Altered electromechanical coupling in the renal microvasculature during the early stage of diabetes mellitus

1. The early stage of type 1 diabetes mellitus (DM) is characterized by renal hyperfiltration, which promotes the eventual development of diabetic nephropathy. The hyperfiltration state is associated with afferent arteriolar dilation and diminished responsiveness of this vascular segment to a variety of vasoconstrictor stimuli, whereas efferent arteriolar diameter and vasoconstrictor responsiveness are typically unaltered. 2. The contractile status of preglomerular vascular smooth muscle appears to be tightly coupled to membrane potential (E-m) and its influence on Ca2+ influx through voltage-gated channels. Efferent arteriolar tone is largely independent of electromechanical events. Hence, defective electromechanical mechanisms in vascular smooth muscle should engender selective changes in preglomerular microvascular function, such as those evident during the early stage of DM. 3. Afferent arteriolar contractile responses to K+-induced depolarization and BAYK8644 are diminished 2 weeks after onset of DM in the rat. Similarly, depolarization-induced Ca2+ influx and the resulting increase in intracellular [Ca2+] are abated in the preglomerular microvasculature of diabetic rats. The intracellular [Ca2+] response to depolarization is rapidly restored by normalization of extracellular glucose levels. These observations suggest that hyperglycaemia in DM impairs regulation of afferent arteriolar voltage-gated Ca2+ channels. 4. Dysregulation of E-m may also contribute to afferent arteriolar dilation in DM. Vasodilator responses to pharmacological opening of ATP-sensitive K+ channels are exaggerated in afferent arterioles from diabetic rats. Moreover, blockade of these channels normalizes afferent arteriolar diameter in kidneys from diabetic rats. These observations suggest that increased functional availability and basal activation of ATP-sensitive K+ channels promote afferent arteriolar dilation in DM. 5. We propose that dysregulation of E-m (involving ATP- sensitive K+ channels) and a diminished Ca2+ influx response to depolarization (involving voltage-gated Ca2+ channels) may act synergistically to promote preglomerular vasodilation during the early stage of DM.