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Postinjury deficits in monocyte tumor necrosis factor receptors (moTNFR) activity may alter beneficial functions during an inflammatory response. Several counter-regulatory hormones elicited during inflammation may modulate tumor necrosis factor (TNF) activity, but little is known about their influence on moTNFR. Also, catecholamines inhibit TNF production, but the adrenoreceptor mechanism of this effect has not been fully clarified. To determine the effect of catecholamines and corticosteroids on moTNFR, whole blood was coincubated for up to 8 (moTNFR) or 24 h (cytokines) in the presence of lipopolysaccharide (100 ng/ml) and 1) epinephrine (Epi, 10−6 M), dexamethasone (Dex, 10−6 M) or both (EpiDex, 10−6 M) to assess the expression of total moTNFR, moTNFR-I, and moTNFR-II. 2) Epi and norepinephrine (EpiNE, 10−6 M) and the α1+2-, β1+2-, β1-, or β2-adrenergic antagonists were used to assess the role of such adrenoreceptors on total moTNFR and TNF production, and N 6,2′- O-dibutyryl adenosine 3′,5′-cyclic monophosphate (DBcAMP) alone or in combination with the phosphodiesterase inhibitor Ro-20–1724/000, to study the cAMP-dependent pathway on total moTNFR. We found that Epi upregulated total moTNFR and moTNFR-II. Dex did not significantly influence total moTNFR or moTNFR-II. Also, EpiNE increased total moTNFR and inhibited TNF by a β2-dependent mechanism. DBcAMP (10−5 M) modestly enhanced total moTNFR. This suggests a common mechanism for acutely enhancing moTNFR and attenuation of soluble TNF appearance during conditions of severe stress.

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.

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