BACKGROUND AND PURPOSEA class of drugs known as KATP‐channel openers induce cardioprotection. This study examined the effects of the novel KATP‐channel opener, the fluorine‐containing pinacidil derivative, flocalin, on cardiac‐specific KATP‐channels, excitability of native cardiac myocytes and on the ischaemic heart.EXPERIMENTAL APPROACHThe action of flocalin was investigated on: (i) membrane currents through cardiac‐specific KATP‐channels (IKATP) formed by KIR6.2/SUR2A heterologously expressed in HEK‐293 cells (HEK‐2936.2/2A); (ii) excitability and intracellular Ca2+([Ca2+]i) transients of cultured rat neonatal cardiac myocytes; and (iii) functional and ultrastructural characteristics of isolated guinea‐pig hearts subjected to ischaemia‐reperfusion.KEY RESULTSFlocalin concentration‐dependently activated a glibenclamide‐sensitive IKATPin HEK‐2936.2/2Acells with an EC50= 8.1 ± 0.4 µM. In cardiac myocytes, flocalin (5 µM) hyperpolarized resting potential by 3–5 mV, markedly shortened action potential duration, reduced the amplitude of [Ca2+]itransients by 2–3‐fold and suppressed contraction. The magnitude and extent of reversibility of these effects depended on the type of cardiac myocytes. In isolated hearts, perfusion with 5 µmol·L−1flocalin, before inducing ischaemia, facilitated restoration of contraction during reperfusion, decreased the number of extrasystoles, prevented the appearance of coronary vasoconstriction and reduced damage to the cardiac tissue at the ultrastructural level (state of myofibrils, membrane integrity, mitochondrial cristae structure).CONCLUSION AND IMPLICATIONSFlocalin induced potent cardioprotection by activating cardiac‐type KATP‐channels with all the benefits of the presence of fluorine group in the drug structure: higher lipophilicity, decreased toxicity, resistance to oxidation and thermal degradation, decreased metabolism in the organism and prolonged therapeutic action.