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)

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

To study the effect of atrial natriuretic factor (ANF) on airway ciliary motility, we measured ciliary beat frequency by a photoelectric method in response to ANF in cultured tracheal epithelial cells from rabbits. Addition of ANF but not [Tyr8]ANF-(5-27) decreased ciliary beat frequency in a dose-dependent fashion; the maximal decrease from the baseline value was 24.1 +/- 1.5% (+/- SE, P less than 0.001), and a half-maximal inhibitory concentration (IC50) was 3 x 10(-12) M. Inhibition of neutral endopeptidase activity by phosphoramidon (10(-6) M) or thiorphan (10(-6) M) potentiated the effect of ANF so that the dose-response curve for ANF was shifted to lower concentrations by approximately 0.5 log units (P less than 0.05, in each case). The inhibition of ciliary motility induced by ANF was not affected by the blockade of arachidonic acid metabolism with indomethacin, piroxicam, or nordihydroguaiaretic acid, but it was blocked by methylene blue, a soluble guanylate cyclase inhibitor, and was potentiated by M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor. The intracellular cGMP levels were increased by ANF, an effect that was further potentiated by phosphoramidon or thiorphan. These results suggest that ANF inhibits ciliary motility presumably through a guanylate cyclase-dependent regulatory pathway and that neutral endopeptidase may play a role in modulating the ANF effect on airway mucociliary transport function.
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PMID:Atrial natriuretic factor inhibits ciliary motility in cultured rabbit tracheal epithelium. 182 49

Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-linked atriopeptin binding sites increases urinary sodium excretion to a greater degree in conscious spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. In the present study, we examined the effects of chronic 10-day intravenous infusions of SC-46542 (des[Phe106,Gly107,Ala115,Gln116] atriopeptin-(103-126] (0.1 mg/kg/hr), thiorphan (1.5 mg/kg/hr), and atriopeptin-(103-126) (100 ng/hr) alone or in combination on direct recording of mean arterial pressure in conscious spontaneously hypertensive rats. During an 11-day time-control infusion of isotonic saline vehicle (100 microliters/hr), mean arterial pressure remained stable. Chronic infusion of atriopeptin-(103-126) decreased mean arterial pressure progressively over the first 3 days; then mean arterial pressure progressively rose to control level over the following 3 days and remained at control level for the remainder of the experiment. Similarly, coinfusions of atriopeptin-(103-126) and SC-46542 or thiorphan, SC-46542 and thiorphan, or the triple infusion of atriopeptin-(103-126), SC-46542, and thiorphan had only transient effects on mean arterial pressure during 10-day infusions. SC-46542 alone had no effect on mean arterial pressure. Similarly, thiorphan alone had no effect on mean arterial pressure except at doses that blocked the acute pressor response to angiotensin I. Chronic infusions of atriopeptin-(103-126), SC-46542, and thiorphan alone or in combination are not effective long-term treatments for hypertension in spontaneously hypertensive rats.
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PMID:Chronic atriopeptin regulation of arterial pressure in conscious hypertensive rats. 214 72

We examined the interaction of a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, SC-46542 (des[Phe106,Gly107,Ala115,Gln116]AP-(103-126], and an endopeptidase 24.11 inhibitor, thiorphan, on mean arterial pressure, urinary sodium excretion, urinary cyclic guanosine monophosphate (cGMP) excretion, plasma cGMP concentration, and plasma AP immunoreactivity (ir) in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Compared to vehicle control rats, coadministration of SC-46542 and thiorphan increased urinary sodium excretion in SHR from 2.1 +/- 0.3 to 11.6 +/- 0.7 microEq/min/100 g body weight and in WKY from 1.6 +/- 0.4 to 4.4 +/- 0.4 microEq/min/100 g body weight, and increased urinary cGMP excretion in SHR from 2.7 +/- 0.5 to 79.0 +/- 17.5 pmol/min/100 g body weight and in WKY from 7.0 +/- 3.0 to 72.4 +/- 10.6 pmol/min/100 g body weight. The change in urinary sodium excretion was greater in SHR than WKY. The coadministration of SC-46542 and thiorphan had greater effects on urinary sodium excretion and urinary cGMP excretion than administration of either compound alone. Coadministration of thiorphan and SC-46542 had no effect on glomerular filtration rate or plasma cGMP concentration, suggesting that the urinary cGMP excretion response was nephrogenous. Compared to vehicle control rats, plasma APir was increased during coadministration of SC-46542 and thiorphan in both SHR (998 +/- 76 v 5.10 +/- 116 pg/mL) and WKY (775 +/- 36 v 414 +/- 36 pg/mL).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atriopeptin regulation and renal function in conscious spontaneously hypertensive rats. 217 64

The physiology, the pharmacology and the biochemistry of the atrial natriuretique factor (ANF) have been investigated and documented by numerous studies and works since its discovery and cloning ten years ago. More recently, the physiopathological aspect of ANF biosynthesis and secretion by the whole heart during overload and congestive heart failure was reported in experimental models and in human patients. Moreover the cyclic GMP which is the ANF second messenger, egressed from endothelial cells, was correlated with the production of ANF. Therefore the activation of heart endocrine function from ANF gene over-expression to peripheral cyclic GMP appeared as an independent prognosis indicator in congestive heart failure. Two types of ANF receptors have been recently cloned. One is the particulate guanylate cyclase, the second is a clearance receptor involved in the endocytosis and lysozomial degradation of ANF in target cells. Neutral endopeptidase, an ectoenzyme present in different tissues and particularly in the kidney is also capable to cleave ANF in unefficient peptide. The blockade of ANF metabolism by clearance receptor antagonists and neutral endopeptidase inhibitor potentializes the biological effect of exogenous and endogenous ANF particularly on the renal function. This approach of ANF metabolism-inhibition opens new ways on the future of ANF in cardiovascular therapeutic.
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PMID:[Atrial natriuretic factor. Current data and future perspectives]. 217 42

Met-enkephalin (ME) exerts a bimodal effect on functional activities of rat peritoneal macrophages (PM); in a range of low concentration (10(-9)-10(-7)M) antibody dependent cellular cytotoxicity (ADCC) was markedly stimulated with a simultaneous decrease of Fc gamma receptor (Fc gamma R) medicated phagocytosis while the opposite was observed at 10(-6)-10(-5)M concentrations. Studying the possible underlying mechanism(s) the followings were recorded: (1) ME in all applied concentrations induced an early Na+ influx which was followed by a Ca2+ efflux in the range of low concentrations. In the range of high concentrations Na+ influx was accompanied by a Ca2+ influx. (2) ME at 10(-8) M concentration induced a rise in cGMP level with a plateau in the 60-120th min of incubation. This effect was prevented by 10(-5) M of naloxone. At 10(-6) M concentration a transient rise of cAMP level was recorded which was not affected by naloxone. (3) Verapamil in 10(-6) M abolished both the Ca2+ influx and the rise in cAMP level induced by 10(-6)-10(-5) M ME but not the rise in cGMP level induced by lower ME concentrations. (4) cAMP elevation by high ME concentrations was abolished by enkephalinase inhibitory puromycin. (5) PM-enkephalinase as assessed by the cleavage of fluorogenic substrate L-alanine beta naphthylamide (ABNA), was inhibited by 10(-6)-10(-5) M of ME. This inhibition was abolished by verapamil, but not affected by naloxone. In the range of low concentrations ME appears to act on specific delta opioid receptors and its action is positively coupled to guanylate cyclase. In relatively higher concentrations ME-action is not mediated by specific delta opioid receptors and it appears to involve Ca2+ influx, adenylate cyclase activation as well as the processing of hormone by PM-enkephalinase.
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PMID:Bidirectional effect of met-enkephalin on macrophage effector functions. 242 Nov 52

We examined the interaction of SC-46542 [des(Phe106, Gly107, Ala115, Gln116)-AP(103-126)], a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, with thiorphan, an inhibitor of endopeptidase 24.11, on mean arterial pressure, urine flow, urinary sodium excretion and plasma AP immunoreactivity in conscious rats. The coadministration of SC-46542 (16 micrograms/kg/min) and thiorphan (30 mg/kg i.v. bolus) produced a greater diuresis and natriuresis (but had no effect on mean arterial pressure) than administration of either compound alone; plasma APir increased 2-fold during coadministration of SC-46542 and thiorphan (from 325 +/- 46 to 676 +/- 86 pg/ml). Administration of SC-46542 or thiorphan alone had small or no effects on mean arterial pressure, urine flow, urinary sodium excretion or plasma APir. Converting enzyme inhibition did not contribute to the effects of thiorphan since coadministration of captopril plus SC-46542 produced effects similar to SC-46542 alone. When a near threshold infusion of AP(103-126) was combined with the coadministration of SC-46542 and thiorphan, there was a potentiation of the depressor, diuretic and natriuretic responses. Neither SC-46542 nor thiorphan alone had these effects. SC-46542 potentiated the depressor but not diuretic or natriuretic responses to low dose AP(103-126) infusion; thiorphan had little or no effect on the responses to low dose AP(103-126). We conclude that blockade of non-guanylate cyclase-linked AP binding sites with SC-46542 combined with inhibition of AP degradation by endopeptidase 24.11 with thiorphan increases diuresis and natriuresis more than inhibition of either system alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of non-guanylate cyclase-linked atriopeptin receptor ligand and endopeptidase inhibitor in conscious rats. 256 86

The inactivation of rat atrial natriuretic factor (ANF) was studied using a bioassay, ANF-stimulated guanylate cyclase activity. Rat kidney membranes degraded ANF into biologically inactive forms. The primary cleavage site appears to be the Cys105-Phe106 bond. The degradation, measured by HPLC, followed classical Michaelis-Menten kinetics. The sensitivity of the enzyme to inhibitors suggested it to be a metalloendopeptidase, resembling neutral endopeptidase 24.11. When this enzyme, characterised by its enkephalin-degrading activity, was compared to the enzyme responsible for ANF inactivation, striking differences were found in tissue distribution, pH-dependence and sensitivity to protein-modifying reagents. It is concluded that an enzyme similar to endopeptidase 24.11 may be responsible for inactivation of atrial peptides in the rat.
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PMID:Degradation of atrial natriuretic peptides by an enzyme in rat kidney resembling neutral endopeptidase 24.11. 297 21

The relaxant effects of the K+ channel openers, NIP-121, (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidin-1-yl)-6H - pyrano[2,3-f]benz-2,1,3-oxadiazole, and cromakalim, were investigated in epithelium-intact and -denuded tracheal spirals isolated from guinea-pigs. In the presence of 5 microM indomethacin, NIP-121 (0.01-1 microM) and cromakalim (0.1-10 microM) relaxed, in a concentration-dependent manner, epithelium-intact and -denuded trachea precontracted with a thromboxane A2 mimetic, U46619, 9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy-prostaglandin F2 alpha (30 nM). The relaxations of epithelium-denuded trachea were significantly decreased as compared with those of epithelium-intact trachea. The relaxations induced by salbutamol or aminophylline were not affected by epithelium removal. In epithelium-intact trachea, the NIP-121- and cromakalim-induced relaxations were not modulated by the neutral endopeptidase inhibitor, phosphoramidon (10 microM), or the nitric oxide synthesis inhibitor, N omega-nitro-L-arginine (100 microM). However, the guanylate cyclase inhibitor, methylene blue (100 microM), significantly reduced NIP-121- and cromakalim-induced relaxation of epithelium-intact trachea. Methylene blue also reduced sodium nitroprusside-induced relaxation but did not affect isoprenaline-induced relaxation. These findings suggest that the K+ channel openers, NIP-121 and cromakalim, may induce, at least in part, epithelium-dependent and methylene blue-sensitive relaxation of the guinea-pig isolated trachea.
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PMID:K+ channel openers produce epithelium-dependent relaxation of the guinea-pig trachea. 749 76

We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute i.v. of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009 +/- 0.002, 0.042 +/- 0.005, and 0.049 +/- 0.007, respectively; urinary excretion of atrial natriuretic peptide by -0.4 +/- 0.8, 3.3 +/- 1.4, and 15.8 +/- 7.4 fmol/min; and cGMP excretion by 0.65 +/- 0.06, 1.65 +/- 0.08, and 4.88 +/- 0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005 +/- 0.002, 0.018 +/- 0.003, and 0.022 +/- 0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3 +/- 1.6, 22.0 +/- 5.0, and 46.6 +/- 10.8 fmol/min) and cGMP excretion (0.96 +/- 0.47, 4.51 +/- 1.27, and 7.06 +/- 1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase-linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 3.4.24.11. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide in chronically hypertensive dogs. 755 24


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