Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life.

Mechanisms of vascular complications in type-2 diabetes patients and animal models are matter of debate. We previously demonstrated that a double-stress model applied to male mice during nursing period produces enduring hyperfunction of endogenous opioid and adrenocorticotropin (ACTH)-corticosteroid systems, accompanied by type-2 diabetes-like alterations in adult animals. Administration of the opioid receptor antagonist naloxone, or of an antisense oligodeoxynucleotide versus proopiomelanocortin mRNA, capable to block the pro-opiomelanocortin-derived peptides β-endorphin and ACTH, selectively prevent these alterations.

Endothelium-dependent noradrenergic hyperresponsiveness induced by thapsigargin in human saphenous veins: role of thromboxane and calcium.

To further investigate the mechanisms which regulate sympathetic vascular tone, we studied the effects of the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, thapsigargin, on the vasoconstriction induced by transmural nerve stimulation and noradrenaline in superfused human saphenous vein rings. The contractions induced by both transmural nerve stimulation and noradrenaline were potentiated by thapsigargin in endothelium-intact, but not in endothelium-denuded vessels. This potentiation was unaffected by the non-selective endothelin ET(A/B) receptor antagonist, Ro 47-0203 (4-tert-Butyyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4yl]benzene sulfonamide), or by the nitric oxide (NO) synthase inhibitor, L-NNA (N(omega)-nitro-L-arginine), but was inhibited by the thromboxane A(2) receptor antagonist, Bay u3405 (3(R)-[[(4-flurophenyl) sulphonyl]amino-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid]) or by the thromboxane A(2) synthase inhibitor, UK 38485 (3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid).