Adrenergic-cholinergic interaction in rat heart : evidence from radioligand binding studies
1
Issued Date
2023
Copyright Date
1993
Language
eng
File Type
application/pdf
No. of Pages/File Size
xxiii, 318 leaves
Access Rights
restricted access
Rights Holder(s)
Mahidol University
Bibliographic Citation
Thesis (Ph.D. (Pharmacology))--Mahidol University, 1993
Suggested Citation
Surin Plasen Adrenergic-cholinergic interaction in rat heart : evidence from radioligand binding studies. Thesis (Ph.D. (Pharmacology))--Mahidol University, 1993. Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/89647
Title
Adrenergic-cholinergic interaction in rat heart : evidence from radioligand binding studies
Alternative Title(s)
อันตรกิริยาระหว่างระบบประสาทอัตโนมัติอะดรีเนอร์จิกและโคลิเนอร์จิกในหัวใจของหนูขาว : ข้อมูลจากการศึกษาวิจัยด้านการจับกับตัวรับยา
Author(s)
Abstract
Adrenergic-cholinergic interaction plays an important role in the control of cardiac functions in both normal and disease states. When both divisions of the autonomic nervous system are stimulated simultaneously, the cholinergic components predominate the adrenergic nervous system. This accentuated antagonism can be clearly demonstrated at the physiological level. In this thesis, the first attempt has been made to demonstrate this interaction at the receptor level by using radioligand binding studies and computer assisted weighted nonlinear least-square curve fitting analysis (LIGAND program). By using [3H](-)DHA as a ?-adrenergic radioligand, it was demonstrated that muscarinic cholinergic receptor agonist, pilocarpine (10(-)7-10(-5) M) decreased the affinity of high affinity binding site for isoproterenol. There was no effect on antagonistic competition with propranolol. Gpp(NH)p (10-610-4 M) decreased the affinity of the ?-adrenergic receptor for isoproterenol for both high and low affinity binding sites. The simultaneous incubation of pilocarpine and Gpp(NH)p resulted in a reversal in affinity for both high and low affinity binding sites similar to those obtained from the control curve. These results s?ggest that muscarinic cholinergic agonist can modulate ?-adrenergic agonist affinity and that the Gpp(NH)p reduction of ?-adrenergic agonist affinity may be reversed by muscarinic cholinergic occupancy. These data are the first study to support that modification of one type of receptor may influence the other one situated nearby. By using [3H](-)QNB as a muscarinic cholinergic radioligand, isoproterenol (10(-6)-10(-5) M) decreased the affinity of high affinity binding site for pilocarpine. Effect on antagonistic competition with atropine could not be demonstrated. Gpp(NH)p (10(-6)-10(-4)M)decreased the affinity of muscarinic receptor for pilocarpine for both high and low affinity binding sites. The simultaneous incubation of isoproterenol and Gpp(NH)p resulted in a further decrease in affinity for both high and low affinity agonist sites. These results s?ggested that ?-adrenergic and muscarinic cholinergic receptor in the heart have interdependent linkage and can modulate agonist binding affinity of each other. Concanavalin A (Con A) was used as a probe to study this type of interaction at cell membrane level. Preincubation with Con A 0.5 ?g/ml for 30 min had no effect on [3H](-)DHA and [3H](-)QNB binding. It can be implied that amplification of agonist-stimulated cAMP generation by Con A is not due to an increase in agonist receptor coupling. Islet-activating protein(IAP) was also used as a probe to explore whether this adrenergic-cholinergic interaction is related to cyclic nucleotide metabolism. In the presence of 10-4 M Gpp(NH)p, 10-5 M pilocarpine cannot reverse the effect of 10-4 M Gpp(NH)p. These results s?ggested that IAP exerts its effects on this interaction at GTP binding protein level by cancelling the effect of pilocarpine in reversing the guanine nucleotide induced decrease in affinity of ?-adrenergic receptor for isoproterenol. It can be concluded that the phenomenon of accentuated antagonism in the heart could be explained for the first time that binding affinity of adrenoceptor may be changed significantly when the cholinoceptor situated nearby are simultaneously activated and this effect may be mediated via GTP binding protein.
Degree Name
Doctor of Philosophy
Degree Level
Doctoral Degree
Degree Department
Faculty of Science
Degree Discipline
Pharmacology
Degree Grantor(s)
Mahidol University