Altered Mechanism of Adenosine-Induced Coronary Arteriolar Dilation in Early-Stage Metabolic Syndrome

Abstract

Onset of the combined metabolic syndrome (MetS) is a complex progressive process involving numerous cardiovascular risk factors. Although patients with established MetS exhibit reduced coronary flow reserve and individual components of the MetS reduce microvascular vasodilation, little is known concerning the impact of early-stage MetS on the mechanisms of coronary flow control. Therefore, we tested the hypothesis that coronary arteriolar dilation to adenosine is attenuated in early-stage MetS by reduced A2 receptor function and diminished K+ channel involvement. Pigs were fed control or high-fat/cholesterol diet for 9 weeks to induce early-stage MetS. Coronary atheroma was determined in vivo with intravascular ultrasound. In vivo coronary dilation was determined by intracoronary adenosine infusion. Further, apical coronary arterioles were isolated, cannulated and pressurized to 60 cmH2O for in vitro pharmacologic assessment of adenosine dilation. Coronary atheroma was not different between groups, indicating early-stage MetS. Coronary arteriolar dilation to adenosine (in vivo) and 2-chloroadenosine (2-CAD; in vitro) was similar between groups. In control arterioles, 2-CAD-mediated dilation was reduced only by selective A2A receptor inhibition, whereas only dual A2A/2B inhibition reduced this response in MetS arterioles. Arteriolar A2B, but not A2A, receptor protein expression was reduced by MetS. Blockade of voltage-dependent K+ (Kv) channels reduced arteriolar sensitivity to 2-CAD in both groups, whereas ATP-sensitive K+ (KATP) channel inhibition reduced sensitivity only in control arterioles. Our data indicate that the mechanisms mediating coronary arteriolar dilation to adenosine are altered in early-stage MetS prior to overt decrements in coronary vasodilator reserve.

Adenosine Receptor Regulation of Coronary Blood Flow in Ossabaw Miniature Swine

“…There are several explanations. First, mRNA does not always correspond directly to protein, as shown by the decrease in porcine coronary arteriolar A 2B protein expression in metabolic syndrome (Bender et al, 2009). Second, A 2A and A 2B proteins may not function normally.…”

“…Dyslipidemia in the present study was manifested as described previously (Sturek et al, 2007;Bender et al, 2009;Edwards et al, 2010). The reason metabolic syndrome or obesity was avoided in the animals was to reduce the factors that may complicate the results, thus allowing the focus on dyslipidemia.…”

“…Patients with dyslipidemia exhibit impaired coronary flow reserve (Camici and Crea, 2007), which has also been shown convincingly in dyslipidemic swine models by in vivo flow measures (Zhu et al, 2009). Because AR functions are highly specific based on AR subtype, vascular bed, and species (Shen et al, 2005;, the vasodilatory effect of adenosine involves A 2 activation (Standen and Quayle, 1998;Bender et al, 2009), and A 1 and A 2 often mediate opposite effects of adenosine (Shen et al, 2005), the balance of A 1 and A 2 may contribute to impaired adenosine-induced CBF in chronic dyslipidemia after stenting.…”

“…Adenosine predominantly dilates arterioles Ͻ100 m in diameter (Camici and Crea, 2007;Duncker and Bache, 2008). The vasodilatory mechanism involves A 2 activation and consequent elevation of cAMP-dependent protein kinase (PKA), resulting in vasodilation mainly via opening of ATP-sensitive K ϩ (K ATP ) channels and voltage-dependent K ϩ (K v ) channels (Standen and Quayle, 1998;Bender et al, 2009). Because A 1 decreases, A 2 increases cAMP (Fredholm et al, 2001) and the roles of A 1 and A 2 subtypes are opposing (Sato et al, 2005), A 1 antagonism could positively modulate coronary vasodilation.…”

HDL-Mediated Protection of Coronary Vasodilator Response to Adenosine in the Hypercholesterolemic Swine

“…In a previous report, CFR measured after a moderate dose of intracoronary adenosine (1 mcg/Kg) in hypercholesterolemic Ossabaw pigs resulted unchanged and arteriolar A2B receptors were found reduced, suggesting that the mechanisms mediating coronary arteriolar dilation to adenosine are altered in early-stage metabolic syndrome prior to overt decrements in coronary vasodilator reserve [8]. However, no correlation with HDL levels was presented and the lack of statistical significance of coronary reserve impairment was probably due to the very low dose of intracoronary adenosine injected (100 times lower than in our study).…”