Abstract
Nitric oxide (NO) mediated slow inhibitory junction potential and mechanical relaxation after electrical field stimulation (EFS) is impaired in diabetes mellitus. Externally added NO donor restore nitrergic function, indicating that this reduction result from diminution of NO synthesis within the pre-junctional nerve terminals. The present study aimed to investigate two specific aims that may potentially provide pathophysiological insights into diabetic nitrergic neuropathy. Specifically, alteration in nNOSα contents within jejunal nerve terminals and a local subcortical transporter myosin Va was tested 16 weeks after induction of diabetes by low dose streptozotocin (STZ) in male Wistar rats. The results show that diabetic rats, in contrast to vehicle treated animals, have: (a) nearly absent myosin Va expression in nerve terminals of axons innervating smooth muscles and (b) significant decrease of myosin Va in neuronal soma of myenteric plexus. In contrast, nNOSα staining in diabetic jejunum neuromuscular strips showed near intact expression in neuronal cell bodies. The space occupancy of nitrergic nerve fibers was comparable between groups. Normal concentration of nNOSα was visualized within a majority of nitrergic terminals in diabetes, suggesting intact axonal transport of nNOSα to distant nerve terminals. These results reveal the dissociation between presences of nNOSα in the nerve terminals but deficiency of its transporter myosin Va in the jejunum of diabetic rats. This significant observation of reduced motor protein myosin Va within jejunal nerve terminals may potentially explain impairment of pre-junctional NO synthesis during EFS of diabetic gut neuromuscular strips despite presence of the nitrergic synthetic enzyme nNOSα.
Highlights
Slow inhibitory junction potentials are recorded using impaled electrodes within gastrointestinal smooth muscles in response to nitric oxide (NO) released from pre-junctional nerve terminals after electrical field stimulation (EFS)
MYOSIN Va IMMUNOREACTIVITY IS SCANT OR NEARLY ABSENT IN THE NEURO-SMOOTH MUSCLE NERVE TERMINALS OF JEJUNUM In contrast to the vehicle treated rats, induction of diabetes by STZ resulted in nearly complete loss of myosin Va within the nerve terminals of the neuronal processes ramifying on the muscularis externa (Figure 1)
Whole mounts of jejunum stained with myosin Va specific antibody failed to show the brown reaction product of DAB staining that was visualized in the enteric tissues of normal rats (Figure 1)
Summary
Slow inhibitory junction potentials (sIJP) are recorded using impaled electrodes within gastrointestinal smooth muscles in response to nitric oxide (NO) released from pre-junctional nerve terminals after electrical field stimulation (EFS). Mechanical studies have confirmed diminution of EFS-mediated nitrergic relaxations in diabetic enteric tissues like ileum and mid-colon [3,4,5,6,7]. Some of these studies have demonstrated restoration of nitrergic mediated responses in diabetic tissues with externally added NO donor to the organ bath [4,5,6], indicating that the diminution of nitrergic function in diabetic gut tissues resulted primarily from reduction or inhibition of NO synthesis within the pre-junctional nerve terminals. Studies have reported normal nNOS enzymatic activity of diabetic whole gut extracts assayed in vitro [11] None of these studies provide unequivocal evidence about nNOS contents within the nerve terminals, the site of inhibitory enteric neuromuscular nitrergic neurotransmission
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