Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Abstract

Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A 1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A 1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619, a novel partial A 1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p Ͻ 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A 1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

A1adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

“…CVT-3619 inhibited cAMP accumulation and FFA release from rat adipocytes (11) and lowered FFA and TG in a dose-dependent manner in rats, and the FFA-lowering effect was not associated with a rebound or cardiovascular effects (8). Furthermore, CVT-3619 potentiated the reduction in plasma FFA concentrations caused by insulin (8).…”

“…Previously, we (8,11) have shown that CVT-3619 is a selective and partial A 1 adenosine receptor agonist with antilipolytic activity. CVT-3619 inhibited cAMP accumulation and FFA release from rat adipocytes (11) and lowered FFA and TG in a dose-dependent manner in rats, and the FFA-lowering effect was not associated with a rebound or cardiovascular effects (8).…”

“…However, the fact that these compounds can have undesirable cardiovascular effects has decreased interest in their potential therapeutic utility (3). On the other hand, recent evidence (8,11) has suggested that it is possible for A 1 agonists to have significant antilipolytic effects at doses that have no or minimal cardiac effects. Furthermore, partial agonists of the A 1 receptor elicit submaximal responses at high concentrations and cause less receptor desensitization than full agonists (38,39).…”

“…Therefore, partial agonists may be particularly attractive as potential therapeutic agents. CVT-3619 (a novel derivative of adeno-sine) is a partial A 1 receptor agonist that inhibits lipolysis and lowers plasma FFA and TG concentrations in rats without any cardiovascular effects (8,11). In this study we have evaluated its metabolic effects in rats and mice with dietary-induced forms of insulin resistance.…”

“…Transgenic mice overexpressing A 1 receptors in adipose tissue had lower plasma FFA concentrations and improved insulin sensitivity compared with wild type on a highfat (HF) diet (9). Thus, adenosine and some of its analogs that bind to the A 1 receptor on adipocytes (1,11) offer an alternative therapeutic approach to lower plasma FFA concentrations (8). Evidence that adenosine analogs may have clinical utility is supported by the results showing that phenylisopropyladenosine administration causes a fall in FFA concentrations, hepatic verylow density lipoprotein-TG secretion rate, and TG concentrations in normal and hypertriglyceridemic rats (17).…”