Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.
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PMID:A structurally unique, potent, and selective oxytocin antagonist derived from Streptomyces silvensis. 254 2

Homozygous Brattleboro rats display pronounced diabetes insipidus and when treated continuously with arginine vasopressin (AVP) acquire the ability to produce concentrated urine. In this study, the effects of continual AVP replacement on the pharmacological properties of the renal medullary V2 receptor and coupling to adenylate cyclase were examined. Osmotic minipumps that delivered AVP at four different rates were implanted into male homozygous Brattleboro rats. At the end of the 14 day treatment period, urine osmolalities were 280 +/- 24, 474 +/- 105, 1777 +/- 304 and 2202 +/- 175 mOsm/kg H2O for the 0, 31.25, 62.5 and 125 ng/hr treatment groups, respectively. Plasma AVP levels were below the level of detection for the 0 and 31.25 ng/hr treatment groups, and were 2.5 +/- 0.5 and 6.5 +/- 1.8 pg/ml for the 62.5 and 125 ng/hr treatment groups. Saturation experiments using [3H] AVP and renal medullary membranes revealed binding site concentrations of 57 +/- 9, 84 +/- 23, 164 +/- 17 and 150 +/- 18 fmol/mg protein for the 0, 31.25, 62.5 and 125 ng/hr treatment groups, respectively. AVP-stimulated cyclic AMP accumulation was enhanced in renal medullary membranes prepared from the 62.5 and 125 ng/hr treatment groups when compared to that in the 0 and 31.25 ng/hr treatment groups. From these results, it appears that circulating AVP is necessary for expression of functional V2 receptors in the homozygous Brattleboro rat renal medulla.
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PMID:Induction of V2 receptors in renal medulla of homozygous Brattleboro rats by arginine vasopressin. 255 68

The adrenergic nervous system profoundly alters water excretion by both renal and extrarenal pathways. The effects of catecholamines on cultured rat inner medullary collecting tubule cells were studied. The beta-adrenergic agonist, isoproterenol, increases cAMP from 19.5 +/- 2.3 to 79.4 +/- 14.4 fm/micrograms protein, P less than 0.001. The response to arginine vasopressin (AVP) is also greater in the presence of isoproterenol, but the increment is unchanged when compared to that seen in the absence of AVP. The agonist effect of isoproterenol is blocked by propranolol but not by the specific beta 1 antagonist, atenolol. The effect of alpha-adrenergic stimulation was studied by the use of norepinephrine (NE) in the background of the beta blocker, propranolol. NE decreases AVP-stimulated cAMP generation from 190 +/- 11 to 117 +/- 10 fm/micrograms, P less than 0.001, N = 6. The specific alpha 2 antagonist, yohimbine, but not the alpha 1 antagonist, prazosin, prevents the NE-induced decrease as AVP-stimulated cAMP is restored to 187 +/- 19 fm/micrograms. Similarly the selective alpha 2 agonist, clonidine, significantly inhibits both AVP- and isoproterenol-mediated cAMP generation. To define the site of alpha 2 inhibition in the adenylate cyclase (AC) complex the effect of pertussis toxin (PT) was investigated. After pretreatment with PT (1-1000 ng/ml), AVP-stimulated cAMP was not inhibited by NE. The alpha 1 agonist, phenylephrine, fails to inhibit AC or to increase cytosolic Ca in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenergic control of cAMP generation in rat inner medullary collecting tubule cells. 256 11

Because of the presence of a high density of vasopressin receptors in the epithelial cells of porcine seminal vesicles similar to the V2 vasopressin receptors of renal tubules, human seminal vesicles and kidney were investigated using quantitative binding and adenylate cyclase studies. Tissues were obtained at surgery from 17 patients with urologic diseases. A homogeneous class of vasopressin binding sites have been found in both seminal vesicles and renal medulla. However, the vasopressin receptors present in these tissues are different in terms of ligand specificity and adenylate cyclase activation. In seminal vesicles, the V1 vasopressin antagonist d(CH2)5 TyrMeAVP is 36-fold, more potent than the V2 agonist dVDAVP in displacing [3H]AVP binding, while in the medullopapillary portion of kidney dVDAVP is 24-fold, more selective than d(CH2)5 TyrMeAVP for the arginine vasopressin binding site. Furthermore, arginine vasopressin induces a dose-dependent increase in adenylate cyclase activity in renal membranes, while it was ineffective in seminal vesicle membranes. These results indicate that a very high affinity (0.2 nM), low capacity (14 fmoles/mg protein) class of vasopressin receptors is present in human seminal vesicles, having pharmacologic characteristics similar to the V1 subtype of vasopressin receptors. The presence of a high affinity (1.6 nM), high capacity (350 fmoles/mg protein) V2 subtype of vasopressin receptors in human renal membranes is also confirmed. The density of the vasopressin receptors present in human seminal vesicles is inversely correlated with patient age, consistent with a physiologic role for vasopressin in the regulation of accessory sex gland activity.
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PMID:Vasopressin receptors in human seminal vesicles: identification, pharmacologic characterization, and comparison with the vasopressin receptors present in the human kidney. 259 68

Specific arginine vasopressin (AVP) binding sites were identified and characterized using Leydig cell membranes prepared from a clonal murine Leydig-derived cell line, TM3. 3H-AVP binding data analyses demonstrated that the radioligand binds to a high affinity, low capacity, homogeneous class of sites with a dissociation constant of 0.5 nM. Characterization of these AVP binding sites included competition studies. Displacement of 3H-AVP binding with high affinity by unlabelled AVP, LVP and the V1 antagonist, d(CH2)5Tyr(Me)AVP, indicated that the Leydig cell AVP receptor is of the V1 type. Furthermore, AVP did not increase adenylate cyclase activity in TM3 membranes, a finding consistent with the V1 type of AVP receptor. No competition with 3H-AVP was found with the V2 agonist, dVDAVP, or the selective oxytocin agonist, [Thr4,Gly7]oxytocin. No specific binding for oxytocin was found in Leydig cell membranes. No specific binding for either 3H-AVP or 3H-oxytocin was observed in membranes prepared from the Sertoli cell line or peritubular cell line. These findings indicate that murine Leydig cells have specific AVP binding sites of the V1 type. These AVP sites are not coupled to the adenylate cyclase system.
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PMID:Identification and characterization of arginine vasopressin receptors in the clonal murine Leydig-derived TM3 cell line. 271 74

Adenohypophysial cells from female Wistar rats were dispersed and maintained for 4 days in primary culture in the presence of [3H]myoinositol. The effects of several releasing hormones, corticotropin-releasing factor (CRF), arginine vasopressin (AVP), angiotensin II (A II), thyrotropin-releasing hormone (TRH), and luteinizing hormone-releasing hormone (LHRH) on the liberation of labelled inositol phosphate (InsP), inositol-bisphosphate (InsP2), and inositol-trisphosphate (InsP3) from prelabelled inositol lipids were tested alone and in combination. Of the corticotropin (ACTH) secretagogues tested, AVP and A II produced a dose-dependent increase in inositol phosphate accumulation. CRF was inactive. The ED50 values of about 1 nM for both AVP and A II were close to the corresponding dissociation constants for binding to pituitary membranes: and, in the case of A II, close to the ED50 for A II-induced inhibition of pituitary membrane adenylate cyclase. The responses to A II and AVP could be inhibited by [Sar1,Ile8]A II and the AVP antagonist d(Et2)-VAVP, respectively. The magnitude of the maximal effect of AVP on accumulation of inositol phosphates was small (25% increase over basal value) suggesting that this effect was restricted to a minor subpopulation of pituitary cells (probably corticotrophes). CRF did not potentiate AVP-induced inositol phosphates accumulation. Maximal A II-induced increase in inositol phosphates accumulation represented 150% of the basal value and was partially additive with that of TRH suggesting that lactotrophes represent the main A II-sensitive subpopulation.
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PMID:Vasopressin and angiotensin induce inositol lipid breakdown in rat adenohypophysial cells in primary culture. 282 20

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 effects of islet-activating protein (pertussis toxin) on bradykinin-mediated inositol trisphosphate labeling, prostaglandin E2 production, and calcium mobilization in rabbit renal papillary collecting tubule cells were assessed. Islet-activating protein induced time and concentration-dependent decreases in bradykinin-stimulated prostaglandin E2 production. Islet-activating protein induced increases in basal cyclic AMP levels but not in arginine vasopressin-stimulated cAMP. This effect could be inhibited by prior incubation with 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase. Although cAMP and cAMP analogues were able to inhibit both basal and bradykinin-stimulated prostaglandin E2 formation, the inhibitory effects of islet-activating protein on prostaglandin E2 formation and inositol trisphosphate labeling were observed in the presence of dideoxyadenosine. Moreover, islet-activating protein lowered both the basal and kinin-stimulated cytosolic calcium concentration as assessed by Quin 2 fluorescence. Finally, incubation of a membrane fraction of papillary cells with islet-activating protein resulted in the ADP-ribosylation of a 39/41-kDa doublet. These data support the role of a guanine nucleotide regulatory protein in bradykinin-mediated signal transduction in rabbit papillary collecting tubule cells.
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PMID:Islet activating protein inhibits kinin-stimulated inositol phosphate production, calcium mobilization, and prostaglandin E2 synthesis in renal papillary collecting tubule cells independent of cyclic AMP. 282 14

Receptors for arginine vasopressin (AVP) were characterized in tubular epithelial basolateral membranes (BL membranes) prepared from the kidneys of male Sprague-Dawley rats. Association of [3H]AVP was rapid, reversible, and specific. Saturation studies revealed a single class of saturable binding sites with a maximal binding (Bmax) of 184 +/- 15 fmol/mg protein and a KD of 0.61 +/- 0.04 nM. IC50S for AVP, lysine vasopressin, and oxytocin were 0.74 nM, 9.7 nM, and greater than 1 microM, respectively. The V2 receptor antagonist was more than 3,700 times as effective in displacing [3H]AVP than was the V1 antagonist. To investigate the physiological regulation of vasopressin receptors, the effects of elevated levels of circulating AVP on receptor characteristics were studied. Seventy-two-hour water deprivation significantly elevated plasma osmolality and caused an 11.5-fold increase in plasma [AVP]. Scatchard analysis revealed a 38% decrease in the number of AVP receptors on the BL membranes from dehydrated animals. The high-affinity binding sites on the BL membranes fit the pharmacological profile for adenylate cyclase-linked vasopressin receptors (V2), which mediate the antidiuretic action of the hormone. We conclude that physiologically elevated levels of AVP can downregulate vasopressin receptors in the kidney.
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PMID:Renal tubular vasopressin receptors downregulated by dehydration. 283 32

The role of calcium (Ca) in the cellular action of arginine vasopressin (AVP) was examined in rat renal papillary collecting tubule cells in culture. AVP increased both the cellular free Ca concentration ([Ca2+]i) using fura-2, and cAMP production in a dose-dependent manner. AVP-induced cellular Ca mobilization was totally blocked by the antagonist to the antidiuretic action of AVP, and somewhat weakened by the antagonist to the vascular action of AVP. 1-Deamino-8-D-AVP (dDAVP). an antidiuretic analog of AVP, also increased [Ca2+] significantly. Cellular Ca mobilization was not obtained with cAMP, forskolin (a diterpene activator of adenylate cyclase), or phorbol-12-myristate-13-acetate. The early phase of [Ca2+]i depended on the intracellular Ca pool, since an AVP-induced rise in [Ca2+]i was obtained in cells pretreated with Ca-free medium containing 1 mM EGTA, verapamil, or cobalt, which blocked cellular Ca uptake. Also, AVP increased 45Ca2+ influx during the initial 10 min, which initiated the sustained phase of cellular Ca mobilization. However, cellular cAMP production induced by AVP during the 10-min observation period was diminished in the cells pretreated with Ca-free medium, verapamil, or cobalt, but was still significantly higher than the basal level. This was also diminished by a high Ca concentration in medium. These results indicate that 1) AVP concomitantly regulates cellular free Ca as well as its second messenger cAMP production; 2) AVP-induced elevation of cellular free Ca is dependent on both the cellular Ca pool and extracellular Ca; and 3) there is an optimal level of extracellular Ca to modulate the AVP action in renal papillary collecting tubule cells.
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PMID:Arginine vasopressin increases cellular free calcium concentration and adenosine 3',5'-monophosphate production in rat renal papillary collecting tubule cells in culture. 284 Oct 93


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