Abstract
A central mechanism participates in sympathetic overdrive during insulin resistance (IR). Nitric oxide synthase (NOS) and nitric oxide (NO) modulate sympathetic nerve activity (SNA) in the paraventricular nucleus (PVN), which influences the autonomic regulation of cardiovascular responses. The aim of this study was to explore whether the NO system in the PVN is involved in the modulation of SNA in fructose-induced IR rats. Control rats received ordinary drinking water, whereas IR rats received 12.5% fructose-containing drinking water for 12 wks to induce IR. Basal SNA was assessed based on the changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to chemicals administered to the PVN. We found an increased plasma norepinephrine level but significantly reduced NO content and neuronal NOS (nNOS) and endothelial NOS (eNOS) protein expression levels in the PVN of IR rats compared to Control rats. No difference in inducible NOS (iNOS) protein expression was observed between the two groups. In anesthetized rats, the microinjection of sodium nitroprusside (SNP), an NO donor, or Nω-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NOS, into the PVN significantly decreased and increased basal SNA, respectively, in both normal and IR rats, but these responses to SNP and L-NAME in IR rats were smaller than those in normal rats. The administration of selective inhibitors of nNOS or eNOS, but not iNOS, to the PVN significantly increased basal SNA in both groups, but these responses were also smaller in IR rats. Moreover, IR rats exhibited reduced nNOS and eNOS activity in the PVN. In conclusion, these data indicate that the decreased protein expression and activity levels of nNOS and eNOS in the PVN lead to a reduction in the NO content in the PVN, thereby contributing to a subsequent enhancement in sympathoexcitation during IR.
Highlights
Sympathetic abnormalities play an important role in the pathophysiology of cardiovascular disease associated with metabolic syndrome, diabetes mellitus and obesity [1,2,3,4]
The findings in this study indicate that in insulin resistance (IR) rats, we observed 1) a decreased level of nitric oxide (NO) in the paraventricular nucleus (PVN) that can be represented by the reduced nitric oxide metabolite (NOx) level (Fig 2B), 2) a reduced protein level of neuronal NO synthase (nNOS) and endothelial NOS (eNOS) in the PVN, 3) an increase in basal sympathetic nerve activity (SNA) in response to the microinjection of the non-selective NO synthase (NOS) inhibitor L-NAME into the PVN, 4) a decrease in basal SNA in response to the microinjection of the NO donor sodium nitroprusside (SNP), and 5) an increase in renal SNA (RSNA) and mean arterial pressure (MAP) in response to the microinjection of either the selective nNOS inhibitor N-Propylor the selective eNOS inhibitor L-NIO into the PVN
The basal SNA responses to L-NAME, SNP, N-Propyl and L-NIO were smaller in IR rats than in Control rats
Summary
Sympathetic abnormalities play an important role in the pathophysiology of cardiovascular disease associated with metabolic syndrome, diabetes mellitus and obesity [1,2,3,4]. Increasing evidence indicates that central mechanisms are a major cause of the sympathetic enhancement observed during IR, obesity, diabetes and hypertension [9,10,11,12,13], such as an increase in excitatory transmitter, angiotension II and superoxide, but a decrease in inhibitory transmitter and NO, which would result in over-activationof the sympathetic nervous system. These complex mechanisms have not been completely elucidated with respect to IR. Whether the alteration of the NOS system in the PVN mediates the elevation in sympathetic outflow in the IR state has not been investigated
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