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This Article Full Text Full Text (PDF) All Versions of this Article: 92/1/147    most recent expphysiol.2006.035097v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Itoh, T. Articles by Abe, K. Search for Related Content PubMed PubMed Citation Articles by Itoh, T. Articles by Abe, K.

¹ Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan

Using a working perfused heart model, we investigated the hypothesis that alterations in the NO–cGMP pathway may exacerbate postischaemic mechanical dysfunction in the hypertrophied heart. Ischaemia for 25 min followed by reperfusion for 30 min produced marked cardiac mechanical dysfunction in both stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY). Exogenous treatment with S-nitroso-N-acetyl-DL-penicillamine (SNAP), a NO donor, had beneficial effects on the cardiac dysfunction induced by ischaemia–reperfusion (I/R) in the WKY heart, but the cardioprotective effect of SNAP was eliminated by guanylyl cyclase inhibitor. Cardiac cGMP levels were increased by SNAP or ischaemia in WKY. In contrast, in SHRSP hearts, SNAP could not alleviate the cardiac dysfunction caused by I/R. Pre-ischaemia, the cardiac cGMP level was significantly higher in SHRSP than in WKY; however, no significant difference was found after SNAP and ischaemia. The myocardial Ca²⁺-dependent NO synthase (NOS) activity increased at the end of ischaemia in WKY. Conversely, the Ca²⁺-independent NOS activity and protein levels were upregulated by I/R in the SHRSP myocardium. In the SHRSP hearts, non-selective NOS and selective Ca²⁺-independent NOS inhibitors or antioxidant treatment alleviated cardiac dysfunction caused by I/R. Moreover, mRNA expression and Western blotting analysis of cGMP-dependent protein kinase type I showed more deterioration of SHRSP hearts compared with WKY. These results suggest that: (1) the NO-dependent cardioprotective effect is depressed; and (2) overproduction of NO derived from Ca²⁺-independent NOS contributes to postischaemic heart injury in the hypertrophied heart of hypertensive status.

(Received 7 July 2006; accepted after revision 5 October 2006; first published online 9 October 2006)
Corresponding author T. Itoh: Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan. Email: tetsuji.itoh{at}shionogi.co.jp