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

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 Ca(2+)-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 Ca(2+)-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/Ca(2+)-activated K(+) channel pathway.