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)

Angiotensin (Ang) II and endothelin (ET-1) can both be regulated by NF-kappaB. They are, to variable degrees, also capable of activating NF-kappaB and increase the expression of NF-kappaB-dependent genes. Ang II-related vascular effects are in part mediated by ET-1. Nitric oxide synthase inhibition facilitates Ang II-related effects, which can be inhibited both by AT1-receptor blockers and by endothelin system inhibitors. This state-of-affairs supports the notion that a combined therapeutic strategy of inhibiting Ang II and ET-1 generation or blocking their effects at the receptor level would be superior to either strategy alone. Animal studies are encouraging but not without conflicting results. Angiotensin-converting enzyme inhibitors and AT1-receptor blockers have a superb track record in experimental animal models and in a host of clinical studies. Selective and nonselective blockers of the ET-1 receptors are important research tools and are also undergoing clinical trials. Inhibitors of the endothelin-converting enzyme have been developed. The recent elucidation of the endothelin-converting enzyme's physical structure should facilitate the development of still more novel compounds to inhibit ET-1 generation. We have recently engendered supportive evidence in this regard.
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PMID:Angiotensin II and endothelin induce inflammation and thereby promote hypertension-induced end-organ damage. 1294 May 29

Various Gq protein-coupled receptor agonists such as the alpha1 adrenoceptor agonist phenylephrine, angiotensin II, and endothelin-1 are potent hypertrophic factors. There is evidence of potential cross talk between these agents, particularly in terms of endothelin-1 as playing a central role in mediating the actions of other hypertrophic factors. Using cultured rat neonatal ventricular myocytes, we assessed the potential cross talk between these factors and sought to examine the potential underlying mechanisms. Twenty-four-hour exposure to either agent produced significant hypertrophy as determined by cell size and molecular markers. Although the hypertrophic effects of phenylephrine and angiotensin II were expectedly prevented by alpha1 and AT1 receptor antagonists, respectively, these effects were also blocked by the ETA receptor antagonist BQ123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] but not by the ETB antagonist BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine). Both phenylephrine and angiotensin II significantly increased protein expression of both endothelin receptor subtypes. Both phenylephrine and angiotensin II produced significant activation of p38 as well as extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase, although this was unaffected by endothelin receptor blockade. Further studies revealed that the effects of phenylephrine and angiotensin II were mediated by stimulated endothelin-1 production occurring via two separate mechanisms: angiotensin II by increasing the levels of the endothelin-1 precursor prepro endothelin-1 and phenylephrine by upregulating endothelin-converting enzyme 1. Our results indicate that the endothelin-1 system plays an obligatory role in the hypertrophic response to both phenylephrine and angiotensin II in cultured myocytes through a mechanism independent of mitogenactivated protein kinase activation.
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PMID:Obligatory role for endogenous endothelin in mediating the hypertrophic effects of phenylephrine and angiotensin II in neonatal rat ventricular myocytes: evidence for two distinct mechanisms for endothelin regulation. 1500 6