Anti-Remodeling Effects of Chronic Phosphodiesterase-Type-5 Inhibition Are Dependent on Impaired cGMP-Dependent Protein Kinase Signaling

Background: Chronic phosphodiesterase type 5 inhibition (PDE5I) may enhance myocardial cGMP and restore cGMP dependent protein kinase (PKG) opposition to G-protein coupled receptor (GPCR) signaling in pressure overload (POL) induced heart failure (HF) and ameliorate maladaptive remodeling. However, if PKG signaling is not disrupted, PDE5I may not alter hypertrophic remodeling in POL states. Hypotheses: 1) Disruption of PKG signaling due to deletion of the natriuretic peptide receptor A (NPRA) is associated with exaggerated maladaptive remodeling in response to POL produced by transverse aortic constriction (TAC). 2) Chronic PDE5I ameliorates maladaptive remodeling in NPRA null TAC mice but not in wild type (WT) TAC mice. Methods: 8 week old NPRA null and WT litter mate mice (C57/BL6-129S background) underwent TAC or sham procedure and were randomized to Tadalafil 60mg/kg/day (oral) versus placebo. After 3 weeks, mice underwent echocardiography, left ventricular catheterization and tissue harvest. Results: See table. In response to TAC, NPRA null mice developed severe hypertrophy and systolic dysfunction while on average, WT mice developed milder hypertrophy without systolic dysfunction. Tadalafil attenuated hypertrophy and systolic dysfunction only in NPRA null mice. Conclusions: Beneficial effects of chronic PDE5I in POL are dependent on impaired cGMP production. In human HF, defects in both nitric oxide and natriuretic peptide mediated cGMP production are present, suggesting therapeutic potential for PDE5I.

	Effect of Tadalafil on Left ventricular Systolic Function, Remodeling and Hemodynamics in Response to Pressure Overload
	Genotype	Wild Type			NPRA null
	Group	SHAM	TAC Placebo	TAC Tadalafil	SHAM	TAC Placebo	TAC Tadalafil
	n	15	16	11	12	6	7
	LV Diastolic Dimension (mm)	3.7 ± 0.3	3.7 ± 0.4	3.7 ± 0.6	4.0 ± 0.7	4.7 ± 0.6∗#	4.0 ± 0.7
	Ejection Fraction (%)	75 ± 9	68 ± 14	73 ± 9	75 ± 9	42 ± 17∗#	70 ± 15 Φ
	Max LVP (mmHg)	99 ± 8	148 ± 40∗	150 ± 26∗	127 ± 13 #	128 ± 23	149 ± 10∗
	LV/Body Weight (mg/gm)	3.7 ± 1.1	5.2 ± 1.7∗	5.9 ± 2.8∗	4.6 ± 1.6	10.1 ± 3.1∗#	7.2 ± 2.3 ∗Φ
	Lung/Body Weight (mg/gm)	6.8 ± 1.4	8.3 ± 3.5	8.6 ± 4.2	7.6 ± 1.6	16.3 ± 5.5∗#	11.4 ± 4.2 ∗Φ
	Plasma cGMP (picomol/ml)	28 ± 18	20 ± 24	81 ± 41∗Φ	14 ± 5	7 ± 5 #	24 ± 13 Φ #

∗p value <0.05 vs SHAM, Φ p value<0.05 vs TAC Placebo, # p value<0.05 vs group matched WT