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Rosiglitazone improves the natriuretic response to atrial natriuretic peptide in rats with experimental congestive heart failure: possible involvement of a post-guanylate cyclase mechanism
© Goltsman et al; licensee BioMed Central Ltd. 2011
- Published: 1 August 2011
- Congestive Heart Failure
- Atrial Natriuretic Peptide
- Natriuretic Response
- Relevant Gene Expression
Congestive heart failure (CHF) in patients and experimental animals is characterized by renal retention of salt and water and a blunted natriuretic/diuretic response to atrial natriuretic peptide (ANP). Recently, we reported that chronic treatment with the PPARγ-agonist rosiglitazone (RGZ) improved the natriuretic and diuretic responses to extracellular fluid volume expansion in rats with aorto-caval fistula, an experimental model of volume-overload CHF . In the present study we explored whether RGZ improves also the natriuretic/diuretic response to ANP in rats with experimental CHF. In addition, we evaluated the effects of the drug on ANP-mediated cGMP signalling in the kidney.
CHF was induced in male Sprague-Dawley rats by surgical formation of a fistula between the aorta and inferior vena cava (1.2 mm O.D.). The natriuretic/diuretic responses and urinary cGMP (UcGMP) excretion in response to rat ANP (15 and 50 µg/kg/hr, low and high doses, respectively) were assessed by clearance methodology in CHF rats following 2 weeks of RGZ (30 mg/kg/day, p.o.) or vehicle (Veh) treatment, and in sham-operated controls (N=6-10). The capacity of isolated glomeruli and collecting ducts to generate cGMP in-vitro in response to ANP (10-11-10-6M, in the presence of 1.0 mM IBMX) was tested. Urinary and tissue cGMP levels were measured using ELISA. Moreover, to screen for relevant gene expression targets of RGZ (renal cortex and medulla samples, N=3 in each group), quantitative real-time PCR was performed using Taqman® array plates testing 32 selected genes related to ANP/cGMP signalling and controls.
In rats with experimental CHF, chronic RGZ treatment enhances renal ANP-induced natriuresis, probably at a step beyond cGMP generation. Furthermore, the data reveal several gene expression targets, including members of the phosphodiesterase family, eNOS and Mas receptor, that may be involved in the improvement in ANP-induced natriuresis.
- Goltsman I, Wang X, Lavallie ER, Diblasio-Smith EA, Ovcharenko E, Hoffman A, Abassi Z, Feuerstein GZ, Winaver J: Effects of chronic rosiglitazone treatment on renal handling of salt and water in rats with volume-overload congestive heart failure. Circ Heart Fail. 2011, 4: 345-354. 10.1161/CIRCHEARTFAILURE.110.960179.View ArticlePubMedGoogle Scholar
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