Background Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treat...
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Background Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. Methods Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. Results Through activation of V-1a and V-2 receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V-2 and dual V-1a/V-2 receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase Serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V-1a receptor antagonism requires further investigation. Conclusions Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.
Background & Aims: Impaired presser function in cirrhosis may be specific to certain agonists and vascular territories. This investigation determined whether responses to arginine vasopressin (AVP) and 5-hydroxytr...
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Background & Aims: Impaired presser function in cirrhosis may be specific to certain agonists and vascular territories. This investigation determined whether responses to arginine vasopressin (AVP) and 5-hydroxytryptamine (5-MT) were impaired in hepatic arteries from cirrhotic patients. Methods: Cumulative concentration-response curves were produced for AVP (10(-11) to 3 x 10(-6) mol/L), 5-HT (10(-9) to 3 x 10(-5) mol/L), and potassium chloride (2.5 -120 mmol/L) in hepatic arteries from liver donors (noncirrhotic) and recipients (cirrhotic), The receptor stimulated by AVP was identified using a V-1-receptor antagonist (d[CH2](5)Tyr[Me]AVP) and a selective V-2-receptor agonist (desmopressin [DDAVP]), Results: Cirrhotic patients had a high heart rate (98 +/- 4 beats/min) and cardiac output (9.87 +/- 0.51 L/min) but low peripheral vascular resistance (711 +/- 35 dyn . s/cm(5)). None of the arteries had a functional endothelium. Maximal contraction (but not sensitivity) to AVP was smaller (P = 0.0002) in hepatic arteries from recipients (34.03% +/- 3.42% KCl) than donors (60.69% +/- 5.56% KCI), 5-HT-mediated contraction was enhanced in recipient hepatic arteries (88.81% +/- 5.43% KCI vs, 71.63% +/- 4.46% KCl;P = 0.01), but sensitivities were similar (P = 0.20), KCl-mediated contractions were similar (P = 0.87) in both groups. Arteries did not respond to DDAVP, but d(CH2)(5)Tyr(Me)AVP produced a concentration-dependent rightward shift in the response to AVP, Conclusions: These results demonstrate a selective impairment of V-1 receptor-mediated contraction in denuded hepatic arteries from cirrhotic patients, suggesting an abnormality within the vascular smooth muscle.
The precise role of vasopressin in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is important for several reasons. Firstly, circulating concentrations of vasopressin are elev...
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The precise role of vasopressin in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is important for several reasons. Firstly, circulating concentrations of vasopressin are elevated in heart failure and some forms of hypertension. Secondly, there is evidence that vasopressin is synthesized not only in the hypophysial-pituitary axis but also in peripheral tissues including the heart where it acts as a paracrine hormone. Thirdly, vasopressin has vasoconstrictor, mitogenic, hyperplastic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Finally, the availability of orally active non-peptide vasopressin receptor antagonists allows vasopressin receptor antagonism to be considered as a therapeutic option in cardiovascular disease.
1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones mas investigated using specific V-1a- nnd V-2-type AVP receptor agonists and antagoni...
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1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones mas investigated using specific V-1a- nnd V-2-type AVP receptor agonists and antagonists. 2. In 97% of AVP-responding neurones (1-3000 nM) V-1a or V-2 receptor type agonists (F-180 and dDAVP, respectively) elicited dose-dependent [Ca2+](i) transients that were suppressed by removal of external Ca2+. 3. The [Ca2+](i) response induced by 1 mu M F-180 or dDAVP JP was selectively blocked by 10 nM of V-1a and V-2 antagonists (SR 49059 and SR 121463A, respectively). The response to V-1a agonist was maintained in the presence of the V-2 antagonist, and the V-2 agonist-induced response persisted in the presence of the V-1a antagonist. 4. The [Ca2+](i) response induced by 1 mu M AVP was partially (61%) blocked by 10 nM SR 121463A. This blockade was increased by a further 31% with the addition, of 10 nM SR 49059. Similarly, the AVP-induced response was partially (47%) decreased by SR 49059, and a further inhibition of 33% was achieved in the presence of SR 121463A. 5. We demonstrate that AVP acts: on the magnocellular neurones via two distinct types of AVP receptors that exhibit the pharmacological profiles of V-1a and V-2 types. However, since V-2 receptor mRNA is not expressed in the supraoptic nucleus (SON), and since V-1b receptor transcripts are observed in the SON, we propose that the V-2 receptor agonist and antagonist act on a 'V-2-like' receptor or a new type of AVP receptor that remains to be elucidated. The possibility that V-2 ligands act on the V-1b receptor cannot be excluded.
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