Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension.
We have found in chronically hypoxic rats that acute intravenous administration of the Rho kinase inhibitor Y-27632 nearly normalizes the pulmonary hypertension (PH) but has no pulmonary vascular selectivity. In this study, we tested if oral or inhaled Y-27632 would be an effective and selective pulmonary vasodilator in hypoxic PH. Although acute oral Y-27632 caused a marked and sustained decrease in mean pulmonary arterial pressure (MPAP), it also decreased mean systemic arterial pressure (MSAP). In contrast, 5 minutes of inhaled Y-27632 decreased MPAP without reducing MSAP. The hypotensive effect of inhaled Y-27632 on hypoxic PH was greater than that of inhaled nitric oxide, and the effect lasted for at least 5 hours. Inhaled fasudil, another Rho kinase inhibitor, caused selective MPAP reductions in monocrotaline-induced PH and in spontaneous PH in fawn-hooded rats, as well as in chronically hypoxic rats. These results suggested that inhaled Y-27632 was more effective than inhaled nitric oxide as a selective pulmonary vasodilator in hypoxic PH, and that Rho kinase-mediated vasoconstriction was also involved in the other models of PH. Inhaled Rho kinase inhibitors might be useful for acute vasodilator testing in patients with PH, and future work should evaluate their efficacy in the long-term treatment of PH.
Nagaoka
Tetsutaro
T
Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B-133, Denver, CO 80262, USA. tetsutaro.nagaoka@uchsc.edu
Fagan
Karen A
KA
Gebb
Sarah A
SA
Morris
Kenneth G
KG
Suzuki
Tsutomu
T
Shimokawa
Hiroaki
H
McMurtry
Ivan F
IF
Oka
Masahiko
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000280:Administration, Inhalation; D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D000860:Hypoxia / Q000150:complications; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D014665:Vasodilator Agents; C108830:Y 27632; D009569:Nitric Oxide; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C049347:fasudil