Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function

Abstract

The [Arg8]vasopressin (AVP) receptor expressed by human hepatocytes was characterized, and compared with the rat hepatic V1a vasopressin receptor subtype. In addition to determining the pharmacological profile of the human receptor, the cellular responses to AVP were measured in human and rat hepatocytes by assaying glycogen phosphorylase alpha activity and DNA synthesis. Marked differences were observed between human and rat hepatocytes regarding vasopressin receptors and the intracellular consequences of stimulation by AVP. Data presented in this paper demonstrate the following, (i) Vasopressin V1a receptors are present in low abundance on human hepatocytes. (ii) Species differences exist between human and rat V1a receptors with respect to the affinity of some selective antagonists. (iii) AVP-stimulated glycogen phosphorylase a activation in human hepatocytes was approx. 5% of that observed in rat cells. (iv) In contrast with rat hepatocytes, DNA synthesis in human cells in culture was not stimulated by AVP. It is concluded that vasopressin plays only a minor role in the regulation of human hepatic function. Furthermore, conclusions drawn from observations made with AVP and its analogues on rat hepatic function cannot be directly extrapolated to the human situation.

Sustained Elevated Levels of Circulating Vasopressin Selectively Stimulate the Proliferation of Kidney Tubular Cells via the Activation of V2 Receptors

“…For this, high levels of circulating AVP were maintained over several days by submitting adult rats to prolonged hyperosmotic stimulation or implanting them with a AVP-containing Alzet osmotic minipump. The rate of cell proliferation was examined within the pituitary expressing V 1b -R (20), the adrenal gland expressing both V 1a -R and V 1b -R (21), the liver expressing V 1a -R (22), and the kidney expressing V 1a -R, V 2 -R (23) and perhaps V 1b -R (24). Our data show that under these conditions, increased cell proliferation was detected only in the kidney.…”

Defining the ligand-binding site for vasopressin receptors: a peptide mimetic approach

“…In contrast, SR49059 is a selective non-peptide antagonist which binds with high affinity to rat liver V,, VPRs (Ki 1.6nM) but exhibits much reduced affinity (Ki 130-1080 nM) at human OTRs [17]. Thus, additional factors must be involved in the binding of non-peptide ligands compared with peptide ligands and for determining the affinity of [17,18]. Thus, the properties of the ECII mimics appear to parallel some features of the pharmacology of native VPRs but do not exclusively determine ligand selectivity.…”

“…To evaluate specificity, an identical protocol was used to determine whether synthetic peptide mimics of neurohypophysial peptide receptors would reduce the specific binding of [3H]angiotensin I1 (['HIAngII,71.5 Ci/ mmol) to the rat liver AT, receptor. Apparent inhibition constants were determined by non-linear regression after the fitting of a simple Langmuir binding isotherm to experimental data using the Effect of receptor mimics on hormone-stimulated glycogen phosphorylase, activity I04 the incorporation of radioactive glucose from [ a-u-[U -''C]glucose 1-phosphate into glycogen [18]. In order to determine whether receptor mimetic peptides could inhibit AVP-and AngIIstimulated GP, activity, we compared two rV,,R ECII mimics.…”

Chemical development of the vasopressin receptor 2 antagonist SR-121463

“…2) with distinct biological functions [3]. Its primary role involves regulation of the renal and cardiovascular functions [4]. To date, 3 subtypes of AVP receptors have been identified and cloned [5,6]: the V 1 -vascular receptor [5], the V 2 -renal receptor [6], and the V 1b or V 3 -pituitary receptor [7,8]; however, their crystallographic structures remain to be established.…”