Single injection of a sustained-release prostacyclin analog improves pulmonary hypertension in rats.
BACKGROUND
Although prostacyclin is recognized as a therapeutic breakthrough for pulmonary hypertension, it needs continuous infusion because of its short action. Therefore, we developed a new drug delivery system for prostacyclin. We prepared ONO-1301MS, a novel sustained-release prostacyclin analog polymerized with poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres.


OBJECTIVE
We examined whether ONO-1301MS attenuates monocrotaline (MCT)-induced pulmonary hypertension in rats, and attempted to elucidate the underlying mechanisms responsible for the beneficial effects of ONO-1301MS.


METHODS
After MCT injection, rats were randomized to receive a single subcutaneous injection of 100 mg/kg ONO-1301MS or vehicle.


RESULTS
We prepared ONO-1301MS, which was polymerized with PLGA to release ONO-1301 for 3 weeks. A single administration of ONO-1301MS achieved sustained elevation of its circulating level and plasma cyclic adenosine 3',5'-monophosphate level for 3 weeks, and attenuated an increase in a metabolite of thromboxane A(2) level. Rats had developed pulmonary hypertension 3 weeks after MCT injection; however, treatment with ONO-1301MS significantly attenuated the increases in right ventricular systolic pressure and right ventricular weight to body weight ratio. ONO-1301MS significantly inhibited hypertrophy of pulmonary arteries. Phosphorylation of extracellular signal-regulated protein kinase (ERK) in the lung was significantly increased in the control group, whereas this increase was markedly attenuated by treatment.


CONCLUSIONS
We developed a new drug delivery system for prostacyclin using PLGA and ONO-1301. A single injection of ONO-1301MS resulted in sustained activity for 3 weeks, and attenuated pulmonary hypertension, partly through its antiproliferative effect on vascular smooth muscle cells via inhibition of ERK phosphorylation.
Obata
Hiroaki
H
Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Sakai
Yoshiki
Y
Ohnishi
Shunsuke
S
Takeshita
Satoshi
S
Mori
Hidezo
H
Kodama
Makoto
M
Kangawa
Kenji
K
Aizawa
Yoshifusa
Y
Nagaya
Noritoshi
N
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004339:Drug Compounding; D011464:Epoprostenol / Q000819:agonists*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D008863:Microspheres; D016686:Monocrotaline; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D011725:Pyridines; C105488:ONO 1301; D016686:Monocrotaline; D011464:Epoprostenol; D048049:Extracellular Signal-Regulated MAP Kinases; D013930:Thromboxane-A Synthase