Homologous and heterologous desensitization mediated by vasopressin in smooth muscle cells.
Prolonged exposure of A-10 cells to Arginine Vasopressin (AVP) resulted in the following responses: (a) loss of vasopressin receptors from the cell surface (30-40%), (b) increased basal levels of inositol and inositol monophosphate, (c) decreased inositol di- and trisphosphate production and decreased intracellular calcium release in response to a second challenge with AVP, (d) attenuation of AVP-mediated inhibition of isoproterenol-stimulated cAMP and ANF-stimulated cGMP accumulation and (e) attenuation of thrombin and ATP-mediated increase in inositol di- and trisphosphate accumulation and intracellular calcium release. All the above responses depended on the time of exposure of the cells to AVP with the responses being attenuated as early as 5-10 min of exposure to AVP. The desensitization also depended on the concentration of AVP used with 50% of maximal desensitization for each response being observed at 5 nM of AVP. This concentration of AVP corresponded well with the Kd of vasopressin for binding to these sites. Desensitization of protein kinase C (PKC) by prolonged exposure of the cells to PDBu or addition of the PKC inhibitor staurosporine during pretreatment with AVP did not prevent AVP-mediated desensitization, suggesting that PKC may not be involved in AVP-mediated desensitization in smooth muscle cells. It is concluded that AVP induced both homologous and heterologous desensitization of phosphatidylinositol turnover and calcium release in smooth muscle cells. The desensitization processes did not appear to be mediated by protein kinase C. The possibility that the locus of the heterologous desensitization may be at the level of substrates such as PI, PIP and PIP2 is discussed.
Nambi
P
P
Department of Mol. Pharmacology, SK&F Laboratories, Philadelphia, PA 19101.
Aiyar
N
N
Whitman
M
M
Grier
C E
CE
Crooke
S T
ST
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D007294:Inositol / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D017483:Receptors, Vasopressin; D013917:Thrombin / Q000494:pharmacology
D007295:Inositol Phosphates; D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D007294:Inositol; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D013917:Thrombin; D007545:Isoproterenol; D002118:Calcium