Alterations in skeletal muscle arteriolar vasoreactivity during the progression of type 2 diabetes in the Zucker Diabetic Fatty rat

Altered vasoreactivity and mechanical properties of skeletal muscle arterioles could impact peripheral insulin resistance and hypertension observed in type 2 diabetes. The purpose was to determine if increased vasoconstrictor reactivity, decreased vasodilator reactivity and alterations in the structural properties of 1A arterioles from both high-oxidative and low-oxidative glycolytic skeletal muscles is present during prediabetes as well as acute and chronic diabetes, and to determine if this dysfunction precedes the development of elevated arterial pressure in type 2 diabetes. Zucker Diabetic Fatty (ZDF) rats and lean age-matched controls were studied at 7 (prediabetes), 13 (acute diabetes) and 20 (chronic diabetes) weeks of age. Following measurement of arterial pressure, vasoconstrictor responsiveness to norepinephrine (NE), potassium chloride (KCl), and increasing intraluminal pressure (MYO), vasodilator responsiveness to acetylcholine (ACh), sodium nitroprusside (SNP) and intraluminal flow and passive mechanical properties were examined in arterioles from soleus and gastrocnemius muscles. Vasoconstriction to NE was enhanced in gastrocnemius muscle arterioles during prediabetes and preceded elevated arterial pressure. Alterations in the passive mechanical properties of arterioles from both muscles were observed throughout the progression of diabetes. Flow-induced vasodilation was decreased in the high-oxidative muscle arterioles during acute diabetes, and was coincident with the emergence of elevated arterial pressure. During chronic diabetes, vasodilation to ACh and flow were reduced in soleus muscle arterioles. The reduced vasodilation to ACh was the result of a loss of NO. Although the vasodilator capacity of low-oxidative glycolytic skeletal muscle arterioles was not diminished throughout the progression of diabetes, the contribution of NO to AChinduced dilation was lost in the prediabetic and acute diabetic rats. The data demonstrate that alterations in both the vasoconstrictor and passive properties of low-oxidative glycolytic skeletal muscle arterioles are present during prediabetes, and precede the development of type 2 diabetes, and that although endothelial dysfunction does not become manifest in these skeletal muscle arterioles, alterations in the signaling mechanisms to achieve that vasodilation are present in prediabetes. Moreover, overt type 2 diabetes results in endothelial dysfunction and altered mechanical properties in high-oxidative skeletal muscle arterioles.