Regulation of pulmonary vasoconstriction by agonists and caveolae.
Sustained pulmonary vasoconstriction contributes to the elevated pulmonary vascular resistance observed in pulmonary arterial hypertension. A rise in cytosolic Ca(2 +) in pulmonary artery smooth muscle cells (PASMCs) is major trigger for pulmonary vasoconstriction. One family of drugs currently being pursued as a potential treatment for pulmonary hypertension are the statins, which act by depleting cholesterol and reducing the number of caveolae. This study aimed at investigating the role of caveolae, membrane receptors, and ion channels (that are potentially located in the caveolae) in agonist-mediated pulmonary vasoconstriction in order to gain a greater understanding of the signaling mechanisms involved in the regulation of pulmonary vascular tone. Chronic treatment of PASMCs with the cholesterol-depleting agent, methyl-beta -cyclodextrin (Mbeta CD), significantly reduced the number of cholesterol rich caveolae regions in the membrane. This disruption of cholesterol in caveolae significantly inhibited pharmacomechanical (induced by phenylephrine), but not electromechanical (induced by elevated extracellular potassium concentration), rat pulmonary artery contraction. These results indicate that receptors may functionally colocalize in caveolae in PASMCs and coordinate to regulate pulmonary vascular tone.
Schach
Christian
C
Department of Medicine, University of California, San Diego, La Jolla, California 92093-0725, USA.
Firth
Amy L
AL
Xu
Minlin
M
Remillard
Carmelle V
CV
Patel
Hemal H
HH
Insel
Paul A
PA
Yuan
Jason X-J
JX
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D021941:Caveolae / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D047392:beta-Cyclodextrins / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D014662:Vasoconstrictor Agents; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D010656:Phenylephrine; D002784:Cholesterol; D002118:Calcium