We studied the effects of treatment with SMe1EC, a hexahydropyridoindole
antioxidant, on vascular reactivity, endothelial function, and oxidonitrosative stress level of thoracic aorta in young and old rats with or without
diabetes mellitus. The rats were grouped as young control (YC 3 months old), old control (OC 15 months old), young diabetic (YD), old diabetic (OD), young control treated (YCT), old control treated (OCT), young diabetic treated (YDT), and old diabetic treated (ODT). Diabetes was induced by
streptozotocin injection and subsequently
SMe1EC2 (10 mg/kg/day, p.o.) was administered to YCT, OCT, YDT, and ODT rats for 5 months. In young and old rats, diabetes resulted in
hypertension,
weight loss,
hyperglycemia, and
hypertriglyceridemia, which were partially prevented by
SMe1EC2.
SMe1EC2 also inhibited the diabetes-induced increase in aorta levels of AGEs (advanced glycosylation end-
protein adducts), 4-HNE (4-hydroxy-nonenal-histidine), 3-NT (3-nitrotyrosine), and RAGEs (receptors for AGEs). The contractions of the aorta rings to
phenylephrine (Phe) and KCL did not significantly change, but
acetylcholine (ACh) and
salbutamol relaxations were reduced in OC compared to YC rats. Diabetes induction increased Phe contractions in YC and OC rats, KCL contractions in YC rats, and did not cause further inhibition in already inhibited ACh and
salbutamol relaxations in OC rats. We have achieved the lowest levels of ACh relaxation in YD rats compared to other groups.
SMe1EC2 did not change the response of aorta to ACh,
salbutamol and Phe in YC rats, and ameliorated ACh relaxations in OC and YD but not in OD rats. In YDT and ODT rats, increased Phe and KCL contractions,
high blood pressure, and impaired
salbutamol relaxations were amended by
SMe1EC2. Phe contractions observed in YD and OD rats as well as KCl contractions observed in OC rats were the lowest levels when the rats were treated with
SMe1EC2. When the bath
solution was shifted to
cyclopiazonic acid (CYP) or CYP plus Ca2+-free medium, the contraction induced by a single dose of Phe (3 × 10-6 M) was more inhibited in YD and OD than in YC but not in OC rats. In SMe1EC2-treated rats, neither the presence of CFM nor CFM plus CYP exhibited a significant change in response of aorta to a single dose of Phe. These findings suggest that α1-adrenergic receptor signaling is activated in both age groups of diabetic rats, diabetes activates K+-depolarization and
calcium mobilization via CaV especially in the aorta of young rats, and sensitizes the aorta of old rats to the regulating effect of
SMe1EC2. ACh relaxations were inhibited in YC rats, increased in OC rats and unchanged in YD and OD rats when aortic rings pretreated with
TEA, an inhibitor of
calcium-activated K+ channels (KCa), or
4-aminopyridine (4-AP), an inhibitor of voltage-sensitive K+ channels (KV). ACh relaxations were inhibited in YCT, OCT, and YDT rats in the presence of 4-AP or
TEA. In ODT rats, 4-AP did not change ACh relaxation but
TEA inhibited. These findings suggest that the contribution of Kv and KCa to ACh relaxation is likely upregulated by
SMe1EC2 when the relaxations were inhibited by aging or diabetes. We conclude that
SMe1EC2 might be a promising agent for aging and diabetes related vascular disorders.