Increased contribution of KCa channels to muscle contraction induced vascular and blood flow responses in sedentary and exercise trained ZFDM rats

Abstract

In resistance arteries, endothelium‐dependent hyperpolarization (EDH)‐mediated vasodilatation is depressed in diabetes. We hypothesized that downregulation of KCa channel derived EDH reduces exercise‐induced vasodilatation and blood flow redistribution in diabetes. To test this hypothesis, we evaluated vascular function in response to hindlimb muscle contraction, and the contribution of KCa channels in anaesthetised ZFDM, metabolic disease rats with type 2 diabetes. We also tested whether exercise training ameliorated the vascular response. Using in vivo microangiography, the hindlimb vasculature was visualized before and after rhythmic muscle contraction (0.5 s tetanus every 3 s, 20 times) evoked by sciatic nerve stimulation (40 Hz). Femoral blood flow of the contracting hindlimb was simultaneously measured by an ultrasonic flowmeter. The contribution of KCa channels was investigated in the presence and absence of apamin and charybdotoxin. We found that vascular and blood flow responses to muscle contraction were significantly impaired at the level of small artery segments in ZFDM fa/fa rats compared to its lean control fa/+ rats. The contribution of KCa channels was also smaller in fa/fa than in fa/+ rats. Low‐intensity exercise training for 12 weeks in fa/fa rats demonstrated minor changes in the vascular and blood flow response to muscle contraction. However, the KCa‐derived component in the response to muscle contraction was much greater in exercise trained than in sedentary fa/fa rats. These data suggest that exercise training increases the contribution of KCa channels among endothelium‐dependent vasodilatory mechanisms to maintain vascular and blood flow responses to muscle contraction in this metabolic disease rat model. Key points Microvascular dysfunction in type 2 diabetes impairs blood flow redistribution during exercise and limits the performance of skeletal muscle and may cause early fatigability. Endothelium‐dependent hyperpolarization (EDH), which mediates vasodilatation in resistance arteries, is known to be depressed in animals with diabetes. Here, we report that low‐intensity exercise training in ZFDM rats increased the KCa channel‐derived component in the vasodilator responses to muscle contraction compared to that in sedentary rats, partly as a result of the increase in KCNN3 expression. These results suggest that low‐intensity exercise training improves blood flow redistribution in contracting skeletal muscle in metabolic disease with diabetes via upregulation of EDH.

Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease

“…Furthermore, exercise training has been shown to upregulate NO-dependent and prostacyclin ( 29 )- and EDH ( 30 , 31 )-dependent mechanisms. Meanwhile, it is well-known that ACh-dependent vasodilation is substantially altered following endothelial dysfunction induced by hypertension ( 32 ), obesity ( 33 ), and diabetes ( 9 , 10 , 31 ). Altered ACh-dependent vasodilation may be improved by exercise training, potentially maintaining endothelial cell homeostasis ( 28 ).…”

“…Altered ACh-dependent vasodilation may be improved by exercise training, potentially maintaining endothelial cell homeostasis ( 28 ). We recently demonstrated that low-intensity exercise training could improve endothelial function in rats with obesity and type 2 diabetes by increasing the contribution of EDH to hind limb arterioles ( 10 ). These findings indicate an association between homeostasis of endothelial function and the ACh-dependent signaling pathway in endothelial cells.…”

“…The ability of ACh to stimulate endothelium-dependent vasodilation has been demonstrated in several vascular beds (9,10,42). The origin of ACh present in vivo, particularly in the bloodstream, acting on vascular endothelial cells, has long been debated (43)(44)(45).…”

“…The physiological response of endothelial cells to exogenous acetylcholine (ACh) is vasodilation ( 7 ), which is markedly attenuated in individuals with hypertension ( 4 ) and diabetes ( 8 ). Reduced responsiveness to ACh is frequently used as a marker of endothelial dysfunction ( 9 , 10 ). Recent studies have highlighted the importance of “endogenous” ACh, whose origin differs from the classical neurotransmitter ACh in the nervous system ( 11 , 12 ).…”