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 aim of this study was to investigate, using spectral analysis, 1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue L-NAME; 2) the involvement of the renin-angiotensin system in these modifications, using the angiotensin II AT1-receptor antagonist losartan. The blockade of the NO synthesis was made by infusion for 1 hour of a low dose (10 micrograms/kg/min, i.v.; n = 10) and a high dose (100 micrograms/kg/min, i.v.; n = 10) of L-NAME. The same treatment was applied in two further groups (n = 2 x 10) after a bolus of losartan (10 mg/kg, i.v.). The low dose of L-NAME increased systolic BP (SBP) on and after thirty min of infusion (+10 +/- 3 mmHg; p < 0.01). BP reached a maximum value 5 min after stopping L-NAME administration (+20 +/- 4 mmHg; p < 0.001). With the high dose of L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg; p < 0.05) and reached a maximum at 40 min (+53 +/- 4 mmHg; p < 0.001); a bradycardia was observed (60 min: -44 +/- 13 batt/min; p < 0.01). The low dose of L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2; p < 0.05). The high dose of L-NAME increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2; p < 0.001) and decreased the mid frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, p < 0.05) of SBP. Losartan did not modify BP levels but had a tachycardic effect (+33 +/- 10 batt/min; n = 27). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2; p < 0.001; n = 27). Losartan prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose. Losartan prevented the amplification of the LF oscillations of SBP induced by the L-NAME; the decrease of the MF oscillations of SBP induced by the L-NAME was reinforced after losartan). We concluded that the renin-angiotensin system is involved in the increase of variability of SBP in the LF range which resulted from the withdrawal of the vasodilatating influence of NO. We proposed that NO could counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.
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PMID:[Contribution of the renin-angiotensin system to the variability of blood pressure in hypertensive rat after blockade of nitric oxide synthesis]. 894 70

Nitric oxide seems to be involved in the mechanisms underlying the antihypertensive and renal responses of losartan in spontaneously hypertensive rats (SHR). We investigated the contribution of nitric oxide to the effect of this angiotensin II (Ang II) type 1 (AT1) receptor antagonist on the constrictor response of phenylephrine in aortic rings from SHR. Furthermore, since it has been suggested that Ang II could bind to unblocked AT2 receptors, during administration of an AT1 receptor antagonist, we also studied the effect of the AT2 receptor antagonist PD 123319 on the contractile response to phenylephrine in aortic rings from SHR. To this end, we studied dose-response curves of phenylephrine (10(-9) to 10(-5) mol/L) in the presence and absence of losartan (10(-9), 10(-7), and 10(-5) mol/L) in SHR aortic rings. Preincubation with losartan reduced the constrictor response to phenylephrine but not to KCl (10 to 120 mmol/L) in a dose-dependent manner. On the other hand, the presence of captopril (10(-5) mol/L) in the incubation medium did not alter the response to phenylephrine, even at the dose of 10(-3) mol/L. The reduced response to phenylephrine in the presence of losartan was abolished in both endothelium-denuded rings and rings treated with a nitric oxide synthesis inhibitor. A similar situation was observed in PD 123319-pretreated rings, in which the effect of losartan on the contractile response to phenylephrine was reversed. Losartan was not able to stimulate the production of aortic cGMP compared with the control group. Likewise, losartan did not modify the relaxing responses to either acetylcholine or sodium nitroprusside in phenylephrine-preconstricted aortic rings. Furthermore, losartan did not alter isometric tension in aortic rings in either basal or phenylephrine-preconstricted conditions. These data demonstrate that Ang II potentiates the vasoconstriction induced by phenylephrine through the stimulation of AT1 receptors. Moreover, AT2 receptors and nitric oxide appear to be involved in this effect.
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PMID:Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Role of nitric oxide and angiotensin II type 2 receptors. 895 84

Ataxia-telangiectasia (A-T) is a human autosomal recessive disease characterised by immunodeficiency, extreme sensitivity to ionising radiation and progressive cerebellar ataxia. The defective gene has recently been cloned and is a member of the phosphatidylinositol 3-kinase family. We have investigated the possibility that the neurodegeneration in A-T might be induced by an endogenously formed mutagen causing radiation-like damage. Nitric oxide is known to be formed in the cerebellum and we present evidence that A-T fibroblasts are hypersensitive to killing by the nitric oxide donor S-nitrosoglutathione (GSNO), as are fibroblasts from a radiosensitive individual without ataxia. Killing was determined as loss of colony forming ability. GSNO induces dose-dependent DNA strand breakage, but to no greater extent in A-T fibroblasts. Breakdown of GSNO to nitrite and nitrate appears to occur to the same extent in both normal and A-T fibroblasts. Cell killing by GSNO appears to be associated in both types of cell with formation of nitrite, rather than nitrate, as the ultimate oxidation product of nitric oxide.
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PMID:Hypersensitivity of ataxia-telangiectasia fibroblasts to a nitric oxide donor. 895 60

Recent studies have shown that angiotensin-(1-7) [Ang-(1-7)] interacts with kinins and augments bradykinin (BK)-induced vasodilator responses by an unknown mechanism. In this study, we evaluated whether the potentiation of the BK-induced vasodilation by Ang-(1-7) may be attributable to inhibition of BK metabolism, release of nitric oxide, or both. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers. 125I-[Tyr0]-BK metabolism was determined in vascular rings by assessing the degradation of the peptide by high-performance liquid chromatography. Ang-(1-7) augmented the vasodilation induced by BK in a concentration-dependent manner in rings preconstricted with the thromboxane analog U46619. The EC50 of BK (2.45 +/- 0.51 nmol/L versus 0.37 +/- 0.08 nmol/L) was shifted leftward by 6.6-fold in the presence of 2 mumol/L concentration of Ang-(1-7). The response was specific for BK. since Ang-(1-7) did not augment the vasodilation induced by either acetylcholine (0.05 mumol/L) or sodium nitroprusside (0.1 mumol/L). Moreover, neither angiotensin I nor angiotensin II (Ang II) duplicated the augmented BK response of Ang-(1-7). Pretreatment of vascular rings with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NA; 100 mumol/L) completely abolished the effects of Ang-(1-7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 mumol/L) was without effect. The potent specific BK B2 receptor antagonist, Hoe 140. nearly abolished the BK and the Ang-(1-7) potentiated responses at 2 mumol/L, whereas at a lower concentration (20 nmol/L) Hoe 140 shifted the response curve to the right for both Ang-(1-7) and vehicle; however, the augmented response to Ang-(1-7) persisted. Preincubation of vascular rings with 20 mumol/L of the AT1 (CV11974), AT2 (PD123319), or nonselective (Sar1 Thr8-Ang II) receptor antagonists had no significant effect on the Ang-(1-7)-enhanced vasodilator response to BK. Lisinopril (2 mumol/L) significantly enhanced the BK-induced vasodilator response while at the same time it abolished the synergistic action of Ang-(1-7) on BK. In addition, pretreatment with 2 mumol/L Ang-(1-7) significantly inhibited the degradation of 125I-[Tyr0]-BK and the appearance of the BK-(1-7) and BK-(1-5) metabolites in coronary vascular rings. Ang-(1-7) inhibited purified canine angiotensin converting enzyme activity with an IC50 of 0.65 mumol/L. In conclusion. Ang-(1-7) acts as a local synergistic modulator of kinin-induced vasodilation by inhibiting angiotensin converting enzyme and releasing nitric oxide.
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PMID:Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. 903 33

Angiotensin (Ang) II is not the only active peptide of the renin-angiotensin system. Several of its degradation products including Ang III (obtained by deletion of the N terminal amino acid), Ang IV (obtained by deletion of the two N terminal amino acids) and Ang II(1-7) (obtained by deletion of the C terminal amino acid) also possess biological functions. These peptides are formed via the activity of several enzymes, aminopeptidase A for Ang III, aminopeptidases A and N for Ang IV, prolylendopeptidase and carboxypeptidases for Ang II(1-7). Ang III possesses most of the properties of Ang II and shares the same receptors. This peptide is particularly important in brain and pituitary physiology and plays a major role in the secretion of arginine vasopressin. Ang IV possesses its own receptors distinct from AT1 and AT2. Some of its effects (for example, stimulation of the synthesis of the type 1 inhibitor of plasminogen activator by endothelial cells) were previously attributed to Ang II. Others are opposed to Ang II effects (renal and cerebral vasodilation). Its role in vascular, renal and cerebral physiology remains to be determined. Ang II(1-7) exhibits direct and indirect effects, the latter resulting from Ang II(1-7)-dependent formation of nitric oxide and vasodilatory prostaglandins. Ang II(1-7) recognizes both specific receptors and AT1 receptors as shown by the partial antagonistic properties of losartan. Ang II(1-7) plays essentially a role in the control of the hydroelectrolytic balance by increasing glomerular filtration rate, urinary output and sodium excretion rate.
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PMID:Active fragments of angiotensin II: enzymatic pathways of synthesis and biological effects. 905 51

1. To determine whether coronary flow regulation by nitric oxide (NO) is impaired in the hypertensive heart (HTH), coronary perfusion was measured in isolated rat hearts using NO synthesis inhibitor L-NG-monomethyl arginine (L-NMMA) in Wistar-Kyoto (WKY) rat and spontaneously hypertensive rat (SHR) with and without chronic Nomega-nitro-L-arginine-methylester (L-NAME) treatment. Moreover, the effect of angiotensin II receptor antagonist (AT1 receptor antagonist) (TCV-116) on the impaired coronary circulation in HTH was examined. 2. Coronary flow (CF) was decreased in HTH accompanied with cardiac hypertrophy. The decreased response of CF to L-NMMA infusion was diminished in HTH. It is suggested that NO production was reduced in coronary vasculature in HTH. 3. In chronic L-NAME treated SHR, blood pressure and cardiac hypertrophy were accelerated. Although coronary flow resistance (CFR) was increased, the increased response of CFR to L-NMMA infusion was not altered. 4. The AT1 antagonist improved total minimal coronary flow resistance (MCFR) restoring CFR response in SHR, although it did not recover CFR response in chronic L-NAME treated SHR. 5. Taken together the findings suggest that NO production was exhausted in the coronary artery even in the developing stage of hypertension and this exhaustion could contribute to the impairment of coronary circulation of HTH.
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PMID:Role of nitric oxide in impaired coronary circulation and improvement by angiotensin II receptor antagonist in spontaneously hypertensive rats. 907 32

The angiotensin AT2 receptor modulates renal production of cyclic guanosine 3',5'-monophosphate (cGMP; J. Clin. Invest. 1996. 97:1978-1982). In the present study, we hypothesized that angiotensin II (Ang II) acts at the AT2 receptor to stimulate renal production of nitric oxide leading to the previously observed increase in cGMP. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) cGMP in response to intravenous infusion of the AT2 receptor antagonist PD 123319 (PD), the AT1 receptor antagonist Losartan, the nitric oxide synthase (NOS) inhibitor nitro--arginine-methyl-ester (-NAME), the specific neural NOS inhibitor 7-nitroindazole (7-NI), or Ang II individually or combined in conscious rats during low or normal sodium balance. Sodium depletion significantly increased RIF cGMP. During sodium depletion, both PD and -NAME caused a similar decrease in RIF cGMP. Combined administration of PD and -NAME decreased RIF cGMP to levels observed with PD or -NAME alone or during normal sodium intake. During normal sodium intake, Ang II caused a twofold increase in RIF cGMP. Neither PD nor -NAME, individually or combined, changed RIF cGMP. Combined administration of Ang II and either PD or -NAME produced a significant decrease in RIF cGMP compared with that induced by Ang II alone. Combined administration of Ang II, PD, and -NAME blocked the increase in RIF cGMP produced by Ang II alone. During sodium depletion, 7-NI decreased RIF cGMP, but the reduction of cGMP in response to PD alone or PD combined with 7-NI was greater than with 7-NI alone. During normal sodium intake, 7-NI blocked the Ang II-induced increase in RIF cGMP. PD alone or combined with 7-NI produced a greater inhibition of cGMP than did 7-NI alone. During sodium depletion, 7-NI (partially) and -NAME (completely) inhibited RIF cGMP responses to -arginine. These data demonstrate that activation of the renin- angiotensin system during sodium depletion increases renal nitric oxide production through stimulation by Ang II at the angiotensin AT2 receptor. This response is partially mediated by neural NOS, but other NOS isoforms also contribute to nitric oxide production by this pathway.
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PMID:The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. 921 2

Reduced nerve perfusion is an important factor in the etiology of diabetic neuropathy. Studies in streptozotocin-induced diabetic rats show that nerve conduction velocity (NCV) and blood flow deficits are corrected by treatment with vasodilator drugs, with angiotensin II and endothelin-1 antagonists being particularly important. The AT1 antagonist ZD7155 also prevents diabetic deficits in regeneration following nerve damage, indicating that hypoperfusion is an important limitation for nerve repair. Metabolic changes include high polyol pathway flux, increased advanced glycosylation, elevated oxidative stress, and impaired omega-6 essential fatty acid metabolism. Aldose reductase inhibitors (ARIs) restore NCV via their effects on perfusion. ARI action probably depends on blocking the conversion of glucose to sorbitol, thus preventing depletion of vasa nervorum glutathione, an important endogenous free radical scavenger. Free radicals cause vascular endothelium damage and reduced nitric oxide vasodilation. Inhibition of advanced glycosylation and autoxidation (autoxidative glycosylation), major sources of free radicals, by aminoguanidine or transition metal chelators, corrects neurovascular dysfunction. Evening primrose oil supplies gamma-linolenic acid (GLA) to improve vasodilator eicosanoid synthesis in diabetes, correcting nerve blood flow and NCV deficits. Interactions between some of these mechanisms have therapeutic implications. Thus, combined ARI and evening primrose oil treatment produced a 10-fold amplification of NCV and blood flow responses. Similarly, GLA effects are markedly enhanced when given in combination with ascorbate as ascorbyl-GLA. Thus, metabolic abnormalities combine to produce deleterious changes in nerve perfusion that make a major contribution to the etiology of diabetic neuropathy. The potential importance of multi-action therapy is stressed.
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PMID:Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. 928 96

The purpose of our study was test the hypothesis that endogenous angiotensin II contributes to the basal coronary artery tone by acting at vascular ATP-sensitive K+ (K+ATP) channels. Coronary blood flow (CBF) and other hemodynamic parameters were measured in anesthetized dogs. Intracoronary infusion of the selective antagonists of angiotensin II AT1 receptors (L-158,809 and E4177) increased CHF without affecting other hemodynamic parameters, indicating that endogenous angiotensin II caused coronary vaso-constriction through the AT1 subtype receptors. Coronary vasodilation in response to AT1 receptor antagonists was blunted by pretreatment with glibenclamide (a specific inhibitor of K+ATP channels; p < 0.01) but not by either an adenosine-receptor antagonist or an inhibitor of nitric oxide synthesis. Coronary vasodilation in response to AT1-receptor antagonists was partly reduced (p < 0.01) by PD-123319 (the AT2-receptor antagonist). Glibenclamide had no effect on coronary vasodilation induced by sodium nitroprusside. These results indicate that in dogs in vivo, coronary vasodilation in response to AT 1-receptor antagonists inhibited markedly by glibenclamide and partly by PD-123319, suggesting that endogenous angiotensin II contributes to the maintenance of basal coronary vascular tone by acting at K+ATP channels through its receptors.
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PMID:Glibenclamide, a specific inhibitor of ATP-sensitive K+ channels, inhibits coronary vasodilation induced by angiotensin II-receptor antagonists. 930 Mar 14

We wished to determine whether the acute toxic effects of oxidized LDL are attenuated in aortas isolated from rats chronically treated with an angiotensin-converting enzyme (ACE) inhibitor. In aortic rings incubated with human oxidized LDL (300 microg/mL), the endothelium-dependent relaxations to acetylcholine were attenuated, but not those to A23187 and to nitroprusside. This toxic effect of oxidized LDL was completely prevented in preparations coincubated with oxidized LDL and the nitric oxide (NO) precursor L-arginine (0.3 mmol/L). In aortas isolated from rats orally treated for 6 weeks with 10 mg/kg ramipril (group 1) or 1 mg/kg ramipril (group 2), this toxic effect of oxidized LDL was also markedly attenuated. In contrast, in aortas isolated from rats cotreated with ramipril (10 mg/kg) for 6 weeks and subcutaneous injections of Hoe 140 (a B2 kinin antagonist), 500 microg/kg per day for the last 2 weeks (group 3) or from rats orally treated for 6 weeks with losartan (an AT1-type angiotensin II receptor antagonist), 20 mg/kg (group 4), the inhibitory effect of oxidized LDL on acetylcholine-induced relaxations was similar to that observed in the control group (group 5). Moreover, long-term treatment with ramipril increased relaxations to acetylcholine in groups 1 and 2 and also relaxations to A23187 and aortic cGMP content in group 1, suggesting an enhanced NO availability. Thus, the protective effect of long-term ACE inhibition against the acute vascular toxicity of oxidized LDL is bradykinin dependent and seems to involve a facilitation of NO release via endothelial B2 kinin receptors.
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PMID:Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins: a bradykinin-dependent mechanism. 931 19


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