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 present study was undertaken to investigate the mechanism of the antilipolytic action of clofibrate (p-chlorophenoxyisobutyrate). Clofibrate, in the dose range of 10-80 mg/199 ml, inhibited the initial rate of norepinephrine-stimulated lipolysis 17-44 percent in isolated rat fat cells. At a dose corresponding to therapeutic levels in vivo (10 mg/100 ml) clofibrate also inhibited hormone-stimulated lipolysis by 20-30 percent in fragments of human subcutaneous fat. Inhibition of lipolysis by clofibrate occurred at all concentrations of norepinephrine and ACTH (0.02-0.1 mug/ml) but did not occur with equilipolytic concentrations of dibutyryl cyclic AMP, suggesting a proximal site of action on the lipolytic sequence. Clofibrate reduced by 60 percent (315plus or minus40 vs. 120plus or minus25 pmol/g lipid; meanplus or minusSEM) the norepinephrine-stimulated initial rise in cyclic AMP, measured 10 min after addition of hormone. Because the antilipolytic effect occurred in the presence of glucose and without altering cellular ATP levels, the reduction in intracellular cyclic AMP levels could not be attributed to uncoupling of oxidative metabolism or to secondary effects of free fatty acid accumulation. In the secondary effects of free fatty acid accumulation. In the presence of procaine-HC1, which blocks hormone-stimulated lipolysis without inhibiting cyclic AMP accumulation, addition of clofibrate prevented the hormone-stimulated rise in cyclic AMP. Clofibrate did not affect the activity of the low-Km 3',5'-cyclic AMP phosphodiesterase in norepinephrine-stimulated adipocytes. These data suggest that the antilipolytic effect of clofibrate is due to its suppression of cyclic AMP production by inhibition of adenylate cyclase. The drug's hypolipidemic action may in part be explained by its antilipolytic effect, which deprives the liver of free fatty acid substrate for lipoprotein synthesis.
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PMID:Inhibition of hormone-stimulated lipolysis by clofibrate. A possible mechanism for its hypolipidemic action. 16 83

The effects of chlofibrate on the adenylate cyclase system of human adipocytes were studied. Clofibrate reduced basal as well as hormone-NaF)stimulated adenylate cyclase activities to about the same extent (45% inhibition at 1 mg/ml clofibrate). The relative extent of hormonal stimulation was not altered by this compound. The inhibitory action of clofibrate was non-competitive with respect to the substrate ATP and cofactors (Mg2+-ions). Inhibition of enzyme activity was detectable after 2.5 min. Our results suggest that the antilipolytic activity of clofibrate is mediated via inhibition of the catalytic subunit of the fat cell adenylate cyclase.
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PMID:Effects of clofibrate on the human fat cell adenylate cyclase system. 19 90

Clofibrate (Atromid-S), nicotinic acid, and insulin are known to be potent hypolipidemic and antilipolytic agents. The present study was undertaken to define the mechanism of action of this latter effect on isolated rat and human fat cells. Sodium clofibrate (0.42 mM), nicotinic acid (0.42 mM), and insulin (100 microU/mL) were shown to inhibit norepinephrine-stimulated lipolysis in rat and human adipose cells and this inhibition was associated with a reduction in intracellular 3',5'-cyclic AMP levels. A similar cyclic AMP lowering effect was demonstrated with insulin in the presence of procaine-HCL, which uncouples the adenylate cyclase system from lipolysis. This insulin effect was attributed to inhibition of adenylate cyclase. A direct and significant inhibition of adenylate cyclase in membrane fractions obtained from isolated human adipocytes was demonstrated for all three antilipolytic agents. The common membrane site of action of these agents whereby adenylate cyclase activity is depressed, thus decreasing cyclic AMP production and free fatty acid (FFA) mobilization from adipose stores, implies a central role for the adenylate cyclase system. These findings are consistent with the view that the hypotriglyceridemic effects of clofibrate, nicotinic acid, and insulin may be partly explained by deprivation of FFA substrate for hepatic very low density lipoprotein synthesis.
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PMID:Inhibition of rat and human adipocyte adenylate cyclase in the antilipolytic action of insulin, clofibrate, and nicotinic acid. 23 99

Individuals with familial hyperbetalipoproteinemia are at increased risk of premature atherosclerosis and thrombosis. Although there is controversy whether platelet survival is shortened or normal in this disease, several in vitro tests of platelet function are abnormal including a decreased threshold concentration for stimulation of aggregation by ADP, epinephrine and collagen and increased release of nucleotides to the same agents. These functional changes are accompanied by an increase of cholesterol to phospholipid ratio in the platelet membrane and in low density lipoprotein in individuals with type IIa hyperlipoproteinemia. Clofibrate and halofenate reverse some of the abnormalities in vitro and the former drug, when administered for 6 weeks to patients with type IIa hyperlipoproteinemia decreases platelet sensitivity to ADP and epinephrine. The platelet hypersensitivity to aggregating agents can be reproduced in vitro by increasing the cholesterol to phospholipid rather in normal platelets. These artificially hypersensitive platelets can be returned to normal by halofenate in vitro. Incorporation of cholesterol into platelet membranes increases the basal level of the membrane associated enzyme adenylate cyclase. However, the enzyme no longer responds to stimulation by prostaglandin E1, and this is associated with relative resistance of the platelet to inhibition by this pharmacologic agent. These functional alterations produced by cholesterol enrichment of platelet membranes occur is parallel with an increase in platelet membrane microviscosity suggesting that the more rigid membrane can alter the behavior of membrane associated enzymes and receptors. A correlation appears to exist between the ability of certain drugs to induce phase separation in model membranes and the potency in inhibitory platelet aggregation.
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PMID:Platelet function in hyperbetalipoproteinemia. 58 Sep 82

Clofibrate is a hypolipidemic agent that causes muscle protein breakdown in rats, and an acute muscular syndrome in man. It also inhibits adenylate cyclase in fat tissue. Muscle protein metabolism has been shown to be regulated by cyclic nucleotides. In the present experiments were measured several parameters of cyclic nucleotide metabolism to determine the role that cyclic nucleotides play in clofibrate-induced muscle protein degradation. It was found that clofibrate treatment did not alter cyclic nucleotide levels, nor did it change the activities of basal or hormone-stimulated adenylate cyclase, or cyclic nucleotide phosphodiesterase in muscle. Our results suggest that muscle protein breakdown in clofibrate-treated rats is not regulated by cyclic nucleotides.
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PMID:Clofibrate does not alter cyclic nucleotide metabolism in muscle. 613 74

Muscarinic acetylcholine M2 and M3 receptor subtypes are coexpressed in many types of smooth muscle including gastrointestinal smooth muscle, urinary bladder and vascular and airway tissue. Activation of M3 receptors, via the G protein Gq, results in increased polyphosphoinositide hydrolysis, release of Ca2+ ions from the sarcoplasmic reticulum and consequently causes contraction. Quantitation of the relative expression of M2 and M3 receptors has shown that the proportion of M2 receptors often predominates over the M3 receptor population by 4:1 or more. Although it is established that M2 receptors preferentially link, via a pertussis-toxin-sensitive G protein Gi, to inhibition of adenylate cyclase activity, relatively little is known concerning the physiological role of the M2 receptor population. In this review, Richard Eglen and colleagues discuss recent data concerning the possible role(s) of muscarinic receptor subtypes in smooth muscle and appraise the pharmacological methods for dissecting the function of muscarinic receptor subtypes in tissues co-expressing multiple receptors.
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PMID:Muscarinic acetylcholine receptor subtypes in smooth muscle. 810 24