![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ENDOCRINE AND DIABETES
Department of Pharmacology, CV Therapeutics, Inc., Palo Alto, California
Received September 21, 2006; accepted January 2, 2007.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
; Reaven, 1995; Roden et al., 1996; Boden, 2001; Bays et al., 2004). Increases of adipose tissue mass and adipocyte cell size are associated with elevated blood FFA content. Enlarged adipocytes become resistant to the antilipolytic actions of insulin and release increased amounts of FFA into the circulation. Consequently, nonadipose tissues become exposed to elevated plasma FFA levels (Reaven, 1995; Boden, 2001; Bays et al., 2004). This results in increased deposition of triglycerides in peripheral tissues such as skeletal muscle, liver, pancreas, and heart, rendering these organs resistant to the actions of insulin (Sako and Grill, 1990; Roden et al., 1996; Itani et al., 2002; Boden et al., 2005). Therefore, because FFAs are central to the development of insulin resistance and lipid abnormalities of diabetes, reduction in elevated FFA levels is a goal in the treatment of insulin resistance and type 2 diabetes.
Despite overwhelming evidence of a role of elevated FFA in insulin resistance and diabetes, very few inhibitors of lipolysis are available for either experimental or clinical use. Nicotinic acid and its analog acipimox are the only well characterized antilipolytic agents that are currently used for treatment of dyslipidemia (Carlson, 2005; Vega et al., 2005). Their therapeutic usefulness is limited because the initial decrease in plasma FFA levels is followed by a rebound that transiently increases FFA and insulin resistance (Poynten et al., 2003). In addition, nicotinic acid has an unfavorable side effect profile and is contra-indicated for the treatment of diabetic patients (McKenny et al., 1994; Grundy et al., 2002; Poynten et al., 2003). Thus, there is a need for novel antilipolytic agents and better understanding of their potential usefulness in the treatment of insulin resistance and diabetes.
A1 adenosine receptor agonists are well recognized antilipolytic agents due to their effect of reducing the formation and release of FFA from adipose tissue (Hoffman et al., 1986b; Gardner et al., 1994; Dhalla et al., 2003; Fraser et al., 2003; Schoelch et al., 2004; Fatholahi et al., 2006). A1 agonists reduce lipolysis [breakdown of triglyceride (TG) to FFA] in adipose tissue by inhibiting adenylyl cyclase activity and cAMP formation (Fain et al., 1972; Schwabe et al., 1974). The use and potential benefits of A1 agonists to reduce lipolysis have been limited by the concurrent cardiovascular effects of this class of agents. The cardiac effects mediated by A1 receptors include slowing of heart rate and atrioventricular nodal conduction, and depression of atrial contractility (Belardinelli et al., 1989). However, due to a greater receptor reserve in adipose tissue compared with cardiac tissue (Wu et al., 2001; Liang et al., 2002), significant antilipolytic effects of A1 agonists have been reported at doses that have either minimal or no cardiac effects (Gardner et al., 1994; Fraser et al., 2003). These findings suggest that it is possible to achieve organ selectivity for A1 receptor-mediated responses. In this regard, partial agonists of the A1 receptor may be useful to minimize unwanted cardiac effects because they elicit only submaximal responses in the heart even at high doses/concentrations (van Schaick et al., 1998; Wu et al., 2001).
CVT-3619, a derivative of adenosine, is a selective, partial agonist for the A1 adenosine receptor that has been shown to inhibit lipolysis in isolated rat adipocytes at concentrations that do not have significant effects in isolated heart (Fatholahi et al., 2006). The present study was undertaken to characterize the antilipolytic and cardiovascular properties of CVT-3619 in vivo. The data show that CVT-3619 lowers plasma FFA and triglyceride levels in a dose-dependent manner without significant cardiovascular effects and also increases the potency of insulin as an antilipolytic hormone.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Experimental Protocol. The antilipolytic effects of CVT-3619 were studied in awake rats. Animals were fasted overnight before experimental use. On the day of the experiment, animals were put in metabolic cages and left undisturbed to acclimate to the environment for 1 to 2 h. An infusion set (21 gauge x 0.75 inches, 3.5 inches, 9-cm tubing, 0.17-ml volume) was connected to the arterial catheter for blood sampling. A 1% sodium citrate saline solution was used to flush the lines. A pretreatment blood sample was obtained from each animal to determine baseline values for FFA and TG. CVT-3619 was given via oral gavage, s.c. injection, i.v. injection, or i.p. injection as described for each different series of experiments. Blood samples were collected into serum separator tubes (Becton Dickinson, Franklin Lakes, NJ) at predetermined times. Blood was allowed to clot and then centrifuged at 8000 rpm for 5 min at 4°C. The serum was stored at –80°C and was thawed at 4°C for determinations of FFA and TG contents.
Cardiovascular Measurements. The effects of CVT-3619 on heart rate and blood pressure were determined in a separate group of animals because heart rate is very easily affected in the unanesthetized animal by animal handling and blood sampling. Rats were instrumented with radiotelemetered transmitters (Data Sciences International, St. Paul, MN) at least 3 weeks before experimentation. The electrocardiogram, blood pressure, and temperature were recorded and heart rate calculated using a Dataquest ART Gold system (version 2.2; Data Sciences International). The system consisted of a transmitter, i.e., biopotential sensor (model TL11M2-C50-PXT), receivers (model RPC-1), a consolidation matrix (BCM 100), a personal computer (Compaq DeskPro Series 3574), and Dataquest 4 software. Heart rate, blood pressure and temperature were measured at 5-min intervals. Each recording lasted 10 s, and all cardiac cycles within this period were averaged.
Chemicals and Reagents. CVT-3619 was synthesized by the Department of Medicinal and Bioorganic Chemistry of CV Therapeutics, Inc.1 Sodium citrate, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), N6-cyclopentyladenosine (CPA), and Triton WR1339 were purchased from Sigma (St. Louis, MO). Nicotinic acid and PEG 400 were purchased from VWR (by EMD Biosciences, San Diego, CA). DPCPX was dissolved in 35% ethanol/65% water. CPA was dissolved in deionized water. Triton WR1339 was diluted in warm saline (
37°C) with frequent vortexing. Nicotinic acid was dissolved in saline. CVT-3619 was dissolved in PEG 400 by sonicating for 20 min and then diluted with distilled water to make a 20% PEG drug solution. FFA and TGs were measured using commercial kits from Wako Chemicals (Richmond, VA).
Data Analysis. All data are reported as mean ± S.E.M. Statistical analysis of data from experiments with two treatment groups was performed using the unpaired Student's t test. Two-way analysis of variance followed by Bonferroni's test was used for multiple comparisons. Differences among treatment groups were considered to be significant when the probability of their occurrence by chance alone was <0.05.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
). As clearly shown in Fig. 1B, pretreatment with DPCPX completely prevented the decrease in FFA caused by CVT-3619 (5 mg/kg).
CVT-3619 reduced serum triglyceride levels in a dose-dependent manner. The effect of three doses of CVT-3619 on serum triglycerides at 60 min post-treatment is shown in Fig. 2. TG levels were significantly decreased (p < 0.05) from 54 ± 4 to 35 ± 4 mg/dl at a dose of 2.5 mg/kg CVT-3619, representing a 36% decrease. Doses of 5 and 10 mg/kg CVT-3619 caused a 41 (32 ± 4 mg/dl, p < 0.01) and 58% (23 ± 1 mg/dl, p < 0.01) reduction in TG levels, respectively, compared with vehicle-treated rats.
|
|
Lack of Tachyphylaxis to Repeated Treatment with CVT-3619. The decrease in FFA levels caused by CVT-3619 was highly reproducible and did not undergo acute tachyphylaxis. As shown in Fig. 4, three repeated i.v. injections of CVT-3619 (1 mg/kg) to rats caused similar decreases in FFA levels to 0.35 ± 0.04, 0.35 ± 0.03, and 0.38 ± 0.03 mM, respectively, from a baseline value of 0.88 ± 0.02 mM. The time course of the decreases in plasma FFA levels caused by the three consecutive injections of CVT-3619 was similar.
|
|
Effect of CVT-3619 and Insulin on FFA Levels. The effect of insulin (0.005–1 U/kg) to reduce serum FFA was determined in the absence and presence of a single dose (0.5 mg/kg) of CVT-3619 (Fig. 6). Baseline FFA levels in vehicle and CVT-3619 groups were 0.84 ± 0.01 and 0.92 ± 0.02 mM, respectively. CVT-3619 alone (0.5 mg/kg) caused an 18% decrease in FFA levels. As expected, insulin lowered FFA levels by up to 67 ± 1% in a dose-dependent manner. The doses of insulin that caused 50% decrease (ED50) in FFA levels in the absence and presence of CVT-3619 were 0.4 and 0.1 U/kg, respectively. Thus, in the presence of CVT-3619, there was a 4-fold leftward shift of the insulin dose-response to lower FFA, suggesting that CVT-3619 increases insulin sensitivity in adipose tissue.
|
|
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). Adipose tissue lipolysis, which is highly regulated by insulin under normal conditions, is the major determinant of plasma FFA concentrations (Arner, 2005). However, the antilipolytic effect of insulin is impaired in insulin-resistant states, leading to an increased rate of lipolysis and high circulating FFA levels. Thus, antilipolytic agents that can normalize the rate of lipolysis in insulin-resistant states should be clinically useful.
Recently, we have shown that CVT-3619 is a selective and partial A1 adenosine receptor agonist, with antilipolytic activity (Fatholahi et al., 2006). CVT-3619 inhibited cAMP accumulation and FFA release from rat adipocytes and had minimal effects on cardiac function in isolated heart preparation (Fatholahi et al., 2006). The present study investigated the in vivo metabolic and cardiovascular effects of CVT-3619 in awake rats. The results show that CVT-3619 lowers FFA and TG in a dose-dependent manner. The FFA-lowering effect does not undergo tachyphylaxis and is not associated with a rebound. The antilipolytic effects occur at doses that have no significant cardiovascular effects. The antilipolytic effects of CVT-3619 were also compared with that of nicotinic acid, a potent and clinically used antilipolytic agent. Last, but importantly, CVT-3619 increased the potency of insulin to reduce plasma FFA concentrations.
CVT-3619 lowered circulating FFA levels in a dose-dependent manner. These data are consistent with previous reports showing that other A1 agonists decrease FFA levels (Hoffman et al., 1986b; Gardner et al., 1994; Fraser et al., 2003; Schoelch et al., 2004). The FFA-lowering effect of CVT-3619 was completely antagonized by pretreatment with an A1 antagonist, DPCPX, confirming that these effects are mediated via A1 receptors. CVT-3619 also caused a significant decrease in TG levels. The decrease in TG secretion is probably due to decreased substrate (FFA) availability in the liver, as has been shown previously (Hoffman et al., 1986b; Gardner et al., 1994). Limiting the supply of FFA to the liver decreases the output of triacylglycerol (VLDL) and ketone bodies, thus producing both hypotriglyceridemic and anti-ketotic effects (Kovoor et al., 1998). Although we did not measure VLDL production, the decrease in TG production by CVT-3619 is also expected to result in decreased VLDL production as previously shown using R-phenylisopropyladenosine (PIA) (Hoffman et al., 1986b).
Tachyphylaxis and receptor desensitization are potential problems when considering a receptor agonist as a drug for long-term use. It has been shown that A1 receptors undergo agonist-induced long-term desensitization but are not subject to rapid acute desensitization (Gao et al., 1999). The antilipolytic effects of CVT-3619 were well maintained over three consecutive administrations. The magnitude and the duration of the FFA-lowering effect of CVT-3619 were similar for all three injections, suggesting that the effect of this agonist does not undergo tachyphylaxis. Desensitization of the antilipolytic effect of A1 receptors has been shown to occur with prolonged and continuous exposure to high concentrations of an A1 agonist, R-PIA (Hoffman et al., 1986a). R-PIA is a full agonist and thus more likely to cause desensitization. In contrast to R-PIA, CVT-3619 is a partial A1 receptor agonist. Partial agonists of GPCRs have been suggested to cause less receptor desensitization than full agonists (Vachon et al., 1987; Kovoor et al., 1998). Whether the antilipolytic effect of CVT-3619 is sustained over long-term use (months) remains to be determined; however, we do have preliminary data showing that the antilipolytic effects of CVT-3619 given twice daily are well maintained up to 6 weeks of treatment (A. K. Dhalla, unpublished data).
The FFA-lowering effect of CVT-3619 was comparable to that of nicotinic acid (10 mg/kg). Nicotinic acid, a ligand for the HM74A receptor, is a short-acting, potent inhibitor of lipolysis (Carlson and Oro, 1962; Tunaru et al., 2003). Its use is limited by side effects such as flushing and a post-treatment rebound increase in FFA (McKenny et al., 1994). The suppression of lipolysis by nicotinic acid is followed by a rebound in FFA release, such that the levels of FFA rise above the baseline upon washout of the effect (Pereira, 1967; Blackard and Heidingsfelder, 1969). The rebound has been suggested to be responsible for the paradoxical decrease in insulin sensitivity observed when using large doses of nicotinic acid (Kelly et al., 2000; Poynten et al., 2003). The mechanism of FFA rebound with nicotinic acid remains unknown. It has been suggested that the magnitude of rebound is dependent upon the magnitude of decrease in FFA, and a significant correlation between FFA lowering and rebound has been shown for nicotinic acid (Blackard and Heidingsfelder, 1969; Schwabe et al., 1974). Rebound increase in plasma FFA levels was not observed with CVT-3619, even though FFA concentrations were decreased by similar extent by both CVT-3619 and nicotinic acid, i.e., 54 and 57% from baseline, respectively. It has been shown that the FFA rebound still exists with an extended-release nicotinic acid formulation (Vega et al., 2005), which suggests that the rebound phenomenon may be unique to nicotinic acid and may not apply to other antilipolytic agents.
The antilipolytic actions of adenosine that are mediated by A1 receptors have been known for many years (Hoffman et al., 1986b; Gardner et al., 1994; Fraser et al., 2003; Schoelch et al., 2004). The metabolic responses after acute administration of many A1 agonists have been reported previously; however, no compound has been developed and approved for clinical use thus far. A possible reason for this is lack of separation between the cardiac (and perhaps central nervous system) and the antilipolytic effects (Dhalla et al., 2003). It is possible, however, to achieve functional selectivity using partial agonists as described previously (van Schaick et al., 1998; Wu et al., 2001). The position of the dose- or concentration-response relationship for the antilipolytic and cardiovascular effects of CVT-3619 are further apart than for full A1 receptor agonists such as CPA (Fig. 8). CPA caused marked bradycardia at a dose (i.e., 20 µg/kg) that caused a similar decrease in FFA levels as that observed with CVT-3619 at 10 mg/kg, which had no effect on heart rate. Although some degree of functional selectivity can also be achieved with full agonists (Fraser et al., 2003), the difference between the effective dose to lower FFA and to depress cardiac function is greater for partial than full agonists, making them much safer drugs. Functional selectivity of CVT-3619 to decrease lipolysis and to lower FFA levels relative to heart rate was greater than 25-fold (compare Fig. 1 with 7). This differential response to CVT-3619 results from the much higher sensitivity of adipose tissue (compared with cardiac tissue) to adenosine analogs. The differential sensitivity to A1 agonists has been explained on the basis of the differences in the receptor reserve in the two tissues (Liang et al., 2002; Fatholahi et al., 2006). The possibility of the existence of different receptors in the heart and adipose tissue has been ruled out previously (Tatsis-Kotsidis and Erlanger, 1999; Fatholahi et al., 2006).
Adenosine has been shown to modulate insulin actions and insulin sensitivity in muscle and adipose tissue (Budohoski et al., 1984; Rolband et al., 1990). In adipocytes, the increase in insulin sensitivity by adenosine was suggested to be mediated by A1 receptors. PIA, an A1 adenosine receptor agonist, potentiated the insulin-induced activation of PI3 kinase, a second messenger for insulin actions, in rat adipocytes (Takasuga et al., 1999). Our data show that in the presence of CVT-3619, the ED50 for insulin to inhibit lipolysis in vivo is decreased 4-fold, suggesting that CVT-3619 increases insulin sensitivity in adipose tissue. This potentiation of the FFA-lowering effect occurs at a much lower dose of CVT-3169 (0.5 mg/kg) than those used for investigating the antilipolytic effects of CVT-3619 alone (1.0 mg/kg and higher). Thus, CVT-3619 could be useful in insulin-resistant states where antilipolytic effect of insulin is impaired, and the rate of lipolysis is increased, leading to high circulating levels of FFA.
In conclusion, data in the present study show that CVT-3619, an A1 adenosine receptor partial agonist, is an effective antilipolytic agent that lowers circulating FFA and TG levels and improves insulin sensitivity in adipose tissue. The antilipolytic effect of CVT-3619 is not associated with a rebound increase FFA. The FFA-lowering effects occur at doses that have no effect on heart rate and blood pressure. The pharmacological properties of CVT-3619 suggest that this compound may have therapeutic utility in metabolic and cardiovascular disorders in which FFA levels are increased.
|
Footnotes |
|---|
ABBREVIATIONS: FFA, free fatty acid; TG, triglyceride; CVT-3619, (2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio) methyl] oxolane-3,4-diol); DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; CPA, N6-cyclopentyladenosine; PEG, polyethylene glycol; VLDL, very low-density lipoprotein; PIA, phenylisopropyladenosine.
1 For complete synthesis process for CVT-3619, refer to Elzein and Zablocki (2006a) and Elzein et al. (2006b). 
Address correspondence to: Dr. Arvinder Dhalla, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: arvinder.dhalla{at}cvt.com
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Arner P (2005) Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 19: 471–482.[CrossRef][Medline]
Bays H, Mandarino L, and DeFronzo RA (2004) Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 89: 463–478.
Belardinelli L, Linden J, and Berne RM (1989) The cardiac effects of adenosine. Prog Cardiovasc Dis 32: 73–97.[CrossRef][Medline]
Blackard WG and Heidingsfelder SA (1969) Effect of adrenergic receptor blockade on nicotinic acid-induced plasma FFA rebound. Metabolism 18: 226–233.[CrossRef][Medline]
Boden G (2001) Obesity, free fatty acids and insulin resistance. Curr Opin Endocrinol Diab 8: 235–239.
Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, Xiang X, Luo Z, and Ruderman N (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-{kappa}B pathway in rat liver. Diabetes 54: 3458–3465.
Budohoski L, Challiss RA, Cooney GJ, McManus B, and Newsholme EA (1984) Reversal of dietary-induced insulin resistance in muscle of the rat by adenosine deaminase and an adenosine-receptor antagonist. Biochem J 224: 327–330.[Medline]
Carlson LA (2005) Nicotinic acid: the broad-spectrum lipid drug: a 50th anniversary review. J Intern Med 258: 94–114.[CrossRef][Medline]
Carlson LA and Oro L (1962) The effect of nicotinic acid on the plasma free fatty acid; demonstration of a metabolic type of sympathicolysis. Acta Med Scand 172: 641–645.[Medline]
Chen YD, Golay A, Swislocki AL, and Reaven GM (1987) Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 64: 17–21.[Abstract]
Dhalla AK, Shryock JC, Shreeniwas R, and Belardinelli L (2003) Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem 3: 369–385.[CrossRef][Medline]
Elzein E and Zablocki J (2006a) inventors; CV Therapeutics, Inc., assignee. A1 adenosine receptor agonists. U.S. patent application number 20060009417. 2006 Jan 12.
Elzein E, Zablocki J, Oigan M, Bilokin Y, Mayer S, Disanti A, Miller S, and Kernast P (2006b) inventors; CV Therapeutics, Inc., assignee. Partial and full agonists of A1 adenosine receptors. U.S. patent application number 20060052330. 2006 Mar 9.
Fain JN, Pointer RH, and Ward WF (1972) Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells. J Biol Chem 247: 6866–6872.
Fatholahi M, Xiang Y, Wu Y, Li Y, Wu L, Dhalla AK, Belardinelli L, and Shryock JC (2006) A novel partial agonist of the A1-adenosine receptor and evidence of receptor homogeneity in adipocytes. J Pharmacol Exp Ther 317: 676–684.
Fraser H, Gao Z, Ozeck MJ, and Belardinelli L (2003) N-[3-(R)-Tetrahydrofuranyl]-6-aminopurine riboside, an A1 adenosine receptor agonist, antagonizes catecholamine-induced lipolysis without cardiovascular effects in awake rats. J Pharmacol Exp Ther 305: 225–231.
Gao Z, Robeva AS, and Linden J (1999) Purification of A1 adenosine receptor-G-protein complexes: effects of receptor down-regulation and phosphorylation on coupling. Biochem J 338: 729–736.
Gardner CJ, Twissell DJ, Coates J, and Strong P (1994) The effects of GR79236 on plasma fatty acid concentrations, heart rate and blood pressure in the conscious rat. Eur J Pharmacol 257: 117–121.[CrossRef][Medline]
Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, et al. (2002) Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of Niaspan Trial. Arch Intern Med 162: 1568–1576.
Hoffman BB, Chang H, Dall'Aglio E, and Reaven GM (1986a) Desensitization of adenosine receptor-mediated inhibition of lipolysis: the mechanism involves the development of enhanced cyclic adenosine monophosphate accumulation in tolerant adipocytes. J Clin Investig 78: 185–190.[Medline]
Hoffman BB, Dall'Aglio E, Hollenbeck C, Chang H, and Reaven GM (1986b) Suppression of free fatty acids and triglycerides in normal and hypertriglyceridemic rats by the adenosine receptor agonist phenylisopropyladenosine. J Pharmacol Exp Ther 239: 715–718.
Itani SI, Ruderman NB, Schmieder F, and Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51: 2005–2011.
Kelly JJ, Lawson JA, Campbell LV, Storlien LH, Jenkins AB, Whitworth JA, and O'Sullivan AJ (2000) Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects. J Hum Hypertens 14: 567–572.[CrossRef][Medline]
Kovoor A, Celver JP, Wu A, and Chavkin C (1998) Agonist induced homologous desensitization of mu-opioid receptors mediated by G protein-coupled receptor kinases is dependent on agonist efficacy. Mol Pharmacol 54: 704–711.
Liang HX, Belardinelli L, Ozeck MJ, and Shryock JC (2002) Tonic activity of the rat adipocyte A1-adenosine receptor. Br J Pharmacol 135: 1457–1466.[CrossRef]
McKenny J, Proctor J, Harris S, and Chinchili V (1994) A comparison of the efficacy and toxic effects of sustained vs immediate-release niacin in hypercholesterolemic patients. J Am Med Assoc 271: 672–710.[Abstract]
Pereira JN (1967) The plasma free fatty acid rebound induced by nicotinic acid. J Lipid Res 8: 239–244.[Abstract]
Poynten AM, Gan SK, Kriketos AD, O'Sullivan A, Kelly JJ, Ellis BA, Chisholm DJ, and Campbell LV (2003) Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content. Metabolism 52: 699–704.[CrossRef][Medline]
Reaven GM (1995) The fourth musketeer: from Alexandre Dumas to Claude Bernard. Diabetologia 38: 3–13.[Medline]
Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, and Shulman GI (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Investig 97: 2859–2865.[Medline]
Rolband GC, Furth ED, Staddon JM, Rogus EM, and Goldberg AP (1990) Effects of age and adenosine in the modulation of insulin action on rat adipocyte metabolism. J Gerontol 45: B174–B178.[Medline]
Sako Y and Grill VE (1990) A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127: 1580–1589.[Abstract]
Schoelch C, Kuhlmann J, Gossel M, Mueller G, Neumann-Haefelin C, Belz U, Kalisch J, Biemer-Daub G, Kramer W, Juretschke HP, et al. (2004) Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies. Diabetes 53: 1920–1926.
Schwabe U, Schonhofer PS, and Ebert R (1974) Facilitation by adenosine of the action of insulin on the accumulation of adenosine 3':5'-monophosphate, lipolysis, and glucose oxidation in isolated fat cells. Eur J Biochem 46: 537–545.[Medline]
Shryock JC, Ozeck MJ, and Belardinelli L (1998) Inverse agonists and neutral antagonists of recombinant human A1 adenosine receptors stably expressed in Chinese hamster ovary cells. Mol Pharmacol 53: 886–893.
Takasuga S, Katada T, Ui M, and Hazeki O (1999) Enhancement by adenosine of insulin-induced activation of phosphoinositide 3-kinase and protein kinase B in rat adipocytes. J Biol Chem 274: 19545–19550.
Tatsis-Kotsidis I and Erlanger BF (1999) A1 adenosine receptor of human and mouse adipose tissues: cloning, expression, and characterization. Biochem Pharmacol 58: 1269–1277.[CrossRef][Medline]
Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, and Offermanns S (2003) PUMA-G and HM74 are receptors for nicotinic acid and mediate its antilipolytic effect. Nat Med 9: 352–355.[CrossRef][Medline]
Vachon L, Costa T, and Herz A (1987) Opioid receptor desensitization in NG 108–15 cells: differential effects of a full and a partial agonist on the opioid-dependent GTPase. Biochem Pharmacol 36: 2889–2897.[CrossRef][Medline]
van Schaick EA, Tukker HE, Roelen HCPF, IJzerman AP, and Danhof M (1998) Selectivity of action of 8-alkylamino analogues of N6-cyclopentyladenosine in vivo: haemodynamic versus anti-lipolytic responses in rats. British J Pharm 124: 607–618.
Vega GL, Cater NB, Meguro S, and Grundy SM (2005) Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia. Am J Cardiol 95: 1309–1313.[CrossRef][Medline]
Wu L, Belardinelli L, Zablocki JA, Palle V, and Shryock JC (2001) A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts. Am J Physiol 280: H334–H343.
This article has been cited by other articles:
|
|
 |
|
  A. K. Dhalla, M. Y. Wong, P. J. Voshol, L. Belardinelli, and G. M. Reaven A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1358 - E1363. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
