Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience.

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

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The present study evaluates the inter-relationship between the alteration in atrial natriuretic factor (ANF) and the renal handling of Na in rats with chronic aortocaval (a-v) fistula, an experimental model of congestive heart failure. Balance studies in these animals showed two distinct patterns of Na excretion: some rats developed progressive Na retention [urinary sodium excretion (UNaV) less than 100 mueq/24 h], whereas others compensated and returned to normal Na balance (UNaV greater than 1,200 mueq/24 h). Base-line plasma ANF levels were equally elevated in Na-retaining and compensated rats with a-v fistula (588 +/- 70 vs. 621 +/- 114 pg/ml, P, NS). However, the response of the two groups to exogenous administration of synthetic rat ANF-(101-126) in incremental doses varied greatly. ANF infusion increased the fractional Na excretion (FENa) in compensated animals from 0.12 +/- 0.03 to 2.6 +/- 0.5%, whereas the rise in FENa in Na-retaining animals was markedly blunted (0.11 +/- 0.06 to 0.89 +/- 0.35%). A similar pattern of ANF action was observed on the glomerular filtration rate and urine flow. The blunted response to ANF in the Na-retaining animals was associated with a marked increase in plasma renin activity (PRA) (35.6 +/- 6.9 vs. 4.5 +/- 0.7 ng ANG I.ml-1.h-1 in sham control rats, P less than 0.05) and plasma aldosterone levels (729.3 +/- 28.2 vs. 42.6 +/- 18.4 ng/dl in sham control rats, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)