Acute Cardiovascular Effects of Sibutramine in Conscious Rats

Abstract

Sibutramine is a serotonin and norepinephrine reuptake inhibitor, used in the treatment of obesity. In this study, cardiovascular effects of sibutramine (0.9, 3, or 9 mg kg Ϫ1 i.p.) were measured in conscious Sprague-Dawley rats, in the absence and presence of ␤-and/or ␣-adrenoceptor antagonism (with propranolol and/or phentolamine, respectively). Sibutramine caused pressor and tachycardic effects, with celiac and mesenteric vasoconstrictions, and hyperemic hindquarters vasodilatation. Pretreatment with propranolol inhibited the tachycardic and hindquarters vasodilator effect of sibutramine, whereas phentolamine inhibited the pressor and vasoconstrictor effects of sibutramine. In the presence of phentolamine, sibutramine caused hyperemic mese nteric vasodilatation. In preconstricted, isolated, mesenteric vessels, sibutramine and its metabolites BTS 54 505 (N-desmethylsibutramine) and BTS 54 354 (N-didesmethylsibutramine) (10 M) produced significant vasodilatations. Neither sibutramine nor BTS 54 505 enhanced vessel sensitivity to norepinephrine, whereas BTS 54 354 produced a significant leftward shift in the concentration-response curve to norepinephrine. Collectively, the results indicate that the overt cardiovascular effects of sibutramine involve ␣-adrenoceptor-mediated celiac and mesenteric vasoconstrictions, and ␤-adrenoceptor-mediated hindquarters vasodilatation and tachycardia. The mesenteric vasodilator response to sibutramine, seen in the presence of phentolamine, may be a direct effect of the drug and/or its metabolites, on vessel tone. The cardiovascular effects of sibutramine in vivo may be secondary to inhibition of peripheral and/or central reuptake of monoamines by the metabolites BTS 54 354 and/or BTS 54 505. It remains to explain why BTS 54 354, but not BTS 54 505, enhanced norepinephrine sensitivity in vitro, because both metabolites are potent inhibitors of the norepinephrine transporter.

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats

“…The dramatic hemodynamic effect of phentolamine administration alone is consistent with previous studies from our laboratory, in which we have shown a substantial component of the hindquarters vasodilatation to be dependent on activation of ␤ 2 -adrenoceptors (Gardiner and Bennett, 1988;Woolard et al, 2004). It was interesting to see, here, that with repeated phentolamine administration, the degree of hindquarters vasodilatation, but not the tachycardia, waned.…”

“…Experiments began the day after catheter implantation. From previous studies using the approaches described here, we have seen no evidence of hangover effects of the anesthetic regimen (Wakefield et al, 2003;Woolard et al, 2004). Furthermore, in the present study, hemodynamic responses to vasoconstrictor and vasodilator challenges were consistent across the four experimental days in vehicle-infused rats (see Results).…”

Simultaneous determination of anti‐diabetes/anti‐obesity drugs by LC/PDA, and targeted analysis of sibutramine analog in dietary supplements by LC/MS/MS

“…Thus LC/MS/MS was applied to elucidate its structure, which was identified as N-desmethylsibutramine. N-desmethylsibutramine is known to be a major sibutramine metabolite in humans (Woolard et al, 2004). It has been reported that sibutramine and sibutramine analog have similar pharmacokinetics and pharmacological profiles (Hind et al, 1999).…”

Involvement of CB1-receptors and β-adrenoceptors in the regional hemodynamic responses to lipopolysaccharide infusion in conscious rats

“…The dose of propranolol used has been shown to abolish hemodynamic responses to isoprenaline (87 ng/kg; Ref. 38).…”