Inhibitory effect of clonidine upon adenylate cyclase activity, cyclic AMP production, and insulin release in rat pancreatic islets

1984 ◽  
Vol 4 (6) ◽  
pp. 511-521 ◽  
Author(s):  
P. Garcia-Morales ◽  
S. P. Dufrane ◽  
A. Sener ◽  
I. Valverde ◽  
W. J. Malaisse
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Inhibitory Action ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Rat Pancreatic Islets

Conflicting opinions were recently expressed concerning the possible effect of α2-adrenergic agonists upon cyclic AMP production in pancreatic islets. In the present: study, clonidine inhibited glucose-induced insulin release from rat pancreatic islets, this inhibitory effect being abolished by idazoxan. Clonidine did not suppress the capacity of forskolin to augment glucose-induced insulin release. In a particulate subcellular fraction derived from the islets, adenylate cyclase was activated by calmodulin (in the presence of Ca2+), NaF, GTP, L-arginine, and forskolin, and slightly inhibited by clonidine. The inhibitory action of clonidine upon basal adenylate cyclase activity was more pronounced in islet crude homogenates. The inhibitory effect of clonidine was antagonized by forskolin whether in the particulate fraction or crude homogenate. At variance with the modest effects of glucagon, D-glucose, L-arginine, or a tumor-promoting phorbol ester upon cyclic AMP production by intact islets, forskolin caused a six-fold increase in cyclic AMP production. Clonidine inhibited cyclic AMP production by intact islets, whether in the absence or presence of forskolin. It is proposed that the inhibitory action of clonidine upon insulin release is attributable, in part at least, to inhibition of adenylate cyclase.

scholarly journals Differential effects of Ca2+-calmodulin on adenylate cyclase activity cyclase activity in mouse and rat pancreatic islets

1982 ◽  
Vol 206 (1) ◽  
pp. 97-102 ◽  
Author(s):  
P Thams ◽  
K Capito ◽  
C J Hedeskov
Keyword(s):  
Adenylate Cyclase ◽  
Pancreatic Islets ◽  
Specific Inhibitor ◽  
Particulate Fraction ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Rat Islets ◽  
Rat Pancreatic Islets ◽  
Mouse Islets

The effects of Ca2+-calmodulin on adenylate cyclase activity in EGTA-washed, 27000 g particulate fractions of mouse and rat pancreatic islets were studied. Ca2+ (10 microM)-calmodulin (1 microM) stimulated adenylate cyclase activity 53.1 +/- 5.2 (N = 6)% in the particulate fraction of rat islets. Trifluoperazine (50 microM), a specific inhibitor of calmodulin, inhibited the Ca2+-calmodulin activation of the adenylate cyclase activity of this fraction of rat islets. These results confirm previous reports dealing with Ca2+-Calmodulin and rat islet adenylate cyclase [Valverde, Vandermeers. Anjaneyulu & Malaisse (1979) Science 206, 225-227; Sharp, Wiedenkeller, Kaelin, Siegel & Wollheim (1980) Diabetes 29, 74-77]. In contrast, however, Ca2+ (1-100 microM)-calmodulin (1-10 microM) did not stimulate the adenylate cyclase activity in the EGTA-washed particulate fraction of mouse islets, and trifluoperazine (50 microM) did not inhibit the adenylate cyclase activity of this fraction of mouse islets, although some remaining calmodulin [0.18 +/- 0.05 (n = 3) microgram/mg of protein] could be demonstrated. GTP (10 microM) enhanced islet adenylate cyclase activity considerably, but did not confer any sensitivity towards Ca2+-calmodulin on mouse islet adenylate cyclase. The results question the role of calmodulin in the Ca2+-dependent rise in cyclic AMP evoked by glucose in pancreatic islets.

scholarly journals Effects of glucose, glucose metabolites and calcium ions on adenylate cyclase activity in homogenates of mouse pancreatic islets

1977 ◽  
Vol 162 (3) ◽  
pp. 569-573 ◽  
Author(s):  
K Capito ◽  
C J Hedeskov
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Pancreatic Islets ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Detectable Effect ◽  
Glycolytic Intermediates ◽  
Mouse Pancreatic Islets ◽  
Glucose Metabolites ◽  
Effect Of Glucose

The effects of glucose, a series of glucose metabolites, nicotinamide nucleotides, Ca2+ and p-chloromercuribenzenesulphonate on adenylate cyclase activity in homogenates of mouse pancreatic islets were studied. The basal activity of the adenylate cyclase was approx. 6 pmol of cyclic AMP formed/30 min per microng of DNA at 30 degrees C. The enzyme activity was stimulated by some 150% by fluoride. Starvation of the animals for 48h had no effect on either the basal or the fluoride-stimulated activity. The adenylate cyclase activity was increased by 40-50% when 17 mM-glucose, 10 micronM-phosphoenolpyruvate or 10 micronM-pyruvate was added to the assay medium. The effect of glucose was unchanged in the presence of 17 mM-mannoheptulose, and mannoheptulose alone had no effect. The other glycolytic intermediates, and the coenzymes NAD+, NADH and NADPH, at concentrations up to 1 mM were without any detectable effect on the rate of formation of cyclic AMP. The insulin secretagogue p-chloromercuribenzenesulphonate inhibited the adenylate cyclase markedly even at a concentration of 10 micronM. Calculated concentrations of free Ca2+ of 10 micronM and 0.1 mM inhibited adenylate cyclase by 29 and 71% respectively. It is concluded that both glucose itself and phosphoenolpyruvate and/or pyruvate are true activating ligands for islet and adenylate cyclase and that inhibition of the cyclase by Ca2+ may be of physiological significance.

Esters of adenosine 5'-phosphate with lipoid hydroxy compounds (adenosine nucleolipids) and their effects on the activity of enzymes of cyclic AMP system

1979 ◽  
Vol 44 (5) ◽  
pp. 1645-1650
Author(s):  
Sixtus Hynie ◽  
Jiří Smrt
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Inhibitory Effect ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Amp System ◽  
Strong Inhibitory Effect ◽  
Activity Of Enzymes ◽  
Hydroxy Compounds

Esters of adenosine 5'-phosphate with lipoid hydroxy compounds exhibit strong inhibitory effect on adenylate cyclase activity. The activities of cyclic AMP phosphodiesterase and protein kinase are moderately inhibited.

Some Biochemical Studies With SQ 26271: A Stable Partial Prostacyclin Agonist In The Human Platelet

1981 ◽  
Author(s):  
Don N Harris ◽  
Marie B Phillips ◽  
Inge M Michel ◽  
Harold J Goldenberg ◽  
James E Heikes ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Partial Agonist ◽  
Blood Platelets ◽  
Fold Increase ◽  
Primary Phase ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Induced Aggregation

A newly synthesized 9α-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26271 (8(S)9(S)11(R)12(S)-9,11-epoxy-9α- homo-5(Z),13(E)-15(R)-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation at concentrations which did not affect thromboxane B2 (TXB2) levels with an I50 value of 0.25 μM. It also was a potent inhibitor of platelet aggregation caused by collagen, 9,11- AzoPGH2, SQ 24810 (9,11-epoxy-9α-homo-5(Z),13(E)-15α- hydroxyprostadienoic acid) and epinephrine (secondary phase). However, it had little or no effect on thromboxane or prostaglandin synthetase activities. Moreover, SQ 26271 also inhibited the primary phase of epinephrine- and ADP- induced aggregation. In addition SQ 26271 caused a 3-fold increase in platelet adenylate cyclase activity, partially blocked prostacyclin stimulated adenylate cyclase activity and caused a 6-fold elevation of cyclic AMP levels in intact platelets, which was blocked by SQ 22536 (9-tetrahy- dro-2-furyl)adenine), an inhibitor of platelet adenylate cyclase activity. Finally, the inhibition of platelet aggregation by SQ 26271 was potentiated by an inhibitor of cyclic AMP phosphodiesterase (SQ 20009, etazolate), and reversed by SQ 22536. The above data indicate that SQ 26271 is a stable partial agonist of the prostacyclin receptor in human blood platelets.

scholarly journals Islet-activating protein blocks glucagon desensitization in intact hepatocytes

1984 ◽  
Vol 222 (1) ◽  
pp. 189-194 ◽  
Author(s):  
C M Heyworth ◽  
E Hanski ◽  
M D Houslay
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Plasma Membranes ◽  
Regulatory Protein ◽  
Inhibitory Effect ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Inhibitory Input ◽  
Pronounced Increase ◽  
Guanine Nucleotide Regulatory Protein

Treatment of intact hepatocytes with islet-activating protein, from Bordatella pertussis, led to a pronounced increase in the ability of glucagon to raise intracellular cyclic AMP concentrations. Islet-activating protein, however, caused no apparent increase in the intracellular concentration of cyclic AMP under basal conditions. These effects were attributed to an enhanced ability of adenylate cyclase, in membranes from hepatocytes treated with islet-activating protein, to be stimulated by glucagon. When forskolin was used to amplify the basal adenylate cyclase activity, elevated GTP concentrations were shown to inhibit adenylate cyclase activity in membranes from control hepatocytes. This inhibitory effect of GTP was abolished if the hepatocytes had been pre-treated with islet activating protein. In isolated liver plasma membranes, islet-activating protein caused the NAD-dependent ribosylation of a Mr-40000 protein, the putative inhibitory guanine nucleotide regulatory protein, Ni. This effect was inhibited if guanosine 5′-[beta‐thio]diphosphate rather than GTP was present in the ribosylation incubations. The ability of glucagon to uncouple or desensitize the activity of adenylate cyclase in intact hepatocytes was also blocked by pre-treating hepatocytes with islet-activating protein. Islet-activating protein thus heightens the response of hepatocytes to the stimulatory hormone glucagon. It achieves this by both inhibiting the expression of desensitization and also removing a residual inhibitory input expressed in the presence of glucagon.

Muscarinic cholinergic inhibition of adenylate cyclase in airway smooth muscle

1987 ◽  
Vol 253 (1) ◽  
pp. C97-C104 ◽  
Author(s):  
C. A. Jones ◽  
J. M. Madison ◽  
M. Tom-Moy ◽  
J. K. Brown
Keyword(s):  
Smooth Muscle ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Inhibitory Effect ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Adrenergic Stimulation ◽  
Biochemical Effect ◽  
Cholinergic Agents ◽  
Muscarinic Cholinergic

The goal of our study was to test for an inhibitory effect of acetylcholine on adenylate cyclase activity in canine trachealis muscle. Therefore, cells were dispersed from the muscle enzymatically and lysed, and adenylate cyclase activity was assayed in a membrane suspension isolated from the lysates. Maximal beta-adrenergic stimulation, in the presence of GTP (10(-4) M), increased the activity of adenylate cyclase twofold above the activity induced by GTP alone. In the presence of GTP, acetylcholine (10(-4) M) decreased activity from 97 +/- 21 to 55 +/- 13 pmol cyclic AMP X min-1 X mg protein-1 (means +/- SE; n = 5; P less than 0.05); in the presence of GTP plus isoproterenol (10(-4) M), the acetylcholine-induced decreases were from 163 +/- 29 to 101 +/- 15 pmol cyclic AMP X min-1 X mg protein-1 (P less than 0.05). These decreases were dose dependent and they were altered by a series of cholinergic agents in a pattern consistent with a muscarinic effect. Our results suggest that one biochemical effect of vagal stimulation in the central airways of dogs may be attenuated adenylate cyclase activity in the smooth muscle.

Cytochemical Evidence for Presynatic β-Adrenergic Regulation of Secretion in the Developing Rat Submandibular Gland

1977 ◽  
Vol 35 ◽  
pp. 430-431
Author(s):  
L.S. Cutler
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Submandibular Gland ◽  
Neonatal Rat ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Parotid Glands ◽  
Adrenergic Agonist ◽  
Rat Submandibular Gland

Many studies previously have shown that the B-adrenergic agonist isoproterenol and the a-adrenergic agonist norepinephrine will stimulate secretion by the adult rat submandibular (SMG) and parotid glands. Recent data from several laboratories indicates that adrenergic agonists bind to specific receptors on the secretory cell surface and stimulate membrane associated adenylate cyclase activity which generates cyclic AMP. The production of cyclic AMP apparently initiates a cascade of events which culminates in exocytosis. During recent studies in our laboratory it was observed that the adenylate cyclase activity in plasma membrane fractions derived from the prenatal and early neonatal rat submandibular gland was retractile to stimulation by isoproterenol but was stimulated by norepinephrine. In addition, in vitro secretion studies indicated that these prenatal and neonatal glands would not secrete peroxidase in response to isoproterenol but would secrete in response to norepinephrine. In contrast to these in vitro observations, it has been shown that the injection of isoproterenol into the living newborn rat results in secretion of peroxidase by the SMG (1).

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