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

To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a non-sulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8 +/- 3.5%; treated: 31.1 +/- 8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4 +/- 3.2 mg/g tissue; treated: 7.4 +/- 1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis.
 ...
PMID:Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. 847 94

Many cell types in myocardial tissue, including cardiocytes, contain receptors for angiotensin-II, but the activation of these receptors requires angiotensin concentrations in the micromolar range, which do not occur in plasma in vivo. However, angiotensins formed locally in the heart can activate these receptors in a paracrine and autocrine mode. In cardiac hypertrophy due to hemodynamic overload, the myocardial angiotensin formation is enhanced due to an augmented expression of angiotensinogen and ACE. Though the mRNA for prorenin is expressed in myocardium, the formation of active renin within the heart has not yet been demonstrated and myocardial renin activity is mainly due to contamination from circulating active renin. Intracoronary application of ACE inhibitors in hypertrophied hearts in vivo and in vitro indicates that the locally formed angiotensin-II contributes to coronary constriction, impairment of diastolic relaxation and marginally to the maintenance of systolic tension development. Angiotensin-II can exert trophic effects on cardiocytes and cardiac fibroblasts, and chronic inhibition of the cardiac RAS by ACE-inhibitors or AT receptor antagonists can induce partial regression of overload hypertrophy, even without normalizing the overload. This anti-trophic action may be partially due to the impairment of the angiotensin axis, but also due to enhancement of bradykinin availability, which results in an augmented release of endothelial anti-trophic signals such as EDRF/NO and prostacyclin. Preliminary evidence is compatible with the hypothesis that an activated local RAS in elastic arteries contributes to the localization and progression of atherosclerosis by suppressing EDRF releasability. However, the anti-atherosclerotic potential of ACE inhibitors and AT receptor antagonists in humans is still unknown.
 ...
PMID:The cardiac renin-angiotensin system: physiological relevance and pharmacological modulation. 851 37

Hypertension is an important cardiovascular risk factor. High blood pressure per se is not a disease but a hemodynamic alteration associated with vascular disease. Two classes of drugs are especially effective in lowering blood pressure and preventing cardiovascular complications, angiotensin converting enzyme (ACE) inhibitors and calcium antagonists. The hemodynamic effects of ACE inhibitors and calcium antagonists are complementary. While ACE inhibitors inhibit the renin-angiotensin system and reduce sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Certain calcium antagonists, such as verapamil, lower heart rate. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are also complementary. While ACE inhibitors inhibit activation of angiotensin I into angiotensin II and prevent the breakdown of bradykinin (which stimulates nitric oxide and prostacyclin formation), calcium antagonists inhibit the effects of vasoconstrictor hormones such as angiotensin II at the level of vascular smooth muscle by reducing calcium inflow and facilitating the vasodilator effects of nitric oxide. Calcium antagonists reduce smooth muscle cell proliferation and atherosclerosis. In hypertensive animals, verapamil and trandolapril normalize endothelial dysfunction. In large angiographic trials, nifedipine and nicardipine reduced the development of new atherosclerotic plaques. After myocardial infarction, verapamil reduces mortality and cardiac events in patients without heart failure. In contrast, ACE inhibitors are effective after myocardial infarction in patients with impaired left ventricular function. Urinary albumin excretion rate decreases during ACE inhibitor therapy or with a calcium antagonist such as verapamil; combination of the two drugs has an additive effect. In resistance arteries, hypertension is associated with an increased media/lumen ratio. ACE inhibitors, but not beta-blockers, markedly improve these structural changes. In summary, ACE inhibitors and calcium antagonists have a complementary profile, both in their hemodynamic and local vascular action. Hence, combination therapy with these two classes of drugs appears particularly useful in patients with hypertension, not only to lower blood pressure, but hopefully to achieve improved cardiovascular protection.
 ...
PMID:Vascular protective effects of ACE inhibitors and calcium antagonists: theoretical basis for a combination therapy in hypertension and other cardiovascular diseases. 856 68

Three enzyme-linked immunosorbent assays for the quantitation of murine tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor 1 (PAI-1), were developed using monoclonal antibodies raised against the autologous proteins in gene-inactivated mice. Dose-response was linear for t-PA and PAI-1 between 5 and 0.1 ng/ml and for u-PA between 50 and 1 ng/ml, with intra-assay, inter-assay and inter-dilution coefficients of variation of 6 to 14%. Assay recoveries of proteins (5 to 100 ng/ml) added to plasma were 73 to 95% for t-PA and PAI-1. Linear correlations (r = 0.65, r = 0.91 and r = 0.92, for t-PA, u-PA and PAI-1 respectively) were found between antigen and activity in plasma, urine and tissue extracts. Levels of t-PA and PAI-1 antigen in murine plasma were 2.5 +/- 1.0 ng/ml (mean +/- SD, n=9) and 1.9 +/- 0.6 ng/ml (mean +/- SD, n = 8), respectively, in wild-type mice and undetectable in gene-inactivated mice. Bradykinin injection in mice provoked a 12-fold increase (p < 0.0002) of t-PA and endotoxin injection an 80-fold increase (p < 0.005) of PAI-1 levels. u-PA antigen levels in urine from wild-type mice ranged between 0.2 and 8.2 micrograms/ml (1.8 +/- 1.9 micrograms/ml, mean +/- SD, n = 17) and were undetectable in gene-inactivated mice. Thus, these assays may be useful for studies on the role of these proteins in tissue remodeling, atherosclerosis, embryogenesis, etc., in established mouse models. Gene-inactivated mice may constitute a general approach for the generation of monoclonal antibodies against the deficient translation products and for the development of specific immunoassays for murine proteins.
 ...
PMID:Immunoassay of murine t-PA, u-PA and PAI-1 using monoclonal antibodies raised in gene-inactivated mice. 860 14

Oxidatively modified low-density lipoprotein(LDL) may be involved in the vasomotor disturbances associated with hypercholesterolemia and atherosclerosis, but effects of this lipoprotein on agonist-induced coronary vasoconstriction have not been reported. This study determined the effects of oxidized LDL on contraction of isolated porcine coronary arteries to several contractile agonists and investigated the mechanism of these effects. Oxidized LDL (10-100 microgram/ml) enhanced 5-hydroxytryptamine (5-HT)-induced contraction in a concentration-dependent manner, whereas native LDL (100 microgram/ml) had no effect. Enhancement of 5-HT-induced contraction was dependent on the presence of endothelium and blocked by L-NG-monomethyl-arginine (100 microM). Oxidized LDL (100 microgram/ml) similarly inhibited endothelium- and nitric oxide-dependent relaxation induced by 5-HT, but had no effect of relaxation induced by sodium nitroprusside. Furthermore, contraction to U46619 and acetylcholine, agonists that did not mediate endothelium-dependent relaxation, was unaffected by oxidized LDL (100 microgram/ml). Lysophosphatidylcholine (10-30 mumol/liter) also enhanced 5-HT-induced contraction and inhibited 5-HT-induced, endothelium-dependent relaxation. Endothelium-dependent relaxation to bradykinin was unaffected by lysophosphatidylcholine (20 muM). Thus, oxidized LDL enhanced 5_HT-induced coronary vasoconstriction in an endothelium dependent manner, actions that were mimicked by relevant concentrations of lysophosphatidylcholine. These in vitro effects of oxidized LDL mimicked effects of hypercholesterolemia and atherosclerosis on 5-HT vasoactivity in human coronary arteries in vivo, suggesting that oxidized LDL may play an important role in the development of vasomotor disturbances in these pathologies.
 ...
PMID:Selective enhancement of 5-hydroxytryptamine-induced contraction of porcine coronary artery by oxidized low-density lipoprotein. 878 40

Nitric oxide (NO)-mediated, endothelium-dependent vasodilation is reduced in atherosclerotic arteries. A number of in vivo studies suggest that infusion of the substrate of NO synthase, L-arginine, partly counteracts this effect. We studied the potential inhibitory effects of native and of oxidized low density lipoproteins (n-LDL, ox-LDL) on NO-dependent cyclic guanidine monophosphate (cGMP) formation in porcine aortic endothelial cells and the role of extracellular L-arginine in counteracting this process. NO-dependent cGMP production in the cells (passage 1; preincubated in L-arginine-free medium for 24 h) was stimulated for 3 min with bradykinin (BK 1 nM) or the calcium-ionophore A23187 (100 nM) or by a 20 min incubation with L-arginine (L-Arg 0.1 mM, 20 min). The endothelium-independent NO-donor, sodium nitroprusside (SNP 1 microM) was used as control stimulus. Experiments were performed in the presence of LDL which was kept as much as possible under antioxidative conditions, further referred to as n-LDL (1 mg/ml), or LDL which was oxidized by incubation with copper (ox-LDL 0.1 mg/ml). The NG-nitro-L-arginine (L-NNA, inhibitor of NO-synthase) -sensitive intracellular cGMP concentration was taken as a measure of endothelial NO formation and determined by radioimmunoassay. BK-induced changes of intracellular free Ca2++ were measured immediately after washout of LDL using the FURA-2 method. n-LDL reduced the cGMP-levels in unstimulated cells as well as the cGMP increase in response to bradykinin (-10%) and the calcium-ionophore A23187 (-80%). The SNP-induced cGMP-increase was, however, not affected. L-arginine increased the intracellular cGMP concentration under both conditions by a similar amount, without affecting intracellular free calcium. Uptake of 3H-L-arginine was not significantly altered by n-LDL treatment. Ox-LDL significantly reduced SNP-induced cGMP-increases but did not alter bradykinin-induced cGMP increases. The BK-induced increase of intracellular free calcium was even enhanced after exposure of the cells to ox-LDL. L-arginine increased cGMP by a similar amount as in untreated cells. It is concluded that both n-LDL and ox-LDL can reduce the NO-dependent cGMP formation in cultured endothelial cells, albeit by different mechanisms. However, a limitation of the uptake or availability of extracellularly applied L-arginine does not appear to be a causal factor, at least not after 2 h exposure.
Atherosclerosis 1995 Oct
PMID:Effects of LDL on intracellular free calcium and nitric oxide-dependent cGMP formation in porcine endothelial cells. 880 62

Genetic variations in the renin-angiotensin and kallikrein-kinin systems could prove to be significant pathophysiological mechanisms affecting coronary heart disease (CHD), particularly given the powerful vasoactivity of products such as angiotensin II and bradykinin. Indeed, studies show that angiotensin converting enzyme (ACE) gene polymorphism is associated with an increased risk of myocardial infarction and death, even in otherwise low-risk subjects. Genetic differences do not appear to be a risk factor for atherosclerosis or hypertension, however. Because ACE polymorphism modulates local production of angiotensin II, a powerful coronary vasoconstrictor, it may influence left ventricular mass in general as well as in coexisting disease states such as hypertension and cardiomyopathy. However, further study is needed to clarify the implications of ACE polymorphism in patients with left ventricular hypertrophy. Interactions between ACE and angiotensin II type-1 receptors may have clinical implications for preventing and managing CHD. Screening for genetic risk, as evidenced by certain variants in receptor coding sequence, may prove worthwhile if detrimental effects can be countered by drugs such as ACE inhibitors and angiotensin II receptor blockers. Given the important roles of angiotensin II and bradykinin as modulators of cellular growth and of vasoactivity, deleterious and beneficial effect at different stages of the atherosclerotic process and during acute events leading to myocardial infarction or sudden death can be suspected.
 ...
PMID:Angiotensin I converting enzyme gene polymorphism and coronary heart disease. 886 31

1. Experimental and clinical studies have demonstrated the efficacy of inhibitors of angiotensin-converting enzyme (ACE) in a variety of cardiovascular diseases. Both structural and functional improvements have been reported. 2. Hypertension, atherosclerosis, congestive heart failure or ageing are accompanied by endothelial dysfunctions. The vasoactive endothelium-derived relaxing factors, nitric oxide, endothelium-derived hyperpolarizing factor and prostacyclin, could be involved, depending on the pathology. 3. Some of the beneficial effects of ACE inhibitors may be due to the augmented release of these endothelial factors resulting from the protection of locally produced bradykinin, particularly at the endothelial level.
 ...
PMID:Endothelium-dependent responses and inhibition of angiotensin-converting enzyme. 888 9

It is recognized that heart failure in patients with atherosclerotic lesion is the result of ischemia. However, there may also be cardiac cell dysfunction independent of ischemia, as factors advancing both of atherosclerosis and heart failure are discovered. The renin-angiotensin system is one of factor and angiotensin-converting enzyme inhibitor (ACEi) prevents progression of atherosclerotic lesion and heart failure. To elucidate the association of atherosclerosis and cardiac cell dysfunction, we investigated the effects of ACEi on cultured cardiac myocytes. Captopril increased beta-receptor density of myocytes and augmented the response to isoproterenol. CV-3480, a ACEi, also up-regulated beta-receptors but angiotensin I, angiotensin II and angiotensin type I receptor antagonist did not. Bradykinin B2 receptor blocker, HOE140, suppressed the effect of captopril on cultured cells. The results suggest that ACEi up-regulated beta-receptors and augmented the response to beta-receptor agonist through BK potentiation.
 ...
PMID:[Association of atherosclerosis and cardiac cell dysfunction]. 895 33

Nitric oxide generated from L-arginine is a messenger for cell-to-cell communication. Abnormalities in nitric oxide release have been implicated in diseases ranging from hypertension and atherosclerosis to septic shock and rheumatoid arthritis. We report here the in vivo and in vitro measurements of nitric oxide in the cardiovascular system using a porphyrinic sensor specific for NO. The sensor has a detection limit 10(-9) M, response time of 0.1-10 ms and diameter of 1-20 microns. Protected by an intravenous catheter or Swan-Ganz catheter, the sensor can be implanted into tissues as well as into the blood stream. Nitric oxide concentrations were measured directly in the heart and also in veins and arteries, ranging in diameter from 100 microns to 5 mm. Nitric oxide production was induced by the action of different physical agents (shear stress, stretching) as well as various chemical substances agonists (bradykinin, acetylcholine, ATP).
 ...
PMID:Direct measurement of nitric oxide in the cardiovascular system. 908 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>