Possible mechanisms involved in the vasorelaxant effect produced by clobenzorex in aortic segments of rats

Abstract

Clobenzorex is a metabolic precursor of amphetamine indicated for the treatment of obesity. Amphetamines have been involved with cardiovascular side effects such as hypertension and pulmonary arterial hypertension. The aim of the present study was to investigate whether the direct application of 10–9–10–5 M clobenzorex on isolated phenylephrine-precontracted rat aortic rings produces vascular effects, and if so, what mechanisms may be involved. Clobenzorex produced an immediate concentration-dependent vasorelaxant effect at the higher concentrations (10–7.5–10–5 M). The present outcome was not modified by 10–6 M atropine (an antagonist of muscarinic acetylcholine receptors), 3.1×10–7 M glibenclamide (an ATP-sensitive K+ channel blocker), 10–3 M 4-aminopyridine (4-AP; a voltage-activated K+ channel blocker), 10–5 M indomethacin (a prostaglandin synthesis inhibitor), 10–5 M clotrimazole (a cytochrome P450 inhibitor) or 10–5 M cycloheximide (a general protein synthesis inhibitor). Contrarily, the clobenzorex-induced vasorelaxation was significantly attenuated (P<0.05) by 10–5 M L-NAME (a direct inhibitor of nitric oxide synthase), 10–7 M ODQ (an inhibitor of nitric oxide-sensitive guanylyl cyclase), 10–6 M KT 5823 (an inhibitor of protein kinase G), 10–2 M TEA (a Ca2+-activated K+ channel blocker and non-specific voltage-activated K+ channel blocker) and 10–7 M apamin plus 10–7 M charybdotoxin (blockers of small- and large-conductance Ca2+-activated K+ channels, respectively), and was blocked by 8×10–2 M potassium (a high concentration) and removal of the vascular endothelium. These results suggest that the direct vasorelaxant effect by clobenzorex on phenylephrine-precontracted rat aortic rings involved stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.

Possible Mechanisms Involved in the Vasorelaxant Effect Produced by Anorexigenic Drugs in Rat Aortic Rings

“…According to the findings of the present study, on the other hand, fenproporex [2], amfepramone [31], clobenzorex [17] and T 3 [27] administered under certain conditions do not increase blood pressure, but instead generate endothelium-dependent vasodilation via nitric oxide, potassium and voltage-dependent calcium channels. Consequently, these drugs could probably be used without adverse cardiovascular effects [2,17,27,31]. Further research is needed to explore the possible involvement of type M1 muscarinic receptors in the mechanism of action of the aforementioned drugs, a mechanism suggested in previous reports.…”

“…Apart from hypertension, severe adverse events include polyuria, severe headaches and palpitations. Moderate side effects consist of depression, diarrhea and vomiting, while mild effects are irritability, dysuria, dry mouth and temporary anxiety [2,11,16,17,18,19].…”

“…A recent study by López et al [17] showed that the acute application of clobenzorex induced an immediate concentration-dependent vasorelaxant effect on endothelium-intact but not on endothelium-denuded phenylephrine-precontracted rat aortic rings. The vasorelaxant effect produced by clobenzorex was significantly attenuated by L-NAME (NG-nitro-l-arginine methyl ester a direct inhibitor of nitric oxide synthase), ODQ (an inhibitor of nitric oxide-sensitive guanylyl cyclase), and KT 5823 (an inhibitor of protein kinase G).…”

“…Furthermore, the vasorelaxation produced by clobenzorex was unaffected by indomethacin (a prostaglandin synthesis inhibitor), clotrimazole (a cytochrome P450 inhibitor) and cycloheximide (a general protein synthesis inhibitor), thus excluding the participation of prostacyclins, endothelial-derived hyperpolarizing factor (EDHF) or protein synthesis in the endothelium-mediated vasorelaxation. Overall, these findings suggest that the NO/cGMP/PKG/Ca 2+ -activated K + channel pathway is a plausible mechanism for the observed vasorelaxant effect [17].…”

Endothelium-dependent vasorelaxant effects of praeruptorin a in isolated rat thoracic aorta

“…The presence of functional endothelium was assessed by applying acetylcholine (1 μM), which induced more than 70% relaxation of vessels after precontraction with 1 μM PE. Less than 10% of relaxation caused by acetylcholine after PE pretreatment was considered to indicate endothelium denudation [ 19 , 20 ].…”