Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium antagonists (calcium channel blockers) constitute a chemically heterogeneous group of drugs which block voltage-operated calcium channels of L-type. They specifically interact with the alpha 1 subunit of the calcium channel. Their mechanism of action has been demonstrated using pharmacological, electrophysiological and radiochemical techniques. Their therapeutic effects are not only related to their hemodynamic action but also to their remodeling effect in hypertrophic heart and arteries, to their anti-ischaemic action and to the preservation of vascular integrity during several pathologies. Drugs belonging to the second generation of calcium antagonists show various pharmacological profiles responsible for their tissue selectivity. The latter is a rational basis for novel therapeutic indications including atherosclerosis and cardiac failure.
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PMID:[Experimental pharmacology of calcium antagonists]. 809 49

The existence of vasoconstrictive factors originating from the endothelium was confirmed by the description of endothelin, a 21-amino-acid peptide derived from a series of precursors, preproendothelin and a 38-amino-acid big endothelin. Three isoforms of endothelin, endothelin-1, -2 and -3, and 3 receptors (ETA, ETB and ETC) have been described and cloned. The cellular mode of action of endothelin seems to involve the modulation of intracellular calcium (through inositol trisphosphate, diacylglycerol and phospholipase C) and activation of calcium channels. The effects of endothelin are predominantly on the cardiovascular system. Its major effect is vasoconstriction, both systemic and pulmonary, with additional positive chronotropic and inotropic effects on the heart. It has also been implicated in homeostatic regulation of kidney microcirculation, and has powerful mitogenic effects on fibroblasts and smooth muscle cells. Many additional effects have been described on the endocrine system and on other systems. However, the clinical relevance of such effects is uncertain. Increased plasma endothelin levels have been reported in many diseases, but as yet it is not certain whether they are a cause or a consequence of the pathology. Pathologies most probably related to endothelin dysfunction are the vasospastic diseases, especially vasospasm after subarachnoid haemorrhage. Endothelin could be implicated to a lesser measure in diseases typical of the elderly population, such as hypertension or atherosclerosis. Drugs are being developed which act on endothelin metabolism, the most promising of which appear to be the inhibitors of endothelin converting enzyme and endothelin receptor antagonists. Some already existing drugs, such as calcium channel blockers or angiotensin converting enzyme inhibitors, probably act at least in part by interfering with endothelin metabolism or effects.
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PMID:Endothelins. A potential target for pharmacological intervention in diseases of the elderly. 819 96

The clinical coincidence of hypertension, obesity and non insulin diabetes mellitus (NIDDM) has long been recognized. Increasing interest has also been recently focused on the possible role of insulin and insulin resistance in mediating this association. There is also evidence that hyperglycemia per se may have a role in the pathogenesis of hypertension and atherosclerosis in NIDDM patients. Glucose is a determinant to cellular ion homeostasis, promoting an increase of intracellular calcium and suppressing intracellular free magnesium and pH. Moreover, hyperglycemia promotes glycosilation of proteins and the consequent accumulation of advanced glycosilation end products in tissues. It has recently been suggested that iter is a cellular ionic basis for the clinical and epidemiological linkage of hypertension, left ventricular hypertrophy (LVH), obesity and non insulin dependent diabetes mellitus (NIDDM). These clinical conditions may be different expressions of a common underlying defect in ion handling, displayed by elevated cytosolic free calcium and suppressed free magnesium levels. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion specific agents, such as calcium channel blocker drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent cardiac, vascular and metabolic aspects of the hypertensive states.
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PMID:Diabetes, hypertension and atherosclerosis: pathophysiological role of intracellular ions. 820 15

Until recently, only three calcium channel antagonists--verapamil, diltiazem and nifedipine--were available for managing cardiovascular disorders such as hypertension and ischemic heart disease. In the past few years, however, several dihydropyridine calcium channel antagonists, including nicardipine, isradipine, felodipine, nimodipine, and amlodipine, have been marketed. Others are currently awaiting FDA approval. In addition, bepridil, which belongs to a new class of calcium channel antagonists, has recently been marketed for refractory angina pectoris. Clinical uses of calcium channel antagonists have been expanded since the 1970s to include management of cardiovascular disorders such as supraventricular arrhythmias, CHF secondary to diastolic dysfunction, and myocardial reinfarction in selected patients. Calcium channel antagonists are also being investigated for prevention of atherosclerosis. Calcium channel antagonists are a heterogeneous group of pharmacologic agents. Differences in tissue selectivity are largely responsible for the variations in hemodynamic and electrophysiologic properties of these agents. Thus, their clinical uses and side effect profiles differ. These differences must be taken into consideration in the selection of the most appropriate agent for a specific indication. Potential advantages of some of the newer dihydropyridine calcium channel antagonists include less frequent dosing (amlodipine and isradipine) and little or no negative inotropic effect (nicardipine, felodipine, amlodipine, isradipine) compared with the prototype calcium channel antagonists. Additional clinical experience with these newer agents is required, however, before their role in the management of cardiovascular disorders can be fully delineated. The availability of sustained-release formulations of verapamil, diltiazem, nifedipine, felodipine, and nicardipine, as well as the recent marketing of calcium channel antagonists with relatively long half-lives (amlodipine and isradipine), makes once- or twice-daily dosing possible with most calcium channel blockers. However, selection of a particular agent will depend on several factors, including clinical efficacy, side effect profile, cost, and patient characteristics such as concomitant disease states and baseline hemodynamic status.
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PMID:Use of calcium channel antagonists for cardiovascular disease. 821 73

Effective treatment of hypertension in the elderly requires an understanding of both the progressive course of the disease and the impact of aging on the cardiovascular system, including physiological, genetic, lifestyle, and environmental factors. Review of the literature that has attempted to define the impact of an "aging process" on cardiovascular structure and function reveals a diversity of findings and interpretations. However, in general, normotensive elderly subjects exhibit the heart and vascular characteristics of "muted" hypertension, including many features of younger hypertensive patients: cardiac hypertrophy, diminution in resting left ventricular early diastolic filling rate, increased arterial stiffness and aortic impedance, diminution in the baroreceptor reflex, a diminished response to catecholamines and diminished renal blood flow, and an increase in peripheral vascular resistance (PVR). Treatment of elderly hypertensives is more challenging because of the greater likelihood of the presence of concomitant diseases, most importantly, coronary and peripheral atherosclerosis, renal dysfunction, and diabetes mellitus. Isolated systolic hypertension (ISH), the most common form of hypertension in the elderly, has also been clearly shown to be an important predictor of cardiovascular morbidity and mortality, including coronary artery disease, congestive heart failure, and stroke. Treatment of ISH has been shown to lower systolic pressure safely and effectively in the elderly. By reducing PVR, and possibly the arterial stiffness, and thus the early reflected pulse waves, vasodilators, including calcium antagonists, may lower these three components of arterial impedance, and hence lower the arterial load on the heart. The cardiac hypertrophy and reduced left ventricular filling rate associated with hypertension in older individuals can also be ameliorated, to some extent, by calcium channel blockers.
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PMID:Hypertension in the elderly: age- and disease-related complications and therapeutic implications. 824 Oct 7

Calcium channel blocking drugs (CCB) have been used to lower blood pressure since 1970. Three classes are currently available, the phenylalkylamines, the benzothiazepines, and the dihydropyridines. The structure of the L-type, voltage dependent calcium channel has been elucidated with molecular techniques and the different binding sites of the various CCB described. CCB have specific effects at the site of target organs. In the kidney, all classes produce natriuresis. Their action appears independent of the level of salt intake. CCB may favorably influence the course of chronic renal disease; the results of a trial comparing nifedipine to the converting enzyme inhibitor captopril showed no difference between the two drugs. CCB may impede the progression of atherosclerosis in the coronary arteries; a prospective study of nifedipine on coronary artery morphology supports this view. In the brain, nimodipine improves the outcome of patients with stroke from subarachnoid hemorrhage. Positive effects on patients with ischemic stroke have not been corroborated. CCB are approved primary treatment for patients with hypertension and are readily combined with other antihypertensive agents. They are well tolerated and have no adverse metabolic side effects. The advent of molecular pharmacology will advance current efforts to develop new CCB, which are highly selective in their site and mode of action.
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PMID:Calcium channel blockers in current medical practice: an update for 1993. 826 89

Secondary causes of hyperlipidemia are important to recognize. In fact, hyperlipidemia may be a clue to the presence of an underlying systemic disorder. It may greatly heighten the risk of atherosclerosis with a raised LDL-c, triglyceride-rich lipoprotein excess, and increased lipoprotein(a) as well as lowered HDL-c. The search for secondary causes may provide a clue as to why patients with primary lipid disorders suddenly develop worsening lipid profiles. The point is a crucial one because some acquired causes of hyperlipidemia, such as alcohol, estrogens, steroids, or pregnancy, when superimposed on a primary familial form of hypertriglyceridemia can result in a saturated removal system and a buildup of chylomicrons, which can lead to life-threatening pancreatitis. A convenient way to remember secondary causes is to think of the four D's of diet, drugs, disorders of metabolism, and diseases. Although diets rich in saturated fats and cholesterol are a common cause of the mild hypercholesterolemia seen in our society, alcohol excess and weight gain can explain much of the tendency toward hypertriglyceridemia. Interestingly anorexia nervosa has long been associated with severe but reversible hypercholesterolemia. Several classes of drugs need to be considered as common causes of altered lipid profiles. Glucocorticoids and estrogens elevate triglycerides and raise levels of HDL-c. Anabolic steroids taken orally markedly reduce levels of HDL-c in contrast to injectable testosterone, which does not adversely affect the LDL-to-HDL ratio. Oral contraceptives affect atherosclerotic risk depending on the kind and doses of progestin/estrogen. In those with an underlying primary hypertriglyceridemia and associated obesity, estrogenic medications can depress triglyceride removal mechanisms, leading to the chylomicronemia syndrome and pancreatitis. Antihypertensives have variable effects on lipids and lipoproteins. Although short-term thiazide usage raises cholesterol, triglycerides, and LDL-c, long-term usage is not necessarily associated with significant alterations in lipid levels. Alpha blockers may cause an increase in HDL-c, whereas beta blockers raise triglycerides and lower HDL-c. Sympatholytics, angiotensin converting enzyme inhibitors, and calcium channel blockers are essentially lipid neutral. Retinoids can be associated with increased LDL-to-HDL ratios and occasionally striking elevations in triglycerides. Cyclosporine raises LDL-c and lipoprotein(a). Classes of drugs that may raise HDL-c include cimetidine, antiepileptic drugs, and tamoxifen, but the effect may be seen primarily in women. Hypothyroidism is the most common secondary cause of hyperlipidemia after dietary causes are considered. A thyroxine and TSH level should be obtained on all new cases of clinically important hyperlipidemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Secondary causes of hyperlipidemia. 828 27

Low current (0.25, 3 mA) stimulation through a miniature electrode cuff encased around the carotid artery of the rat was used to induce intimal hyperplasia, an important feature of the atherosclerotic plaque and a phenomenon limiting the long term success of angioplasty. Compared to contralateral unstimulated arteries, 11-14 days of daily transmural stimulation of cuffed arteries (20 min period) significantly increased the amount of extracted DNA (diphenylamine colorimetric assay). Low current (0.25 mA) was as effective as 3 mA in producing an increase in extractable DNA. The cuff alone without applied current also stimulated an increase in DNA content but to a smaller degree than in arteries receiving current. Infusion of a calcium channel antagonist, diltiazem, at a dose which achieved therapeutic drug levels, significantly reduced the amount of electrode cuff-induced DNA content but had no effect on the increase in DNA induced by the presence of the cuff without applied current. Gene expression of PDGF-A chain, PDGF-B chain and PDGF-beta receptor (beta r) (Northern analysis of extracted carotid RNA) increased within 4 h after electrical stimulation with 3 mA. Lower current (0.25 mA) and the presence of the cuff also enhanced PDGF gene expression but with a delayed onset of several days. The pattern of gene expression for PDGF ligands and beta r during the 11-14 days of stimulation differed, but each remained above contralateral control levels. It is concluded that the continued coexpression of PDGF and one of its receptors may contribute to induced hyperplastic changes.
Atherosclerosis 1993 Apr
PMID:Electrode cuff-induced changes in DNA and PDGF gene expression in the rat carotid artery. 831 55

Diabetes and hypertension have a higher than expected comorbidity. They share common etiology, pathophysiology, and organ effects. Long-term therapeutic goals are to prevent renal failure and atherosclerosis. Management should inhibit pathophysiologic mechanisms and avoid stimulating them. The most appropriate pharmacologic agents to treat hypertension in the diabetic are ACE inhibitors, selected calcium channel blockers, alpha adrenengic blockers, and certain central alpha agonists. The only diuretics that should be used are indapamide and torsemide.
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PMID:Diabetes and hypertension. 856 30

Lipid peroxidation causes cellular damage during aging and various diseases, including atherosclerosis. Chronic administration of highly lipophilic calcium channel blockers (CCB) may reduce lipid peroxidation as a result of concentration in cell membranes and altering physico-chemical properties of the lipid bilayer. In the study, small angle X-ray scattering was used to examine reconstituted cardiac membrane lipid bilayers in the presence of CCB with various antioxidant activities, including nisoldipine, nifedipine, and diltiazem. Analysis of one-dimensional electron density profiles demonstrated that these compounds have different molecular distributions relative to the center of the membrane: diltiazem (+/- 14-22 A), nifedipine (+/- 12-22 A), and nisoldipine (+/- 7-22 A). The overall hydrocarbon core width for control samples was 44 A and was unaffected by the addition of drugs at these concentrations (< 1% by mass). High resolution differential scanning calorimetry indicated that CCB markedly perturbed the thermotropic properties of liposomes, including thermal phase transition temperature and enthalpy, relative to control samples. The effects of these compounds on membrane thermotropic properties correlate with their reported antioxidant activities. These data support the hypothesis that calcium channel blockers have potent physico-chemical interactions with the membrane lipid bilayer, which may underlie their antioxidant activity.
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PMID:Differential membrane interactions of calcium channel blockers. Implications for antioxidant activity. 861 2


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