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At least 397 records · Page 22Linked to original sources

PubMed1977

Local specificity in responses of canine coronary vessels to oxygen deficiency and antianginal drugs.

Influence of oxygen deficiency and vasodilating drugs on coronary arterial tonus was investigated. In the fibrillating heart, hypoxia initially decreased total coronary resistance, later increased it, and exerted little effect on large coronary arteries. Dilation of helically cut specimens of the small coronary arteries occurred more readily than observed in large arteries in response to N2 bubbling or KCN. In the small arteries, the mitochondrial population was more numerous in cellular units and succinic dehydrogenase activity was greater, suggesting that these vessels are more dependent on aerobic metabolism for the maintenance of integrity. Nitrate vasodilators relaxed selectively the large arteries, while adenosine, prenylamine and carbochromen dilated preferentially the small arteries. Dipyridamole, iproveratril, papaverine and propranolol relaxed both arteries equally; however, except for propranolol, these drugs produced preferential relaxation of the small vessels in the fibrillating hearts.

Adenosine↗

PubMed1977

[Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations].

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.

Animals↗

PubMed1982

Selective inhibition of Na+-induced Ca2+ release from heart mitochondria by diltiazem and certain other Ca2+ antagonist drugs.

The effect of Ca2+ antagonist drugs on Ca2+ uptake and Na+-induced Ca2+ release by isolated rabbit heart mitochondria has been studied using arsenazo III and dansylaziridine-labeled troponin C as Ca2+ indicators. Mitochondria accumulated 20 nmol of Ca2+/mg of protein by a respiration-dependent process. A23187, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, or Na+ induced a release of Ca2+ from Ca2+-loaded and ruthenium red (RR)-treated mitochondria. Ca2+ antagonist drugs had no effect on the Ca2+ uptake process or on Ca2+ release induced either by A23187 or by carbonyl cyanide p-trifluoromethoxyphenylhydrazone but they were effective in inhibiting the Na+-induced Ca2+ release process. The drug concentrations that resulted in 50% inhibition of Na+-induced Ca2+ release were 7, 12, 13, 66, and 150 microM for diltiazem, prenylamine, fendiline, nifedipine, and verapamil, respectively. In the absence of RR, the net amount of Ca2+ released by Na+ was less than that which occurred in the presence of RR due to the simultaneous operation of both the Ca2+ uptake and the Ca2+ release processes. Under these conditions, the inhibition of Ca2+ uptake by RR brought about a complete release of Ca2+ from the mitochondria, and the inhibition of the Na+-induced Ca2+ release by diltiazem resulted in an apparent uptake of Ca2+ by the mitochondria. These results indicate that diltiazem and certain other Ca2+ antagonist drugs may be selective inhibitors of the Na+/Ca2+ antiporter in heart mitochondria much like ruthenium red is a selective inhibitor of the Ca2+ uniporter.

Animals↗

PubMed1983

Calcium antagonists. Some chemical-pharmacologic aspects.

Ca++ serves multiple roles as a regulator and initiator of cellular events. A variety of mechanisms serve to control cellular Ca++ levels and there exists a corresponding diversity of drugs which possess, with varying degrees of potency and selectivity, Ca++-antagonistic properties. Particular interest attaches to a group of agents designated as Ca++-channel or Ca++-entry blockers and includes verapamil, nifedipine, diltiazem, cinnarizine, and prenylamine. These agents function by blockade of the potential dependent Ca++-channel. However, their obvious chemical heterogeneity suggests that several sites and mechanisms of action may exist. A review of some basic questions concerning the action of the Ca++ channel antagonists is presented. The existence of discrete structure-activity relationships is consistent with the concept that these agents have specific sites of action, rather than serving, for example, as, nonspecific membrane-stabilizing agents. This view is further supported by their selectivity of action seen both in tissue selectivity and selectivity of antagonism of agonist responses. Studies of the relationship of these compounds to Ca++ show that they appear to function competitively against Ca++ and to block cellular Ca++ uptake. Moreover, both contractile responses and cellular Ca++ uptake appear equisensitive to these antagonists, providing further evidence that inhibition of Ca++ uptake underlies their inhibition of mechanical response. Of particular importance is the question of selectivity of action. It is quite clear that the Ca++ channel antagonists do not show equal activity toward all Ca++ channels and that major differences in selectivity occur between cardiac and smooth muscle. It is possible that selectivity of antagonism may occur between different vascular beds. Furthermore, Ca++ channels controlling stimulus-secretion coupling appear to be less sensitive to these antagonists than the channels involved in excitation-contraction coupling. Finally, the actions of Ca++ antagonists on non-Ca++-mediated processes, including Na+-dependent and receptor-binding events, are noted. These actions are seen at higher concentrations than those needed to inhibit Ca++ channel events, and their contribution to the therapeutic actions exerted by these antagonists is unknown.

Animals↗

PubMed1983

The action of forskolin on muscle cells is modified by hormones, calcium ions and calcium antagonists.

Forskolin, a drug isolated from the Indian plant Coleus forskohlii, exerts its actions on cells by directly activating the catalytic subunit of adenylatecyclases. The primary effect on heart muscles is the positive inotropic one, at higher forskolin concentrations, an acceleration of the pacemaker activity can be observed. External Ca2+ is required for this augmentation of contraction, verapamil, prenylamine and tetrodotoxin depress these effects. The action of forskolin and digitalis glycosides are to a certain degree additive. Incubation of rat heart slices with forskolin depresses the membrane bound Na+K+-ATPase activity. In smooth muscle cells, forskolin lowers the contractions, evoked by K+, norepinephrine and by angiotensin II. The results are discussed in respect to a forskolin induced enlargement of the Ca2+-uptake of heart muscle cells and a lowering of the Ca2+-sensitivity of the contractile system of smooth muscle cells.

Adenylyl Cyclases↗

PubMed1983

History of calcium antagonists.

The discovery of Ca++ antagonism as a new principle of action of coronary drugs reaches back to 1964, when we reported that two new compounds, later given the generic names verapamil (Iproveratril) and prenylamine, mimicked the cardiac effects of simple Ca++ withdrawal in that they diminished Ca++-dependent high energy phosphate utilization, contractile force, and oxygen requirement of the beating heart without impairing the Na+-dependent action potential parameters. Since these effects, clearly distinguishable from beta-receptor blockade, could promptly be neutralized with elevated Ca++, beta-adrenergic catecholamines, or cardiac glycosides, measures that restored the Ca++ supply to the contractile system, we introduced in 1969 the term Ca++ antagonist as a novel drug designation. In an extensive search for other Ca++ antagonists, a considerable number of substances that also met these criteria were identified in our laboratory, i.e., D 600, nifedipine, niludipine, nimodipine, perhexiline, fendiline, terodiline. In 1975 Japanese pharmacologists contributed diltiazem to this group. According to our studies, all specific Ca++ antagonists interfere with the uptake of labelled Ca++ into the myocardium and prevent myocardial necrotization arising from deleterious intracellular Ca++ overload; they also block excitation-contraction coupling of vascular smooth muscle, and in this manner, lower Ca++-dependent coronary vascular tone and neutralize all types of experimental coronary spasms. According to our voltage-clamp studies, these antagonists basically act as specific inhibitors of the slow transsarcolemmal Ca++ influx but do not (or only slightly) affect the fast Na+ current that initiates normal myocardial excitation. However, Ca++ antagonists can counteract SA and AV nodal automaticity, AV conduction, and ectopic impulse discharge because, in these cases, Ca++ ions necessarily act as transmembrane electric charge carriers.

Aniline Compounds↗

PubMed1984

Tissue heterogeneity of calcium channel antagonist binding sites labeled by [3H]nitrendipine.

Calcium channel antagonist binding sites have been labeled in cerebral cortex, heart, ileum, and skeletal muscle with [3H]nitrendipine. While the dissociation constants of the site from cortex, heart, and ileum are similar, KD approximately equal to 0.1-0.2 nM, the value in skeletal muscle is 2 nM. This difference is affinity is also reflected in the Ki values of dihydropyridine calcium channel antagonists, nifedipine, nimodipine, PY108068, SKF24260, and nisoldipine, and the calcium channel agonist CGP 28392, all of which show lower affinity for the skeletal muscle binding site. The diphenylalkylamine calcium channel antagonists, lidoflazine, cinnarizine, flunarizine, and prenylamine, however, show a 3- to 10-fold increase in affinity in skeletal muscle relative to the other three tissues. EDTA treatment of membranes decreases binding in cortex, heart, and ileum but increases binding in skeletal muscle. These changes are reversible upon addition of CaCl2, SrCl2, or BaCl2. The different properties of [3H]nitrendipine binding in various tissues may relate to the varying tissue sensitivity to organic calcium channel antagonists.

Animals↗

PubMed1976

[Treatment of rhythm disorders by fenoxedil hydrochloride].

Fenoxedil chlorhydrate (FC), which is used as a treatment for cerebral circulatory failure and peripheral vascular disease, has been given to 100 patients with a cardiac arrhythmia: atrial fibrillation (78 cases), atrial flutter (4 cases), atrial tachysystole (2 cases), ventricular extrasystoles (12 cases), and supraventricular extrasystoles (4 cases). FC has been prescribed alone, or as a complement to current anticoagulant or digitalis treatment; combination with prenylamine, amiodarone, dysopyramide or a drug of the quinidine group must always be avoided, and the potassium level checked and corrected if necessary before treatment. In 78 cases of atrial fibrillation, the authors found that sinus rhythm was restored in 58 (74.4%); four cases of flutter were restored, and one case out of two of atrial tachycardia. In case of supraventricular and ventricular extrasystoles the results are less clear, and merit a further study with a larger number of cases. The electrocardiographic disorders encountered in this series have been evaluated: lenghthening of the QT interval, disorders of atrioventricular conduction, sinus inhibition. They were either produced by or aggravated by the FC. No cases of axis deviation were encountered. The authors make mention of the complications observed by other authors, but draw a distinction between the prescription of FC in cases of cerebral vascular insufficiency, without previous knowledge of the exact cardiac status of the patient (otherwise there is a risk of severe accidents), and the use of FC in cases of arrhythmia which have undergone full assessment before the drug is used. According to this study, FC appears to be a very effective anti-arrhythmic agent, but its use demands very rigorous clinical and electrocardiographic supervision.

Anti-Arrhythmia Agents↗

PubMedDate not supplied

Diagnosis and treatment of Prinzmetal's variant angina.

The presentation, diagnosis (including provocative testing), and therapy of Prinzmetal's variant angina are reviewed. Prinzmetal's variant angina (PVA) is a form of angina caused by coronary-artery vasospasm (CAS) and is not associated with exertion. It is diagnosed by history, electrocardiogram, or coronary-artery angiography. Provocative tests, such as the cold-pressor test or intravenous ergonovine maleate, are sometimes used to aid diagnosis of PVA. Nitrates, adrenergic - blocking agents, and calcium-channel blocking agents can be used in treating PVA. Nitroglycerin and isosorbide dinitrate effectively relieve CAS. However, long-term prospective studies on the use of these drugs for PVA are lacking in the literature. Studies on treating PVA with adrenergic-blocking agents have been equivocol, with some studies reporting improvement and some reporting worsening. Calcium-channel blocking agents are promising drugs for PVA. Nifedipine is generally considered the prototype of this class for antianginal activity. It is administered orally in PVA patients and is effective. Side effects are mild and do not usually require termination of therapy. Verapamil hydrochloride, the prototype calcium-channel blocking agent for arrhythmias, is effective for PVA, but only 10-20% of an orally administered dose reaches systemic circulation because of the first-pass effect. Other calcium-channel blockers, including perhexilene maleate, diltiazem hydrochloride, prenylamine, and lidoflazine, have been tested in a few CAS patients with some success; adverse effects and toxicities limit the use of some of them, especially perhexilene. Therapy, using combinations of nitrates, adrenergic-blocking agents, and calcium-channel blocking agents, is needed in some patients. Dosing guidelines for all drugs are given in the paper. Treatment of PVA should begin with oral nitrates. Calcium-channel blocking agents are indicated in the patient who has failed to respond or is intolerant to maximum doses of nitrates given in various forms.

Angina Pectoris, Variant↗

PubMedDate not supplied

[Effect of guanclofin on catecholamine release by the adrenal medulla].

The influence of guanoclofine, an adrenergic neurone-blocking agent, on catecholamine release from isolated perfused bovine adrenal glands was studied. Guanclofine inhibited the amine liberation induced by carbachol, aminophylline, prenylamine, and snake venoms. Guanoxane and guanethidine at equimolar concentrations were less effective. The inhibitory effect of guanclofine is assumed to be due to a nonspecific effect on the cell membrane.

Adrenal Medulla↗

PubMed1981

[Interaction of coronary-active compounds and anti-inflammatory drugs on the coronary vascular system (author's transl)].

The effect of acemetacin (Rantudil) and indomethacin, respectively, on coronary flow and O2-pressure in coronary sinus blood before and after i.v. injections of coronary active compounds was permanently registered in anesthetised closed-chest dogs. It was found that i.v. infections of 2 mg acemetacin/kg extended effects of i.v. injected morocromen. After administration of morocromen (4.0 mg/kg), carbocromen (2.0 mg/kg), or dipyridamole (0.4 mg/kg) the application of acemetacin or indomethacin, respectively, produced a markedly increased effect on the coronary blood vessels. Comparative studies of indole-derivatives, the Ca-antagonizing compounds prenylamine, verapamil, nifedipine, and the phosphodiesterase inhibitor papaverine showed no similar effects.

Animals↗

PubMed1980

Overdrive pacing in quinidine syncope and other long QT-interval syndromes.

Prolongation of QT interval is associated with repetitive paroxysm of a particular ventricular tachycardia. It is a typical complication of quinidine therapy but may occur in various other conditions. We used endocardial pacing in nine patients with prolongation of the QT interval who suffered from bouts of ventricular tachycardia and fibrillation. In six patients, the syndrome was due to quinidine and in three, to prenylamine. Acceleration of heart rate resulted in immediate suppression of all arrhythmias. Pacing was continued until the condition producing the QT prolongation disappeared. In one case, a permanent pacemaker was implanted, as the QT prolongation was congenital and permanent. The absolute QT interval was shortened by overdrive pacing from a mean value of 0.65 s to 0.50 s. The corrected QT interval remained prolonged (about 0.56 s). Thus, the arrhythmia was associated with the duration of the actual QT interval, and overdrive pacing was able to suppress it without shortening the corrected QT interval.

Adult↗

PubMed1978

Influence of prostaglandins, prostaglandin-precursors and of a linoleic acid rich and free diet on the cardiac effects of isoprenaline and vasodilators.

In isolated auricle preparations of guinea pigs arachidonic acid diminished the increase in cardiac performance by isoprenaline in a similar way as PGE1 and propranolol. Long term pretreatment of rats with a linoleic acid (LA) supplemented diet increased in vivo the maximal systolic pressure and decreased the heart rate. In hearts in vitro the LA rich diet decreased the heart rate, increased the coronary flow and showed a tendency to enhance the contraction force. The release of cardiac prostaglandin-like substances was increased. Simultaneously the LA rich diet reduced the heart rate increase and the positive inotropic effect of isoprenaline without changing the increase in the coronary flow and without any effect on the heart performance of coronary vasodilators like oxyfedrine and prenylamine.

Animals↗

PubMed1997

In vitro and in vivo characterization of a calcium modulator of the diphenylalkylamine type with selective coronary dilatory properties.

UNLABELLED: VUF 8929 (N-¿2-[bis(p-fluorophenyl)methoxy]ethyl¿-(2-phenyl)ethylamine maleate, CAS 140890-71-7) is a diphenylalkylamine derivative structurally related to prenylamine. The calcium antagonistic properties of this compound have been studied in in vitro and in vivo systems. VUF 8929 has affinity for the voltage-operated calcium channel. Its pKD for the displacement of [3H]nitrendipine bound to cerebral rat cortex is 6.27 (+/- 0.17). The compound influences the [3H]nitrendipine binding through an allosteric interaction with a site adjacent to the dihydropyridine binding site. Competitive experiments with the additional presence of the phenylalkylamine gallopamil showed that this allosteric site is a property common to diphenyl- and phenylalkylamines. It was further observed that VUF 8929 has a high affinity for calmodulin as it shows high potency in inhibiting the calmodulin mediated activation of PDE. The inhibition of K+ (IC50 0.5 mumol/l)- and noradrenaline (IC50 1.3 mumol/l)-induced contractions of rabbit aorta rings was in the same concentration range as found for the calmodulin inhibitory activity. In vitro platelet aggregation was also inhibited in the same concentration range when washed platelets were used. Thus calmodulin antagonism may contribute to the observed effects on aorta ring contractions and platelets aggregation. Platelet aggregation, however, in media in which albumin was added or in platelet rich plasma was not affected. It is assumed that due to the high lipophilicity, common to many diphenylalkylamines, VUF 8929 has a strong binding to plasma proteins. This may also explain why orally administered VUF 8929 did not affect the alpha 2-induced pressor response in pithed rats and the ex vivo collagen induced aggregation response. The haemodynamic profile in anaesthetized dogs showed that intravenous injected VUF 8929 reduced the workload of the heart while coronary blood flow increases at a dose of 0.3 mg/kg. Reversible occlusion of the coronary artery, which leads to S-T segment elevation and local venous acidosis, were reduced by VUF 8929 indicating that the compound has anti-ischaemic properties. IN CONCLUSION: VUF 8929 is a calcium antagonist which has anti-ischaemic properties, reduces the workload of the heart and increases coronary flow. Due to these properties VUF 8929 is a potential cardioprotective agent.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1965