Key result
In hypertensive Dahl salt-sensitive rats, NF kappaB inhibition with pyrrolidine dithiocarbamate significantly improved endothelium-dependent relaxation, insulin sensitivity, and aortic hypertrophy.
Why the study?
Does pyrrolidine dithiocarbamate improve endothelial dysfunction and insulin resistance in Dahl salt-sensitive rats on a high-salt diet?
Does pyrrolidine dithiocarbamate improve endothelial dysfunction and insulin resistance in Dahl salt-sensitive rats on a high-salt diet?
Inhibition of NF kappaB activation improves vascular injury, systemic inflammation, and insulin resistance in salt-sensitive hypertension, suggesting a key role for this inflammatory pathway.
NF-κB inhibition improves vascular and metabolic markers in salt-sensitive hypertensive rats; leaves open translation to human endothelial dysfunction or insulin resistance.
OBJECTIVES: Activation of the nuclear factor kappa B (NF kappaB) inflammatory pathway by angiotensin II and reactive oxygen species may play an important role in the development of insulin resistance and cardiovascular injury in hypertensive and metabolic diseases. We have shown that in hypertensive Dahl salt-sensitive rats, upregulation of angiotensin II and reactive oxygen species contributed to increased vascular inflammatory gene expression, endothelial dysfunction, and insulin resistance. Herein, we investigated whether activation of NF kappaB contributes to the development of endothelial dysfunction, vascular injury, and vascular and peripheral insulin resistance in salt-sensitive hypertension. METHODS: Dahl salt-sensitive rats were fed a normal (0.5% NaCl) or high-salt diet (4% NaCl), or high-salt diet and pyrrolidine dithiocarbamat (150 mg/kg in drinking water), an inhibitor of NF kappaB activation, for 6 weeks. RESULTS: Hypertensive Dahl salt-sensitive rats manifested impaired endothelium-dependent relaxation to acetylcholine, aortic hypertrophy (35%), increased plasma C-reactive protein (25%), vascular superoxide (O2) production (148%), and expression of monocyte chemoattractant protein-1, tumor necrosis factor alpha, phospho-I kappaB alpha, and phospho-(Ser536)-p65NF kappaB. Pyrrolidine dithiocarbamat significantly improved endothelium-dependent relaxation, reduced vascular O2, and normalized aortic hypertrophy and systemic and local inflammation, despite only mildly reducing blood pressure. Hypertensive Dahl salt-sensitive rats also manifested impaired insulin-mediated vasorelaxation and Akt/endothelial nitric oxide synthase phosphorylation and decreased insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate, -32%). Pyrrolidine dithiocarbamat significantly improved insulin-mediated vascular relaxation and Akt/endothelial nitric oxide synthase phosphorylation as well as insulin sensitivity. CONCLUSION: The current findings strongly suggest that activation of the NF kappaB inflammatory pathway by angiotensin II-induced reactive oxygen species generation may importantly contribute to vascular injury, systemic inflammation, as well as vascular and peripheral insulin resistance in salt-sensitive hypertension.
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Zhou et al. (2010) studied Salt-sensitive hypertension. Pyrrolidine dithiocarbamate vs. High-salt diet alone or normal diet was evaluated on Endothelium-dependent relaxation, aortic hypertrophy, and insulin sensitivity. In hypertensive Dahl salt-sensitive rats, NF kappaB inhibition with pyrrolidine dithiocarbamate significantly improved endothelium-dependent relaxation, insulin sensitivity, and aortic hypertrophy.
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