deamino-arginine-vasopressin and Heart-Failure

Involvement of AVP in several pathological states is now established and specific modulation of the different AVP receptor subtypes (V1a, V1b and V2) offers new clinical perspectives for treating major diseases. Recent years have marked a turning point with the design and the use of the first nonpeptide vasopressin receptor antagonists expressing various selectively profile. In that field, we report here the characterization of SR 121463A a highly selective, orally-active antagonist of vasopressin V2 receptors in several models in vitro and in vivo. This compound displayed competitive nanomolar affinity for V2 receptors in various species including man and exhibited a highly selective AVP V2 profile. In vitro, SR 121463A potently antagonized AVP-stimulated adenylyl cyclase activity in human kidney preparations (Ki = 0.26 +/- 0.04 nM) without any intrinsic agonistic effect. In normally-hydrated rats, SR 121463A induced dose-dependent powerful and long-lasting aquaresis after intravenous (0.003 to 0.3 mg/kg) or oral (0.03 to 10 mg/kg) administration. The action of SR 121463A is purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In vasopressin-deficient Brattleboro rats, SR 121463A is devoid of any V2 antidiuretic agonist properties. In addition, this compound potently antagonized DDAVP extrarenal V2 effects on hemostasis factor release (FVIII, vW and t-PA) in dogs (ID50 approximately 10 micrograms/kg i.v.). Thus, SR 121463A is the most potent and selective, orally-active V2 antagonist yet described. It is a useful ligand for exploring V2 receptors and the therapeutical usefulness of pure V2 aquaretic agents in several water-retaining diseases and congestive heart failure.

Topics: Adenylyl Cyclases; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Deamino Arginine Vasopressin; Dogs; Heart Failure; Humans; Kidney; Morpholines; Rats; Rats, Inbred BB; Receptors, Vasopressin; Spiro Compounds; Water-Electrolyte Imbalance

The objective was to examine the renal effects of long-term increased angiotensin II and vasopressin plasma levels in early-stage heart failure (HF). We investigated the regulations of the V2 vasopressin receptor, the type 1A angiotensin II receptor, the (pro)renin receptor, and the water channels AQP2, AQP1, AQP3, and AQP4 in the inner medulla of rat kidney.. HF was induced by coronary artery ligation. Sixty-eight rats were allocated to six groups: Sham (N = 11), HF (N = 11), sodium restricted sham (N = 11), sodium restricted HF (N = 11), sodium restricted sham + DDAVP (N = 12), and sodium restricted HF + DDAVP (N = 12). 1-desamino-8-D-arginine vasopressin (0.5 ng h-1 for 7 days) or vehicle was administered. Pre- and post-treatment echocardiographic evaluation was performed. The rats were sacrificed at day 17 after surgery, before cardiac remodeling in rat is known to be completed.. HF rats on standard sodium diet and sodium restriction displayed biochemical markers of HF. These rats developed hyponatremia, hypo-osmolality, and decreased fractional excretion of sodium. Increase of AQP2 and p(Ser256)-AQP2 abundance in all HF groups was blunted compared with control groups even when infused with DDAVP and despite increased vasopressin V2 receptor and Gsα abundance. This was associated with decreased protein abundance of the AT1A receptor in HF groups vs. controls.. Early-stage HF is associated with blunted increase in AQP2 and p(Ser256)-AQP2 despite of hyponatremia, hypo-osmolality, and increased inner medullary vasopressin V2 receptor expression. Decreased type 1A angiotensin II receptor abundance likely plays a role in the transduction of these effects.

Topics: Analysis of Variance; Angiotensin II; Animals; Aquaporin 2; Deamino Arginine Vasopressin; Echocardiography; Heart Failure; Immunoblotting; Immunohistochemistry; Kidney; Rats; Receptor, Angiotensin, Type 1; Receptors, Vasopressin

In a state of chronic arginine vasopressin (AVP)-induced antidiuresis, the antidiuretic efficacy has been attenuated: a phenomenon known as "AVP escape". We compared the experimental SIADH rats with 1-deamino-8-D-AVP (dDAVP)-excess rats. The SIADH rats, but not the dDAVP-excess rats, showed a marked attenuation of urinary concentrating ability. This is closely associated with diminished up-regulation of aquaporin-2 (AQP-2) mRNA and protein expression. The following in vitro study clarified tonicity-response elements in the 5'-flanking region of AQP-2 gene. There are at least more than two hypertonicity-response elements, and a hypotonicity-response element resided at tonicity-response enhancer (TonE) (-570 to -560bp) in the AQP-2 gene. Hypotonicity directly reduced the cAMP-induced AQP-2 promoter activity by mediating JNK kinase. Reduction in transcriptional regulation of AQP-2 under hypotonic state may support the in vivo finding of AVP escape phenomenon in chronic AVP-induced antidiuresis.

Topics: Animals; Aquaporin 2; Arginine Vasopressin; Bucladesine; Deamino Arginine Vasopressin; Disease Models, Animal; Diuresis; Gene Expression Regulation; Genes, Reporter; Heart Failure; Inappropriate ADH Syndrome; Kidney; Luciferases; Promoter Regions, Genetic; Rats; RNA, Messenger; Water-Electrolyte Imbalance

In heart failure, reduced cardiac contractility is accompanied by blunted cAMP responses to beta-adrenergic stimulation. Parathyroid hormone (PTH)-related peptide and arginine vasopressin are released from the myocardium in response to increased wall stress but do not stimulate contractility or adenylyl cyclase at physiological concentrations. To bypass the defective beta-adrenergic signaling cascade, recombinant P1 PTH/PTH-related peptide receptors (rPTH1-Rs) and V(2) vasopressin receptors (rV(2)-Rs), which are normally not expressed in the myocardium and which are both strongly coupled to adenylyl cyclase, and recombinant beta(2)-adrenergic receptors (rbeta(2)-ARs) were overexpressed in cardiomyocytes by viral gene transfer. The capacity of endogenous hormones to increase contractility via the heterologous, recombinant receptors was compared. Whereas V(2)-Rs are uniquely coupled to Gs, PTH1-Rs and beta(2)-ARs are also coupled to other G proteins. Gene transfer of rPTH1-Rs or rbeta(2)-ARs to adult cardiomyocytes resulted in maximally increased basal contractility, which could not be further stimulated by adding receptor agonists. Agonists at rPTH1-Rs induced increased cAMP formation and phospholipase C activity. In contrast, healthy or failing rV(2)-R-expressing cardiomyocytes showed unaltered basal contractility. Their contractility and cAMP formation increased only at agonist exposure, which did not activate phospholipase C. In summary, we found that gene transfer of PTH1-Rs to cardiomyocytes results in constitutive activity of the transgene, as does that of beta(2)-ARS: In the absence of receptor agonists, rPTH1-Rs and rbeta(2)-ARs increase basal contractility, coupling to 2 G proteins simultaneously. In contrast, rV(2)-Rs are uniquely coupled to Gs and are not constitutively active, retaining their property to be activated exclusively on agonist stimulation. Therefore, gene transfer of V(2)-Rs might be more suited to test the effects of cAMP-stimulating receptors in heart failure than that of PTH1-Rs or beta(2)-ARS:

Topics: Adenoviridae; Adenylate Cyclase Toxin; Animals; Arginine Vasopressin; Culture Media, Conditioned; Cyclic AMP; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Gene Transfer Techniques; Genetic Vectors; Green Fluorescent Proteins; GTP-Binding Proteins; Heart Failure; Luminescent Proteins; Myocardial Contraction; Myocardium; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Peptide Fragments; Proteins; Rabbits; Radioligand Assay; Receptors, Cell Surface; Receptors, Parathyroid Hormone; Receptors, Vasopressin; Recombinant Fusion Proteins; Signal Transduction; Transgenes; Type C Phospholipases; Virulence Factors, Bordetella

Topics: Aged; Deamino Arginine Vasopressin; Enuresis; Heart Failure; Humans; Renal Agents; Time Factors; Urinary Incontinence

Peripheral vasodilatation in response to muscarinic agonists has been shown to be subnormal during heart failure. However, a more recent study suggested that the abnormal muscarinic-induced vasodilatation was not due to abnormal nitric oxide synthase activity. This study was designed to show that nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation and to determine whether vasodilatation mediated by nitric oxide synthase is abnormal during heart failure.. Desmopressin (10, 50, and 100 ng/min) was infused into the brachial artery of 10 healthy subjects and eight patients with heart failure, and forearm blood flow was measured by venous occlusion plethsymography. Desmopressin responses were then recorded during inhibition of nitric oxide synthase with L-monomethylarginine or after aspirin.. In healthy subjects, desmopressin caused a significant (p < 0.001) dose-dependent increase in forearm blood flow of 0.9 +/- 0.6, 4.0 +/- 2.6, and 7.9 +/- 2.6 ml/min/dl, respectively. Desmopressin responses in heart failure of 0.8 +/- 0.6, 1.7 +/- 1.4, and 3.1 +/- 1.0 ml/min/dl were significantly less (p < 0.001) than normal. L-Monomethylarginine reduced desmopressin responses in normal subjects (p < 0.01), and this inhibitory effect was significantly (p < 0.01) greater than in patients with heart failure. Aspirin did not affect desmopressin-induced vasodilatation.. Nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation. In response to desmopressin, patients with heart failure have subnormal vasodilatation mediated through nitric oxide synthase.

Topics: Adult; Aspirin; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Forearm; Heart Failure; Humans; Male; Middle Aged; Nitric Oxide Synthase; omega-N-Methylarginine; Plethysmography; Renal Agents; Vasodilation