Received July 17, 2006
Revised August 4, 2006
Accepted after revision October 5, 2006

¹ Shionogi & Co., LTD.

^* To whom correspondence should be addressed. E-mail: tetsuji.itoh{at}shionogi.co.jp.

	Abstract

Using a working heart perfused model, we investigated the hypothesis that alterations in the nitric oxide (NO)-cGMP pathway may become aggravated to cause post-ischaemic mechanical dysfunction in the hypertrophied heart. Ischaemia for 25 minutes 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 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 treatment in WKY. In contrast, in SHRSP hearts, SNAP could not alleviate the cardiac dysfunction caused by I/R. The cardiac cGMP level was significantly higher than in WKY at pre-ischaemia, however, no significant difference was found after SNAP and ischaemia treatment. The myocardial Ca2+-dependent NO synthase (NOS) activity increased during the ischaemic condition in WKY. Conversely, the Ca2+-independent NOS activity and protein levels were upregulated by I/R in the SHRSP myocardium. In the SHRSP hearts, nonselective NOS and selective Ca2+-independent NOS inhibitors or anti-oxidant 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 post-ischaemic heart injury in the hypertrophied heart of hypertensive status.

Key Words: Heart, Ischaemia, Nitric oxide