CST is a CgA-derived peptide that exerts cardiovascular effects. CST plasma levels decrease in hypertensive patients and in their offsprings. Exogenous CST rescues arterial hypertension in CgA knockout mice. In healthy cohorts, ischemic and pharmacological PostC reduce infarct size (IS) via pro-survival signaling cascades. Whether PostC-induced protection is maintained in the setting of comorbidities is largely unexplored. We aimed to assess the consequences of hypertension on the infarct-sparing effect of either ischemic PostC or pharmacological CST-Post by using normotensive (WKY) and SHR rat. Isolated hearts from WKY an SHR underwent the following protocols: (a) 30-min ischemia and 120-min reperfusion (I/R); (b) PostC (I/R + 5 cycles 10-s I/R); (c) CST-Post (I/R + CST 75nM for 20-min). Developed left ventricular pressure (dLVP) and IS were measured. IS was 47±6% and 68±11% in WKY_I/R and SHR_I/R, respectively. Ischemic PostC reduced IS in WKY (31±7%), but not in SHR (58±7%). Yet CST-Post reduced IS in both strains; in particular, in SHR IS was 24±3% (p<0.001 vs both SHR_I/R and SHR_PostC). While CST-Post reduced contracture in both SHR and WKY, ischemic PostC reduced it in WKY only. In both WKY and SHR, dLVP recovery was slightly improved by PostC, being marked in CST-Post. We provide evidence for a hypertension-induced defect in the protective efficacy of PostC which is overcame by CST-Post.