Organic mononitrites of 1,2-propanediol act as an effective NO-releasing vasodilator in pulmonary hypertension and exhibit no cross-tolerance with nitroglycerin in anesthetized pigs

Abstract

PurposeClinically available intravenous (IV) nitric oxide (NO) donor drugs such as nitroglycerin (GTN) cause systemic hypotension and/or tolerance development. In a porcine model, novel NO donor compounds – the organic mononitrites of 1,2-propanediol (PDNO) – were compared to GTN with regard to pulmonary selectivity and tolerance development. The vasodilatory effects of inorganic nitrite were investigated.Materials and methodsIn anesthetized piglets, central hemodynamics were monitored. At normal pulmonary vascular resistance (PVR), IV infusions of PDNO (15–60 nmol kg−1 min−1), GTN (13–132 nmol kg−1 min−1), and inorganic nitrite (dosed as PDNO) were administered. At increased PVR (by U46619 IV), IV infusions of PDNO (60–240 nmol kg−1 min−1) and GTN (75–300 nmol kg−1 min−1) before and after a 5 h infusion of GTN (45 nmol kg−1 min−1) were given.ResultsAt normal PVR, PDNO (n=12) and GTN (n=7) caused significant dose-dependent decreases in mean systemic and pulmonary arterial pressures, whereas inorganic nitrite (n=13) had no significant effect. At increased PVR, PDNO (n=6) and GTN (n=6) significantly decreased mean systemic and pulmonary pressures and resistances, but only PDNO reduced the ratio between pulmonary and systemic vascular resistances significantly. After the 5 h GTN infusion, the hemodynamic response to GTN infusions (n=6) was significantly suppressed, whereas PDNO (n=6) produced similar hemodynamic effects to those observed before the GTN infusion.ConclusionPDNO is a vasodilator with selectivity for pulmonary circulation exhibiting no cross-tolerance to GTN, but GTN causes non selective vasodilatation with substantial tolerance development in the pulmonary and systemic circulations. Inorganic nitrite has no vasodilatory properties at relevant doses.

Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study

“…Despite cardiovascular effects of GTN and organic nitrates being well established for decades, the search for novel NO-donors for clinical use is still ongoing, and the study of the mechanisms involved in tolerance development continues [ 32 , 33 , 34 , 35 ]. In the search for new products available both as potential drugs and for use as probes to further examine the mode of action of organic nitrates, in a previous work we characterized compounds 1 – 3 for their in vitro NO-dependent vasodilating activity [ 23 ].…”

NO-Donation Increases Visceral Circulation in a Porcine Model of Abdominal Hypertension

“…In contrast, organic nitrite NO-donors are associated with less tolerance development and have therefore been presented as an attractive alternative. Previously, we designed a novel NO-donor, comprising the organic mononitrites of 1,2-propanediol, nitrosooxypropanol (PDNO), and found that it was an effective vasodilator in some different models of acute pulmonary hypertension [7,[9][10][11], and that it ameliorated renal ischemia reperfusion injury [12]. A phase I study in humans is ongoing (Eura-daCT No.…”

“…As a cardiovascular signalling molecule, nitric oxide (NO) has been shown to positively affect both lung and kidney function after aortic cross clamping by having a mitigating effect on the systemic inflammatory response [ 7 , 8 ]. Organic nitrate NO-donors (e.g., nitroglycerin) have the drawback of tolerance development in both the systemic and the pulmonary circulation [ 9 ]. In contrast, organic nitrite NO-donors are associated with less tolerance development and have therefore been presented as an attractive alternative.…”

Treatment with new organic nitrites in pulmonary hypertension of acute experimental pulmonary embolism

“…18 The two novel organic mononitrites, 2-hydroxy propyl nitrite and 2-hydroxy-1-methylethyl nitrite (henceforth referred to as PDNO, Supplementary Figure S1 for molecular structure) are of particular interest to investigate in experimental acute PE, because this composition exhibited increased vasodilator selectivity toward the pulmonary circulation compared to for example nitroglycerin. 18,22 In addition, the vasodilatory action of PDNO was devoid of cross tolerance with nitroglycerin in the systemic and pulmonary circulations, indicating bioactivation via another pathway. 22 We hypothesized that PDNO intravenously can counteract the pulmonary hypertension in acute experimental PE, without inducing systemic side effects or gas exchange disturbances, nor methemoglobinemia.…”

“…18,22 In addition, the vasodilatory action of PDNO was devoid of cross tolerance with nitroglycerin in the systemic and pulmonary circulations, indicating bioactivation via another pathway. 22 We hypothesized that PDNO intravenously can counteract the pulmonary hypertension in acute experimental PE, without inducing systemic side effects or gas exchange disturbances, nor methemoglobinemia. To distinguish the effects of the PDNO solution from inorganic nitrite and NO gas, we first performed in vivo dose-response experiments with measurement of FENO, pulmonary and systemic hemodynamics, methemoglobin and plasma nitrite both in naive animals and in animals with pharmacologically induced pulmonary hypertension.…”