Vasopeptidase inhibition reverses myocardial vasoactive intestinal peptide depletion and decreases fibrosis in salt sensitive hypertension.
We have shown previously that the concentration of Vasoactive Intestinal Peptide (VIP) in the heart is inversely correlated with the degree of fibrosis in a number of experimental models of early myocardial fibrosis. Vasopeptidase inhibition and angiotensin converting enzyme inhibition both decrease myocardial fibrosis. In this study, we sought to determine whether this myocardial protective effect might reflect increased VIP concentrations in the heart. We compared the effects of 4 weeks treatment of the vasopeptidase inhibitor omapatrilat and the angiotensin converting enzyme inhibitor enalapril on the degree of fibrosis and the concentration of VIP in the heart in salt sensitive hypertension induced by treatment with L-nitro-omega-methylarginine (L-NAME). Systolic blood pressure decreased in both treatment groups compared with control (omapatrilat P<0.005; enalapril P<0.001). Myocardial fibrosis was less for omapatrilat than control (P<0.0005) and enalapril (P<0.0005) groups. Myocardial VIP was greater in omapatrilat than in controls (P<0.005) and enalapril-treated rats (P<0.05). We conclude that vasopeptidase inhibition exerts a greater myocardial protective effect than angiotensin converting enzyme inhibition. Further, this myocardial protective effect is associated with increased VIP in the heart suggesting a pathogenetic role for VIP depletion in the development of fibrosis in the heart.
Ye
Victor Z C
VZ
Hypertension Service, University of New South Wales Clinical School, South Western Sydney Area Health Service, Bankstown-Lidcombe Hospital, Eldridge Road, Bankstown, Sydney NSW 2200, Australia.
Hodge
George
G
Yong
Jim L C
JL
Duggan
Karen A
KA
D000818:Animals; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D005355:Fibrosis; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D013841:Thiazepines / Q000494:pharmacology / Q000627:therapeutic use; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D014660:Vasoactive Intestinal Peptide; D004656:Enalapril; D010447:Peptide Hydrolases