**1. Introduction**

Thiazolidinediones (TZDs) are a class of anti-diabetic drugs that sensitize fat cells to insulin [1] through activation of the peroxisome proliferator-activated receptor-gamma (PPARγ). PPARγ activation has been postulated to activate endothelial nitric oxide synthase, which plays a key role in cardioprotection [2,3]. Therefore, TZDs have cardioprotective e ffects in ischemia/reperfusion (IR) injury, as reported both in in- and ex-vivo models [4–10]. Moreover, since the PPARγ antagonist GW9662 abolishes both endogenous [11] and exogenous [11,12] cardioprotection against IR injury,

the notion that TZDs could be beneficial indirectly through controlling diabetes and through direct cardioprotection against IR injury appears attractive.

However, reports about the deleterious cardiovascular side effects of one of the TZDs, rosiglitazone, first in animals [13–17] and later in humans [18,19] have dampened these hopes. As a result rosiglitazone was taken off the market in Europe and had been put under sales restriction in the USA for several years [20,21]. Pioglitazone, another popular TZD, has a better cardiovascular safety profile [22], but was subsequently taken off the market in several countries after reports of an increased incidence of bladder cancer [23–25]. Although rosiglitazone was subsequently not found to be associated with increased ischemic events [26] and the sales restrictions were lifted in the USA, both drugs remain contra-indicated in patients with heart failure [27,28].

One potential mechanism of this process may involve mitochondria, which play a key role in cell signaling and cell death, and can attenuate or aggravate IR injury [29]. The goal of our study was to investigate if TZDs affect the mitochondrial redox state in rat isolated hearts.

#### **2. Material and Methods**

Our isolated heart model has been described in detail [30–33]. All drugs were purchased from Sigma (St. Louis, MO, USA) unless otherwise indicated. Rosiglitazone, pioglitazone, and GW 9662 were dissolved in dimethyl sulfoxide (DMSO) and 1000-fold diluted in Krebs solution to yield the indicated final drug concentrations in 0.1% DMSO.
