Changes in cAMP formation in mononuclear leukocytes of heart and renal transplant recipients.
In mononuclear leukocytes (MNL) of renal transplant recipients treated with cyclosporine A and prednisone, an increase of basal cAMP generation has been observed. In order to characterize the mechanisms underlying changes of cAMP generation in patients who were treated with immunosuppressives following heart transplantation, we investigated the beta-adrenoceptor--G protein--adenylate cyclase signal transduction cascade in heart transplant recipients and for comparison in renal transplant recipients as well as controls. Basal cAMP formation in MNL was elevated in heart transplant recipients by 272% and in renal transplant recipients by 148% compared to controls. Following beta-adrenoceptor stimulation with isoprenaline, cAMP formation in MNL of heart transplant recipients was similar to the controls, but was enhanced in renal transplant recipients to 138%. Investigation of beta-adrenoceptor density on MNL as a possible cause for increased cAMP formation revealed similar receptor numbers in controls and in cardiac or renal transplant recipients. Furthermore, the increase of the beta-adrenoceptor density on MNL, which is observed following infusion of isoprenaline, was similar in controls and heart transplant recipients. The amount of pertussis- and cholera toxin substrates was the same in heart transplant recipients as in controls. In contrast, MNL of renal transplant recipients showed a marked increase of Gs alpha by 45% and a smaller albeit significant increase of Gi alpha by 15%, as judged by cholera toxin and pertussis toxin labeling, respectively. Investigation of inotropic parameters by echocardiography under control conditions and during the infusion of increasing concentrations of isoprenaline revealed no difference in the basal contractility and the inotropic response to beta-adrenergic stimulation in controls and heart transplant recipients. It is concluded that changes of G-protein expression are involved in the increase of the cAMP-generation in MNL of heart transplant recipients. These alterations in MNL cannot be taken as a model of cellular function in the transplanted heart, but it is reasonable to suggest that elevations of cAMP formation in MNL may contribute to the immunosuppressive effects of the treatment with cyclosporine A or corticosteroids, the mechanism of which could be an alteration of Gs alpha or the catalyst in renal transplant recipients and the catalyst in heart transplant recipients which occurs without any changes of beta-adrenoceptors.
Lensche
H
H
Klinik III für Innnere Medizin, Universität zu Köln, Cologne, Germany.
Diet
F
F
von Scheidt
W
W
Uberfuhr
P
P
Reichart
B
B
Erdmann
E
E
Böhm
M
M
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004452:Echocardiography; D019204:GTP-Binding Proteins / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007545:Isoproterenol / Q000494:pharmacology; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D016131:Lymphocyte Subsets; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D037342:Pertussis Toxin; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D007166:Immunosuppressive Agents; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol