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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obstetric hemorrhage may occur throughout pregnancy and the puerperium. The purpose of this study was to investigate the reactivity of isolated, suffused uterine arteries from obstetric patients with uncontrollable uterine bleeding and to compare those blood vessels with uterine arteries from patients undergoing cesarean hysterectomy for other medical reasons (control patients). The uterine arteries from the control patients (n = 9) responded with maximal or near-maximal constriction to norepinephrine (30 mumol/L, 3.6 +/- 1 gm), potassium chloride (75 mmol/L, 10.2 +/- 3 gm), prostaglandin F2 alpha (30 mumol/L, 1.8 +/- 1 gm), and arginine vasopressin (1 mumol/L, 18.8 +/- 2.6 gm). In uterine arteries from five patients with uncontrollable bleeding, the constrictor responses to the same drugs were markedly depressed: norepinephrine (30 mumol/L, 0.5 +/- 0.2 gm), potassium chloride (75 mmol/L, 1.9 +/- 0.8 gm); prostaglandin F2 alpha (30 mumol/L, 0 gm), and arginine vasopressin (1 mumol/L, 0.2 +/- 0.05 gm). Uterine arteries from two patients exhibited no constrictor responses to norepinephrine (30 mumol/L), potassium chloride (75 mmol/L), prostaglandin F2 alpha (30 mumol/L), or arginine vasopressin (1 mumol/L). The impaired responses to the vasoconstrictor drugs were not reversed by indomethacin (1 mumol/L), which is an inhibitor of prostaglandin synthetase; methylene blue (10 mumol/L), which is a blocker of endothelium-derived relaxing factor activation of guanylate cyclase; or propranolol (1 mumol/L), a beta-adrenergic receptor antagonist. The levels of adenosine 3':5'-cyclic monophosphate were not elevated in the uterine arteries from the patients with obstetric hemorrhage. The impaired reactivity to the multiple vasoconstrictors implies that a mechanism involved in constriction common to all of the constrictors is depressed or blocked. Furthermore, the depression or lack of reactivity of these isolated uterine arteries is not mediated by vasodilatory prostaglandins, endothelium-derived relaxing factor, beta-adrenergic receptors, or elevated levels of adenosine 3':5'-cyclic monophosphate. The results suggest that obstetric hemorrhage involves, in part, a lack of constrictor reactivity of the uterine vasculature.
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PMID:Lack of reactivity of uterine arteries from patients with obstetric hemorrhage. 131 76

Some evidence suggests homologous and heterologous regulation of atrial natriuretic peptide (ANP) receptors. We have examined the effects of exposure to ANP, angiotensin II (ANG II), arginine vasopressin (AVP), and endothelin (ET), on binding of ANP to cultured rat vascular smooth muscle cells (VSMC) and on guanylate cyclase-coupled and -uncoupled ANP receptors. The latter were studied by examining production of guanosine 3',5'-cyclic monophosphate (cGMP) in response to ANP and binding of ANP to Triton X-100-solubilized VSMC membranes, irreversible cross-linking with disuccinimidyl suberate, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in presence of dithiothreitol, followed by radioautography. Exposure to 100 nmol/l ANP for 18 h reduced ANP sites to 43% of control. However, if acid wash of VSMC membranes at pH 5.0 was performed before binding, no decrease in density of ANP binding sites was detected. On SDS-PAGE, a 130-kDa band bound 42 vs. 46% of 125I-labeled ANP in acid-washed membranes from control vs. cells exposed to ANP; the remainder was bound to a 67-kDa band. ANG II (100 nmol/l), AVP (1 mumol/l), or ET-1 or ET-3 (100 nmol/l) did not produce changes in density of ANP sites or in binding to the 130- and 67-kDa bands. cGMP production in response to ANP showed exaggerated response in ANG II but not in AVP- or ET-treated VSMC. Effect of ANG II was abolished by the ANG II antagonist [Sar1-Ile8]ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of ANP, angiotensin, vasopressin, and endothelin on ANP receptors in cultured rat vascular smooth muscle cells. 184 18

Previous work has shown that corticosterone, cell-membrane permeant analogs of cGMP, as well as activators of guanylyl cyclase inhibit secretagogue-stimulated ACTH release. In the present study we have examined whether cGMP mediates the inhibitory effect of corticosterone in perifused isolated rat anterior pituitary cells. A brief 22.5-min exposure to corticosterone strongly inhibited ACTH secretion evoked by arginine vasopressin (AVP), 48 mM KC1, and two types of combined stimuli, i.e. 41-residue CRF and AVP (0.05 and 0.5 nM, respectively; CRF/AVP), or ionomycin and phorbol-dibutyrate (200 and 10 nM, respectively; PdBu/IM). The time course of inhibition by corticosterone was similar in all cases; a rapid approximately 30% reduction in ACTH was evident within 25 min, which increased to 60% by 50-70 min and will be referred to as the delayed effect. The corticosteroid inhibition of PdBu/IM-induced ACTH release was fully antagonized by the glucocorticoid/progestin antagonist RU 38486, indicating that it is exerted through type II glucocorticoid receptors. In contrast to corticosterone, the cGMP derivative 8-bromo-cGMP failed to suppress ACTH release evoked by PdBu/IM, whereas it effectively inhibited the action of CRF/AVP. Furthermore, ionomycin reversed the reduction of CRF/AVP-stimulated ACTH release by 8-bromo-cGMP, but had no effect on the delayed inhibition caused by corticosterone. These data indicate that there are two distinct cellular pathways of inhibiting stimulus-evoked ACTH secretion in vitro. One of these is activated by corticosterone, whereas the other involves cGMP as a cellular messenger.
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PMID:Evidence for distinct glucocorticoid and guanine 3',5'-monophosphate-effected inhibition of stimulated adrenocorticotropin release in vitro. 215 98

Although guanosine 3',5'-cyclic monophosphate (cGMP) is present in renal nephron segments, there is no information on the role of cGMP as a mediator of renal tubular transport events. We found that an activator of guanylate cyclase (nitroprusside) and 8-bromocGMP (8-BrcGMP) significantly increased hydraulic conductivity in rabbit and rat cortical collecting tubules (CCT) perfused in vitro. The effect of 10(-4) M 8-BrcGMP to increase CCT hydraulic conductivity was reversible and comparable in magnitude and time course to that produced by maximal concentrations of arginine vasopressin. In rabbit CCT, cGMP increased hydraulic conductivity in the presence of phosphodiesterase inhibition with methylisobutylxanthine and in the presence of supramaximal concentrations of arginine vasopressin. Neither nitroprusside nor 8-BrcGMP stimulated adenylate cyclase activity in microdissected CCT. These data demonstrate that cGMP can act independently of either stimulation of adenylate cyclase activity or inhibition of phosphodiesterase activity to increase hydraulic conductivity in the mammalian CCT.
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PMID:Cyclic guanosine monophosphate increases hydraulic conductivity in rabbit and rat CCT. 246 Oct 96

The natriuretic effects of atrial peptide hormones have been attributed, at least in part, to their stimulation of guanylate cyclase activity in renal cell membranes. The effects of atrial natriuretic factor (ANF) on stimulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation were investigated in cloned human kidney tumor (hKT) cells and parent cells from a human renal tumor epithelial cell line (SK-NEP-1). Human ANF-(99-126) (10(-6)M) stimulated (p less than 0.001) cellular cGMP accumulation in a dose-dependent manner from a basal level of 0.26 +/- 0.04 to 3.73 +/- 0.81 pmol/mg protein/5 mi (mean +/- SEM, n = 13). ANF stimulation of cGMP accumulation was specific, in that high concentrations (10(-6)M) of atriopeptin I [rat ANF-(103-123)], angiotensin II, arginine vasopressin, and amiloride (10(-4)M) did not increase basal cGMP. Amiloride (10(-4)M) enhanced (p less than 0.01, n = 6) the ANF stimulation of cGMP accumulation (1.24 +/- 0.39 pmol/mg protein/5 min), particularly at low doses of ANF (10(-10)M) where stimulation by ANF without amiloride (0.34 +/- 0.08 pmol/mg protein/5 min) was barely distinguishable from a basal level (0.19 +/- 0.02 pmol/mg protein/5 min) of cGMP accumulation. The stimulatory effect of ANF (1.59 +/- 0.07 pmol/mg protein/5 min) was attenuated (0.75 +/- 0.06 pmol/mg protein/5 min, p less than 0.01, n = 6) by preincubation of the cells with pertussis toxin but not by cholera toxin. ANF (4.56 +/- 0.93 pmol/mg protein/5 min, n = 8) did not affect cAMP accumulation (4.32 +/- 0.98 pmol/mg protein/5 min) in hKT cells. This is the first report of an ANF responsive human renal cell line, and its use should facilitate investigation of ANF-receptor interactions.
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PMID:Atrial natriuretic factor effects on cyclic nucleotides in a human renal cell line. 256 5

We tested the ability of the following putative vasoactive agents to stimulate guanylate cyclase activity in isolated rat cerebral microvessels: angiotensin II, arginine vasopressin, atrial natriuretic peptide, bradykinin, carbachol and thrombin; at concentrations ranging between 10(-3) and 10(-9) M. The ability of cerebral microvessels to increase their cyclic GMP generation was ascertained in the presence of sodium nitroprusside. Of all the agents tested, only atrial natriuretic peptide stimulated cyclic GMP generation in isolated rat cerebral microvessels. Such stimulation was dose-dependent, reaching its maximum at 1 microM concentration. These results are consistent with the finding of atrial natriuretic peptide receptors in brain microvessels, and suggest that this peptide has an important role in modulating the function of brain capillaries, which constitute the blood-brain barrier. If receptors for the other vasoactive agents exist in brain microvessels, their action does not seem to be mediated by cyclic GMP as a second messenger.
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PMID:Effect of several vasoactive agents on guanylate cyclase activity in isolated rat brain microvessels. 257 27

The sequence of atrial natriuretic factor (ANF) has been determined, as well as the complete structure of the rat and human complementary DNA and gene. ANF and ANF messenger RNA are present not only in atria but also in ventricles. The circulating form of ANF has been identified as the C-terminal of the molecule, ANF (Ser 99-Tyr 126). The isolated secretory granules of rat atrial cardiocytes contain only pro-ANF (Asn 1-Tyr 126). An enzyme (IRCM-SP1) has been isolated from heart atria and ventricles. This enzyme is highly specific in cleaving ANF (Asn 1-Tyr 126), to yield ANF (103-126), (102-126), and (99-126). In target cells, ANF produces a rise in cyclic guanosine 3',5'-monophosphate (cGMP) due to activation of particulate guanylate cyclase, and inhibition of adenylate cyclase leading in some cases to a decrease in cyclic adenosine 3',5'-monophosphate (cAMP). ANF produces relaxation of rabbit and rat aortic strips, inhibits steroidogenesis in both zona glomerulosa and zona fasciculata cells, and inhibits the release of arginine vasopressin from the isolated rat hypothalamohypophysial preparation in vitro but decreases AVP release in vivo only at pharmacological doses. In all forms of experimental hypertension, plasma levels of ANF are increased and, at some time periods, atrial levels are also decreased. The ventricular levels of immunoreactive ANF are also increased in renal hypertension. Infusion of ANF by minipumps decreases the blood pressure near control levels in several models of experimental hypertension. In cardiomyopathic hamsters with heart failure, the atrial levels of immunoreactive ANF are decreased while the plasma and ventricular levels are increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The heart as an endocrine gland. 282 60

The cellular mechanism of the action of atrial natriuretic factor (ANF) is thought to involve activation of guanylate cyclase. Increasing evidence shows a direct tubular effect of ANF. Part of the ANF-induced diuresis has been suggested to be due to inhibition of the action of arginine vasopressin (AVP) in the cortical collecting tubule. In this study we investigated the effect of ANF on cyclic nucleotide production in primary cultures of cortical collecting tubule cells immunodissected with a monoclonal antibody. ANF caused a dose-dependent stimulation in cyclic guanosine 3',5'-monophosphate (cGMP) production; the half-maximal stimulation was observed at approximately 1 nM of ANF. ANF (0.01-100 nM) had no effect on cyclic adenosine 3',5'-monophosphate (cAMP) accumulation in cortical collecting tubule cultures. AVP caused a dose-dependent increase in cAMP production, and this effect was not altered by the simultaneous addition of ANF (100 nM). Similarly, ANF-induced cGMP stimulation was not influenced by AVP (10 nM). We conclude that 1) ANF has a direct stimulatory action on cGMP production by cultured cortical collecting tubule cells and 2) any interaction between ANF and AVP is likely to occur at steps distal to cyclic nucleotide formation.
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PMID:Effects of atrial natriuretic factor and vasopressin on cyclic nucleotides in cultured kidney cells. 283 39

The effect of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), and oxytocin (OT) on cAMP and cGMP accumulation was investigated in LLC-PK1 kidney epithelial cells. The addition of ANP, AVP, and OT to intact cells produced a time- and concentration-dependent increase in cGMP accumulation. ANP produced a 1.7-fold increase in cGMP at 10 pM and a maximal 28-fold increase in cGMP at 1 microM. ANP had no effect on basal or AVP-induced stimulation of cAMP accumulation. OT was 10-fold more potent than AVP at increasing cGMP levels, producing a 2.1-fold increase in cGMP at 0.1 nM, whereas AVP was 100-fold more potent at increasing cAMP levels. At a concentration of 1 microM, AVP and OT produced a maximal 12 to 14-fold increase in cGMP, while OT and AVP produced 50- and 90-fold increase in cAMP, respectively. The selective OT agonist [Thr4, Gly7]oxytocin was very effective at increasing cGMP, but not at increasing cAMP levels. The V2-vasopressin agonist [deamino-Pen1,Val4, D-Arg8]vasopressin did not increase cGMP levels, but produced a 20-fold increase in cAMP levels. The addition of ANP together with either AVP or OT produced an additive increase in cGMP content. Simultaneous addition of AVP and OT did not lead to a greater increase in cAMP or cGMP levels. These results suggest that the AVP- and OT-induced increase in cGMP is mediated by OT receptors, whereas the increase in cAMP is probably mediated by vasopressin receptors. ANP increased the activity of particulate guanylate cyclase by 6-fold, while AVP and OT has no effect on particulate guanylate cyclase activity. The relatively selective inhibitor of soluble guanylate cyclase, methylene blue, had no effect on the ANP-induced increase in cGMP content in intact cells, but produced a 50% inhibition of the increase in cGMP by AVP and OT. Methylene blue did not alter the stimulation of cAMP by AVP or OT. These results demonstrate that ANP, AVP, and OT increase cGMP in LLC-PK1 kidney epithelial cells. The increase in cGMP by ANP is mediated by particulate guanylate cyclase, whereas AVP and OT probably increase cGMP by interacting with OT receptors coupled to soluble guanylate cyclase.
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PMID:Atrial natriuretic peptide, oxytocin, and vasopressin increase guanosine 3',5'-monophosphate in LLC-PK1 kidney epithelial cells. 289 98

The mechanism and profile of antagonism of thromboxane receptors were studied in isolated perfused cat coronary arteries and in rat aortic rings. In cat coronary arteries, the thromboxane receptor antagonist (TxRA) BM-13,505 at concentrations from 3 to 300 ng/ml, significantly attenuated the vasoconstrictor effects of both a thromboxane A2 analog (CTA2) and an endoperoxide analog (U-46,619) and did not alter the constrictor responses to leukotriene D4, arginine vasopressin, or angiotensin II. In rat aortic rings precontracted by CTA2 or U-46,619, the effective threshold concentration of BM-13,505 for relaxation was 5 ng/ml. Lower concentrations of BM-13,505 exerted no relaxation, and higher concentrations exhibited faster relaxation to the precontracted baseline levels. This relaxation was not observed in aortic rings precontracted by norepinephrine or angiotensin II. The action of TxRA was not influenced by the absence of the endothelium or by pretreatment with a selective guanylate cyclase inhibitor, methylene blue. Also, thromboxane receptor antagonists do not appear to block thromboxane induced constriction by action as free radical scavengers. It can be concluded that replacing thromboxane A2 on the vascular receptor by a TxRA is the main factor responsible for the antagonism of thromboxane induced vasoconstriction in vascular smooth muscle preparations, not, the presence of the endothelium, activation of guanylate cyclase, or scavenging of superoxide free radicals.
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PMID:Mechanism of antagonism of thromboxane receptors in vascular smooth muscle. 303 Jul 73


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