INTRATRACHEAL INSTILLATION OF A NOVEL NO NUCLEOPHILE ADDUCT SELECTIVELY REDUCES PULMONARY-HYPERTENSION/

We examined the pulmonary and systemic hemodynamic effects of administ ering soluble nitric oxide (NO) donor compounds (NO/nucleophile adduct s, i.e., NONOates) directly into the trachea of animals with experimen tally induced pulmonary hypertension. Steady-state pulmonary hypertens ion was created by using the thromboxane agonist U-46619. Yorkshire pi gs were randomly assigned to one of four groups: group 1, intratrachea l saline (control; n = 8); group 2, intratracheal sodium nitroprusside (n = 6); group 3, intratracheal ethylputreanine NONOate (n = 6); and group 4, intratracheal 2-(dimethylamino)ethylputreanine NONOate (DMAEP /NO; n = 6). Pulmonary and systemic hemodynamics were monitored after drug instillation. Group 4 had significant reductions in pulmonary vas cular resistance index (PVRI) at all time points compared with steady state and compared with group 1 (P < 0.05), whereas systemic vascular resistance index did not change. The mean change in mean pulmonary art erial pressure in group 4 was -33.1 +/- 1.2% compared with +6.4 +/- 1. 3% in group 1 (P < 0.001), and the mean change in mean arterial pressu re was -9.3 +/- 0.7% compared with a control value of -0.9 +/- 0.5% (P < 0.05). Groups 2 and 3 had significant decreases in both PVRI and sy stemic vascular resistance index compared with steady state and with g roup 1. In conclusion, intratracheal instillation of a polar-charged t ertiary amine NONOate DMAEP/NO results in the selective reduction of P VRI. Intermittent intratracheal instillation of selective NONOates may be an alternative to continuously inhaled NO in the treatment of pulm onary hypertension.