Upregulation of the alpha1-adrenoceptor-induced phosphoinositide and inotropic response in hypothyroid rat heart.
In this study, we examined changes in the biochemical and inotropic events of the alpha(1)-adrenoceptor signaling pathway in hypothyroid rat hearts. Hypothyroidism was induced by treating experimental animals with 0.05% 6-n-propyl-2-thiouracil (PTU) in drinking water for 7 weeks. A significant decrease of beta- and an increase in alpha(1)-adrenoceptor density as well as an increase in the basal activity of the phosphoinositide (4,5) bisphosphate hydrolyzing phospholipase C was observed in sarcolemmal membranes purified from hypothyroid hearts as compared to age-matched euthyroid controls. Following stimulation with 10 microM phenylephrine (in the presence of 10 microM atenolol), the increase of contractile parameters over baseline values was significantly higher in hypo- than euthyroid hearts, while the opposite occurred under beta-stimulation with 0.1 microM isoproterenol. Interestingly, the increase in phenylephrine-mediated positive inotropy was accompanied by a significant increase in the sarcolemmal phospholipase C activity and in the inositol 1,4,5-trisphosphate content in hypothyroid as compared to euthyroid controls. Our results suggest that cardiac alpha(1)-adrenoceptor and its associated phosphoinositide signaling pathway may act as a reserve for catecholamine inotropic response in hypothyroidism, where the beta-adrenoceptors are compromised.
Jalali
Shahrzad
S
Division of Stroke and Vascular Disease, St. Boniface General Hospital Research Centre, Winnipeg, Canada.
Durston
Melanie
M
Panagia
Vincenzo
V
Mesaeli
Nasrin
N
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007037:Hypothyroidism / Q000188:drug therapy / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011441:Propylthiouracil / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013268:Stimulation, Chemical; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
D013956:Antithyroid Agents; D019269:Phosphatidylinositol 4,5-Diphosphate; D018340:Receptors, Adrenergic, alpha-1; D011441:Propylthiouracil; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases