The objective of this proposal is to determine how differences in hormone-receptor binding kinetics and binding-response coupling affect responses to peptide hormones. Variation in receptor kinetics might be a third way (in addition to variations in hormone secretion and elimination) by which organisms control their hormonal functions.
Specific aims are: (1) Completion of a graphic mathematical exposition of the expected effects of varying peptide-receptor association and dissociation rate constants and other parameters on the time courses of in vivo responses to injected or infused peptides, (2) Experimental investigation of the effects of varying peptide-receptor association and dissociation rate constants on the time courses of in vivo responses to injected or infused peptides, (3) Experimental investigation of the effects of varying binding-response coupling of in vivo responses to injected or infused peptides. The in vivo effects of varying peptide-receptor binding kinetics and binding-response coupling will be studied for the four tissues (mammary, uterine, kidney, and vascular) responsive to oxytocin and vasopressin. A series of oxytocin and vasopressin analogs (both agonists and antagonists) differing in association and dissociation rate constants will be used to study the effects of varying these parameters on the time courses of responses to these analogs. Three """"""""double-response"""""""" assays, assays in which the responses of two tissues to the same injection of an analog are monitored in a single rat, will be used to investigate binding-response coupling. These assays are vasopressor-milk ejection, vasopressor-uterine, and uterine-antidiuretic. The results, in addition to their usefulness in investigating binding and binding-response coupling as a possible means of physiological control, will also be useful in the study of drug kinetics.
| Buku, A; Gazis, D (1990) Probes for vasopressin receptors. Attachment of affinity and fluorescent groups in vasopressin. Int J Pept Protein Res 35:128-32 |
| Gazis, D; Gonzalez, G; Mendlowitz, M (1989) Adrenergic interactions in uterus and vascular smooth muscle in rats in vivo. Can J Physiol Pharmacol 67:1586-90 |
| Buku, A; Gazis, D; Eggena, P (1989) Photoaffinity, biotinyl, and iodo analogues as probes for vasotocin receptors. J Med Chem 32:2432-5 |
| Buku, A; Yamin, N; Gazis, D (1989) Effects of the substitution of photoreactive groups in positions 4 and 8 of vasopressin. Int J Pept Protein Res 34:28-32 |
| Buku, A; Yamin, N; Gazis, D (1988) Fluorescent, photoaffinity, and biotinyl analogs of oxytocin. Peptides 9:783-6 |
| Gazis, D (1987) In vivo apparent peptide-receptor dissociation rate constants for arginine vasopressin analogs estimated from inhibition of rat pressor responses. Can J Physiol Pharmacol 65:2099-103 |
