Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to assess whether N-acetylcysteine (NAC) is able to prevent tolerance to a 48-hour infusion of nitroglycerin (NTG) in the setting of normal left ventricular function. In 16 patients, the hemodynamic response to 0.8 mg sublingual (s.l.) NTG was assessed by measuring mean arterial, pulmonary artery, pulmonary capillary wedge and right atrial pressures, cardiac output, and calculation of the systemic and pulmonary vascular resistances. The parameters were obtained at baseline and 1 to 10 minutes after the s.l. NTG application (day 1). NTG was started at 1.5 microg/kg/min; concomitantly, a bolus of 2,000 mg of NAC was administered, followed by an infusion of 5 mg/kg/hour. Both infusions were continued for 48 hours, and the hemodynamic study was repeated (day 3). The same measurements were obtained in a matched control group of 15 patients with NTG infusion alone. Plasma renin activity, aldosterone, and norepinephrine were measured before and after the infusion period. The first s.l. NTG infusion (day 1) caused a significant decrease in mean arterial (p <0.01), pulmonary artery (p <0.001), and right atrial pressures (p <0.001), and in systemic (p <0.01) and pulmonary vascular resistances (p <0.001) in both groups. After the 48-hour infusion (day 3), there was a total loss of nitrate-mediated vasodilation (pressure values and vascular resistances day 3 > day 1) in 5 of 16 patients (NAC nonresponders), whereas in the other 11 of 16 patients (NAC responders), there was significant vasodilation throughout the infusion period. Tolerance had developed in 14 of 15 patients with NTG infusion alone. The same difference (responder vs nonresponder vs NTG alone) held true regarding the response to the second s.l. NTG infusion after 48 hours. The neurohormonal counter-regulation and intravascular volume expansion (increase in plasma renin activity, p <0.001, and norepinephrine, p <0.05; decrease in aldosterone, p <0.01) did not differ between responders and nonresponders. We conclude that NAC attenuates tolerance development to a continuous NTG infusion in a specific patient subgroup and that this occurs despite the same amount of neurohormonal counter-regulation and intravascular volume expansion compared with patients with tolerance development.
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PMID:N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function. 902 31

The physiological role of endogenous nitric oxide in regulation of renal function in humans is unclear. Eight healthy men received an inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (L-NMMA, 3 mg/kg), and saline placebo intravenously on two occasions. L-NMMA significantly increased mean arterial pressure (+7%) and total peripheral resistance (+36%). However, because renal plasma flow did not decrease significantly, the increase in renal vascular resistance (+21%) was significantly less than the increase in total peripheral resistance. Glomerular filtration rate (-19%), filtration fraction (-10%), urine flow rate (-18%), sodium (-28%), and free water excretion (-25%) all decreased significantly. Fractional distal, but not proximal, sodium reabsorption increased. L-NMMA also significantly decreased plasma nitrate and urinary excretion of nitrate and dopamine. There were no significant changes in plasma renin activity, plasma endothelin, and aldosterone or in platelet number and ex vivo aggregation. L-NMMA had a plasma half-life of 75 min. Basal generation of nitric oxide appears to contribute less to vascular tone in the kidney than systemically but may alter afferent arteriolar tone. Decreased fractional sodium excretion supports an important physiological role for nitric oxide in inhibition of tubular sodium reabsorption, possibly mediated by the renal dopaminergic system.
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PMID:Physiological role of nitric oxide in regulation of renal function in humans. 908 80

The goals of this study were to determine whether long-term nitric oxide (NO) synthesis inhibition in dogs results in an increase in the sodium sensitivity of arterial pressure and whether changes in plasma renin activity or the plasma concentrations of arginine vasopressin (AVP) and aldosterone play an important role in this hypertension. Studies were conducted in a control group and groups that received NO inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) at 10 or 25 microg x kg(-1) x min(-1). Each group was challenged with normal, low, and high sodium intake for periods of 5 days each. Urinary nitrate + nitrite excretion (UNOx) more than doubled in the control group during high sodium intake. In both L-NAME groups, UNOx decreased significantly, there was a hypertensive shift in the relation between urinary sodium excretion and arterial pressure, and urinary sodium excretion remained normal even in the high-sodium intake period. L-NAME infusion did not change the sodium sensitivity of arterial pressure or plasma renin activity, plasma aldosterone, and plasma AVP. In conclusion, the data suggest that, in dogs, increases in NO synthesis are not necessary to excrete a chronic sodium load, and decreases in NO do not increase the sodium sensitivity of arterial pressure.
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PMID:Role of nitric oxide in the arterial pressure and renal adaptations to long-term changes in sodium intake. 914 16

1. To investigate the role of nitric oxide (NO) in diabetic nephropathy the effect of nitric oxide synthase (NOS) inhibition by NG-nitro-L-arginine methyl ester (L-NAME) was observed in a streptozotocin diabetic spontaneously hypertensive rat (SHR) model. 2. Two groups of SHR (n = 8) with streptozotocin-induced diabetes were studied. One group was given L-NAME 5 mg/kg bodyweight per day in the drinking water for 8 weeks while both groups received daily subcutaneous injections of Ultratard insulin. Creatinine clearance, urinary protein excretion, urinary nitrate concentration and systolic blood pressure were measured at fortnightly intervals. Rats were killed at 8 weeks and plasma angiotensin II (AngII) was measured by radioimmunoassay. 3. Renal function (endogenous creatinine clearance) remained stable in both groups. In the L-NAME group, however, there was a progressive increase in proteinuria that was highly significant at 6 weeks (22.1 +/- 2.9 compared with 6.5 +/- 0.7 mg/ 24 h per 100 g in control SHR diabetic rats P < 0.001). 4. Systolic blood pressure was significantly elevated in the L-NAME group throughout the study compared with the control group. 5. Plasma AngII was significantly elevated in the L-NAME group compared with controls (42.8 +/- 10.3 vs 15.1 +/- 1.9 pmol/L, respectively; P < 0.05). 6. Activation of the renin-angiotensin system may account, at least in part, for the resulting vasoconstrictor activity with chronic nitric oxide depletion.
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PMID:Nitric oxide synthase inhibition in a spontaneously hypertensive rat model of diabetic nephropathy. 917 57

The effect of nitrite on blood pressure and heart rate was studied in anaesthetized (non-telemetric method) and free-moving rats (biotelemetry system). In anaesthetized rats, NaNO2 (10-1000 mumol/kg), infused over 5 min, induced a dose-related decrease in blood pressure. The maximal decrease in mean arterial blood pressure (MAP), caused by 1000 mumol/kg NaNO2 and measured 15 min after infusion was 55.9 +/- 3.2% (n = 3). After NaNO2 infusion, in the plasma, rapid conversion of nitrite into nitrate was observed. However, sodium nitrate (NaNO3, 100 mumol/kg) did not decrease blood pressure and there was no conversion of nitrate into nitrite. Free-moving rats received KNO2 which was added to drinking water (36 mmol/litre) for a period of 3 days. KNO2 decreased the MAP and increased the heart rate during the rat's activity phase at night but not during their resting phase in the day. An equal concentration of potassium (KCl, 36 mmol/litre added to drinking water) for 3 days did not decrease blood pressure. It is concluded that nitrite decreases blood pressure in rats, which probably induces, by renin-angiotensin system activation, hypertrophy of the adrenal zona glomerulosa.
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PMID:Effect of nitrite on blood pressure in anaesthetized and free-moving rats. 922 20

Blood pressure decreases during early pregnancy in association with a decrease in peripheral vascular resistance and increases in renal plasma flow and glomerular filtration rate. These early changes suggest a potential association with corpora lutea function. To determine whether peripheral vasodilation occurs following ovulation, we studied 16 healthy women in the midfollicular and midluteal phases of the menstrual cycle. A significant decrease in mean arterial pressure in the midluteal phase of the cycle (midfollicular of 81.7 +/- 2.0 vs. midluteal of 75.4 +/- 2.3 mmHg, P < 0.005) was found in association with a decrease in systemic vascular resistance and an increase in cardiac output. Renal plasma flow and glomerular filtration rate increased. Plasma renin activity and aldosterone concentration increased significantly in the luteal phase accompanied by a decrease in atrial natriuretic peptide concentration. Serum sodium, chloride, and bicarbonate concentrations and osmolarity also declined significantly in the midluteal phase of the menstrual cycle. Urinary adenosine 3',5'-cyclic monophosphate (cAMP) excretion increased in the luteal compared with the follicular phase, whereas no changes in urinary cGMP or NO2/NO3 excretion were found. Thus peripheral vasodilation occurs in the luteal phase of the normal menstrual cycle in association with an increase in renal plasma flow and filtration. Activation of the renin-angiotensin-aldosterone axis is found in the luteal phase of the menstrual cycle. These changes are accompanied by an increase in urinary cAMP excretion indicating potential vasodilating mediators responsible for the observed hemodynamic changes.
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PMID:Systemic and renal hemodynamic changes in the luteal phase of the menstrual cycle mimic early pregnancy. 937 41

The anti-ischemic effects of organic nitrates are rapidly attenuated due to the development of nitrate tolerance. The mechanisms underlying this phenomenon likely involve several independent factors. As a vasodilator, nitroglycerin activates compensatory neurohumoral mechanisms such as the renin-angiotensin system and increases catecholamine and vasopressin levels, all of which may attenuate its vasodilator potency. Tolerance may be also due to the inability of the vessel to dilate after prolonged treatment with the nitrate. More recent experimental studies have challenged traditional tolerance concepts by demonstrating that tolerance is not associated with sulfhydryl group depletion, reduced nitroglycerin biotransformation, or desensitization of the target enzyme guanylyl-cyclase. Experimental and clinical observations suggest that tolerance may be the consequence of intrinsic abnormalities of the vasculature, including enhanced endothelial production of oxygen-derived free radicals secondary to an activation of NAD(P)H-dependent oxidases and an activation of PKC. Superoxide degrades nitric oxide derived from nitroglycerin (NTG) while C activation causes enhanced sensitivity of the vasculature to circulating neurohormones such as catecholamines, angiotensin II, and serotonin, all of which may compromise the vasodilator potency of NTG. Interestingly, these vascular consequences of in vivo NTG treatment such as superoxide production and PKC activation can be mimicked in vitro by incubating cultured endothelial and smooth muscle cells with angiotensin II. Furthermore, nitrate tolerance and rebound following sudden cessation of prolonged NTG therapy can be prevented by concomitant treatment with high-dose angiotensin-converting enzyme inhibition, angiotensin type 1 receptor blockade, or antioxidants such as hydralazine. Thus one can conclude that neurohumoral counterregulatory mechanisms such as increased circulating levels of angiotensin II may be at least in part responsible for tolerance mechanisms at the cellular level.
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PMID:Evidence for a role of oxygen-derived free radicals and protein kinase C in nitrate tolerance. 942 22

We conducted longitudinal measurements of blood pressure and renal function in the conscious, chronically catheterized rat before and during acute nitric oxide synthase inhibition (N-nitro-L-arginine methylester [L-NAME], 37 micromol/kg IV) and then chronic administration of oral L-NAME (approximately 37 micromol/kg per 24 hours). These studies specifically investigate the impact on plasma and renal renin as well as volume status during the evolution of this hypertension in rats not subjected to acute experimental stress. Blood pressure progressively increased with chronic administration of L-NAME and reached values greatly above those seen with acute administration of L-NAME. There were parallel increases in renal vascular resistance and development of proteinuria, and glomerular filtration rate began to decline at day 21, coincident with the appearance of renal damage. Twenty-four-hour urinary nitrite and nitrate excretion remained depressed, reflecting reduced nitric oxide synthesis. The plasma renin activity was variable and only increased transiently at 21 days, thus the angiotensin II dependence of this hypertension is not caused by stimulated plasma renin activity. Despite severe hypertension, sodium intake and excretion were unchanged over the 21 days of L-NAME administration. Plasma volume was significantly reduced at days 2 and 12 of L-NAME administration; thus the prolonged plasma volume contraction must result from the acute natriuretic response to the initial acute L-NAME administration.
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PMID:Evolution of chronic nitric oxide inhibition hypertension: relationship to renal function. 944 85

The use of nitrates for treatment of heart failure is encumbered by tolerance, caused by whatever mechanism, which has been reported only in a few instances with sydnonimines. Accordingly, we compared molsidomine (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to maximal hemodynamic effects, rapidity and extent of attenuation, and underlying mechanisms by means of constant infusions over 24 h each in 15 patients with chronic congestive heart failure (NYHA II-III) with a placebo-controlled, double-blind, randomized, crossover protocol. Hemodynamic measurements and determinations of neurohormones were performed at baseline and at 2, 8, and 24 h after the beginning of infusions. With molsidomine, reductions of diastolic pulmonary artery pressure by 29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus placebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8 h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding times. Increases in renin activity amounted to 130% (p < 0.001), 117% (p < 0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0 (each NS) with the nitrate at the corresponding times. Hematocrit was reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with molsidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate. We conclude that neurohumoral counterregulation or fluid shift, which is even more pronounced with molsidomine despite longer-lasting effects, has no essential role in nitrate-tolerance development. With molsidomine, such a role cannot be ruled out, although alternatively, a fluid shift from arterial to the low-pressure arm of circulation during the later course of infusion would be even more likely.
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PMID:Infusions with molsidomine and isosorbide-5-mononitrate in congestive heart failure: mechanisms underlying attenuation of effects. 947 62

S-Nitrosocaptopril (S-NO-Cap), a nitrate and an angiotensin-converting enzyme (ACE) inhibitor, may be produced after coadministration of nitroglycerin (NTG) and captopril (CAP). We synthesized S-NO-Cap and investigated its in vivo tolerance. In open-chest dogs, S-NO-Cap [300 microg; intracoronary (i.c.)] and NTG (50 microg, i.c.) increased coronary blood flow (CBF) similarly (8.0 vs. 9.0 ml/min; p = NS; n = 5). After a 2-h i.c. NTG infusion at high dose (1.32 micromol/min), NTG (50 microg, i.c.) had no significant effect on CBF, whereas S-NO-Cap (300 microg, i.c.) still produced an attenuated increase in CBF (4.9 ml/min; p < 0.05 vs. control). On the other hand, after a 2-h i.c. infusion of S-NO-Cap (1.32 micromol/min), the CBF response to S-NO-Cap (300 microg) showed no attenuation, whereas that to NTG (50 microg) was potentiated (8.8 vs. 12.6 ml/min; p < 0.05; n = 6). Under basal conditions, S-NO-Cap (30-300 microg, i.c.) increased CBF dose dependently, whereas CAP (30-300 microg, i.c.) had no effect on CBF, suggesting that S-NO-Cap dilates coronary vessels by a nitrate action but not by an ACE-inhibitory action. In nonsurgical dogs, 2-h intravenous (i.v.) infusion of S-NO-Cap (1.32 micromol/min) had a stable hypotensive effect, whereas that of NTG (1.32 micromol/min) gradually attenuated the effect. Plasma NO3-, an oxidative product of nitric oxide (NO), increased after both infusions, suggesting that S-NO-Cap may act partially as an NO donor, similarly to NTG. Plasma ACE activity was reduced after an S-NO-Cap infusion (5.84 vs. 4.10 IU/L; p < 0.01; n = 5), and plasma aldosterone was markedly increased after NTG infusion relative to that after S-NO-Cap infusion (243.0 vs. 38.6 pg/ml; p < 0.05). Plasma norepinephrine increased after both infusions (393.6 vs. 289.0 pg/ml; p = NS). As judged by the increase in CBF, whereas S-NO-Cap showed partial tolerance with NTG, no tolerance was found with S-NO-Cap itself. The in vivo coronary vascular response to S-NO-Cap may, therefore, be partially reduced by activation of the adrenergic or renin-angiotensin-aldosterone systems or both induced by NTG, because S-NO-Cap showed no cross-tolerance with NTG in our earlier in vitro study.
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PMID:No cross-tolerance between S-nitrosocaptopril and nitroglycerin in dog coronary arteries in vivo. 947 64


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