TMB-8 prevents the hydroosmotic response to ADH in rabbit cortical collecting tubules.
Both AVP and dDAVP effect a transient increase in cytosolic free calcium (iCa2+) in cortical collecting tubule (CCT) cells. To investigate the physiological role of this increase in iCa2+, we examined the effect of TMB-8, a putative inhibitor of iCa2+ release, on the initial and sustained phase of AVP- and dDAVP-stimulated water permeability (Pf) in isolated, perfused CCTs. Pretreatment of tubules with TMB-8, 50 microM, suppressed the increase in osmotic water permeability (Pf) induced by 10 microU/ml AVP and dDAVP, but had no effect on the sustained phase of the response. When increased to 100 microM. TMB-8 inhibited the sustained phase of AVP action. A similar pattern was observed on AVP-stimulated adenyly cyclase activity in rabbit renal membranes. Pretreatment of tubules with 50 microM TMB-8 attenuated the initial increase in Pf in response to cholera toxin but not to 8-Br-cAMP or forskolin. There was no effect of this concentration of TMB-8 on the sustained phase of these agonists. These studies suggest that, in lower concentrations, TMB-8 inhibits the mobilization of iCa2+, which is important for the interaction of Gs with the catalytic unit of adenylyl cyclase and the initial increase in AVP-stimulated Pf. In higher concentrations, TMB-8 inhibits adenylyl cyclase activity directly.
Leite
M
M
Department of Medicine, Baylor College of Medicine, Houston, Texas.
Rouse
D
D
Lederer
E
E
Abramowitz
J
J
Suki
W N
WN
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001834:Body Water / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000201:enzymology; D009995:Osmosis / Q000187:drug effects; D010477:Perfusion; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D014667:Vasopressins / Q000037:antagonists & inhibitors*
D002121:Calcium Channel Blockers; D014667:Vasopressins; D001127:Arginine Vasopressin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D003894:Deamino Arginine Vasopressin; D002118:Calcium