Selective pulmonary vasodilation by intravenous infusion of an ultrashort half-life nucleophile/nitric oxide adduct.
BACKGROUND
PROLI/NO (C5H7N3O4Na2 x CH3OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 degrees C and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension.


METHODS
In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 microg x kg-1 x min-1 of SNP or 0.75, 1.5, 3, 6, and 12 microg x kg-1 x min-1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized.


RESULTS
Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 microg x kg-1 x min-1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 microg x kg-1 x min-1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled).


CONCLUSIONS
The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.
Adrie
C
C
Department of Anesthesia and Critical Care, Harvard Medical School at Massachusetts General Hospital, Boston 02114, USA.
Hirani
W M
WM
Holzmann
A
A
Keefer
L
L
Zapol
W M
WM
Hurford
W E
WE
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D007262:Infusions, Intravenous; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D009589:Nitrogen Oxides; D009599:Nitroprusside / Q000494:pharmacology; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012756:Sheep; D014664:Vasodilation / Q000187:drug effects*
D009589:Nitrogen Oxides; C102043:proline-nitric oxide; D009599:Nitroprusside; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011392:Proline