Abstract
Although hydralazine and organic nitrates have proven clinical benefits for heart failure, the underlying mechanism of action of this combination remains obscure. Spontaneously Hypertensive Heart Failure (SHHF) rats are a representative heart failure model which shares common phenotypic features with human failing hearts. We have recently shown that SHHF cardiomyocytes exhibit depressed contractility and calcium transient amplitude in response to increasing rate and increased sarcoplasmic reticulum (SR) calcium leak, typical characteristics observed in heart failure. The purpose of this study was to test the hypothesis that hydralazine, alone or in combination with nitroglycerin, restores calcium cycling and contractile performance in cardiomyocytes from SHHF rats. We measured sarcomere length (SL) shortening and calcium transient amplitude (Δ[Ca
2+
]
i
) in isolated cardiac myocytes from male SHHF rats (22–24 months old, n=4) and their normotensive controls Wistar-Kyoto rats (18–22 months old, n=4) during pacing (0.5–4 Hz). Both SL shortening and Δ[Ca
2+
]
i
responses to increasing pacing in SHHF cardiomyocytes were augmented by 10 μM hydralazine. The same concentration of nitroglycerin alone did not significantly affect these parameters. In response to the combination of these two drugs, there was a strong trend toward improved contractility and normal Δ[Ca
2+
]
i
. We also assessed SR Ca
2+
leak by a brief incubation with tetracaine following by a caffeine challenge, a regimen designed to test SR Ca
2+
load. At matched SR Ca
2+
content, Ca
2+
leak was not significantly changed by nitroglycerin or hydralazine alone. However, in combination they restored the leak in SHHF myocytes to the normal levels seen in WKY myocytes. Hydralazine improves cardiac excitation-contraction coupling that is impaired in this model, whereas nitroglycerin does not exert a significant effect on this response. However, when administered together, nitroglycerin appears to modulate the enhancing effect induced by hydralazine and helps to restore normal SR calcium leakage. These data offer new insights into the mechanisms underlying the actions of hydralazine and organic nitrates on heart failure.