Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to: (a) clarify the comparative renal potency of bolus injection of the natriuretic peptides urodilatin and ANF99-126 in the rat; (b) establish whether or not intravenous (i.v.) infusion of urodilatin (200 ng/min) combined with dopamine (UD) to maintain mean arterial pressure could improve GFR or renal histology in established experimental ischemic acute renal failure (ARF) induced by 30 minutes of bilateral renal artery clamping; (c) assess comparative efficacies of nitroprusside, an activator of soluble guanylate cyclase, combined with dopamine (ND) or control infusions of dopamine alone (DA), under equivalent conditions; and (d) determine effects of intra-renal arterial infusions of the stable cGMP analogue dibutyryl-cGMP immediately after renal artery clamping (RAC). After initial dose finding studies, i.v. infusion of UD 24 hours after 30 minutes of RAC improved GFR over five hours from 0.24 +/- 0.04 to 1.0 +/- 0.16 ml/min in association with a threefold rise in plasma cGMP and a 13-fold increase in urinary cGMP excretion. Plasma creatinine dropped by 41% from 230 +/- 16 to 135 +/- 18 microM/liter and was still reduced 24 hours later with values averaging 106 +/- 14 compared to 274 +/- 53 microM/liter in non-treated animals. During infusion, UV and FENa+ increased from 1.4 +/- 0.2 to 8.3 ml/min, and from 2.9 +/- 0.5 to maximum values of 15.8 +/- 2.4%. ND or DA alone were less effective, increasing GFR only to 14 and 20%, respectively, of normal values, but improvements were not sustained; in contrast to UD, ND did not alter plasma or urinary cGMP. In addition, DBcGMP was ineffective in improving GFR during early ARF. Histologically UD, but not ND, markedly reduced the incidence of granular casts, tubular desquamation and tubular necrosis in cortical areas and increased the incidence of medullary mitoses.
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PMID:Urodilatin, not nitroprusside, combined with dopamine reverses ischemic acute renal failure. 145

Elevated concentrations of atrial natriuretic peptide reportedly mitigate acute renal failure in vivo and in the isolated perfused kidney (M. Nakamoto, J.I. Shapiro, P.F. Shanley, L. Chan & R.W. Shrier (1987) J. Clin. Invest. 80, 698-705; S.G. Shaw, J. Weidmann, J. Hodler, A. Zimmermann & A. Paternostro (1987) J. Clin. Invest. 80, 1232-1237). Since atrial natriuretic peptide has been shown to be a potent vasodilator, this beneficial effect may be due entirely to improved haemodynamics. To determine whether atrial natriuretic peptide also has a protective effect at the cellular level, rat hepatocyte cell cultures were treated with atrial natriuretic peptide prior to or after induction of cell damage by hypoxia (0.5% O2 for 4 h) or reactive oxygen (hypochlorous acid). Bleb formation, degradation of radiolabeled trichloroacetic acid-precipitable peptides, release of lactate dehydrogenase and trypan blue exclusion were used as indicators of cell damage. Atrial natriuretic peptide treatment distinctly protected the cell cultures against damage in both cases. This beneficial effect of atrial natriuretic peptide was partly mimicked by sodium nitroprusside, which, like atrial natriuretic peptide, largely increased the cellular cGMP content. 6-Anilino-5,8-quinolinedione (Ly 83583), an inhibitor of particulate guanylate cyclase, blocked the protective effect of atrial natriuretic peptide. Therefore a cGMP-mediated mechanism seems to be involved in the cytoprotective action of atrial natriuretic peptide. Fluorometric measurements using the Ca2+-sensitive dye Quin-2 showed that the elevation of intracellular Ca2+ after cellular insult by hypochlorous acid is prevented by atrial natriuretic peptide. These results suggest that atrial natriuretic peptide may attenuate hypoxic and toxic cell damage by increasing cGMP and reducing intracellular Ca2+.
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PMID:Atrial natriuretic peptide protects hepatocytes against damage induced by hypoxia and reactive oxygen. Possible role of intracellular free ionized calcium. 255 49

Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED50 = 1.8 nM) and was reduced in NPR-C binding by approximately 200-fold. When infused into conscious rats at 0.325 microg/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 microg/min of rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure.
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PMID:Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats. 877 Aug 69

Atrial Natriuretic Peptide (ANP), has protective effect on the outcome of acute renal failure in animals when infused over short periods of time. Escherichia Coli heat-stable enterotoxin (STa) acts on a particulate guanylate cyclase receptors leading to an increase in cytosolic cGMP similar to ANP. STa has longer duration of action and induces significant natriuresis in the healthy kidney, however. Therefore the effects of prolonged infusion of STa and ANP on the outcome of ischemic Acute Renal Failure (ARF) was assessed in the rat. Three groups of rats were used in the experiment, control group (n = 6), had ischemic ARF induced by 30 minutes of left renal pedicle clamping and right nephrectomy. SG group (n = 7) had similar surgery to the control group followed by 1 microg intraperitoneal (i.p.) loading dose of STa and placement of mini-osmotic pumps delivering 0.1 microg/hour of STa for 72 hours. AG group (n = 8) also had similar surgery to the control group followed by i.p. injection of 10 microg of ANP and placement of mini-osmotic pumps delivering 1 microg/hour of ANP for 72 hours. 72 hours post the induction of ARF, there were no statistical differences among the three groups' creatinine levels, hematocrit and body weights. ANP level was significantly higher in the AG group compared to controls, 5387.6 +/- 878.8 and 36.2 +/- 10.0 pg/mL respectively, p < 0.001. Urinary sodium (U(Na)) on the other hand reached highest levels in the SG group compared to controls 16.4 +/- 5.0 and 5.0 +/- 0.0 meq/L respectively, p = 0.028. In conclusion Sta induces significant natriuresis in ischemic ARF without changing the course of renal impairment. Likewise prolonged infusion of ANP does not alter the course of ischemic ARF.
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PMID:Effects of prolonged infusion of the natriuretic peptides Escherichia coli enterotoxin and atrial natriuretic peptide on the outcome of acute ischemic renal failure in the rat. 1071 80

Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.
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PMID:L-arginine as a therapeutic tool in kidney disease. 1525 78