Background:
Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca
2+
-ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF.
Methods:
Left ventricular (LV) and myocyte function and the protein levels of myocyte β
1
- and β
3
- AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group):
HF
, 3 months (M) after receiving ISO (170 mg/kg sq for 2 days);
HF/SIL
, 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and
Controls
(C).
Results:
Compared with controls, ISO-treated rats progressed to severe HF at 3 M after ISO followed by significantly decreased LV contractility (E
ES
, HF: 0.7 vs C: 1.2 mmHg/μl) and slowed LV relaxation, reductions in the peak velocity of myocyte shortening (77 vs 136 μm/sec), relengthening (62 vs 104 μm/sec) and [Ca
2+
]
iT
(0.15 vs 0.24) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10
-8
M). These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β
1
-AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLB
Ser16
/PLB ratio (0.24 vs 0.40) and eNOS (0.28 vs 0.46), but significantly increases in protein levels of β
3
-AR (0.29 vs 0.10) and iNOS (0.18 vs 0.08) with relatively unchanged nNOS. Chronic SIL prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca
2+
]
iT
,
and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β
1
- and β
3
-AR, SERCA2a were restored close to control values, but eNOS was significantly elevated than controls (0.77).
Conclusions:
Chronic SIL prevents HF-caused downregulation of cardiac β
1
-AR and reverse contrast changes between iNOS and β
3
-AR with SERCA 2a and eNOS expression, leading to the preservation of LV and myocyte function, [Ca
2+
]
iT
, and β-adrenergic reserve.
Increased expression of constitutive nitric oxide synthase III, but not inducible nitric oxide synthase II, in human heart failure 11During publication process the following related paper has been published by Vejlstrup NG, Bouloumie A, Boesgaard S, Andersen CB, Nielsen-Kudsk JE, Mortensen SA, Kent JD, Harrison DG, Busse R, Alsershvile J. Inducible nitric oxide synthase (iNOS) in the human heart: Expression and localization in congestive heart failure. J Mol Cell Cardiol 1998;30:1215–23.
