THE EFFECTS OF ITI-214 (A NEW PHOSPHODIESTERASE 1 INHIBITOR) ON VASCULAR AGEING FEATURES ASSOCIATED TO DNA REPAIR RESPONSE IN MICE

Abstract

Objective: DNA damage and repair responses have been linked to accelerated vascular aging. Accordingly, mice with a genetic deletion of ERCC1 (Ercc1d/- mice), a DNA repair protein, display a rapid onset of vascular aging. A hallmark hereof is disturbed NO-cGMP signalling, in which an increase of the cyclic nucleotide-metabolizing enzyme phosphodiesterase 1 (PDE1) is implicated. We hypothesized that specific PDE1 inhibition has beneficial effects in the aged vasculature. To test this, we evaluated the effects of chronic and acute PDE1 inhibition with ITI-214 in Ercc1d/- mice and WT littermates. Design and method: ITI-214 (treated), or no drug (control), was given in drinking water from the age of 6 to 14 weeks. Blood pressure (BP) and in vivo vasodilator responses (hindleg reactive hyperemia:RH) were measured in week 12 and 13. At 14 weeks aortic tissue was obtained for ex vivo wire myograph studies to analyse endothelium-dependent and endothelium-independent relaxations to acetylcholine (Ach) and nitric oxide donor (sodium nitroprusside: SNP) respectively. Results: There were significant reductions in systolic (93.39 ± 3.406 vs. 111.7 ± 5.238 mmHg, P = 0.009) and diastolic (64.47 ± 2.7 vs. 76.43 ± 4.699 mmHg, P = 0.038) BP in treated Ercc1d/- vs. controls. RH was 50% lower in control Ercc1d/- vs. WT (P = 0.025). ITI-214 treatment did not improve RH. In contrast, ITI-214 enhanced the aortic maximal Ach response from 70.24 ± 3.24 to 76.96 ± 4.76% (P = 0.002) and the SNP response from 64.83 ± 6.10 to 85.24 ± 7.58% (P = 0.0001) in WT but not in Ercc1d/-. In contrast to chronic treatment, acute administration of ITI-214 in organ baths enhanced the SNP response in both control WT (from 64.83 ± 6.10 to 79.32 ± 5.63%, P = 0.003) and control Ercc1d/- mice (from 45.61 ± 11.6 to 75.45 ± 3.61%, P = 0.0001). Conclusions: The acute effect of ITI-214 confirms the role of PDE1 in mediating decreased NO-cGMP signalling caused by defective DNA repair. Therefore, PDE1 inhibition is a strategy to acutely improve vasodilation in the aged vasculature.