| Research Abstract |
1. Endothelin (ET)-1 not only causes potent vasoconstriction but also leads to fluid retention, which are both mediated by ETA and/or ETB receptors. We administered either the selective ETA receptor antagonist FR173657 (FR) or the mixed ETA/ETB receptor antagonist TAK-O44 (TAK) to dogs with heart failure (HF) induced by rapid ventricular pacing, FR increased urinary excretion in association with increased renal plasma flow (RPF) and glomerular filtration rate (GFR) with no significant changes in the fractional reabsorption of water distalfy (FRWD). In contrast, despite increased GFR, TAK did not alter urine volume or RPF with significantly increased FRWD. The incremental magnitude of GFR and RPF induced by FR was significantly larger than that by TAK. These findings indicate that ETB receptor activation may result in diuresis by renal vasodilatation and blunting water reabsorption in the distal tubules and collecting ducts.
2. We administered K-8794, an orally active selective ET-B rece
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ptor antagonist, to dogs with HF. Plasma renin activity and aldosterone increased in both control and K8794 groups, however, levels in the K-8794 group were significantly lower than dose in the control group. In the K-8794 group, it was quite interesting to note that Na excretion and urine flow rate were higher than in the control group. Although ET-B receptor antagonism possesses some hemodynamic disadvantages, it can successfully prevent body fluid retention through the suppression of the activation of the renin-angiotensin-aldosterone system in dogs with HF.
3. We examined the combination effects of an ET-converting enzyme inhibitor (FR901533) and an ACE inhibitor (enalapril) on changes in hemodynamics, the expression of molecular markers of HF and the histomorphometry compared with those of monotherapy in dogs with HF. Although there were no differences observed in LV ejection fraction, combination therapy of both inhibitors significantly decreased LV filling pressure, shortened the time constant of relaxation and upregulated the expression of sarcoplasmic reticulum Ca2+-ATPase mRNA. The combination also decreased the expression of collagen type III mRNA and cardiac collagen deposits compared with those of monotherapy. Combining these two modes of enzyme inhibition may further improve LV diastolic dysfunction rather than systolic dysfunction, via modification of nitric oxide rele and Ca2+ handling as well as suppression of collagen accumulation in HF. Less
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