Cardioprotective effects of novel tetrahydroisoquinoline analogs of nitrobenzylmercaptopurine riboside in an isolated perfused rat heart model of acute myocardial infarction

Abstract

We have investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analog nucleoside transport (NT) inhibitors, compounds 2 and 4, in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min of treatment with compound 2, compound 4, or vehicle (control) followed by 30 min of global ischemia and 120 min of reperfusion. For determination of infarct size, reperfusion time was 180 min. At 1 microM, compounds 2 and 4 provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end-diastolic pressure (EDP) increase of 82.9 +/- 4.0% (P<0.001) and 14.1 +/- 2.0 mmHg (P<0.03) for compound 2-treated hearts and 79.2 +/- 5.9% (P<0.002) and 7.5 +/- 2.7 mmHg (P<0.01) for compound 4-treated hearts compared with 41.6 +/- 5.2% and 42.5 +/- 6.5 mmHg for control hearts. LVDP recovery and EDP increase were 64.1 +/- 4.2% and 29.1 +/- 2.5 mmHg for hearts treated with 1 microM NBMPR. Compound 4 was the best cardioprotective agent, affording significant cardioprotection, even at 0.1 microM, with LVDP recovery and EDP increase of 76.0 +/- 4.9% (P<0.003) and 14.1 +/- 1.0 mmHg (P<0.03). At 1 microM, compound 4 and NBMPR reduced infarct size, with infarct area-to-total risk area ratios of 29.13 +/- 3.17 (P<0.001) for compound 4 and 37.5 +/- 3.42 (P<0.01) for NBMPR vs. 51.08 +/- 5.06% for control hearts. Infarct size was more effectively reduced by compound 4 than by NBMPR (P<0.02). These new tetrahydroisoquinoline NBMPR analogs are not only potent cardioprotective agents but are, also, more effective than NBMPR in this model.

Nucleoside and nucleobase transporters of primary human cardiac microvascular endothelial cells: characterization of a novel nucleobase transporter

“…In fact, cardiovascular drugs like dipyridamole inhibit NTs, thereby extending the lifespan of adenosine in the vasculature (25). Analogs of NBMPR (29) and dipyridamole (18) are now being designed and tested for the potential to act as cardioprotective agents, thus highlighting the importance of vascular NTs as potential therapeutic targets.…”

Equilibrative Nucleoside Transporters 1 and 4

“… 42 Second, pharmacological inhibition of ENT1 and ENT2 by NBMPR and dipyridamole reduces the incidence of ventricular fibrillation and attenuates regional contractile dysfunction mediated by myocardial infarction due to reperfusion injury. 43 – 46 Genetic knockout or pharmacological inhibition of ENT1 is supposed to potentiate the effect of endogenous adenosine by reducing and retarding the disappearance of adenosine. In addition, inhibition of ENTs may also cause retention/trapping of adenosine within cardiomyocytes, which helps replenish essential adenine nucleotides (eg, ATP).…”

Bidirectional transport of 2-chloroadenosine by equilibrative nucleoside transporter 4 (hENT4): Evidence for allosteric kinetics at acidic pH

“…Under normal physiological conditions, cellular adenosine flux is inwards due to its rapid intracellular metabolism to adenine nucleotides 8 . Inhibition of ENT1 ( SLC29A1 ; equilibrative nucleoside transporter 1), the most studied of this family of transporters, causes vasodilation due to enhancement of the activity of adenosine at its receptors in the vasculature, and this has been shown to be cardioprotective 9–12 . However, ENT1 inhibitors have not proven effective clinically as they lead to vasodilation throughout the tissue, not just in the ischaemic regions; this can actually worsen the injury due to the ‘stealing’ of blood flow from the ischaemic areas 13,14 .…”