Discovery and Development of Calcium Channel Blockers.

In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions.

Calcium channel blockers in cardiovascular pharmacotherapy.

This paper summarizes the pharmacological properties of calcium channel blockers (CCBs), their established therapeutic uses for cardiovascular disorders and the current improvement of their clinical effects through drug combinations. Their identification resulted from study of small molecules including coronary dilators, which were named calcium antagonists. Further experiments showed that they reduced contraction of arteries by inhibiting calcium entry and by interacting with binding sites identified on voltage-dependent calcium channels.

Risperidone enhances the vulnerability to stroke in hypertensive rats.

Background: Stroke is the second most common cause of death and a major cause of disability worldwide. Risperidone is an atypical antipsychotic drug that may increase the risk of stroke. The present work examined whether risperidone enhances the vulnerability to stroke in hypertensive rats and the potential mechanisms underlying such action.

[Traditional and translational medicine].

In the second half of the 20th century, the development of experimental pharmacology led to the discovery of powerful new therapeutic agents, but production has since faltered, particularly in Europe. The purpose of this paper is to review how the gap in the production of novel medicines between Europe and the USA could be filled by proper use of molecular biology data. The European program entitled 'The Innovative Medicines Initiative' could facilitate the translation of information from benchtop to bedside.

The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells.

Objectives: Amlodipine is a calcium channel blocker (CCB) known to stimulate nitric oxide production from endothelial cells. Whether this ancillary property can be related to the capacity of amlodipine to concentrate and alter the structure of cholesterol-containing membrane bilayers is a matter of investigation. Here, we reasoned that since the endothelial nitric oxide synthase is, in part, expressed in cholesterol-rich plasmalemmal microdomains (e.

Calcium-channel modulators for cardiovascular disease.

It is generally accepted that hypertension doubles the risk of cardiovascular disease, of which coronary heart disease is the most common and lethal. Hypertension is a predisposing factor for the development of stroke, peripheral arterial disease, heart failure and end-state renal disease. Atherosclerosis-causing coronary heart disease is related to the severity of hypertension.

Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis.

Drugs currently known as calcium channel blockers (CCB) were initially called calcium antagonists because of their ability to inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has been the basis for the use of CCBs in the management of hypertension and coronary heart disease.

Calcium channel blocker inhibits Western-type diet-evoked atherosclerosis development in ApoE-deficient mice.

Calcium channel blockers slow the progression of atherosclerosis. The purpose of the present experiments was to examine the action of lacidipine in a condition that accelerates the development of atherosclerosis in order to test the hypothesis that the protective action of lacidipine in atherosclerosis is unrelated to the reduction of blood pressure. Male ApoE-deficient mice (6 weeks old) were exposed either to normal chow (ND) or to a Western-type diet (WD, adjusted calorie diet containing 42% from fat) for 8 weeks.

Effect of prolonged incubation with copper on endothelium-dependent relaxation in rat isolated aorta.

1 We investigated the effects of prolonged exposure to copper (Cu(2+)) on vascular functioning of isolated rat aorta. 2 Aortic rings were exposed to CuSO(4) (3-24 h) in Dulbecco's modified Eagle medium with or without 10% foetal bovine serum (FBS) and then challenged with vasoconstrictors or vasodilators in the absence of Cu(2+). 3 Exposure to 2 micro M Cu(2+) in the absence of FBS did not modify the response to phenylephrine (PE) or acetylcholine (ACh) in aortic rings incubated for 24 h.

The role of pharmacology in drug discovery.

The International Union of Pharmacology (IUPHAR) enthusiastically welcomes the decision by the Nature Publishing Group to launch its new journal, Nature Reviews Drug Discovery. The title of the new journal poses interesting questions for pharmacologists. Why 'Drug Discovery'? Would we have preferred 'Pharmacology'? And do these distinctions even matter, as aren't all pharmacologists involved somehow in drug discovery?

[Calcium channel blockers and tissue remodeling in hypertension].

Calcium channel blockers and tissue remodeling in hypertension. Calcium channel blockers (calcium antagonists) are members of various chemical groups. They share the ability to inhibit calcium entry into depolarized smooth muscle cells.

Effects of amlodipine and lacidipine on cardiac remodelling and renin production in salt-loaded stroke-prone hypertensive rats.

1. Calcium channel blockers (CCBs) are anti-hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long-acting CCBs and their protective effect against cardiac and renal damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP).

New insights into the therapeutic mechanism of action of calcium channel blockers in salt-dependent hypertension: their interaction with endothelin gene expression.

It appears that the beneficial action of calcium channel blockers (CCBs) in hypertension may be related to short-term and long-term effects. This paper summarises pharmacological studies aiming to characterise those effects. The primary consequence of the short-term effects is the decrease of blood pressure related to a selective interaction of CCBs with calcium channels in hypertensive vessels.

Lacidipine prevents endothelial dysfunction in salt-loaded stroke-prone hypertensive rats.

Endothelium-dependent vasorelaxation is defective in hypertensive rats, especially in conduit arteries. In the stroke-prone spontaneously hypertensive rat, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. Because treatment with lacidipine, a long-acting calcium channel blocker, protects against stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endothelium-dependent vasorelaxation in the aorta.

Effect of nitro-L-arginine on electrical and mechanical responses to acetylcholine in the superior mesenteric artery from stroke-prone hypertensive rat.

1. High salt diet is known to aggravate the vascular pathology in spontaneously hypertensive stroke-prone rats (SHR-SP). The aim of the present study was to assess the involvement of endothelial dysfunction in this effect.

Carvedilol and lacidipine prevent cardiac hypertrophy and endothelin-1 gene overexpression after aortic banding.

Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.

1,4-Dihydropyridine calcium channel blockers inhibit plasma and LDL oxidation and formation of oxidation-specific epitopes in the arterial wall and prolong survival in stroke-prone spontaneously hypertensive rats.

Background And Purpose: Calcium-channel blockers (CCBs) reduce systolic blood pressure and stroke-related mortality in stroke-prone spontaneously hypertensive rats (SPSHR). Brain ischemia is associated with loss of intracellular antioxidants. Increased formation of oxygen radicals and oxidation of LDL may enhance arterial vasoconstriction by various mechanisms.

Functional reduction and associated cellular rearrangement in SHRSP rat basilar arteries are affected by salt load and calcium antagonist treatment.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a strain with high incidence of cerebrovascular accidents increased by salt-rich diet and decreased by calcium-antagonist treatment. In the SHRSP rat basilar artery the authors have previously shown reduced contractility and altered structure including regions of smooth muscle cell (SMC) disorganization. The aims of this study have been to analyze (1) the morphology of these abnormal regions, (2) the structural modifications responsible for the reduced function, and (3) the effect of salt and calcium-antagonist treatment on vascular structure and function.