Myocardial vasoactive intestinal peptide and fibrosis induced by nitric oxide synthase inhibition in the rat.
OBJECTIVE
In both normotensive and hypertensive rats, the degree of myocardial fibrosis is inversely correlated with the concentration of vasoactive intestinal peptide (VIP) in the myocardium. Treatment with nitric oxide (NO) synthase inhibitors also causes myocardial fibrosis. In this study, we sought to determine whether the myocardial fibrosis induced by treatment with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) was also associated with depletion of VIP in the myocardium.


METHODS
Male Wistar Kyoto (WKY) and spontaneous hypertensive rats (SHR) rats treated with l-NAME were randomized to low, intermediate or high salt content diets. After 4 weeks, the hearts were harvested, the degree of fibrosis quantified and VIP concentration measured.


RESULTS
In WKY, systolic blood pressure increased with increasing dietary sodium (P < 0.05). Myocardial fibrosis also increased with increasing dietary sodium (P < 0.005). Myocardial VIP concentration decreased with increasing dietary sodium (P < 0.025). In contrast, in the SHR treated with l-NAME, systolic blood pressure increased but the increase was not affected by sodium intake. Further, myocardial fibrosis and myocardial VIP were unchanged by increased dietary sodium. Higher doses of l-NAME in the SHR did not increase the systolic blood pressure, increase the degree of myocardial fibrosis or decrease the myocardial concentration of VIP. These differences in myocardial VIP concentration may reflect differing effects of l-NAME on VIP metabolism, as l-NAME increased VIP metabolism in the WKY (P < 0.05) but did not change VIP metabolism in the SHR.


CONCLUSIONS
We conclude that depletion of VIP in the myocardium is associated with increasing myocardial fibrosis in l-NAME treated WKY. As VIP depletion occurs in other models of myocardial fibrosis, it appears to be a common mechanism. Myocardial VIP depletion may therefore be a new and important factor in the pathogenesis of cardiac fibrosis.
Ye
V Z C
VZ
Hypertension Service and Department of Anatomical Pathology, South Western Sydney Area Health Service, Sydney, Australia.
Hodge
G
G
Yong
J L C
JL
Duggan
K A
KA
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D008297:Male; D008657:Metabolic Clearance Rate; D009206:Myocardium / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009929:Organ Size; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012982:Sodium, Dietary / Q000008:administration & dosage; D014660:Vasoactive Intestinal Peptide / Q000032:analysis* / Q000097:blood
D004791:Enzyme Inhibitors; D012982:Sodium, Dietary; D014660:Vasoactive Intestinal Peptide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester