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)

1. The effect of probucol on the vascular reactivity of different arteries isolated from rabbits was studied as well as its effects on the development of atherosclerosis in a cholesterol-fed rabbit model. 2. Probucol 10(-6)-5 x 10(-4)M produced a concentration-dependent inhibition of the contractile responses induced by KCI (80 mM), the sequence for the IC50 was: mesenteric artery (5th branch, 4.8 +/- 2.6 x 10(-5) M) > aorta (8.2 +/- 2.3 x 10(-5) M) > femoral artery (> 5 x 10(-4) M). The response to noradrenaline was: mesenteric artery (5th branch, 4.2 +/- 1.3 x 10(-5) M) > aorta (3.2 +/- 3.0 x 10(-4) M) > femoral (> 5 x 10(-4) M). 3. In the aorta, probucol (10(-5)-10(-4) M) shifted the concentration-response curves to Ca2+ downward and to the right. 4. Probucol at 5 x 10(-5) M and 5 x 10(-4) M showed a reduction in the 45Ca2+ uptake in resting, non-stimulated aortic rings as well as the uptake induced by both noradrenaline 10(-6) M and KCI 80 mM. 5. In experiments in vivo, probucol did not affect lipid profiles; however, drug-treatment significantly decreased the cholesterol content of aortic tissue and the extent of intimal surface covered with atherosclerotic lesions. 6. The vascular reactivity was recovered in femoral arteries from rabbits on the atherogenic diet plus probucol. 7. It is concluded that the effect of probucol in vascular smooth muscle can be attributed to an inhibition of Ca2+ entry through both potential- and receptor-operated pathways. Moreover our findings suggest that the effects of probucol on movement of calcium in vascular smooth muscle may play an important role in the mechanism of antiatherogenic properties of this drug.
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PMID:Action of probucol in arteries from normal and hypercholesterolaemic rabbits. 884 26

The lipoxygenase product 15-hydroxyeicosatetraenoic acid (15-HETE) was shown to be the most important eicosanoid formed in the atherosclerotic rabbit aorta. The aim of the present study was to compare the effects of 15-HETE and its hydroperoxy precursor 15-HpETE with those of other vasoconstrictor and vasodilator agents in arteries from rabbits fed either a control or a cholesterol-rich diet for 16 and 30 weeks. 5-Hydroxytryptamine (5-HT) aggregated platelets and thrombin caused contractions of isolated rabbit aortas. The contractile responses elicited by platelets from control animals were similar to those evoked by platelets from atherosclerotic rabbits. After 16 weeks of hypercholesterolemia, the contractile responses were either augmented (5-HT), unchanged (platelets) or reduced (thrombin). After 30 weeks of hypercholesterolemia, the responses to all contractile agents used had decreased. In both aortas and pulmonary arteries the endothelium-dependent relaxations to the calcium ionophore, A23167, and to acetylcholine were progressively lost and the endothelium-independent relaxations to nitroglycerin were reduced by the progressing hypercholesterolemia. The 15-lipoxygenase metabolites contracted the isolated thoracic aorta and pulmonary artery from control rabbits and to a lesser extent those of the cholesterol-fed rabbits. After raising the tone in these vessels with prostaglandin F2 alpha PGF2 alpha) or noradrenaline, 15-HpETE induced relaxations which were not significantly influenced by the development of fatty streaks. Our data illustrate that the contractions of the blood vessel wall to 15-HETE, like those to other vasoconstrictors, are markedly reduced by developing atherosclerosis. In contrast, the relaxations to 15-HpETE in the rabbit arteries remain unaltered after 16 to 30 weeks of hypercholesterolemia. This is unlike the reactions to other vasodilators, which are markedly reduced.
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PMID:Influence of hypercholesterolaemia on the reactivity of isolated rabbit arteries to 15-lipoxygenase metabolites of arachidonic acid: comparison with platelet-derived agents and vasodilators. 884 33

1. Cytomegalovirus (CMV) is a major pathogen in immunocompromised individuals and may participate in the pathogenesis of atherosclerosis in the general population. We evaluated whether CMV-infection alters the function of arterial smooth muscle. 2. Blood pressure (BP) and arterial reactivity were recorded in immunosuppressed rats that had been infected with CMV (10(5) plaque forming units i.p.). Furthermore, the reactivity of isolated arteries was compared between CMV-infected rats and rats injected with bacterial endotoxin (LPS). 3. Initially resting BP and heart rate (HR) were not modified in CMV-infected rats, but baroreflex control of HR was impaired. By the eighth day post-CMV, BP dropped precipitously and could no longer be raised by phenylephrine (PHE). 4. In mesenteric resistance arteries, isolated at this stage from CMV-infected rats, contractile responses to nerve stimulation, noradrenaline, PHE and 5-hydroxytryptamine (5-HT) were virtually absent while those to high potassium and vasopressin (AVP) were not modified. In aortae of CMV-infected rats, responses to 5-HT and AVP were impaired while those to PHE or potassium were hardly affected. Reduced contractile responses could not be restored by NG-nitro-L-arginine methyl ester (L-NAME). 5. Continuous treatment of CMV-infected rats with prazosin (0.1 mg kg-1 day-1) prevented blood pressure lowering and resistance artery changes. 6. Observations in arteries of LPS-treated rats (5-10 mg kg-1, i.p.) differed markedly from those in vessels of CMV-infected animals. The contractile reactivity of their mesenteric resistance arteries was not altered while in their aortae, responses to PHE, 5-HT and AVP were reduced. With the exception of the AVP responses, this was more pronounced in the presence of 1-arginine and reversed by L-NAME. 7. These findings indicate that CMV-infection results in a reduction of resistance artery reactivity and hypotonia. This seems not to involve cytokine-mediated induction of NO synthase in the vascular wall but may be due to alterations of excitation-contraction coupling in arterial smooth muscle in response to increased sympathetic nervous input.
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PMID:Impaired arterial reactivity following cytomegalovirus infection in the immunosuppressed rat. 890 36

Recent studies have been reported indicating that angiotensin II may potentiate neointimal formation. In the present study, we examined the antagonistic effect of tranilast on angiotensin II. Losartan was used as the reference compound. First, tranilast inhibited the angiotensin II-induced contraction of rabbit aortic strips in a noncompetitive manner (pD'(2) = 3.7), whereas it had little effect on the contraction induced by noradrenaline or endothelin-l. Second, tranilast inhibited the binding of (125)I-labeled angiotensin II to angiotensin AT1 receptors in rat liver membranes with an IC(50) value of 289 mu M. Finally, functional antagonism of tranilast (100 and 300 mu M) was demonstrated by its blockade of angiotensin II (10(-8)M)-induced (45)Ca(2+) -efflux from human vascular smooth muscle cells (VSMC). However, tranilast (30-300 mu M) exerted no influence on PDGF-induced formation of inositol triphosphates which cause an increase in [Ca(2+)]i in human VSMC. The antagonistic activity of tranilast towards angiotensin II may be involved in part in preventing restenosis after percutaneous transluminal coronary angioplasty (PTCA).
Atherosclerosis 1996 Apr 05
PMID:Tranilast antagonizes angiotensin II and inhibits its biological effects in vascular smooth muscle cells. 912 91

Animal studies have provided clearcut evidence that sympathetic factors are involved in the development and maintenance of high blood pressure (BP). This also appears to be the case in humans, in which sympathetic activation, detected through plasma noradrenaline measurement, noradrenaline spillover technique and direct recording of muscle sympathetic nerve activity, has been shown to characterize the early phases of the hypertensive state and parallel its severity. Sympathetic factors also play in a variety of pathophysiological states frequently associated with hypertension, such as obesity, insulin resistance and atherosclerosis. In addition evidence has been collected that adrenergic factors represent one of the mechanisms involved in determining BP variability, which is strictly associated with end organ damage. Taken together these findings underline the importance that the therapeutical approach to hypertension is aimed not only at lowering BP but also at reducing sympathetic activity.
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PMID:Sympathetic activity, blood pressure variability and end organ damage in hypertension. 932 34

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

Little is known about how the vascular reactivity of the coronary microcirculation is affected by upstream atherosclerotic disease. We have examined, with a wire myograph, the responses of intramyocardial arteries from hearts in which the epicardial vessels were either free of atherosclerotic lesions (non-diseased group) or were affected by atherosclerosis (diseased group). Vasodilator responses of preconstricted vessels to substance P (84.1 +/- 12.6 compared to 42.0 +/- 19.7%) were less in vessels from the diseased group (p < 0.05). In contrast, the relaxation to bradykinin (70.2 +/- 21.2 compared to 100.6 +/- 7.9%) was increased in vessels from the diseased group (p < 0.05). The dilator responses to acetylcholine, adenosine diphosphate, histamine and sodium nitroprusside showed no significant differences between arteries from each group. 5-Hydroxytryptamine was without any significant vasodilator effect in arteries from either group. Assessment of contractile function revealed that the responses to 5-hydroxytryptamine, acetylcholine, U46619, endothelin-1 and L-N(G)-monomethylarginine in each group were not significantly different. Histamine, noradrenaline and dopamine were without any significant contractile response. These results demonstrate that upstream atherosclerosis does not confer any global impairment of endothelium-dependent vasorelaxant responses or smooth muscle hyperreactivity to vasoconstrictors in the arteries that penetrate the myocardium.
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PMID:Reactivity of small intramyocardial arteries from atherosclerotic and non-atherosclerotic human hearts. 964 31

SYMPATHETIC NERVOUS SYSTEM AND HYPERTENSION: Biochemical, electrophysiological, pharmacological and haemodynamic findings support the existence of sympathetic nervous system activation in primary human hypertension. Analysis of regional sympathetic nervous system function, using both neurophysiological methods for measuring sympathetic nerve firing rates, and neurochemical techniques for quantifying regional noradrenaline spillover to plasma has demonstrated activation of the sympathetic nervous outflows to the heart, the kidneys, and skeletal muscle vasculature, particularly in younger patients. The initiating cause of this sympathetic nervous stimulation is unknown, but estimation of central nervous system noradrenaline turnover in hypertensive patients, using measurements of the washout of noradrenaline and its lipophilic metabolites into the internal jugular veins, indicates that activation of forebrain pressor noradrenergic nuclei is the probable underlying mechanism. CONSEQUENCES OF INCREASED SYMPATHETIC ACTIVITY: The sympathetic activation present in human hypertension no doubt contributes to the blood pressure elevation, and is a legitimate target for therapeutic intervention with imidazoline receptor-binding agents such as rilmenidine. In addition, the sympathetic nervous activation seems to have adverse consequences in hypertensive patients beyond initiating the blood pressure elevation. There is evidence that neural vasoconstriction has metabolic effects, in skeletal muscle impairing glucose delivery to muscle, causing insulin resistance and hyperinsulinaemia, and in liver retarding postprandial clearing of lipids, contributing to hyperlipidaemia. Cardiac sympathetic activation is demonstrably a cause of sudden death in heart failure patients; a comparable arrhythmogenic effect is probable in hypertension. A trophic effect of sympathetic activation on cardiovascular growth is also likely, contributing to the development of left ventricular hypertrophy. Rilmenidine, through its central nervous system actions, has been demonstrated to powerfully reduce sympathetic nervous activity in essential hypertension patients. INHIBITING THE SYMPATHETIC SYSTEM: As the clinical consequences of sympathetic nervous activation in essential hypertension appear to go beyond that of hypertension pathogenesis, extending to a causal influence in atherosclerosis development, cardiovascular hypertrophy and cardiac arrhythmias, it is possible that, of all antihypertensive drugs, those inhibiting the sympathetic nervous system might best reduce cardiovascular risk. This remains to be tested.
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PMID:High blood pressure management: potential benefits of I1 agents. 974 6

Clodronate, etidronate and pamidronate are bisphosphonates introduced in the treatment of hypercalcaemia and osteoporosis. Interestingly, they also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vitro whether these hydrophilic compounds 1) accumulate in the wall of the human artery, 2) influence human arterial tone, and 3) interfere with the vascular action of L-type Ca2+ antagonists. Human internal mammary artery rings were incubated with 14C-labelled bisphosphonates. After a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 mumol/l of clodronate were, respectively, 3.0 +/- 0.5 (mean +/- S.E.M.) and 1.3 +/- 0.2, with 4 and 40 mumol/l of etidronate 7.4 +/- 0.9, and 3.2 +/- 0.4, and with 0.4 and 4 mumol/l of pamidronate 4.7 +/- 0.7 and 3.9 +/- 0.8. Both tested bisphosphonates, clodronate and pamidronate, reduced the arterial contractile force induced by alpha-adrenergic stimulation with noradrenaline and membrane depolarization with high concentration of KCl. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca2+ with KCl as the agonist, and had an additive inhibitory effect on this response with the L-type Ca2(+)-channel blocker nifedipine. The results demonstrate that 1) bisphosphonates accumulate markedly in human artery, 2) clodronate and pamidronate reduce human arterial contactile force to alpha-adrenergic and depolarizing stimuli, and 3) as shown with clodronate, bisphosphonates may exert an additive inhibitory effect on human arterial contractions with an L-type Ca2(+)-channel blocker.
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PMID:Accumulation of bisphosphonates in human artery and their effects on human and rat arterial function in vitro. 978 31


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