title: Tonic inhibition of renal response to vasopressin by a pertussis toxin substrate.
abstract: The putative role of the inhibitory guanine nucleotide binding protein (Gi) in modulating the renal response to vasopressin was investigated using islet activating protein (IAP). IAP treatment in rats in vivo abolished the capacity of alpha 2-adrenoceptors to reverse vasopressin-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in microdissected cortical collecting tubule (CCT) segments. IAP pretreatment also caused a marked upward shift in the dose-response curve of vasopressin (10(-10) to 10(-4) M)-induced cAMP accumulation. Augmentation of the response to vasopressin in rat CCT was dependent on the in vivo dose of IAP and paralleled the loss in alpha 2-adrenoceptor responsiveness. In the isolated perfused kidney the antinatriuretic and antidiuretic effects of the V2-receptor agonist desamino-8-D-arginine vasopressin (DDAVP) (1 pM) were enhanced following IAP pretreatment. alpha 2-Adrenoceptor stimulation (30 nM epinephrine) inhibited the renal effects of DDAVP (1 pM) in kidneys from control but not IAP-pretreated rats. Interestingly, IAP pretreatment alone caused increased urine flow rate and enhanced excretion of sodium and chloride without affecting potassium excretion or renal hemodynamics in vitro. Our results suggest that an IAP substrate, probably Gi, 1) is required for signal transduction by renal alpha 2-adrenoceptors, 2) may tonically modulate the response to vasopressin in the CCT but not of parathyroid hormone in the proximal convoluted tubule, and 3) participates in renal water and electrolyte reabsorption independent of exogenous adenylate cyclase stimulation.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, Dallas 75235.
authors.forename: W B
authors.initials: WB
authors.lastname: Jeffries
authors.forename: R
authors.initials: R
authors.lastname: Fallet
authors.forename: G D
authors.initials: GD
authors.lastname: Gong
authors.forename: P
authors.initials: P
authors.lastname: Van Dreal
authors.forename: W A
authors.initials: WA
authors.lastname: Pettinger
mesh_terms: D037361:Adenylate Cyclase Toxin; D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D012016:Reference Values; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
chemical_list: D037361:Adenylate Cyclase Toxin; D000316:Adrenergic alpha-Agonists; D011942:Receptors, Adrenergic, alpha; D010566:Virulence Factors, Bordetella; C016986:apraclonidine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D003894:Deamino Arginine Vasopressin; D003000:Clonidine; D004837:Epinephrine