Temporal changes in vascular reactivity in early diabetes mellitus in rats: role of changes in endothelial factors and in phosphodiesterase activity

Abstract

The aims of this study were to study the influence of the duration of diabetes, the role of endothelial-derived vasodilators, and the role of phosphodiesterase (PDE) isoform activity in the early changes in vascular reactivity of aortic rings from diabetic rats. Diabetes mellitus was induced in female rats by intravenous streptozotocin (85 mg/kg). Two or 4 wk later, thoracic aortic rings from control and diabetic rats were isolated, and vascular responses to acetylcholine (ACh), S-nitroso-N-acetylpenicillamine (SNAP) [nitric oxide (NO) donor], DMPPO (PDE5 inhibitor), and phenylephrine (PE) were obtained in the presence and absence of endothelium or other drugs. PDE isoform activity was also measured. At 2 wk, responses to ACh and DMPPO were enhanced, whereas those to PE were attenuated in diabetic rats relative to controls. Indomethacin and SQ-29548 (a thromboxane A(2) receptor antagonist), but not N(G)-nitro-L-arginine methyl ester, corrected these differences. The responses to SNAP, and cAMP and cGMP hydrolytic activities, were similar in the two groups. In contrast, at 4 wk, ACh, DMPPO, and PE produced similar responses in the two groups: N(G)-nitro-L-arginine methyl ester rendered the response to PE lower in the diabetic group, and this was corrected by indomethacin, but not SQ-29548, treatment. The response to SNAP was greater in the diabetic group, and this was corrected by DMPPO. Activity of all PDEs was decreased at 4 wk. We conclude that, at 2 wk, there is modulation of thromboxane A(2) production, but no change in the NO system or PDE isoform activities. At 4 wk, a reduction in NO activity is superimposed; at this stage, PDE activity is reduced, together with increased production of vasodilating prostaglandins, possibly as a compensatory mechanism to maintain normal vascular reactivity.

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

“…Contraction responses of the aorta rings are expressed as mean absolute values and relaxation responses are expressed as the percentage relaxation of the tone induced by phenylephrine by the concentration–response curves of carbachol (Abboud et al., 2009). …”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Genetic mutations in parkin have been shown to be associated with familial PD (400). Although the role of parkin is still under investigation, it has been recently studied as a therapeutic for Parkinson's disease, as it is reportedly neuroprotective (1,102). UCH-L1 removes ubiquitin molecule from the Cterminal end of the poly ubiquitin polymer after attachment of the protein to the proteasome.…”

“…PD has two forms: familial and sporadic, the latter being the more common form. Mutations in a-synuclein, parkin, DJ-1, LRRK2, UCH-L1, and PINK1 1 and IPL 2 regions. DRP2 and aldolase are common targets of nitration between MCI and EAD.…”

Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: a shift in the relative importance of EDRFs

“…There are also some reports of enhanced EDV in diabetes (7,74). Conflicting data were also obtained when responses to vasoconstricting factors were studied (1,42,85,93). The source of these discrepancies is not clear.…”

“…The source of these discrepancies is not clear. However, the duration of disease, among other factors, may play an important role in alteration of vascular reactivity to vasodilating or vasoconstricting agents in diabetes (1,68). Thus the initial aim of our study was to determine whether STZ-induced diabetes impaired the responses to endothelium-dependent and -independent vasodilators as well as vasoconstrictors in mesenteric arteries of rats.…”