Threshold and Receptor Reserve in the Action of Neurohypophyseal Peptides : A study of synergists and antagonists of the hydroosmotic response of the toad urinary bladder

The interrelationship of several physiological receptors which influence the hydroosmotic response of the toad urinary bladder was studied employing neurohypophyseal peptides, prostaglandin E₁, theophylline, and cyclic nucleotides. The binding property of agonists (pD₂), synergists (pS₂), competitive antagonists (pA₂), and noncompetitive antagonists (pD₂') was determined after a suitable methodology had been developed. A series of neurohypophyseal peptides was examined in detail for their catalytic activity. It was found that the replacement of the hydroxy radical of the tyrosine residue in oxytocin by a methoxy and then by an ethoxy radical led to a progressive decline in the catalytic activity of the hormone—corresponding to a change from agonist to partial agonist to competitive antagonist. [4-Leucine]-mesotocin behaved as a competitive antagonist of oxytocin. Prostaglandin E₁ (PGE₁) was found to be a noncompetitive inhibitor of neurohypophyseal peptides and theophylline; whereas the maximal hydroosmotic response of the bladder to [2-O-methyltyrosine]-oxytocin and theophylline was greatly depressed by PGE₁, the response to saturating concentrations of oxytocin was only slightly diminished—a finding which reveals a "receptor reserve" for oxytocin. Saturating concentrations of [2-O-ethyltyrosine]-oxytocin, inactive per se, potentiate theophylline—disclosing a "threshold phenomenon" for the mediation of neurohypophyseal hormone action. It is concluded that neurohypophyseal peptides are capable of producing graded effects on adenyl cyclase both below and above the range of enzyme activity which evokes graded changes in membrane permeability.