Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme activity was not affected in the adventitia. The MAP kinase activation was inhibited by either the angiotensin AT1 receptor antagonist losartan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT2 receptor antagonist PD 123,319 and the endothelin ETB receptor antagonist BQ 788 did not affect the MAP kinase activation. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) caused an activation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitroprusside inhibited the MAP kinase activation induced by endothelium removal or angiotensin II. These results suggest that even in isolated arteries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media are tonically released to cause MAP kinase-stimulating effects in medial smooth muscle.
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PMID:Evidence that angiotensin II, endothelins and nitric oxide regulate mitogen-activated protein kinase activity in rat aorta. 965 1

Inotropic effects on isolated neonatal and adult mouse myocardium of endothelin I and angiotensin II were examined. Endothelin I produced a sustained positive inotropic response in the neonate but a sustained negative response in the adult. Both were concentration-dependent and were inhibited by the endothelin ETA receptor antagonist, BQ-123 (Cyclo(D-a-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl)). Angiotensin II produced a sustained positive inotropic response in the neonate while a sustained negative response in the adult. Both were concentration-dependent and were inhibited by the angiotensin AT1 receptor antagonist, YM358 (2,7-diethyl-5-((2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl-5H-pyrazolo(1,5-b)(1,2,4)tria zole potassium salt monohydrate). These results indicate that inotropic responses of the mouse heart to cardioactive peptides are unique among experimental animal species and may be reversed during development.
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PMID:Developmental conversion of inotropism by endothelin I and angiotensin II from positive to negative in mice. 1042 85

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.
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PMID:Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. 1135 55

Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.
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PMID:Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan. 1240 81

Activation of renal mechanosensory nerves is enhanced by a high-sodium diet and suppressed by a low-sodium diet. Angiotensin (Ang) II and endothelin (ET)-1 each contributes to the impaired responsiveness of renal mechanosensory nerves in a low-sodium diet. We examined whether stimulation of ETA receptors (Rs) contributes to Ang II-induced suppression of the responsiveness of renal mechanosensory nerves. In anesthetized rats fed a low-sodium diet, renal pelvic administration of the Ang type I receptor (AT1-R) antagonist losartan enhanced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mm Hg from 7+/-2% to 15+/-2% and the prostaglandin (PG) E(2)-mediated substance P release from 0+/-1 to 8+/-1 pg/min. Adding the ETA-R antagonist BQ123 to the renal pelvic perfusate containing losartan did not produce any further enhancement of the ARNA response or PGE(2)-mediated release of substance P (17+/-3% and 8+/-1 pg/min). Likewise, renal pelvic administration of BQ123 and BQ123+losartan resulted in similar enhancements of the ARNA responses to increased renal pelvic pressure and PGE(2)-mediated substance P release. In high-sodium-diet rats, pelvic administration of Ang II reduced the ARNA response to increased renal pelvic pressure from 27+/-4% to 8+/-3% and the PGE(2)-mediated substance P release from 9+/-0 to 1+/-1 pg/min. Adding BQ123 to the renal pelvic perfusate containing Ang II restored the increases in ARNA and the PGE(2)-mediated substance P release toward control (27+/-6% and 7+/-1 pg/min). In conclusion, stimulation of ETA-R plays an important contributory role to the Ang II-mediated suppression of the activation of renal mechanosensory nerves in conditions of low-sodium diet.
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PMID:Activation of endothelin-a receptors contributes to angiotensin-induced suppression of renal sensory nerve activation. 1706 May 3

This project assesses the treatment role with insulin and (or) angiotensin II receptor subtype-1 (AT1-R) blocker (ARB) on insulin receptor and endothelin-1 receptor subtype (ETA-R and ETB-R) regulation in rat hearts suffering from insulin-dependent diabetes mellitus (IDDM). Animals were divided into 6 groups: groups 1, 3, and 5 were controls consisting of normal, diabetic (streptozotocin-treated, once at 0 time), and diabetic supplemented daily with insulin, respectively, whereas groups 2, 4, and 6 were the controls treated daily with losartan. One month after enrollment, rats were sacrificed and samples of cardiac tissue were snapped frozen for immunostaining and Western blotting. Insulin receptor density was observed to be upregulated in the cardiomyocytes of diabetic animals, but downregulated with insulin supplementation alone. Cotreatment with insulin and an ARB resulted in drastic increase in insulin-receptor density in the diabetic rats. In addition, expression of ETA-R in cardiomyocytes was upregulated and was consistently maintained within the various treatment modalities. However, ETB-R expression was significantly reduced in the diabetic group treated with both insulin and an ARB. The changes in the expression of the insulin, the ETA-Rs, and the ETB-Rs at the various sites of the myocardium and the effect of both insulin treatment and blockade of the AT1-R explain the new benefits related to the halting of myocardial remodeling in IDDM rats.
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PMID:Effect of type-1 diabetes mellitus on the regulation of insulin and endothelin-1 receptors in rat hearts. 1748 63

We investigated the role of angiotensin II and endothelin-1 using the angiotensin AT1 receptor antagonist losartan and the endothelin ETA receptor antagonist atrasentan, in malignant hypertension and renal failure and damage induced by nitric oxide (NO) synthase inhibition in Harlan Sprague-Dawley (SD) rats. We also evaluated whether the protective effects of losartan go beyond the blood pressure reduction. Within only 3 weeks of treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), Harlan SD rats developed malignant hypertension with renal failure and injuries. The latter were comprised of fibrinoid necrosis of small arteries and glomerular and tubular necrosis. Although both losartan and atrasentan attenuated the development of hypertension and renal failure, losartan only prevented the renal damage. In contrast to antrasentan, the vasodilator hydralazine reduced blood pressure and prevented the renal injuries similar to losartan. However, when these treatments were prolonged to 5 weeks, losartan, but not hydralazine, was still effective in reducing renal failure and damage, despite a marked increase in blood pressure. Our results indicate that angiotensin II and endothelin-1 play a differential role in the pathogenesis of malignant hypertension and in vascular and renal damage induced by L-NAME in Harlan SD rats. Although the protective effects of atrasentan may depend on the reduction of blood pressure, which was shown to retard the development of renal injury using hydralazine, those of losartan go beyond the blood pressure reduction. Hence, tissue protective effects of angiotensin AT1 receptor blockade may be pivotal for long-term vascular and renal protection.
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PMID:Protective effects of angiotensin AT1 receptor blockade in malignant hypertension in the rat. 1932 69