Review of preclinical data of calcium channel blockers and atherosclerosis.

A variety of animal models have been used to determine whether calcium channel blockers exert an inhibitory effect on atherosclerotic lesion formation. These models include the cholesterol-fed rabbit, in which the lesions resemble the fatty-streak stage of atherosclerotic lesion development in humans. Diet-induced atherosclerosis in monkeys is also used and, in this case, the lesions resemble those found in humans, both in pathology and distribution.

New therapeutic trends in calcium antagonism. Are they meaningful?

Recent advances in the field of calcium antagonism include the development of long-acting calcium antagonists, some of which have a slow onset of action. Some of these newly developed calcium antagonists are dihydropyridine derivatives. Others, including monatepil (AJ-2615), are chemically unrelated to either the dihydropyridine (nifedipine), phenylalkylamine (verapamil), or benzothiazepine (diltiazem) prototypes of the group.

Therapeutic approaches to the control of coronary atherosclerosis.

Atherosclerosis is a multifactorial disease which culminates in the ruptured plaque seen at autopsy. Hypercholesterolaemia, subintimal accumulation of lipid, monocyte adhesion followed by penetration across the endothelium, the conversion of monocytes to macrophages and smooth muscle cell proliferation and migration are some of the events involved in the early stages of lesion formation. Late events include the formation of excess ground substance and collagen, and the formation of the fibrotic cap.

End-organ involvement and calcium antagonist therapy: animal studies.

Hypertension is a complex disease, the treatment of which should not only lower systolic and diastolic blood pressure but also attenuate the secondary consequences of the disease. These include vascular injury (including atherosclerosis), stroke, left ventricular hypertrophy, and renal damage. To establish whether the long-acting, vascular-selective calcium antagonist amlodipine attenuates some of these secondary consequences of hypertension, 5-week-old stroke-prone hypertensive and 8-week-old spontaneously hypertensive rats were treated (orally) with 5 mg/kg/day and 10 mg/kg/day amlodipine, respectively, for 30 weeks.

The antiatherosclerotic effect of the calcium antagonists and their implications in hypertension.

Calcium-dependent processes involved in atherosclerotic lesion formation include platelet aggregation, monocyte adhesion, release of growth factors, cell proliferation and migration, protein and collagen secretion and synthesis, and endothelial necrosis. In addition, the calcium (Ca2+) component of smooth muscle cell contraction contributes to one of the main risk factors, hypertension. The ability of the calcium channel blockers (CCBs) to interrupt the sequence of events that culminates in the formation of atherosclerotic lesions has been demonstrated in animal models and clinical trials.

Pharmacological aspects of calcium antagonism. Short term and long term benefits.

Calcium antagonists are widely used in the management of a variety of cardiovascular disorders, including angina pectoris, myocardial infarction, atherosclerosis and hypertension. At the cellular level these drugs act primarily by limiting calcium ion (Ca++) entry through voltage-sensitive, Ca(++)-selective channels. This effect contributes to the antiatherogenic properties of calcium antagonists and is primarily responsible for their ability to reduce systolic and diastolic blood pressure, and to protect the myocardium.

The effects of Ca(2+)-free perfusion and the calcium paradox on [125I] endothelin-1 binding to rat cardiac membranes.

The binding characteristics of [125I]endothelin-1 (ET-1) to cardiac membranes isolated from rat hearts subjected to Ca(2+)-free perfusion or the Ca2+ paradox were examined. The effect of treatment with 2, 3 butanedione monoxime (BDM), which inhibits the tissue damage associated with the calcium paradox, was also investigated. Membranes from rat hearts perfused under control conditions bound [125I]ET-1 to a single population of sites with a Bmax of 107.

The antiatherogenic effects of amlodipine: promise of preclinical data.

Atherosclerosis is a complex and multifactorial disease, the endpoint of which is the formation of a calcified plaque. Intermediate events include intimal injury, smooth muscle cell proliferation and migration, macrophage infiltration, lipid accumulation and excess formation of ground substance. To determine whether the newly developed, long-acting calcium antagonist, amlodipine, slows the development of atherosclerotic lesions under experimental conditions, young New Zealand white rabbits were fed on a diet of 2% cholesterol plus 1% peanut oil for up to 12 weeks.

Effect of amlodipine pretreatment on ischaemia-reperfusion-induced increase in cardiac endothelin-1 binding site density.

Endothelin-1 (ET-1) may be implicated in the pathophysiology of myocardial ischaemia. To determine whether the long-acting calcium antagonist amlodipine attenuates the ischaemia- and reperfusion-induced increase in cardiac ET-1 binding sites, hearts from rats pretreated with amlodipine (0.25 or 0.

Effect of age on endothelin-1 binding sites in rat cardiac ventricular membranes.

To establish whether the density, affinity, or selectivity of endothelin-1 (ET-1) binding sites in cardiac ventricular membranes varies with age, membranes were harvested from 5- to 7-day-, 20-day-, and 8- to 9-week-old Sprague Dawley rats and labeled with [125I]ET-1. Selectivity was established by using cold ET-1, ET-2, ET-3, big ET-1, and (+)PN200-110 to inhibit specific binding of [125I]ET-1. Over the age span studied, selectivity and affinity of the [125I]ET-1 binding sites was unchanged, but density (Bmax) decreased from 209.

Calcium channels and their involvement in cardiovascular disease.

The widespread distribution of L-type Ca2+ channels in the cardiovascular system makes that system a natural 'target' for drugs which inhibit L-type Ca2+ channel activity. Now that tissue-dependent differences in the chemical composition of the calcium antagonist binding sites have been recognized it may be possible to develop drugs with enhanced tissue selectivity. The search for new compounds should not be restricted to improvements in tissue selectivity, however.

The molecular basis for the use of calcium antagonists in ischaemic heart disease.

Calcium antagonists are useful for the management of patients with ischaemic heart disease, particularly when used prophylactically. At the cellular level, these drugs act primarily by limiting calcium ion (Ca++) entry through the voltage-sensitive Ca(++)-selective channels, an effect that contributes markedly to their 'energy sparing' properties. However, the long term use of these drugs has additional advantages, particularly with respect to their ability to slow Ca(++)-dependent processes involved in the formation of atherogenic lesions, partially antagonise the effects of the raised levels of circulating endothelin-1 encountered during ischaemia-induced heart failure and hypertension, and trap and immobilise oxyradicals.

Calcium, calcium antagonism, atherosclerosis, and ischemia.

Calcium is a ubiquitous cation involved in a wide variety of physiological processes. Normally, cytosolic calcium is maintained within narrow limits but under certain conditions the levels rise--either because of excess calcium entry, internal release, or failure of the extrusion mechanisms. Such conditions include hypertension and myocardial ischemia.

The role of oxygen radicals during reperfusion.

Oxy and hydroxy radicals produced during postischemic reperfusion may contribute to the mechanisms responsible for the sustained contractile dysfunction and ultrastructural injury that occur under these conditions. At the molecular level, the consequent peroxidation of membrane-located lipids (including membranes that delineate the sarcoplasmic reticulum, the mitochondria, and the myocytes) probably contributes to the associated loss of Ca2+ homeostasis. Protection against oxy and hydroxy radical-induced injury can be approached in several ways.

The role of calcium in the toxic effects of tert-butyl hydroperoxide on adult rat cardiac myocytes.

Oxidant stress has been implicated in reoxygenation damage following hypoxia and can lead to loss of membrane integrity and cell death. In this study the effects of oxidant stress, induced by tert-butyl hydroperoxide (tBHP), on cell conformation and intracellular free calcium ([Ca2+]i) of cardiac myocytes isolated from rat ventricles were examined. Incubation in the presence of 1 mM tBHP lead to a rise in [Ca2+]i, hypercontracture and loss of membrane integrity (as judged by trypan blue staining and loss of fluorescence of fura-2 loaded cells).

The inhibitory effect of [D-Arg1,D-Phe,D-Try7,9,Leu11] substance P on endothelin-1 binding sites in rat cardiac membranes.

The specific binding of [125I]ET-1 to rat cardiac membrane fragments was inhibited by [D-Arg1,D-Phe, D-Try7,9,Leu11] substance P [substance P(D)], a potent bombesin antagonist. This inhibitory effect required high concentrations (greater than 3X10(-6)M) of substance P(D) and was accompanied by a steep increase in non-specific binding, and not a decrease in total binding. Such results indicate that substance P(D) does not competitively inhibit the specific binding of [125I]ET-1 to rat cardiac membrane fragments.

The unique binding properties of amlodipine: a long-acting calcium antagonist.

Amlodipine is a 'second generation', long-acting calcium antagonist. To characterise the binding properties of this drug saturation binding studies were undertaken using (-)[3H]amlodipine and rat cardiac membrane fragments. (-)[3H]Amlodipine bound to a single population of high affinity binding sites with a KD of 1.

Concentration-dependent desensitization of isolated porcine coronary arterial segments to acetylcholine.

Acetylcholine elicited an increase in developed tension on isolated porcine coronary arterial rings at concentrations exceeding 1.1 x 10(-7) M. However, at concentrations greater than 3.

Vascular injury: mechanisms and manifestations.

Abnormalities in regulatory mechanisms for calcium handling play a key role in cell death and tissue necrosis. In the cardiovascular system this applies to the vasculature and the myocardium alike. In the aged population, where hypertension is a known risk factor, manifestations of vascular injury include atherogenesis and stroke.

(-)[3H]amlodipine binding to rat cardiac membranes.

Amlodipine is a newly developed long-acting dihydropyridine-based calcium antagonist. To characterize the binding properties of this compound, saturation binding studies were undertaken, using (-)[3H]amlodipine and rat cardiac membrane fragments. (-)[3H]Amlodipine bound to a single population of high-affinity binding sites with a KD of 1.

Vascular and myocardial effects of amlodipine: an overview.

Amlodipine is a long-acting dihydropyridine calcium antagonist with vascular selectivity. Although structurally related to nifedipine, amlodipine differs in several important respects, including its slow rate of onset and slow recovery. These effects probably reflect the relatively slow rate of association and dissociation of amlodipine with its binding site.

Cardioprotective aspects of calcium antagonists.

The use of calcium antagonists as cardioprotective agents is based on the assumption that uncontrolled Ca2+ gain is a key factor in causing cell death and tissue necrosis. This uncontrolled gain in Ca2+ is the ultimate expression of a series of metabolic events triggered by inadequate perfusion. One of the early events is a rise in cytosolic Ca2+ (Cai2+).