The cardiac tissue from the area at risk was excised and transcript and protein expression levels of Gai2 and Gai3 were measured and compared to samples from sham-operated controls. The Gai2-specific mRNA was up regulated more than threefold after one hour of ischemia while there was no significant change in the protein level. In the following early phase of reperfusion Gai2 transcripts peaked with an eightfold increase with subsequent more than twofold increase in the protein level during late phase of reperfusion. Similarly, Gai3 mRNA was also regulated during ischemia and reperfusion time in a similar manner but less intense. Interestingly, protein levels increased Saclofen statistically significant more than twofold during reperfusion phase. The role of Gi-protein-dependent receptor signaling in the cardiovascular system is still a matter of intense investigations. A variety of therapeutics acting on Gi-PCRs is currently in use for regulation of heart function and protection. Therefore, cardiovascular Gi-PCRs are the most targeted receptors in the pharmacological treatment of cardiac diseases. In principle all these receptors can couple to two Gai-isoforms, i.e. Gai2 and Gai3. However, current thinking implies only Gai2 as the isoform responsible for eliciting biological effects whereas a role for Gai3 is neglected in this scenario. Hence, the aim of our study was to focus on a role for Gai3 in cardiac ischemia. Here, we show for the first time that the absence of Gai2 or Gai3 have opposite effects on the severity of myocardial IR injury in knockout mice. In particular, Gai2-deficiency led to enhanced myocardial infarct size whereas the absence of Gai3 was SA 57 highly protective. Whereas the first observation confirms and extends previous studies, the latter finding was unexpected. The increased infarct size visible in Gai2-deficient mice underlines a protective role of Gai2 signaling which was reported in previous studies making use of different experimental approaches. For instance, in vivo administration of PTX being considered a functional pan-Gi-inhibitor in combination with an infarct model demonstrated a cardio-protective effect of these G-proteins in rat hearts. We performed similar experiments using our acute mouse model of 60 min. of regional myocardial ischemia followed by 120 min. reperfusion in vivo. Interestingly, infarct sizes of the PTX-treated animals were even more pronounced as compared to those seen in Gai2-deficient mice, i.e. 67.064.8% vs. 56.663.7%, respectively, whereas the values for the controls in either group were almost the same. The latter data argue for a reliable procedure as indicated by similar values in both control groups.