Effect of a novel stobadine derivative on isolated rat arteries

Abstract

The antioxidant and reactive-oxygen-species-scavenging activity of stobadine has been demonstrated in previous studies. Recently, chemical modification of this leading structure led to the synthesis of other pyridoindole derivatives with significantly increased intrinsic antioxidant efficacy. Further structural modifications of stobadine provided the opportunity to increase bioavailability and attenuate unwanted side effects, such as α-adrenolytic activity. The aim of the work was to evaluate the direct effect of a novel pyridoindole, SMe1EC2, on the vascular wall ex vivo. The vasomotor effect of SMe1EC2 (1×10–8–1×10–4 mol/l) was measured on isolated and pressurized rat cerebral and coronary arterioles using video-microscopy. The effect of SMe1EC2 (1×10–6 and 1×10–5 mol/l) on high potassium-, phenylephrine- or serotonin-induced contraction or acetylcholine-induced relaxation was also determined in aortic rings. We found that SMe1EC2 (1×10–8–1×10–4 mol/l) elicited significant dilatations in both cerebral and coronary arterioles (max dilatation: 25±8% and 18±5% respectively). Yet, SMe1EC2 (1×10–6 and 1×10–5 mol/l) did not influence the tone of aortic rings nor did it affect high potassium-, phenylephrine- or serotonin -induced contractions and acetylcholine-induced relaxation. Thus SMe1EC2 was able to dilate resistance arteries but did not affect aortic contractility. It is likely that SMe1EC2 does not possess α1-adrenolytic and anti-serotoninergic activity in the vascular wall.

A pyridoindole antioxidant SMe1EC2 regulates contractility, relaxation ability, cation channel activity, and protein-carbonyl modifications in the aorta of young and old rats with or without diabetes mellitus

“…Present findings are in agreement with the previous works showing that SMe1EC2 has an anti-dysrhythmic effect through regulation of cardiac K Ca (Félétou 2009;Broskova and Knezl 2011). Accordingly, mother substance stobadine has been shown to decrease aortic stiffness and arterial blood pressure in diabetic rats (Broskova et al 2013). In addition, we cannot exclude the possibility of inhibition of other vasoconstrictors as a potential mechanism of action of SMe1EC2 to preserve aortic relaxation and to protect the increased vasoconstrictive response to phenylephrine.…”

“…This is in agreement with the reported endothelial function protecting effect of SMe1EC2 and its mother substance stobadine in hyperglycemic rats (Zúrová-Nedelcevová et al 2006;Sotníková et al 2011). Conversely, there is also an in vitro study showing that SMe1EC2 does not affect the responses of aortic rings to Phe, KCL, and ACh (Broskova et al 2013).…”

“…In a previous experiment, SMe1EC2 has been shown to improve vascular endothelial function damaged by hyperglycemic PSS in vitro (Zúrová-Nedelcevová et al 2006). It has been shown that SMe1EC has no effect on the basal tone of the aorta (Broskova et al 2013), but increases NO-dependent vascular relaxation in short-term diabetic rats (Sotníková et al 2011). Therefore, it is reasonable to test the effects of SMe1EC2 on the prevention of oxidative stress-sensitive vascular abnormalities in aging and diabetes animal models.…”

Pyridoindole SMe1EC2 as cognition enhancer in ageing-related cognitive decline

“…Nevertheless, in our study, SMe1EC2 did not show any significant efficacy in suppression of the proinflammatory production of primary reactive species, superoxide anion radical and nitric oxide, by activated BV-2 microglia, measured as tetrazolium salt reduction and nitrite concentration in media, respectively. This is in agreement with previously reported observation that SMe1EC2, lacking the ability to scavenge superoxide radical, had no influence either on basal tone or on acetylcholine-induced relaxation of rat arterial endothelium (Broskova et al ., 2013 ). Also, stobadine showed lack in efficacy to inhibit NO production by LPS-stimulated BV-2 microglia along with deficiency to profoundly suppress other inflammatory markers, TNF-α release and iNOS expression (Račková et al ., 2014 ).…”

Antioxidant SMe1EC2 modulates pentose phosphate pathway and glutathione-dependent enzyme activities in tissues of aged diabetic rats

“…In extensive preclinical studies, dietary supplementation with a potent antioxidant 2-ethoxycarbonyl-8methoxy-2, 3,4,4a,5,9b-hexahydro-1H-pyrido[4, 3-b] indolinium dichloride (SMe1EC2), which is a hexahydropyridoindole derivative, revealed significant anti-oxidant, anti-inflammatory, vasculoprotective, antidysrhythmic and neuroprotective effects (Drimal et al , 2008 ; Stefek et al , 2013 ; Broskova et al , 2013 ; Gasparova et al , 2014 ). However, the regulating role of SMe1EC2 on pentose phosphate pathway (PPP) and glutathione-dependent enzymatic activities is not yet known, while PPP is one of the major sources of reduction equivalents for the glutathione peroxidase (GPx)/glutathione reductase (GR) antioxidant system, which plays a key role in preventing oxidative stress (Stanton, 2012 ; Ulusu, 2015 ).…”