Molecular modelling of the vasopressin V2 receptor/antagonist interactions.

We predict some essential interactions between the V2 vasopressin renal receptor (V2R) and its selective peptide antagonist desGly9-[Mca1,D-Ile2,Ile4]AVP, and compare these predictions with the earlier ones for the non-peptide OPC-36120 antagonist- and the [Arg8]vasopressin (AVP) agonist-V2 receptor interactions. V2R controls antidiuresis in mammals and belongs to the superfamily of the heptahelical transmembrane (7TM) G protein-coupled receptors (GPCR)s. V2R was built, the ligands docked and the structures relaxed using advanced molecular modeling techniques. Both the agonist and the antagonists (no matter whether of peptide- or non-peptide type) appear to prefer a common V2R compartment for docking. The receptor amino-acid residues, potentially important in ligand binding, are mainly in the TM3-TM7 helices. A few of these residues are invariant for the whole GPCR superfamily while most of them are conserved in the subfamily of neurohypophyseal receptors, to which V2R belongs. Some of the equivalent residues in a related V1a receptor have been earlier reported as critical for the ligand affinity.

Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor.

The disease is characterised by cobalamin (Cbl) deficiency in children 0-5 years old, causing failure to thrive, infections, megaloblastic anaemia, neuropathy, and mild general malabsorption; slight proteinuria is common. Cbl injections produce remission, but Cbl malabsorption and proteinuria persist. About 250 cases have been reported. Dogs also have it. The heredity is autosomal and recessive. The physiological and pathological absorption mechanisms are described: Cbl liberated from food by digestion is first bound to haptocorrin, but in the intestine it is transferred to intrinsic factor. In the ileum the complex attaches to a receptor on the enterocytes; this requires neutral pH and Ca2+. The receptor is a membrane-bound glycoprotein consisting of multiple subunits. The receptor-ligand complex is endocytosed and degraded in lysosomes, and the vitamin is transferred to transcobalamin which carries it to tissues. The same receptor is strongly expressed in the kidneys, but urine also contains its activity which can be assayed for diagnosis. The basic lesion is an error in the ileal receptor. In the affected dogs the synthesised receptor is retained intracellularly. Urine and ileal biopsies from human cases contained little receptor but it had conserved affinity for the ligand. Recently examined Arab patients did not excrete reduced amounts of the receptor. Apparently, the disease has subsets, such as different structural errors in the receptor and possibly faulty transport inside the enterocyte. The cause of the proteinuria is unknown but kidney damage due to severe Cbl deficiency and an error in a multiligand renal receptor are among the possibilities.

Tonic descending modulation of spinal neuronal responses to activation of renal receptors

Experiments were conducted in anesthetized cats to determine if spinal neuronal responses to activation of renal receptors are tonically modulated by descending spinal pathways. Eighty-seven thoracolumbar spinal neurons with renal and somatic input were tested for responses to occlusion of the renal vein, renal artery, and ureter before, during, and after cooling the spinal cord rostral to the recording site. Cooling increased the number of neurons that responded as well as the magnitude of the responses to renal vein (RVO), renal artery (RAO), and ureteral occlusion (UO). RVO increased cell activity of 21 neurons from 12.5 +/- 2.7 to 31.7 +/- 6.0 spikes/s during cooling. UO increased cell activity of 24 neurons from 9.0 +/- 2.1 before cooling to 25.0 +/- 4.9 spikes/s during cooling. Cold block increased the magnitude of both types of responses to RAO that were due to mechanical deformation of the renal artery and prolonged renal ischemia. These data show that the majority of spinal neuronal responses to renal receptor stimulation are modulated by tonic inhibitory influences. Thus these results provide a mechanism by which the brain may control spinal circuitry that underlies reflexes of renal origin.

Effects of renal receptor stimulation on neurons within the ventrolateral medulla of the cat

Experiments were performed to determine if activation of renal receptors by occlusion of the renal artery, renal vein, or ureter would alter activity of cells within the ventrolateral medulla of the cat. Extracellular unit recordings were obtained from 195 cells located within the rostral ventrolateral medulla of 90 alpha-chloralose-anesthetized cats. Fifty-five of 195 cells (28.2%) tested for responses to renal receptor activation responded to at least one of the occlusions. Occlusion of the ureter increased the activity of 25 cells from 9.7 +/- 3.7 to 23.0 +/- 6.5 impulses/s and decreased the activity of 5 cells from 11.9 +/- 3.6 to 3.5 +/- 1.2 impulses/s. Occlusion of the renal vein increased the activity of seven cells from 7.5 +/- 3.3 to 22.3 +/- 7.3 impulses/s and decreased the activity of six cells from 13.8 +/- 3.8 to 4.1 +/- 2.0 impulses/s. Renal artery occlusion elicited solely excitatory responses from 43 cells. Thirty-one of the 43 cells increased their activity within 0-3 s of the onset of renal artery occlusion from 4.1 +/- 0.8 to 12.6 +/- 1.2 impulses/s. Renal artery occlusion increased the activity of 10 out of 43 cells with a mean latency of 26.1 +/- 6.5 s from 8.3 +/- 2.5 to 29.6 +/- 9.3 impulses/s. Twenty-four of the 55 (43.6%) responders were responsive to two or more forms of renal receptor activation. These results demonstrate that activation of renal mechanoreceptors and chemoreceptors affects cells within the ventrolateral medulla of the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of renal receptor activation on neurosecretory vasopressin cells

Electrical stimulation of afferent renal nerves (ARN) has been shown to excite neurosecretory vasopressin (AVP) cells of the supraoptic nucleus (SON). To investigate the sensory modality of the ARN involved, the present study examined in pentobarbital-anesthetized rats the responses of putative AVP cells to procedures intended to differentially activate renal receptor populations. Neurosecretory SON cells were identified by antidromic invasion from the neurohypophysis and classified as AVP secreting on the basis of spontaneous activity patterns and responses to arterial baroreceptor activation. Neither elevation of systemic arterial pressure (50-100 mmHg, 9 cells) following sinoaortic and cardiopulmonary afferent nerve transection nor renal venous occlusion (15 cells) altered AVP cell discharge. Renal ischemia, produced by renal arterial occlusion (50-120 s, 14 cells), and renal arterial infusion of adenosine (1-50 micrograms, 8 cells) were also without effect. However, infusions into the renal artery of bradykinin (1-3 micrograms) excited 9/15, of capsaicin (1-3 micrograms) excited 13/15, and of sodium cyanide (5-40 micrograms) excited 1/11 AVP cells examined. These data demonstrate that, in the anesthetized rat, putative neurosecretory AVP cells in the SON are responsive to activation of bradykinin- and capsaicin-sensitive renal receptors and suggest that activation of these receptors contributes to the hormonal regulation of the circulation.