Modulation of Agonist and Antagonist Interactions at Kidney Alpha 1-adrenoceptors by Nucleotides and Metal Ions

In order to characterize putative high- and low-affinity states of the renal alpha 1-adrenoceptor, binding sites for the selective antagonist radioligand [3H]prazosin were examined in washed membranes prepared from rat renal cortex and medulla. Norepinephrine competition curves at [3H]prazosin sites were biphasic and were best fit by a two-site model. Na+ and GTP selectively decreased the proportion of sites exhibiting a high affinity for norepinephrine. In contrast, Mg2+ facilitated high-affinity interactions of norepinephrine at the renal alpha 1-receptor. Guanine nucleotides and Na+ increased the affinity of some antagonists [( 3H]prazosin, WB-4101), but not others (phentolamine). Mg2+ again had opposite effects. The effects of ions and nucleotides on both agonist and antagonist interactions were concentration-dependent. The order of potencies for monovalent cations (Na+ greater than Li+ much greater than K+), divalent cations (Mn2+ greater than Mg2+) and nucleotides (Gpp (NH)p, GTP much greater than GMP, ATP) were similar to those reported for cyclase-coupled receptor systems. However, unlike other divalent cations Ca2+ decreased both agonist and antagonist binding, possibly due to a Ca2+-sensitive proteinase. Receptor binding properties were similar in renal cortex and medulla. Renal alpha 1-receptor sites appear to display high- and low-affinity states with respect to agonists, and the equilibrium between these states may be modulated by guanine nucleotides and mono- and divalent metal ions. Some antagonists appear to bind preferentially to sites with low agonist affinity, and this effect is probably independent of retained endogenous catecholamines.