 microM). As a whole, these results extend the histamine H1 antagonistic activity of cicletanine to human coronary arteries. If histamine is involved in the promotion of vasospasm, then cicletanine could be of potential benefit to patients, without apparently affecting the relaxant response to histamine in non-cardiac patients.
Adult↗
The role of histamine in the cardiovascular system.
This article reviews briefly the role of histamine through its H1 and H2 receptors on the cardiovascular system and its action on calcium and catecholamines. The analogy between the adrenergic and the histaminergic systems is well demonstrated and there is evidence that histamine participates in myocardial damage and arrythmias, but the question of its exact role in the early stages of cardiovascular diseases, such as myocardial ischaemia and atherosclerosis, requires further study.
Animals↗
Competitive and stereoselective histamine H1 antagonistic effect of cicletanide in guinea-pig isolated ileum.
The histamine H1 antagonistic effects of the racemic form and the enantiomers of cicletanide, a new antihypertensive furopyridine derivative, were investigated in guinea-pig isolated ileum. Both the racemic and the (-) enantiomer behaved as competitive histamine antagonists (pA2 values of 6.8 and 7.2, respectively). The (+) enantiomer was at least 100 times less potent than the (-) enantiomer. The H1-blocking effect of cicletanide is the most potent and is the only stereoselective property so far reported for the drug.
Animals↗
Histamine-operated calcium channels in intestinal smooth muscle of the guinea-pig.
The effects of Bay K 8644 and of nifedipine on histamine-induced mechanical and electrical responses were studied in the longitudinal smooth muscle of the ileum and in the taenia coli isolated from the guinea-pig. Nifedipine (10(-9)-10(-7) M) depressed the tonic and phasic components of histamine contraction. Phasic tension was less sensitive to nifedipine inhibition than was tonic tension (I50: 27 +/- 6 and 2.6 +/- 0.4 nM respectively). Bay K 8644 (10(-8)-10(-7) M) increased tension and rhythmic activity of intestinal smooth muscle and potentiated the histamine responses. The phasic tension evoked by histamine 10(-5) M and the phasic tension evoked by the KCl depolarizing solution showed the same sensitivity to nifedipine inhibition (I50: 28 +/- 5 nM) and were similarly potentiated by Bay K 8644. The tonic tension in response to the KCl-depolarizing solution was more sensitive to nifedipine inhibition than was the tonic tension in response to histamine and was not potentiated by Bay K 8644. These results indicate that different Ca entry pathways, dependent or not on modification of the membrane potential, are involved in the contractile response evoked by histamine in intestinal smooth muscle.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Classification of calcium antagonists.
Drugs of several chemical families have been identified as calcium antagonists. This article examines some pharmacologic properties of these drugs to clarify their terminology and their classification and to provide a rationale for their clinical use. Studies with nifedipine show quantitatively that the therapeutic effect in angina is related to the interaction of this drug with membrane calcium channels in human coronary arteries. This gives support to a classification based on studies at the molecular, tissue and organ levels. Among calcium antagonists, calcium entry blockers are defined as agents able to block calcium inward fluxes evoked by various stimuli. They may be subdivided in 2 groups. Group I is the group of selective calcium entry blockers. Group IA consists of those agents selective for slow calcium channels in myocardium (slow channel blockers); the leading agents are verapamil, nifedipine and diltiazem. Group IB contains agents without action on slow calcium channels in myocardium but with selective action on arteries; the leading agents are cinnarizine and flunarizine. Group II is the group of nonselective calcium entry blockers. Group IIA contains agents acting at similar concentration on calcium and on fast sodium channels. Group IIB consists of agents interacting with calcium channels while having another primary site of action. Other agents modulate calcium movements by an action on sodium-calcium exchange and by an action within the cell. Their identification requires the use of cell biology. The actual clinical uses of these drugs are consistent with this pharmacologic classification.
Animals↗
The actions of nifedipine and nisoldipine on the contractile activity of human coronary arteries and human cardiac tissue in vitro.
We have studied the action of nifedipine and nisoldipine on the contractile activity of human isolated coronary arteries and human isolated auricular and ventricular muscles. Nisoldipine depressed dose dependently the spontaneous rhythmic contractions displayed by the coronary artery preparations and at 1 nM abolished these contractions. Nisoldipine was twenty times more potent than nifedipine as an inhibitor of increase in tone induced by depolarization (100 mM K+). The rhythmic activity induced by serotonin (10 microM) was about five times more sensitive to nisoldipine than to nifedipine. In both auricular and ventricular preparations, isoprenaline evoked an increase in the rate of force development and in the rate of relaxation. Nifedipine was five times (ventricular muscles) and ten times (auricular muscles) more potent than nisoldipine as a negative inotropic agent. The present observations in human isolated preparations indicate that nisoldipine shows a higher vascular selectivity than nifedipine.
Adolescent↗