Plasma vasopressin (AVP) and endothelin (ET) levels are often elevated in congestive
heart failure (CHF) and have been linked to edema formation commonly observed in this clinical setting. The mechanisms by which these two hormones contribute to edema remain obscure. In vivo and in vitro studies were designed to further understand the role of AVP in CHF and to examine its interaction with ET receptors. Clearance studies were performed to compare the renal excretory function in UM-X7.1 cardiomyopathic (CM) hamsters (280 to 300 days old) and age-matched healthy controls. Both
groups had well-maintained glomerular filtration rates throughout the experiments. Exogenous administration of AVP (0.3 ng-kg⁻¹-min⁻¹) had no effect on any of the measured clearance parameters in the CM animals but markedly reduced the fractional excretion of sodium (FE[sub Na]) and water (FE[sub H₂O]) in the controls by 40 and 46%, respectively. Combined infusion of a V₁ antagonist
and a V₂ agonist at the same dose similarly decreased FE[sub Na] and FE[sub H₂O] in the healthy animals. However, the CM group exhibited an attenuated response in all of the measured hemodynamic and clearance parameters even though their cAMP production was five-fold higher than that of normal animals. Additional studies support the notion that basal salt and water reabsorption in CHF was
maximal, which would account for the lack of response to infusions of AVP or combined V₁
antagonist and V₂ agonist. Nonselective blockade with the V₁ and V₂ antagonists 0.3 ng-kg⁻¹-min⁻¹ produced natriuresis and diuresis in the CM hamsters (FE[sub Na] 4.8 + 0.6 vs. 7.9 + 1.1%, p<0.05; FE[sub H₂O] 1.5 + 0.2 vs. 2.2 + 0.3%, p<0.05) but did not affect fluid reabsorption in the normal hamsters. Profuse diuresis in the diseased animals may be partially attributed to an alteration in V₂
receptor signaling as reflected by decreased urinary cAMP levels. Hence, increased basal cAMP synthesis in the kidney potentially impairs salt and water excretion in the pathophysiological state. Altered regulation of other hormonal systems might have contributed to the apparent AVP
hypersensitivity in decompensated heart failure. Previous studies have indicated ET inhibits the actions of AVP within the kidney. Whether the reverse relationship exists and what the implications are in CHF have not been investigated extensively. Accordingly, the mechanisms that reduce ET receptors (ETA and ETB subtypes) in inner medullary collecting duct (IMCD) were
determined to show how AVP controls ET function at the receptor level. Competitive binding experiments were performed to examine the effects of a AVP signaling pathway on ET receptor binding. Overnight incubation of rat IMCD cells with AVP significantly reduced the maximal
binding capacity, B[sub max], of ET. Activation of adenylate cyclase by forskolin decreased the total ET receptor binding and preferentially reduced ET[sub B] receptor density by ∼42% with no effect on the ET[sub A] subtype. Involvement of the PKA pathway in ET[sub B] receptor downregulation was strongly
implicated by the observation that a cAMP analogue, Rp-cAMPS, blocked the inhibitory influence of AVP on ET⁻¹ binding. The data further indicate that the IQ values of the ET receptors were decreased significantly and demonstrate that AVP reduced ET receptor density and increased the affinity of the existing receptors. Altogether, the competitive binding experiments suggest the following novel idea: AVP
controls sodium and water reabsorption by activating its receptors and downregulating ET[sub B] receptors via a cAMP-dependent pathway. Since ET[sub A] and ET[sub B] subtypes have different actions, changes in their distribution in vivo would affect normal hemodynamics, natriuresis, and diuresis. Hence, AVP-induced heterologous regulation of ET[sub B] receptors may result in salt and water
retention, exacerbating the condition of congestive heart failure. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/5925 |
| Date | 05 1900 |
| Creators | Wong, Bonita P. H. |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Format | 13422131 bytes, application/pdf |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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