Upregulation of eNOS and unchanged energy metabolism in increased susceptibility of the aging type 2 diabetic GK rat heart to ischemic injury

Abstract

We investigated the tolerance of the insulin-resistant diabetic heart to ischemic injury in the male Goto-Kakizaki (GK) rat, a model of type 2 diabetes. Changes in energy metabolism, nitric oxide (NO) pathway, and cardiac function were assessed in the presence of physiological substrates. Age-matched control Wistar (n = 19) and GK (n = 18) isolated rat hearts were perfused with 0.4 mM palmitate, 3% albumin, 11 mM glucose, 3 U/l insulin, 0.2 mM pyruvate, and 0.8 mM lactate for 24 min before switching to 1.2 mM palmitate (11 rats/group) during 32 min low-flow (0.5 ml·min(-1)·g wet wt(-1)) ischemia. Next, flow was restored with 0.4 mM palmitate buffer for 32 min. A subset of hearts from each group (n = 8 for control and n = 7 for GK groups) were freeze-clamped for determining baseline values after the initial perfusion of 24 min. ATP, phosphocreatine (PCr), and intracellular pH (pH(i)) were followed using (31)P magnetic resonance spectroscopy with simultaneous measurement of contractile function. The NO pathway was determined by nitric oxide synthase (NOS) isoform expression and total nitrate concentration (NOx) in hearts. We found that coronary flow was 26% lower (P < 0.05) during baseline conditions and 61% lower (P < 0.05) during reperfusion in GK vs. control rat hearts. Rate pressure product was lower during reperfusion in GK vs. control rat hearts (P < 0.05). ATP, PCr, and pH(i) during ischemia-reperfusion were similar in both groups. Endothelial NOS expression was increased in GK rat hearts during baseline conditions (P < 0.05). NOx was increased during baseline conditions (P < 0.05) and after reperfusion (P < 0.05) in GK rat hearts. We report increased susceptibility of type 2 diabetic GK rat heart to ischemic injury that is not associated with impaired energy metabolism. Reduced coronary flow, upregulation of eNOS expression, and increased total NOx levels confirm NO pathway modifications in this model, presumably related to increased oxidative stress. Modifications in the NO pathway may play a major role in ischemia-reperfusion injury of the type 2 diabetic GK rat heart.

Bladder and erectile dysfunctions in the Type 2 diabetic Goto-Kakizaki rat

“…This increased fat mass in GK rats compared with Wistar rats is observed until 6 -8 mo of age and fails to expand with age, thereby yielding lower body weight overall. Although the GK rat is not strictly speaking a model of metabolic syndrome, it exhibits several features of metabolic syndrome as they are hyperglycemic, insulin resistant even if they are not hypoinsulinemic, they have an increased fat mass versus lean mass even if they are not obese, abnormal cholesterol levels even if their triglycerides are decreased rather than increased and exhibit a slightly increased blood pressure (13,51) and a defective cardiac function (21,29). Finally, diabetic nephropathy, one of the most common complications of diabetes Type 2, characterized by increased urinary protein and loss of renal function, has also been reported in the GK rat (46,47).…”

Aging, Reactive Nitrogen Species and Myocardial Apoptosis Induced by Ischemia/Reperfusion Injury

“…Reduced coronary flow, upregulation of eNOS expression, and increased total NOx levels confirm NO pathway modifications in this model, presumably related to increased oxidative stress. Modifications in the NO pathway may play a major role in I/R injury of the type 2 diabetic GK rat heart (Desrois et al, 2010). Our results show that aging induces phenotypic upregulation of iNOS in the heart, in which -AR stimulation interacts with ischemia and triggers a markedly increased NO production, which creates a nitrative stress, generates toxic peroxynitrite, activates apoptosis, and eventually causes cardiac dysfunction and myocardial injury.…”

Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto–Kakizaki rats

“…47,48 Left ventricular hypertrophy with enhanced activity of the myocardial Na/H exchanger, increased myofilament sensitivity to calcium concentration, and impaired energy metabolism resulting from cardiac mitochondrial alterations, in conjunction with insulin resistance, endothelial dysfunction, and perivascular inflammation, have all been found to contribute to the cardiovascular morbidity in GK rats. [48][49][50][51] The absence of age-dependent reductions in HR variability suggested an autonomic dysfunction in GK rats. 52 The present study investigated brainstem mechanism of cardiovascular mortality in T2D and focuses on TRH, an critical signaling molecule involved in the control of sympathovagal coordination and the focus of our research for many years.…”