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)

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor antagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin II, and arginine vasopressin were investigated in the hind-limb vascular bed of the cat. Under constant-flow conditions, intraarterial injections of endothelin-1 and sarafotoxin 6c induced biphasic changes in hind-limb perfusion pressure characterized by an initial decrease followed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 and sarafotoxin 6c were reduced by bosentan, and the endothelin receptor antagonist reduced baseline systemic arterial and hind-limb perfusion pressures. Bosentan decreased vasoconstrictor responses to lower doses of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, acetylcholine, bradykinin, levcromakalim, PGE1, adrenomedullin, and calcitonin gene-related peptide were not altered. Vasoconstrictor responses to ET-1 were not altered by the angiotensin AT1 receptor antagonist DuP 532 or the AT2 receptor antagonist PD123,319. The results of the present study show that bosentan attenuates vasodilator and vasoconstrictor responses to endothelin-1 and sarafotoxin 6c and vasoconstrictor responses to lower doses of angiotensin II in the hind-limb vascular bed of the cat. These results suggest that endothelin may be involved in mediating responses to lower doses of angiotensin II and in the maintenance of baseline tone in the systemic vascular bed of the cat.
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PMID:Analysis of effects of bosentan (Ro 47-0203), a nonpeptide endothelin ETA/ETB receptor antagonist, in the hind-limb vascular bed of the cat. 963 52

Recent advances in the molecular characterization for angiotensin II (A II) related to nitric oxide, endothelin-1, prostaglandin, and adrenomedullin are reviewed. A II, the main biological active peptide of the renin-angiotensin system, plays an important role in cardiovascular homeostasis such as regulation of blood pressure and tissue remodeling. A II produces vasoconstriction by a direct action on smooth muscle cells via AT1 receptor. This action can be due to circulating A II but also to A II produced within the tissues. Nitric oxide and adrenomedullin are potent vasorelaxant substances. These substances may play a role as local antimigration factors, and antagonize the effect of A II. Whereas endothelin-1 and thromboxane A2 are vasoconstrictor substances, and may have a role as growth factors. A II and these vasoactive substances mutually exert several biological actions in cardiovascular diseases.
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PMID:[Interaction between angiotensin II and other local vasoactive substances]. 1036 43

The object of this review is to describe the role of the renin-angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin-angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT1 and AT2 receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT1 receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and amplified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described.
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PMID:Angiotensin and aldosterone. 1042 51

Vascular remodeling is characterized by the dysfunction of endothelial cells, vascular smooth muscle cell (SMC) proliferation and migration, and the increased accumulation of extracellular matrix. Angiotensin II causes SMC growth and migration, and stimulates the expression of vascular remodeling-related genes. Angiotensin II activates a diversity of intracellular signal transduction cascades, and transactivation of epidermal growth factor and platelet-derived growth factor receptors via AT1 receptor seems to be responsible for the development of vascular remodeling. Not only angiotensin II but also endothelin-1, nitric oxide, c-type natriuretic peptide and adrenomedullin play an important role in the development of vascular remodeling.
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PMID:[Vasoactive substance and vascular remodeling]. 1042 49

1. The functional involvement of the vasodilator peptides, adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP), in the haemodynamic sequelae of continuous infusion of lipopolysaccharide (LPS) was assessed in conscious, male, Long Evans rats, by the use of peptide antagonists. 2. It was demonstrated that ADM (22-52) at a dose of 500 nmol kg-1 h-1 caused significant inhibition of the effects of ADM (1 nmol kg-1), without affecting responses to CGRP (0.1 or 1 nmol kg-1). 3. Even when the regional vasodilator responses to LPS infusion were enhanced (by pre-treatment with dexamethasone and the endothelin antagonist, SB 209670, or by pretreatment with SB 209670 and the AT1-receptor antagonist, losartan), ADM (22-52) had no significant cardiovascular effects. In contrast, the CGRP1-receptor antagonist, CGRP (8-37), caused small, but significant, inhibitions of the hypotensive and renal and mesenteric vasodilator effects of LPS, but only 6 h after onset of infusion in the presence of dexamethasone and SB 209670. 4. The results indicate that, in this model of endotoxaemia, the marked regional vasodilatations seen in the presence of dexamethasone and SB 209670 do not involve ADM, but do involve CGRP, albeit only to a small extent.
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PMID:Influence of CGRP (8-37), but not adrenomedullin (22-52), on the haemodynamic responses to lipopolysaccharide in conscious rats. 1045 17

In spite of several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly due to the fact that all available drugs are short-lasting (24 hr or less), have side effects, and are not highly specific. Gene therapy offers the possibility of producing longer-lasting effects with precise specificity from the genetic design. Preclinical studies on gene therapy for hypertension have taken two approaches. Chao et al. have carried out extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin nitric oxide synthase into different rat models. Their results show that blood pressure can be lowered for 3-12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the beta 1-adrenoceptor, TRH, angiotensin gene activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been two methods of delivery antisense; one is short oligodeoxynucleotides, and the other is full-length DNA in viral vectors. All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligonucleotides are safe and nontoxic. The adeno-associated virus delivery antisense to AT1 receptors is systemic and in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to Phase I trials for testing the antisense ODNs, first and later the AAV.
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PMID:Gene therapy for hypertension: the preclinical data. 1188 75

Blood vessel remodeling is crucial to the formation of the definitive vasculature, but little is known about the mechanisms controlling this process. We show that Delta-like ligand 4 (Dll4)/Notch pathway regulates vessel regression in normal pathologic conditions. Genetic and pharmacologic inhibition of Dll4/Notch prevented retinal capillary regression in the oxygen-induced retinopathy (OIR) model and during normal development. Deletion of the Notch-regulated ankyrin repeat protein, a negative regulator of the Notch pathway, produced an opposite phenotype. Inhibition of Dll4/Notch reduced vessel occlusion, maintaining blood flow that is essential for survival of microvessels. Dll4/Notch inhibition up-regulated the expression of vasodilators adrenomedullin and suppressed the expression of vasoconstrictor angiotensinogen. Angiotensin II induced rapid nonperfusion and regression of developing retinal capillaries, whereas Ace1 and AT1 inhibitors and adrenomedullin attenuated vasoobliteration in OIR, indicating that both pathways are involved in modulating vessel remodeling. In contrast, inhibition of vascular endothelial growth factor-A (VEGF-A) did not result in a pervasive loss of retinal capillaries, demonstrating that reduced expression of VEGF-A is not the proximate cause of capillary regression in OIR. Modulation of VEGF-A and Dll4/Notch signaling produced distinct changes in blood vessel morphology and gene expression, indicating that these pathways can have largely independent functions in vascular remodeling.
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PMID:The Dll4/Notch pathway controls postangiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow. 2149 71