To further gain insights into the mechanisms underlying impaired urine concentration in hypercalcemia, effects of increasing Ca2+ concentrations in the incubation medium on cAMP production in response to 10(-8) M arginine vasopression (AVP) were examined in thick ascending limbs of Henle (MTAL) and collecting tubules (MCT) dissected from outer medulla of mouse kidney. Increasing Ca2+ in the incubation medium from 1.0 mM to either 2.0 mM or 5.0 mM inhibited AVP-dependent cAMP production in MTAL but not in MCT. This inhibition of AVP-dependent cAMP production by 2.0 mM Ca2+ in MTAL was not reversed by verapamil or diltiazem. Also, Ca2+ ionophore A23187 did not inhibit AVP-dependent cAMP production in MTAL in the presence of 1.0 mM Ca2+. Increasing medium Ca2+ from 1.0 to 5.0 mM inhibited cAMP production in MTAL in response to both glucagon and forskolin by the magnitude comparable to that seen in response to AVP. These results show that high Ca2+ inhibits AVP-dependent cAMP production only in MTAL and not in MCT. In addition, the lack of effects of Ca2+ channel blockers and Ca2+ ionophore suggests that high ambient Ca2+ per se may inhibit AVP-dependent cAMP production in MTAL. The fact that high Ca2+ also suppressed cAMP production in response to glucagon or forskolin suggests that Ca2+ may inhibit AVP-dependent adenylate cyclase at postreceptor site(s), one of which is the catalytic unit of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)