Receptor-independent sensitization of the adenylyl cylase after chronic treatment with cyclosporine A.
Chronic treatment with cyclosporine A (CyA) is often complicated by severe hypertension. If activation of the beta-adrenergic-receptor-linked adenylyl cyclase (AC) system contributes to hypertension is unresolved. Rats were treated with CyA (20 mg kg(-1) day(-1)) for 7 days. beta-adrenergic, muscarinic, and alpha-adrenergic receptors, G-proteins, and the activity of AC were determined in cardiac and pulmonary plasma membranes. The density of cardiac beta-adrenergic receptors, muscarinic receptors, alpha-adrenergic receptors, G(alphas) and, G(alphai) remained unchanged after treatment with CyA. However, CyA increased the responsiveness of AC to different stimulators. The responsiveness of AC was even more pronounced after solubilization and partial purification, suggesting a direct modulation of the enzyme. These data suggest that CyA modulates the activity of the sympathoadrenergic system by a direct, receptor-independent sensitization of AC, suggesting that this pathway contributes to hypertension in patients treated with CyA.
Simonis
G
G
Department of Medicine/Cardiology, Dresden University of Technology, Dresden, Germany. gsimonis@gmx.de
Christ
T
T
Bährle
S K
SK
Pena
M
M
Schoen
S P
SP
Marquetant
R
R
Ravens
U
U
Strasser
R H
RH
D000262:Adenylyl Cyclases / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019393:Arrestin / Q000096:biosynthesis; D002462:Cell Membrane / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D051552:beta-Adrenergic Receptor Kinases / Q000096:biosynthesis
D000318:Adrenergic beta-Agonists; D019393:Arrestin; D007166:Immunosuppressive Agents; D011943:Receptors, Adrenergic, beta; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; D016572:Cyclosporine; D051552:beta-Adrenergic Receptor Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol