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Biomedical subjects

A Fleckenstein

Publications and source records attributed to A Fleckenstein.

At least 37 records · Page 2Linked to original sources
PubMed1988

Historical overview. The calcium channel of the heart.

The present historical paper concentrates on the roots of the pharmacodynamic concept of Ca++ antagonism, and on the various therapeutic consequences of transmembrane Ca++ entry inhibition, i.e., normalization of hyperkinetic cardiac disorders, suppression of arterial and arteriolar spasms, relief of systemic arterial hypertension, stopping of cardiac dysrhythmias. Obviously in all these cases, medicine makes use of the different manifestations of one and the same fundamental action, that is to say, dose-dependent restriction of transmembrane inward Ca++ movements in active myocardium, vascular smooth muscle, or cardiac pacemaker cells. Interestingly, the origin of the principle of Ca++ antagonism and the discovery of drugs that possess Ca++-antagonistic potencies preceded the detection of the "slow Ca++ channels" by some years. However, the subsequent identification of the "slow channels" (or analogous Ca++ transport systems) as the decisive site of action of specific Ca++ antagonists has to be considered a keystone of the actual concept. The present paper does not treat tissue protection by Ca++ antagonists which is provided against intracellular Ca++ overload and its histopathological sequelae, as for instance Ca++-induced myofibrillar or mitochondrial disintegration. However, the inclusion of morphological topics, such as preservation of myocardial and vascular integrity by Ca++ antagonists, would exceed the limits of this article.

Animals↗
PubMed1987

Future directions in the use of calcium antagonists.

There are several reasons to expect that the use of calcium antagonists to treat cardiovascular disease will continue to spread. The scope of indications for existing calcium antagonists is expanding; new calcium antagonists with more selective organ affinity are being developed and these drugs may be given over the long term for prophylaxis against hypertension and for vasoprotection. In all probability, the long-term prophylactic use of calcium antagonists offers the most promise. The long-term effects of calcium antagonists for treating hypertension as well as for preventing vascular damage due to calcinosis and sclerosis will be discussed.

Animals↗
PubMed1986

Antihypertensive and arterial anticalcinotic effects of calcium antagonists.

In vascular smooth muscle (as in myocardial fibers), a transmembrane supply of calcium ions is required for active tension development. In consequence, calcium antagonists possess a wide scope of action against practically all types of vasoconstrictor or spastic responses of arterial smooth muscle cells. Calcium antagonists are the drugs of choice for the treatment of coronary, pulmonary, cerebral or mesenteric artery spasms. Other clinically important targets of calcium antagonists are the systemic resistance vessels that rapidly dilate, which explains why calcium antagonists are increasingly used for the treatment of acute hypertensive crises as well as for antihypertensive long-term therapy. In physiologic experiments, calcium antagonists normalize the blood pressure of spontaneously hypertensive rats, neutralize various vasoconstrictor agents (if they act via promotion of transmembrane calcium influx), and greatly reduce the sensitivity of the systemic arteries and arterioles to mechanical stimuli, which can produce additional vasoconstriction, if a rise in intraluminal pressure stretches the vascular wall (Bayliss effect). Calcium antagonists also prevent noxious arterial calcium overload in animals. In the human arterial walls, at an advanced age, pathogenic degrees of calcium accumulation are reached and probably play an important role in both the development of hypertension and of arteriosclerotic lesions. Hypertensive rats exhibit progressive arterial calcium overload that responds well to the calcium antagonists nifedipine, nimodipine, nisoldipine and nitrendipine, as well as to verapamil.

Aging↗
PubMed1986

On a possible role for calcium antagonists in atherosclerosis. A personal view.

An overview is provided of current thinking regarding the origin(s) of atherosclerosis on the basis of clinical evidence, experimental models and pharmacological investigations with calcium antagonists. Because this group of drugs inhibits the influx of Ca2+ into the smooth muscle cell of the cardiovascular wall, it has been argued that when endothelial damage is anticipated or has occurred, the 'protective' action of calcium antagonists might avoid, delay or even help to repair the calcium overload seen with cell membrane damage. In the real world the situation must be far more complex as will become evident but as a concept the avoidance of Ca2+ overloading is enticing. In fact, based on circumstantial evidence, a major clinical trial is currently in progress in which the long term effect of nifedipine on coronary atherosclerosis is being evaluated in a double blind randomized fashion. The end-point of this study lies in the reduction of the severity and number of coronary artery lesions. Although not yet completed, the design and goals of that study are provided.

Animals↗
PubMed1985

Experimental basis of the long-term therapy of arterial hypertension with calcium antagonists.

In vascular smooth muscle (as in myocardial fibers) a transmembrane supply of Ca++ ions is required for active tension development. In consequence, Ca++ antagonists, which restrict transmembrane Ca++ delivery, possess a wide scope of action against practically all types of vasoconstrictor or spastic reactions on coronary, pulmonary, cerebral, renal or mesenteric arteries. Another important target of Ca++ antagonists is the resistance vessels of systemic circulation in both animals and humans. Thus, Ca++ antagonists are successfully used for the treatment of acute hypertensive crises as well as for long-term antihypertensive therapy. Spontaneously hypertensive rats (SHRs) also respond to suitable Ca++ antagonists with a dramatic fall in blood pressure. The acute spasmolytic effects of Ca++ antagonists can be directly visualized by ophthalmoscopic examination of the arterioles in the ocular fundus. In untreated SHRs these arterioles are always heavily constricted, and aneurysm-like luminal protuberances develop. In contrast, after 1 adequate Ca++ antagonist dose, blood pressure instantaneously falls to its normal level while the retinal arterioles dilate. A further important effect of Ca++ antagonists that we have demonstrated in experiments on SHRs is the prevention of progressive arterial Ca++ overload, which otherwise produces severe calcinotic or arteriosclerotic damage of the arterial walls. However, with the help of Ca++ antagonists, arterial integrity can be totally preserved. Interestingly, this anticalcinotic arterial protection by Ca++ antagonists may also manifest itself independent of any blood pressure change. This is true of arterial calcinosis in normotensive rats because of advanced age, alloxan diabetes or intoxication with overdoses of vitamin D3, dihydrotachysterol or nicotine.

Animals↗
PubMed1984

[Possibilities in the future application of calcium antagonists. Is the prevention of blood vessel calcinosis possible?].

One of the most important effects of the new pharmacological family of Ca-antagonistic drugs is the prevention of deleterious myocardial Ca overload which is the decisive etiological factor in the production of cardiac necroses, as for instance b-adrenergic overstimulation. However, at an advanced age, also in the human arterial walls, cytotoxic degrees of Ca overload are reached, which probably play an important role in the pathogenesis of arteriosclerotic lesions. It is interesting that severe diabetics and heavy smokers exhibit a much faster progression of age-dependent arterial calcinosis than normal human subjects. In rats the Ca antagonists verapamil and diltiazem not only prevented arterial calcinosis due to overdoses of vitamin D and dihydrotachysterol, but also counteracted age-dependent Ca accumulation. Most impressive effects were also obtained in spontaneously hypertensive rats; chronic oral treatment with nifedipine and other 1,4-dihydropyridines as well as with verapamil kept both blood pressure and Ca content of the arterial walls (aorta, A. mesenterica) in the normal range. Our findings nourish the hope that suitable Ca antagonists can possibly interfere with arterial calcinosis also in humans, thus bearing a new vasoprotective indication.

Animals↗
PubMed1983

Consequences of uncontrolled calcium entry and its prevention with calcium antagonists.

Heart muscle fibres always undergo severe functional and structural alterations, finally resulting in necrotization, if free extracellular Ca2+ ions penetrate abundantly through the sarcolemma membrane into the myoplasm, so that the capacities of the Ca2+ binding or extrusion processes become overpowered. The crucial reaction consists of high-energy phosphate exhaustion which is brought about (a) by excessive activation of Ca2+-dependent intracellular ATPases, and (b) by Ca2+-induced impairment of the mitochondria. Intracellular Ca2+ overload proved to the common denominator in the pathogenesis of severe myocardial fibre injury and death produced under the following circumstances: Overdoses of beta-adrenergic catecholamines, dihydrotachysterol or vitamin D3, alimentary K+ or Mg2+ deficiency, hereditary cardiomyopathy of Syrian hamsters. Moreover, intracellular Ca2+ overload develops in the course of myocardial hypoxia or ischaemia thus causing additional precipitous damage of the mitochrondria. Following our first observations made in 1968, it has turned out that in all these cases, Ca2+ antagonists are capable of protecting myocardial cell integrity in that they prevent excessive transmembrane Ca2+ uptake. This is also true of the Ca2+ paradox: Ca2+ antagonists possibly inhibit the development of sarcolemmal leaks in the Ca2+-deprived myocardium. However, it is more likely that Ca2+ antagonists restrict the exaggerated influx of Ca2+ through these leaks, when the Ca+-deprived myocardial fibres return to a normal Ca2+-containing medium.

Adenosine Triphosphate↗
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↗