Inhibition of vasopressin action in vascular smooth muscle by the V1 antagonist OPC-21268.
In vascular smooth muscle cells arginine vasopressin acting through the V1 receptor increases intracellular Ca2+, leading to vasoconstriction. Recent studies have also shown that vasopressin activates mitogen-activated protein kinase (MAP kinase), which may contribute to vasopressin-induced hypertrophy of vascular smooth muscle cells. We examined the ability of an orally active, nonpeptide selective V1 antagonist (OPC-21268) to block vasopressin binding and postreceptor signaling in these cells. [3H]Vasopressin binding at 2 x 10(-9) mol/L was half-maximally blocked at 10(-9) mol/L OPC-21268. To compare effects of OPC-21268 on binding and postreceptor signaling, we stimulated cells with 10(-8) mol/L vasopressin. At this vasopressin concentration, half-maximal inhibition of binding occurred at 5 x 10(-9) mol/L OPC-21268. Half-maximal inhibition of Ca2+ efflux or increases in intracellular free Ca2+ required higher concentrations of antagonist (10(-7) mol/L), and half-maximal inhibition of vasopressin-stimulated MAP kinase was observed only at 10(-6) mol/L OPC-21268. These results indicate that this agent selectively blocks both vasopressin binding and postreceptor signaling in vascular smooth muscle cells. The requirement of higher concentrations of OPC-21268 for blocking increases in intracellular Ca2+ and activation of MAP kinase suggests that binding to a fraction of V1 receptors generates maximal levels of second messengers or the existence of subtypes of the V1 receptor with differential affinity for this antagonist. These data have implications for the clinical use of this compound.
Li
X
X
Department of Medicine, University of Colorado School of Medicine, Denver.
Kribben
A
A
Wieder
E D
ED
Tsai
P
P
Nemenoff
R A
RA
Schrier
R W
RW
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D001127:Arginine Vasopressin; C068644:OPC 21268; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D002118:Calcium