[Effects of total flavones of Hippophae rhamnoides L on cultured rat heart cells and on cAMP level and adenylate cyclase in myocardium].
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When total flavones of Hippophae rhamnoides L (TFH) 100 ug/ml were added to the medium. the spontaneous arrhythmias of the cell clusters disappeared in 14/19 experiments. TFH 100 ug/ml significantly counteracted the positive chronotropic effects of CaC12 and isoproterenol. with the maximal response being markedly decreased in the cultured rat heart cells. TFH 100 ug/ml reduced the level of cAMP in both ischemic and nonischemic myocardium in the isolated perfused rat heart. TFH 100 and 400 ug/ml inhibited adenylate cyclase of the rat ventricular myocardium. These results suggest that the antiarrhythmic effects of TFH are exerted on the heart cells directly. and that the calcium antagonizing action and inhibition of adenylate cyclase with a reduction in the cAMP level may be an important mechanism related to the antiarrhythmic effects.Keywords:
Flavones
Hippophae rhamnoides
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Hormone-stimulated lipolysis is reduced in genetically obese rodents and may contribute to the increased adiposity characteristic of the obese state. Endogenously released adenosine, acting via the A1 receptor coupled to the inhibitory guanosine 5'-triphosphate binding protein, Gi, provides a tonic inhibition of lipolysis in rat adipocytes. Removal of this inhibition by the addition of adenosine deaminase frequently results in maximal lipolytic activity. Adipocytes isolated from lean Zucker (Fa/?) rats responded normally to adenosine deaminase, where lipolysis in adipocytes from obese Zucker (fa/fa) rats remained approximately 50% inhibited. Adipocyte adenylate cyclase was equally responsive to activation by forskolin, but lipolytic hormones were significantly less effective in stimulating adenosine 3',5'-cyclic monophosphate (cAMP) production in the obese adipocytes. These cells also exhibited an increased sensitivity to inhibition by the adenosine agonist, N6-(L-2-phenylisopropyl)-adenosine, either in combination with forskolin or beta-adrenergic hormone stimulation. Treatment of isolated adipocytes with pertussis toxin, which uncouples receptor-mediated Gi function, had little effect in cells from lean rats but increased isoproterenol stimulated cAMP production of cells from obese rats to levels observed in the lean cells. In addition, the adenosine A1 antagonist, 8-phenyltheophylline, increased cAMP and lipolytic activity in the obese adipocytes while having little significant effect in the lean adipocytes. These results suggest that hormonal control of lipolysis is altered in the obese Zucker rat because of an alteration in A1-adenosine receptor-mediated inhibition of adenylate cyclase.
Adenosine A1 receptor
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We have examined the effect of parathyroid hormone (PTH) on the adenylate cyclase activity of newborn osteopetrotic rat calvaria, to study a possible molecular basis for the reduced response of this mutant to PTH. Phenotypically normal littermates served as controls. We also measured the effect of PTH on kidney adenylate cyclase activity and on lactic acid accumulation in short term cultures of calvaria. PTH stimulated calvarial adenylate cyclase activity in a dose-dependent manner in both mutant rats and normal littermates. Lactic acid production was also enhanced by PTH, and no significant difference between mutants and normal littermates was observed. These findings indicate that the reduced response of the young osteopetrotic rats to PTH is not due to an absence of PTH receptors coupled to adenylate cyclase. (Endocrinology102: 1501, 1978)
Calvaria
Pseudohypoparathyroidism
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The dwarf (dw) mutation in rats results in 40–50% growth retardation associated with a selective reduction in pituitary somatotroph number, GH content, and GH mRNA levels and a decreased GH secretory response to GH-releasing factor (GRF). Recent studies in freshly dispersed pituitary cells have provided evidence for a defect in adenylate cyclase-linked GRF signal transduction in dw somatotrophs. To further examine this defect in a more specific cell population, we developed a somatomammotroph cell line (DP) derived from anterior pituitaries of male dw rats. A similar cell line from normal rats (vPo) was used as control. We studied acute GH (4-h release) and cAMP (30-min intracellular accumulation) responses to GH secretagogues known to interact with the adenylate cyclase system. Basal GH release in both cell lines was 80–130% of the cell content, thus limiting the capacity for further GH responses. GRF (10−8 M) produced a doubling of cAMP levels in Po and DP cells (P < 0.01), but inconsistent effects on GH release. (Bu)2cAMP (5 x 10−3 M) increased GH secretion by 50-100% in both groups (P < 0.01). Cholera toxin (10−9 M) increased GH release by 50% in both Po and DP (P < 0.01), but the cAMP response in DP cells was only half that in Po cells (P < 0.01). Forskolin (10−5 M), a direct stimulator of adenylate cyclase, doubled GH release in both groups (P < 0.01). However, cAMP generation was impaired in DP, with a maximal response to forskolin less than one third that in Po (P < 0.01). In somatotrophs, cAMP mediates not only GRF-stimulated GH release, but also GH synthesis and mitogenesis. The impairment in maximal cAMP generation in DP cells, while not affecting acute GH release, may underlie the defect in somatotroph cell number and GH content in the dw pituitary gland. (Endocrinology129: 3410–3416,1991)
Cholera toxin
Cyclic adenosine monophosphate
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Abstract. Zinc deficiency and altered myocardial adenylate cyclase activity commonly occur in diabetes. To determine whether the zinc intake of the animal can account for the altered β-adrenergic receptor activity in the diabetic heart, we determined the β-adrenergic receptor number and isoproterenol-, NaF- and forskolin-stimulated adenylate cyclase activity in diabetic and control rats maintained on low, normal and high zinc diets for 3 weeks. Scatchard analysis of [ 125 I]iodocyanopindolol binding to control heart membrane preparations revealed a binding capacity of 17.3 ± 1.3 fmol/mg protein with a K d of 35 ± 1.0 pmol/l. Neither the diabetic state nor the zinc status altered these binding parameters. The isoproterenol-stimulated adenylate cyclase acticity was significantly lower in diabetic rats on low zinc diets compared with controls. The NaF- (65.1 ± 5.4 vs 60.8 ± 6.4 pmol cAMP·mg protein −1 ·min −1 ) and forskolin-stimulated adenylate cyclase activities (161 ± 9.3 vs 154 ± 21.2 pmol cAMP·mg protein −1 · min −1 ) were not significantly altered in diabetic rats. Low dietary zinc intake compared with high zinc diet significantly increased NaF- and forskolin-stimulated adenylate cyclase activity both in diabetic rats and controls. The effect of dietary zinc content on isoproterenol-stimulated adenylate cyclase was significant in control rats only. Thus zinc intake appears to be an important determinant of cardiac adenylate cyclase activity level. Additional factors peculiar to the diabetic state are involved in the modulation of β-adrenergic responsiveness of the diabetic heart.
Iodocyanopindolol
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The aim of this study was to establish the mechanism by which adrenalectomy promotes the antilipolytic effect of the adenosine analog (_)-N6-(R-phenyl-isopropyl)adenosine (R-PIA) in rat fat cells. This action of adrenalectomy was not specific for R-PIA, since it was also observed with nicotinic acid and was prevented by phosphodiesterase inhibitors. In contrast, the inhibitory effect of R-PIA and nicotinic acid toward isoproterenol- stimulated cAMP accumulation was unaltered by adrenalectomy regardless of whether phosphodiesterase inhibitors were present. Whatever the conditions used, however, the cAMP levels in adrenalectomized rat adipocytes were one quarter to one third of those in sham-operated rats and remained below the limit over which variations in cAMP had no more influence in lipolysis. Both total and particulate low Km cAMP phosphodiesterase activities per adipocyte were decreased in adrenalectomized rats, but the stimulatory responses of the particulate enzyme to RPIA remained unchanged. Pertussis toxin-catalyzed ADP ribosylation studies revealed a marked decrease in the total amount of the α-subunits of Go and the adenylate cyclase inhibitory regulatory protein Gi after adrenalectomy. However, the inhibitory dose-response curves of adenylate cyclase to R-PIA, nicotinic acid, GTP, guanylylimidodiphosphate, and guanosine 5'-O-(3-thiotriphosphate) were unaltered by adrenalectomy, indicating that the inhibitory function of Gi is unimpaired by adrenalectomy. Lastly, adrenalectomy resulted in a 60% reduction of the Mn2+-stimulated adenylate cyclase activity/adipocyte, which indicates that adrenalectomy causes a defect in adenylate cyclase catalytic activity. Thus, enhanced antilipolytic effects of R-PIA induced by adrenalectomy do not involve increased function of the adenosine receptor Gi-coupled adenylate cyclase inhibitory pathway, but are related to abnormally low intracellular cAMP levels due to defective adenylate cyclase catalytic activity. (Endocrinology124: 1131-1139, 1989)
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Basal, NaF- and ACTH-stimulated activity of adenylate cyclase was studied in "shadows" of fatty cells from intact and adrenalectomized rats with spontaneous hypertension (SHR strain) as compared with the corresponding controls. Activity of ACTH-adenylate cyclase was decreased in control adrenalectomized animals; the enzymatic activity was similar in normal rats, in adrenalectomized animals of the SHR strain and in the intact SHR rats. Basal and NaF-stimulated activities of adenylate cyclase were the same in all the animal groups studied.
Basal (medicine)
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Adipocytes contain adenosine receptors, termed A1 receptors, which inhibit lipolysis by decreasing adenylate cyclase activity. The inhibition of lipolysis by adenosine agonists in vivo acutely suppresses the plasma concentrations of free fatty acids (FFA) and triglycerides. We have found that infusions of the adenosine receptor agonist phenylisopropyladenosine (PIA) initially decreases plasma FFA concentrations; however, with prolonged exposure (6 d), rats become very tolerant to the effects of the drug. Adipocytes isolated from epididymal fat pads from PIA-infused rats have altered lipolytic responses. When lipolysis is stimulated with a relatively high concentration of isoproterenol (10(-7) M), PIA does not inhibit lipolysis in adipocytes from the infused animals. However, PIA inhibits isoproterenol-stimulated cyclic AMP (cAMP) accumulation in adipocytes from the infused rats although with decreased sensitivity compared with controls. The explanation for the impaired antilipolytic effect appears to be due to the fact that isoproterenol-stimulated cAMP accumulation is markedly increased in cells from infused rats. Indeed, basal lipolysis and lipolysis stimulated with lower concentrations of isoproterenol (10(-9), 10(-8) M) are effectively inhibited by PIA. cAMP accumulation is greatly increased in adipocytes from infused rats when stimulated by isoproterenol, ACTH, and forskolin. The results have some striking analogies to changes induced in nerve cells by prolonged exposure to narcotics. These data suggest that tolerance to PIA develops in adipocytes as a consequence of enhanced cAMP accumulation.
Cyclic adenosine monophosphate
Adenosine A1 receptor
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The effect of two atrial natriuretic peptides, rat ANP (3-28) and synthetic ANP (Arg101-Tyr126), on pituitary adenylate cyclase activity was measured in rats. Neither one was effective on basal, forskolin- or guanylylimidodiphosphate (GMP-PNP)-stimulated adenylate cyclase levels measured in homogenates of anterior and neurointermediate pituitary lobes. High concentrations (10(-7) and 10(-6) M) of ANPs further stimulate NaF-induced high adenylate cyclase activity - ANP (3-28) in both lobes, ANP (Arg101-Tyr126) only in the anterior lobe-but they were without effect in 10(-8) M or lower concentrations. These data indicate that ANP may not influence adenylate cyclase/cAMP system in the rat pituitary gland.
Atrial natriuretic peptide
NPR2
Basal (medicine)
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Isolated fat cells prepared from the epididymal fat pads of adrenalectomized rats exhibited a reduced lipolytic response to epinephrine. Reduced responsiveness was first observed at 3 hr and was maximal at 24 hr following surgery. Plasma levels of corticosterone had fallen to near zero by 3 hr. The lipolytic responses to ACTH, dibutyryl cyclic AMP and theophylline were also reduced. Maximum lipolytic rates produced by a combination of epinephrine and theophylline were not altered. Loss of lipolytic response to epinephrine could be prevented by subcutaneous injection of hydrocortisone. Basal, epinephrinestimulated, and sodium fluoride—stimulated adenylate cyclase activity in fat cell homogenates were not altered by adrenalectomy; however, the response to ACTH was nearly abolished. Elevations in intracellular levels of cyclic AMP by ACTH were greatly reduced by adrenalectomy while the response to epinephrine was reduced to a lesser extent. With both hormones the effect of adrenalectomy was greater when the cells were incubated in the absence of theophylline than when the phosphodiesterase inhibitor was present. (Endocrinology91: 504, 1972)
Corticosterone
Phosphodiesterase inhibitor
Bucladesine
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The basal adenylate cyclase activity of the bovine adrenal medullais similar to that of the adrenal cortex. The medullary enzyme is less responsive in vitro to stimulation by optimal fluoride ion concentrations (8 HIM), and is not elevated by ACTH. Medullary adenylate cyclase activity is also unaffected by carbamylcholine, nerve-growth factor, prostaglandin E1, or dexamethasone. (Endocrinology94: 591, 1974)
Medulla
Basal (medicine)
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