Aerobic exercise improves microvascular dysfunction in fructose fed hamsters

Highlights

• Fructose is an important component of Western daily diets.

• Fructose solution alters glucose metabolism in hamsters.

• Constant sugar ingestion elicits microvascular dysfunction.

• Aerobic exercise has positive effects on fructose microcirculatory deleterious events.

• Microvascular dysfunction elicited by continuous fructose ingestion precedes weight gain.

Abstract

Fructose is a major diet component directly related to severe damages to the microcirculation and to diseases such as obesity, diabetes and hypertension to which physical activity is pointed out as an important non-pharmacological treatment since its positive effects precede anthropometric improvements. In this study we have investigated the effects of a light/moderate aerobic exercise training (AET) on microcirculatory dysfunction elicited by carbohydrate overload during a period of 5 months. Male hamsters (Mesocricetus auratus) whose drinking water was substituted (F) or not (C) by 10% fructose solution, during 20 weeks, associated or not to AET in the last 4 weeks (EC and EF subgroups) had their microcirculatory function evaluated on the cheek pouch preparation, glucose and insulin tolerance (GTT and ITT) tested. Arterial blood was collected for pO₂, pCO₂, HCO₃⁻, pH, total CO₂, saturated O₂ and lactate determinations. Liver fragments were observed using an electron microscope. Microcirculatory responses to acetylcholine [Ach, an endothelium-dependent vasodilator; 10^− 8 M — *123.3 ± 7.5% (C), 119.5 ± 1.3% (EC), *98.1 ± 3.2% (F) and 133.6 ± 17.2% (EF); 10^− 6 M — *133.0 ± 4.1% (C), 135.6 ± 4.3% (EC), *103.4 ± 4.3% (F) and 134.1 ± 5.9% (EF); 10^− 4 M — *167.2 ± 5.0% (C), 162.8 ± 5.4% (EC), *123.8 ± 6.3% (F) and 140.8 ± 5.0% (EF)] and to sodium nitroprusside [SNP, an endothelium-independent vasodilator; 10^− 8 M — 118.8 ± 6.8% (C), 114.0 ± 5.0% (EC), 100.2 ± 2.9% (F), 104.9 ± 4.4% (EF); 10^− 6 M — 140.6 ± 11.7% (C), 141.7 ± 5.5% (EC), 125.0 ± 4.7% (F), 138.3 ± 2.8% (EF); 10^− 4 M — 150.4 ± 10.9% (C), 147.9 ± 6.5% (EC), 139.2 ± 7.3% (F), 155.9 ± 4.7% (EF)] and macromolecular permeability increase induced by 30 min ischemia/reperfusion (I/R) procedure [14.4 ± 3.5 (C), 30.0 ± 1.9 (EC), *112.0 ± 8.8 (F) and *22.4 ± 0.9 leaks/cm² (EF)] have shown that endothelium-dependent vasodilatation was significantly reduced and I/R induced macromolecular permeability augmented in sedentary fructose (F) subgroup and both improved after AET. Electron microscopy analysis of the liver showed significant differences between exercised and sedentary subgroups with greater amount of glycogen in F subgroups compared to other ones. No significant changes on mean arterial pressure, heart rate or blood gase between subgroups could be detected. Our results point out that AET could normalize microcirculatory dysfunction elicited by long term substitution of drinking water by 10% fructose solution.

Introduction

Humans tend to choose a more palatable diet and sugars such as fructose and glucose operate as ordinary sweeteners. Given the substantial participation of fructose in Western diet, it appears important to elucidate its metabolic effects and potential cardiovascular risk. For this purpose, the microcirculation could be a primary evaluation spot in individual's health, even in the absence of ill symptoms. The endothelium is essential to autoregulatory mechanisms and nitric oxide (NO) production plays an important role on vascular tone and health (Moncada and Higgs, 1993). Adequate microvascular flow should match organ function and its impairment is associated to organ failure in critically ill patients (Sakr et al., 2004). Endothelial dysfunction (ED) is characterized by reduction in the bioavailability of vasodilators, mainly NO, and activation of endothelial cells elicited by a predominant pro-inflammatory, proliferative and pro-coagulant milieu state (Anderson, 1999). Therewith, altered blood flow and inflammation incite changes on vascular hemodynamic, which in terms of macromolecular permeability is reflected on altered solute diffusion and raise in exchange membrane area. Vascular and microvascular permeability make it possible to correlate extravasation spots to microvascular morphology in several preparations, like for instance the hamster cheek pouch.

The cheek pouch, an invagination of the oral mucosa that extends under the subcutaneous tissue down to the shoulder region, is an appropriate preparation to study microcirculatory function/dysfunction. Its blood supply comes mainly from the carotid arteries and it remains stable for 5 to 6 h (Duling, 1973). There are several advantages to the use of this preparation (1) ease access, (2) highly vascularized with all classes of microcirculatory vessels, (3) clarity and (4) the possibility to observe either skeletal muscle or subcutaneous microcirculatory beds.

Studies concerning fructose intake have been reported to induce insulin resistance, hyperglycemia, hypertriglyceridemia in rats (Tobey et al., 1982, Zavaroni et al., 1980), to reduce glucose uptake by adipocytes in vitro and endothelium-dependent vasodilation elicited by acetylcholine in aortic strips (Kotchen et al., 1997), to reduce tyrosine phosphorilation of IRS-1 in the soleus muscle (Hyakukoku et al., 2003), to significantly increase fasting plasma insulin without hyperglycemia, to decrease muscarinic receptors and to increase the dependence on nitric oxide and to impair α₂-adrenergic-mediated relaxation (Takagawa et al., 2001). However few novel data have shown its effects on microvascular permeability. Taking these data into account, strategies that set microcirculation as therapeutic target could be of great importance.

Physical activity has gained visibility as non-pharmacological treatment to obesity and its co-morbidities. The skeletal muscle constitutes approximately 40% of total body weight and is considered the most important determinant of peripheral vascular sensibility to insulin (Smith and Muscat, 2005) and the place for capitation, storage and liberation of glucose (Nuutila et al., 1992). Regular exercise practice is associated to reduction in primary (Myers et al., 2002) and secondary (Piepoli et al., 2010) vascular events, reduction of adiposity, and improvement of several metabolic risk factors including triglycerides (TG), high density lipoprotein-C (HDL-C), insulin and HOMA-IR when both regimens result in similar energy expenditure (Cho et al., 2011). Physical exercise benefits are not necessarily related to adiposity loss but also to improvement on vascular hemodynamic, and as a consequence, an improvement of type 2 diabetes and obesity related cardiovascular risks even without weight loss.

Therefore, our objectives in the present investigation were to evaluate microcirculatory effects, using the hamster cheek pouch preparation, of the substitution of the drinking water by 10% fructose solution during 20 weeks and the possibility of reversing these effects with a light/moderate aerobic exercise training program (AET) applied during the last 4 weeks of carbohydrate overload. Our hypothesis consisted on determining the capacity of reversion of the microvascular damage elicited by carbohydrate overload using a non-pharmacological way of treatment which, in this case, was the AET.