Combined Inhibition of Phosphodiesterase-5 and -9 in Experimental Heart Failure.
JACC Heart Fail
; 12(1): 100-113, 2024 Jan.
Article
em En
| MEDLINE
| ID: mdl-37921801
ABSTRACT
BACKGROUND:
Intracellular second messenger cyclic guanosine monophosphate (cGMP) mediates bioactivity of the natriuretic peptides and nitric oxide, and is key to circulatory homeostasis and protection against cardiovascular disease. Inhibition of cGMP-degrading phosphodiesterases (PDEs) PDE5 and PDE9 are emerging as pharmacological targets in heart failure (HF).OBJECTIVES:
The present study investigated dual enhancement of cGMP in experimental HF by combining inhibition of PDE-5 (P5-I) and PDE-9 (P9-I).METHODS:
Eight sheep with pacing-induced HF received on separate days intravenous P5-I (sildenafil), P9-I (PF-04749982), P5-I+P9-I, and vehicle control, in counterbalanced order.RESULTS:
Compared with control, separate P5-I and P9-I significantly increased circulating cGMP concentrations in association with reductions in mean arterial pressure (MAP), left atrial pressure (LAP), and pulmonary arterial pressure (PAP), with effects of P5-I on cGMP, MAP, and PAP greater than those of P9-I. Only P5-I decreased pulmonary vascular resistance. Combination P5-I+P9-I further reduced MAP, LAP, and PAP relative to inhibition of either phosphodiesterase alone. P9-I and, especially, P5-I elevated urinary cGMP levels relative to control. However, whereas inhibition of either enzyme increased urine creatinine excretion and clearance, only P9-I induced a significant diuresis and natriuresis. Combined P5-I+P9-I further elevated urine cGMP with concomitant increases in urine volume, sodium and creatinine excretion, and clearance similar to P9-I alone, despite the greater MAP reductions induced by combination treatment.CONCLUSIONS:
Combined P5-I+P9-I amalgamated the superior renal effects of P9-I and pulmonary effects of P5-1, while concurrently further reducing cardiac preload and afterload. These findings support combination P5-I+P9-I as a therapeutic strategy in HF.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Insuficiência Cardíaca
Limite:
Animals
/
Humans
Idioma:
En
Revista:
JACC Heart Fail
Ano de publicação:
2024
Tipo de documento:
Article