Reduction of the serotonin 5-HT1B and 5-HT2A receptor-mediated contraction of human pulmonary artery by the combined 5-HT1B receptor antagonist and serotonin transporter inhibitor LY393558

被引:4
作者
Baranowska-Kuczko, Marta [1 ,2 ]
Kozlowska, Hanna [1 ]
Schlicker, Eberhard [3 ]
Gothert, Manfred [3 ]
MacLean, Margaret R. [4 ,5 ]
Kozlowski, Miroslaw [6 ]
Kloza, Monika [1 ]
Sadowska, Olga [1 ]
Malinowska, Barbara [1 ]
机构
[1] Med Univ Bialystok, Dept Expt Physiol & Pathophysiol, Mickiewicz Str 2A, PL-15089 Bialystok, Poland
[2] Med Univ Bialystok, Dept Clin Pharm, Bialystok, Poland
[3] Univ Bonn, Dept Pharmacol & Toxicol, Bonn, Germany
[4] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark, Scotland
[5] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland
[6] Med Univ Bialystok, Dept Thorac Surg, Bialystok, Poland
关键词
5-HT1B receptor; 5-HT2A receptor; LY393558; Pulmonary arterial hypertension; Serotonin; Serotonin transporter; 5-HYDROXYTRYPTAMINE TRANSPORTER; HYPERTENSION; GENE;
D O I
10.1007/s43440-020-00105-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background LY393558 is a combined antagonist of serotonin (5-HT) 5-HT1B receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and remodelling of rat and/or mouse pulmonary arteries. The aim of our study was to examine the effect of LY393558 on the 5-HT-stimulated vasoconstriction of human pulmonary arteries (hPAs) and to determine the underlying mechanism(s). Methods Vascular effects of 5-HT receptor agonists, antagonists and a SERT inhibitor were examined in organ bath studies on intralobar hPAs obtained from patients during resection of lung carcinoma. Results Serotonin and agonists of the 5-HT1B receptor (5-carboxamidotryptamine, 5-CT) and 5-HT2A receptor (alpha-methyl-5-HT) contracted endothelium-intact hPAs in a concentration-dependent fashion. The 5-HT1B antagonists SB224289 and GR55562 reduced responses induced by 5-HT and 5-CT and the 5-HT2A antagonist ketanserin inhibited the effects of 5-HT and alpha-methyl-5-HT. Administration of the SERT inhibitor citalopram (at a concentration that failed to modify the 5-HT-induced vasoconstriction) in combination with SB224289 or GR55562 was more effective in inhibiting the response to 5-HT than the 5-HT1B antagonists alone. LY393558 showed the greatest antagonistic effect against the vasoconstriction elicited by 5-HT, 5-CT and alpha-methyl-5-HT. Conclusions LY393558 reduces the 5-HT-induced contraction antagonizing 5-HT1B and 5-HT2A receptors probably due to synergic interaction between SERT inhibition and 5-HT1B receptor antagonism. Thus, it might represent a valuable future option in the pulmonary arterial hypertension therapy.
引用
收藏
页码:756 / 762
页数:7
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