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 A(2A) receptor inhibition, whereas only dual A(2A/2B) inhibition reduced this response in MetS arterioles. Arteriolar A(2B), but not A(2A), receptor protein expression was reduced by MetS. Blockade of voltage-dependent K+ (K(v)) channels reduced arteriolar sensitivity to 2-CAD in both groups, whereas ATP-sensitive K+ (K(ATP)) 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.

Figure 1

Representative positive control Western blot signals for adenosine A₂ receptor subtypes in porcine coronary arterioles (Art) and rat brain (RB) extract.

Figure 2

Quantification of coronary atheroma in left circumflex artery by intravascular ultrasound (IVUS). A: Coronary atheroma, expressed as percent wall coverage, in control (n = 3) and MetS (n = 3) swine. Values are mean ± SE. B: Example of an IVUS ‘serial section’ depicting the IVUS catheter (dotted black line), luminal border (solid black line), internal elastic lamina (dashed white line) and neointima (shaded area between solid black and dashed white lines). The white double arrow curve depicts the number of luminal degrees covered by neointima that is then converted to percent wall coverage.

Figure 3

Concentration-response curves of coronary arterioles from control and MetS pigs to 2-chloroadenosine (A; 2-CAD) and sodium nitroprusside (B; SNP). Values are mean ± SE, sample size in parentheses.

Figure 4

Effect of adenosine A_2A receptor inhibition with ZM241385 and A_2B receptor inhibition with alloxazine on 2-CAD-mediated dilation of coronary arterioles from control (A) and MetS (B) pigs. Values are mean ± SE, sample size in parentheses represents the number of paired dose-response measurements to 2-CAD made with each drug treatment. * P < 0.05 versus control in either group.

Figure 5

Effect of K_v channel inhibition with 4-AP and K_ATP channel inhibition with GB on 2-CAD-mediated dilation of coronary arterioles from control (A; n = 6) and MetS (B; n = 5) pigs. Values are mean ± SE, sample size in parentheses represents the number of paired dose-response measurements to 2-CAD made with each drug treatment. * P < 0.05 versus control (within group); ** P = 0.054 versus control.

Figure 6

Immunoblot analysis of adenosine A_2A (A) and A_2B (B) receptors in coronary arterioles from control and MetS pigs. Values are percent of control protein expression ± SE, sample size in parentheses (5 pooled arterioles per animal in each sample). * P < 0.05 versus control.