Signaling Pathways Involved in Enhanced 5‐HT‐Induced Contraction of Pulmonary Artery Segments From Guinea‐Pigs With Hyperthyroidism

Abstract

We have previously reported that hyperthyroidism in rats resulted in enhanced 5‐HT‐induced contractions of pulmonary artery segments by a mechanism involving activation of calcium‐activated chloride channels. We have investigated other possible pathways that might be involved in this response in this study. Pulmonary artery ring segments were set up in Krebs’ solution for isometric tension recording. 5‐HT‐induced contraction was significantly enhanced in main pulmonary artery segments from guinea‐pigs with hyperthyroidism compared with a similar preparation from control guinea pigs. Nifedipine (10−6M) and tempol (3×10−3M) significantly reduced 5‐HT‐induced contraction in artery segments from thyroxine‐treated while having no effect in artery segments from control guinea pigs. Y‐27632 (10−5M) and SB 202190 (10−5M) but not PD 98059 (10−5M) significantly reduced 5‐HT‐induced contractions in artery segments from control and thyroxine‐treated guinea pigs. However, the reduction was greater in artery segments from thyroxine‐treated guinea pigs. Genistein (10−5M) significantly reduced 5‐HT‐induced contractions in artery segments from control or thyroxine‐treated guinea pigs. Genistein was equipotent in both cases. These results would suggest that hyperthyroidism‐induced increased 5‐HT‐induced contraction of the guinea pig pulmonary artery is mediated by multiple signaling pathways including increased influx of extracellular calcium through L‐type dihydropyridine channels, tyrosine kinase pathway, Rho‐kinase pathway of calcium sensitization, increased generation of reactive oxygen species and p38 MAPK pathway.