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Background Chronic activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Increasing evidence indicates that other than the circulating RAS, a local RAS exists in several tissues, including the heart. The present study was carried out to quantify cardiac, renal, and pulmonary mRNA levels of renin, angiotensin-converting enzyme (ACE), and types 1 and 2 angiotensin II receptors (AT-1 and AT-2), in rats with different severities of heart failure. Methods and Results Heart failure was induced by the creation of an aortocaval fistula below the renal arteries. Rats with aortocaval fistula either compensate and maintain a normal sodium balance or decompensate and develop severe sodium retention. Six days after placement of the aortocaval fistula, heart weight (normalized to body weight) increased 35% ( P P P P P P Conclusions The development of heart failure is associated with a remarkable increase in the expression of a local RAS in the heart, which may contribute to the pathogenesis of this clinical syndrome.

It is believed that the hypertensive effect of diaspirin crosslinked hemoglobin, a viable blood substitute, can be resolved by polymerization, which reduces the diffusion of this derivative into the interstitial space between nitric oxide-producing endothelium and the target vascular smooth muscle. We studied the systemic and renal responses to infusion of three cell-free human hemoglobins in anesthetized isovolemic rats: unmodified (HbA0), crosslinked (alpha-DBBF), and polymerized crosslinked (poly alpha-DBBF). HbA0 produced a significant increase in mean arterial blood pressure (MAP) throughout the 60-minute infusion. alpha-DBBF, on the other hand, produced a more marked and prolonged increase in MAP over 120 minutes. Only a moderate increase in MAP was observed in rats after a 30-minute infusion with poly alpha-DBBF. The extent of renal insufficiency produced by these proteins, as determined by the glomerular filtration rate, was in the following order: HbA0 > poly alpha-DBBF > alpha-DBBF. Infusion of poly alpha-DBBF, under hypovolemic but not isovolemic conditions in rats, produced an increase in heart rate, cardiac output, and stroke volume and a decrease in total peripheral resistance after 60 minutes. Chemical polymerization to increase the size of alpha-DBBF does not appear to improve its hemodynamic properties in rats, especially under partial exchange transfusion, a more clinically relevant indication for a hemoglobin-based blood substitute.

Abstract Congestive heart failure is characterized by avid sodium retention and a blunted renal response to exogenous and endogenous atrial natriuretic peptide. Inhibition of neutral endopeptidase EC 3.4.24.11 , the main enzyme that degrades natriuretic peptides, produces a natriuretic response in different models of congestive heart failure. This raises the possibility that an increase in either the expression or activity of neutral endopeptidase is responsible for these phenomena. In the present study, we examined (1) the renal effects of SQ-28,603, a neutral endopeptidase inhibitor, in rats with moderate and severe congestive heart failure induced by an aortocaval fistula compared with sham controls, and (2) neutral endopeptidase expression and activity in the lungs and kidneys of these rats. Infusion of SQ-28,603 (40 mg/kg IV) induced a significant natriuretic response in normal rats and rats with moderate congestive heart failure. This response was blunted in rats with severe congestive heart failure. Surprisingly, renal neutral endopeptidase mRNA levels, assessed by quantitative reverse transcriptase–polymerase chain reaction; protein levels, assessed by Western blotting; and activity, assessed by gelatin gels, were comparable in all groups. Pulmonary neutral endopeptidase mRNA levels decreased by 45% in rats with severe congestive heart failure but not in rats with mild congestive heart failure. In addition, pulmonary neutral endopeptidase immunoreactivity levels and activity were significantly decreased in congestive heart failure in correlation with the severity of the disorder. We conclude that an increase in neutral endopeptidase expression or activity does not occur in rats with congestive heart failure, and therefore, an upregulation of neutral endopeptidase is unlikely to account for the blunted natriuretic response to the atrial natriuretic peptide and the positive sodium balance in congestive heart failure.

Abstract Increasing evidence suggests that endothelin, a potent vasoconstrictor, is implicated in cyclosporin A (CsA)–induced nephrotoxicity. Increased levels of urinary and circulating endothelin have been described in CsA-treated humans and animals. The exact mechanisms by which CsA induces these increases are still unknown, and no data indicate whether these elevated levels reflect increased synthesis or decreased clearance of endothelin. In the present study, we investigated the effects of CsA administration (50 mg/kg per day IP for 6 days) to rats on plasma and urinary levels of endothelin; expression of endothelin-1 (ET-1), ET-3, and endothelin-converting enzyme in renal tissue; clearance of infused 125 I–ET-1; and degradation of 125 I–ET-1 by recombinant neutral endopeptidase. Rats given CsA for 6 days developed severe renal insufficiency, as shown by a 74% decrease in creatinine clearance rate (Ccr) ( P P P 125 I–ET-1 from the blood or the renal and pulmonary uptake of the peptide. Moreover, CsA did not affect the degradation of 125 I–ET-1 by highly purified recombinant neutral endopeptidase, a well-known endothelinase. Taken together, these data suggest that the elevated urinary endothelin levels obtained after CsA treatment originate from the kidney and reflect increased renal synthesis of ET-1. Moreover, the production of endothelin appears to be regulated at the mRNA transcription level, and expressions of ET-1 and ET-3 are regulated independently.