Abstract 3929: Basis of Impaired Coronary Metabolic Dilation in Obesity and Insulin Resistance
The Zucker obese fatty rat (ZOF), a model of obesity and insulin resistance, shows progressive deterioration in cardiac function. This deterioration occurs in the absence of large vessel disease; thus we hypothesized that deranged microvascular metabolic dilation causes microareas of inadequate perfusion. To test this, enzymatically isolated cardiac myocytes (CMs) and isolated, cannulated arterioles were studied from lean (LN, n=16) and ZOF (n=18) rats. CMs were stimulated (400/min) for 20 min, and the conditioned buffer (CndBf) from CMs was applied to arterioles (dilation measured via microscopy). ZOF and LN arterioles dilated equivalently to CndBf from LN. Dilation of LN arterioles to ZOF-CndBf was greater than that of ZOF arterioles, but arteriolar dilation (either group) to CndBf from LN was greater than to ZOF-CndBf (P<0.05). This suggests production of metabolites by CMs is different in ZOF and LN, and that arteriolar responses were also altered in ZOF. Dilation to CndBf from ZOF was totally inhibited by catalase, suggesting complete dependence on H2O2; whereas, dilation to CndBf from LN was reduced 70% by catalase, and the remaining component was blocked by 8-parasulfophenyltheophylline (purinergic A1/A2 antagonist). To identify the vasodilator metabolites, CndBf from ZOF and LN was analyzed for H2O2 (Apollo 4000) and purines (HPLC). CndBf from ZOF had higher (P<0.05) levels of H2O2 (2.2±0.3 uM) than LN (0.9±0.2 uM). CndBf from LN had high levels of ADP and AMP, 46±24 nM and 49±4 nM, respectively, but adenosine was not detected. In contrast, CndBf from ZOF had ATP and ADP <10 nM (P<0.05 vs LN). To demonstrate the loss of purinergic dilation in ZOF translated to impaired metabolic flow control, we increased arterial pressure in anesthetized rats (>180 mmHg, i.v. norepinephrine) and analyzed myocardial tissue for microareas of hypoxia using Hypoxyprobe. Myocardial sections from ZOF had discrete areas of hypoxic tissue, but none were observed in LN. We suggest that impaired coronary metabolic dilation in ZOF rats, due to impaired production of purinergic dilators and blunted arteriolar responses, may lead to microareas of malperfusion, which can play a role in the progression of cardiac dysfunction occurring in this model of obesity and insulin resistance.