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 generat ion has been observed. In order to characterize the mechanisms underly ing changes of cAMP generation in patients who were treated with immun osuppressives following heart transplantation, we investigated the bet a-adrenoceptor - G protein - adenylate cyclase signal transduction cas cade in heart transplant recipients and for comparison in renal transp lant recipients as well as controls. Basal cAMP formation in MNL was e levated 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 transpla nt recipients was similar to the controls, but was enhanced in renal t ransplant recipients to 138%. Investigation of beta-adrenoceptor densi ty on MNL as a possible cause for increased cAMP formation revealed si milar 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 sim ilar in controls and heart transplant recipients. The amount of pertus sis- and cholera toxin substrates was the same in heart transplant rec ipients as in controls. In contrast, MNL of renal transplant recipient s showed a marked increase of G(s alpha) by 45% and a smaller albeit s ignificant increase of G(i alpha) by 15%, as judged by cholera toxin a nd pertussis toxin labeling, respectively. Investigation of inotropic parameters by echocardiography under control conditions and during the infusion of increasing concentrations of isoprenaline revealed no dif ference 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 func tion in the transplanted heart, but it is reasonable to suggest that e levations of cAMP formation in MNL may contribute to the immunosuppres sive effects of the treatment with cyclosporine A or corticosteroids, the mechanism of which could be an alteration of G(s alpha) or the cat alyst in renal transplant recipients and the catalyst in heart transpl ant recipients which occurs without any changes of beta-adrenoceptors.