Cardiovascular and Antilipolytic Effects of the Adenosine Agonist GR79236

Abstract

Adenosine is known to produce cardiovascular effects such as bradycardia and hypotension via activation of myocardial (A₁) and vascular (A₂) receptors and antilipolytic effects through activation of adipocyte (A₁) receptors. We established the cardiovascular and antilipolytic profile of the adenosine A₁ agonist GR79236 (N⁶-[(lS, trans)-2-hydroxycyclopentyl]-adenosine) and compared it with CPA (N⁶-cyclopentyl-adenosine). GR79236 was approximately 3-fold less potent than CPA in inhibiting in vitro lipolysis. In conscious rats, both agents were shown to have antilipolytic and glucose-lowering properties. In rats instrumented with telemetry transmitters, orally administered CPA was one log unit more potent than GR79236 as a hypotensive and bradycardic agent. In summary, GR79236 is an A₁-selective adenosine agonist which reduces heart rate and mean arterial pressure and produces decreased plasma lipids and glucose levels.

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

“…Moreover, the close correlation between inhibition of lipolysis in rat and human adipocytes found for both AMP 579 and CPA is in agreement with data reported on the A 1 selective agonist GR 79236 in rat and human adipocytes Heseltine et al, 1995). The ability of adenosine agonists to inhibit lipolysis in vitro has long been known and has been described for various N 6 -substituted adenosine A 1 -selective agonists, including R-PIA (Fredholm, 1978), BM11.189 (Wieser and Pendleton, 1979), GR 79236 Merkel et al, 1995), and SDZ-WAG 994 (Deems et al, 1994). Nonselective adenosine A 1 /A 2 agonists, such as NECA (Fredholm, 1978;Gurden et al, 1993), and A 2A -selective agonists, such as CGS21680 and CV1808 , have also been evaluated and their order of potency confirmed that inhibition of lipolysis is indeed an A 1 -mediated event.…”

N-[3-(R)-Tetrahydrofuranyl]-6-aminopurine Riboside, an A1Adenosine Receptor Agonist, Antagonizes Catecholamine-Induced Lipolysis without Cardiovascular Effects in Awake Rats

“…Although it has been long known that A 1 agonists are potent and efficacious inhibitors of lipolysis, limited efforts have been directed at the development of A 1 agonists as potential therapeutic antilipolytic agents, mainly due to the potential for adverse cardiovascular effects. Previous work with GR79236, an A 1 agonist, revealed that with this agonist it was not possible to obtain a substantial separation between its lipid-lowering and cardiovascular effects (Merkel et al, 1995). With CVT-510, NEFA levels can be lowered by approximately 60 to 70% at doses that this agonist does not cause bradycardia, whereas with GR79236, at concentrations that reduced glycerol 60%, heart rate was lowered approximately 30% (Merkel et al, 1995).…”

“…Previous work with GR79236, an A 1 agonist, revealed that with this agonist it was not possible to obtain a substantial separation between its lipid-lowering and cardiovascular effects (Merkel et al, 1995). With CVT-510, NEFA levels can be lowered by approximately 60 to 70% at doses that this agonist does not cause bradycardia, whereas with GR79236, at concentrations that reduced glycerol 60%, heart rate was lowered approximately 30% (Merkel et al, 1995). Work by van Schaick et al (1997) on the other hand, with N-6-(p-sulfophenyl) adenosine did show some tissue selectivity in vivo (van Schaick et al, 1997).…”

“…In addition to these direct effects, by inhibiting the activity of adenylyl cyclase, A 1 receptor activation counteracts the effects of ␤-adrenergic agonists (Dobson et al, 1987). A 1 agonists have been shown to be potent antilipolytic agents (Strong et al, 1993;Merkel et al, 1995;van Schaick et al, 1997), through the inhibition of hormone-sensitive lipase activity, thereby preventing the breakdown of triglycerides to free fatty acids and glycerol, leading to reduced free fatty acid formation and serum concentrations. The putative benefits of A 1 receptor agonists on serum fatty acid concentrations have not been fully explored due to the potential for overlapping cardiovascular effects with this class of compounds.…”

A Novel Partial Agonist of the A1-Adenosine Receptor and Evidence of Receptor Homogeneity in Adipocytes

“…A reduction of lipolysis in adipocytes is of potential benefit in treatments of dyslipidemia, type II diabetes, and metabolic syndrome (Bergman et al, 2001;Boden and Laakso, 2004;DeFronzo, 2004;Lebovitz and Banerji, 2004). However, A 1 AdoR agonists have potential unintended side effects as a result of the presence of A 1 AdoR in many other tissues (Merkel et al, 1995).…”