PO07 | PLATELET INHIBITION BY THE NOVEL NITRIC OXIDE-DONOR NITROSOOXYPROPANOL

M. Lindkvist, J. Jakobsson, F. Lynfeldt, B. Sandberg, K. Fransén, K. Nilsson, M. Grenegård | Cardiovascular Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

Introduction. The multiple roles of nitric oxide (NO) in human physiology include platelet inhibition and vasodilation, both important to prevent cardiovascular disease events like thrombosis and ischemia, common complications in cancer. NO-donating drugs, such as the clinically established nitroglycerin, have been used for decades; however, current NO-delivering therapies often suffer from limitations such as the development of tolerance or the requirement for metabolic activation. The novel organic nitrite Nitrosooxypropanol (PDNO) has shown potent cardiovascular effects in vivo, and preclinical studies have confirmed its safety and efficacy in models of acute pulmonary hypertension. Compared to conventional NO-donors, PDNO exhibits a superior pharmacological profile, marked by rapid onset and lack of tolerance. Due to PDNO’s rapid release of bioavailable NO, treatment can be targeted to different vascular beds (depending on site of administration) and thereby reduce the risk of systemic side effects. Taken together, these properties position PDNO as an ideal candidate for drug repurposing beyond cardiopulmonary indications.

Aim. This project aims to elucidate the potential inhibitory capacity of PDNO on human platelets, which is yet unexplored and could be beneficial in new treatment strategies in indications of thrombosis.

Materials and Methods. Effects of PDNO on human platelet aggregation and secretion were investigated using impedance aggregometry in whole blood and light transmission aggregometry in platelet-rich plasma and isolated platelets. Molecular evidence was investigated by measuring cytosolic calcium mobilization and by Western blot.

Results. Platelet aggregation and secretion induced by the thrombin receptor agonist SFLLRN were concentration-dependently inhibited by PDNO. Pharmacological comparison of platelet inhibition revealed that PDNO was more potent than the clinically used NO-donor nitroglycerin. Moreover, PDNO triggered NO/cGMP signaling, demonstrated by Ser239-specific phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Measurements of cytosolic calcium showed that PDNO had a similar capacity to reduce Ca²⁺ mobilization as the spontaneous NO-donor SNAP. The platelet inhibitory capacity of PDNO showed a rapid on-set of action and a surprisingly long-acting effect, from 10 seconds to 60 minutes.

Conclusions. The novel NO-donor PDNO elicits significant platelet inhibitory capacity and antithrombotic therapeutic potential.