Vasopressin renal actions

CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin (p. 164) leads to polyuria and thirst. Thyroid function is impaired (p. 244), with compensatory development of (euthyroid) goiter. 

Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. They are discussed in Chapter 37. Their renal action appears to be mediated primarily via V2 receptors although Vla receptors may also be involved. 

A variety of tumours, e.g. oat-cell limg cancer, can make vasopressin, and of course they are not subject to normal homeostatic mechanisms. SIADH also occurs in some CNS and respiratory disorders (infection). Dilutional hyponatraemia follows, i.e. low plasma sodium with an inappropriately low plasma osmolality and high urine osmolality. When the plasma sodium approaches 120 mmol/I treatment should be with fluid restriction (< 500 ml/day). Treatment is primarily of the imderlying disorder accompanied by fluid restriction. Chemotherapy to the causative tumour or infection is likely to be the most effective treatment. Demeclocycline, which inhibits the renal action of vasopressin, is useful Infusion of isotonic or hypertonic saline must be reserved for extreme emergencies, associated with stupor, and undertaken with great caution. Rapid correction of hyponatraemia must be avoided because of the risk of central pontine myelinolysis the rate of correction must not exceed 12 mmol/1 per 24 h. 

In most cases the mechanism is not known. Stimulators of vasopressin secretion include vincristine, cyclophosphamide, tricyclic antidepressants, nicotine, epinephrine, and high doses of morphine. Lithium, which inhibits the renal effects of vasopressin, also enhances vasopressin secretion. Inhibitors of vasopressin secretion include ethanol, phenytoin, low doses of morphine, glucocorticoids, fluphenazine, haloperidol, promethazine, oxilorphan, and butorphanol. Carba-mazepine has a renal action to produce antidiuresis in patients with central diabetes insipidus but actually inhibits vasopressin secretion via a central action. 

RENAL ACTIONS OF VASOPRESSIN Several actions of vasopressin in the kidney involve both Vj and receptors. Vj receptors mediate contraction of mesangial cells in the glomerulus and vascular smooth muscle cells in the vasa recta and efferent arteriole. Indeed, Vj-receptor-mediated reduction of inner medullary blood flow contributes to the maximum concentrating capacity of the kidney (Figure 29-4). Vj receptors also stimulate prostaglandin synthesis by... 

Electrolyte balance In a retrospective analysis of data obtained from 84 patients with lupus nephritis or non-Hodgkin s lymphoma, 112 treatment episodes with low-dose intravenous pulse cyclophosphamide (500-750 mg/m ) were evaluated [28. All received 0.45% saline as hydration to prevent hemorrhagic cystitis. There was cyclophosphamide-induced hyponatremia during 15 treatment episodes in 12 patients. Patients with hyponatremia were significantly older than those without, although no factors independently predicted hyponatremia in a multivariate analysis, including cyclophosphamide dose. Cyclophosphamide potentiates the renal action of vasopressin, thereby reducing the ability of the kidney to excrete water, which should warrant the use of hypotonic solutions for prophylactic hydration to prevent hyponatremia. 

Vasopressin (antidiuretic hormone) is a peptide synthesized in the hypothalamus and secreted from the neurohypophysis of the pituitary gland. This substance plays an important role in the long-term regulation of blood pressure through its action on the kidney to increase reabsorption of water. The major stimulus for release of vasopressin is an increase in plasma osmolarity. The resulting reabsorption of water dilutes the plasma toward its normal value of 290 mOsM. This activity is discussed in more detail in Chapter 10 (the endocrine system) and Chapter 19 (the renal system). 

Li+ also inhibits several hormone-stimulated adenylate cyclases which, in some cases, appear to be related to side effects of Li+ therapy. For instance, Li+ inhibits the hydro-osmotic action of vasopressin, the antidiuretic hormone which increases water resorption in the kidney [136]. This effect is associated with polyuria, a relatively harmless side effect sometimes experienced with Li+ treatment, which arises from the inability of the kidney to concentrate urine. Li+ has been shown to inhibit vasopressin-stimulated adenylate cyclase activity in renal epithelial cells. Additionally, Li+ is reported to enhance the vasopressin-induced synthesis of prostaglandin E2 (PGE2) in vitro in kidney. PGE2 inhibits adenylate cyclase activity by stimulation of Gj, and, therefore, this effect may contribute to the Li+-induced polyuria. 

Vasopressin occurs in two variations arginine-vasopressin (AVP) and lysine-vasopressin (LVP), in which Arg is replaced by Lys. The conformation of these hormones is almost identical to that of oxytocin, except that the terminal tail is con-formationally free and not held by the ring. The physiological role of the vasopressins is the regulation of water reabsorption in the renal tubules (i.e., an antidiuretic action). In high doses, they promote the contraction of arterioles and capillaries and an increase in blood pressure hence the name of these hormones. Because of their very similar structures, OT and VP overlap in a number of effects. 

Administration of ANP produces prompt and marked increases in sodium excretion and urine flow. Glomerular filtration rate increases, with little or no change in renal blood flow, so that the filtration fraction increases. The ANP-induced natriuresis is due to both the increase in glomerular filtration rate and a decrease in proximal tubular sodium reabsorption. ANP also inhibits the secretion of renin, aldosterone, and vasopressin these changes may also increase sodium and water excretion. Finally, ANP causes vasodilation and decreases arterial blood pressure. Suppression of ANP production or blockade of its action impairs the natriuretic response to volume expansion, and increases blood pressure. 

Desmopressin f/V-deamino-8-D-arginine vasopressin, dDAVP) is a longer acting analogue of vasopressin. It has very little vasoactive effect but is antidiuretic by an action on vasopressin V2 receptors in the renal tubule and is used to treat central diabetes insipidus and nocturnal enuresis. 

Desmopressin has little vasoconstrictor effect but has potent antidiuretic action, through renal vasopressin V2 receptors, and at high doses hemostatic properties, by increasing concentrations of factor VIII and von Willebrand factor in the blood. 

Conivaptan hydrochloride (1) represents the first FDA-approved agent for the treatment of hyponatremia to modulate electrolyte-free water reabsorption in the renal collecting ducts by antagonizing the action of AVP on vasopressin receptors. As such, 1 represents a novel approach toward the treatment of hyponatremia that could significantly affect the pharmacotherapy of a range of diseases characterized by abnormal water retention. 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

Vasopressin, also called antidiuretic hormone (ADH), is a cyclic nonapeptide hormone, which is released from the posterior pituitary. Its primary function in the body is to regulate extracellular fluid volume by affecting renal handling of water. Specific actions include inhibition of... 

Reduction of portal pressure. Vasopressin (anti-duiretic hormone, see p. 711), in addition to its action on the renal collecting ducts (through receptors), constricts smooth muscle (Vj receptors) in the cardiovascular system (hence its name), and particularly in splanchnic blood vessels, so reducing blood flow in the portal venous system. Unfortunately, coronary vasoconstriction can also occur, and treatment has to be withdrawn from 20% of patients because of myocardial ischaemia. Glyceryl trinitrate (transdermally, sublingually, or intravenously) reduces the cardiac risk and, advantageously, further reduces portal venous resistance and pressure. 

Arginine vasopressin (AVP) is a potent vasoconstrictor that preferentially reduces renal medullary blood flow through the stimulation of the vasopressin Via receptor (VlaR). Studies have also shown that the vasopressin V2 receptor (V2R) may modulate AVP-mediated vasoconstriction. The transcriptional and translational sites of the VlaR and V2R in micro-dissected intrarenal vascular segments from both the cortex and medulla was studied [154]. The results indicate that VlaR mRNA and proteins are present in the isolated cortical or medullary vasculature, but the V2R mRNA and proteins were not found. This study suggests that the vasoconstrictor action of AVP within the renal medulla is mediated through the VlaR and that the modulatory V2R- mediated vasodilation is probably through the release of paracrine hormones found within the renal interstitial or tubular cells. 

Deficient production or action of vasopressin results in polyuria caused by the failure of the renal tubules to reabsorb soiute-fi. ee water. Under normal circumstances, urine output is largely dependent on fluid mtake thus an arbitrary hmit for normal urine output cannot be defined. When urine output is >2.5L/day, an investigation is usually indicated with complete deficiency of AVP, urine output may approach 1 L/hr. If tire thirst response is normal, increased ingestion of fluid (polydipsia) will follow. If access to water is not restricted, plasma osmolality and serum electrolytes will usually remain normal. 

C signal transduction pathway. Secretion of calcitonin is stimulated by hypercalcemia but the effect of the hormone on calcium transport appears to be secondary to increased phosphate uptake by target cells. The number and activity of osteoclasts are decreased, and urinary excretion of hy-droxyproline is decreased, Calcitonin may also inhibit release of calcium from the extracellular fluid calcium pool, but it increases calcium and phosphate excretion by renal tubules. Some tubular cells respond to calcitonin, PTH, and vasopressin, while others respond only to one or two of these hormones. In general, the actions of calcitonin in kidney and in bone are antagonistic to those of PTH. Calcitonin decreases secretion of gastrin and of gastric acid, and inhibits bile flow. 

Chlorpromazine may have weak diuretic effects because of a depressant action on the secretion of vasopressin (antidiuretic hormone, ADH), inhibition of reabsorption of water and electrolytes by a direct action on the renal tubule, or both. The syndrome of idiopathic polydipsia and hyponatremia sometimes associated with psychotic illness has respotuled to clozapine, presumably via... 

---