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2017 ; 7
(1
): 89-97
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Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model
of pulmonary arterial hypertension
#MMPMID28680568
Schreiber C
; Eilenberg MS
; Panzenboeck A
; Winter MP
; Bergmeister H
; Herzog R
; Mascherbauer J
; Lang IM
; Bonderman D
Pulm Circ
2017[Mar]; 7
(1
): 89-97
PMID28680568
show ga
Alterations in the nitric oxide (NO) pathway play a major role in pulmonary
arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH(4)) are
main substrates in the production of NO, which mediates pulmonary vasodilation.
Administration of either LA or BH(4) decrease pulmonary artery pressure (PAP). A
combined administration of both may have synergistic effects in the therapy of
PAH. In a telemetrically monitored model of unilateral pneumonectomy and
monocrotaline-induced PAH, male Sprague-Dawley rats received either LA
(300?mg/kg; n?=?15), BH(4) (20?mg/kg; n?=?15), the combination of LA and BH(4)
(300?mg/kg, 20?mg/kg; n?=?15), or vehicle (control group; n?=?10) from day 28
after monocrotaline induction. Therapy was orally administered once daily over
consecutive 14 days. LA, BH(4), or both equally lowered PAP, increased pulmonary
vascular elasticity, restored spontaneous locomotoric activity, prevented body
weight loss and palliated small vessel disease of severely pulmonary hypertensive
rats. BH(4) substitution lowered asymmetric dimethylarginine levels sustainably
at 60?min after administration and downregulated endothelial NO synthase mRNA
expression. No significant survival, macro- and histomorphologic or hemodynamic
differences were found between therapy groups at the end of the study period.
Administration of LA and BH(4) both mediated a decrease of mean PAP, attenuated
right ventricular hypertrophy and small vessel disease in monocrotaline-induced
pulmonary hypertensive rats, though a combined administration of both substances
did not reveal any synergistic therapy effects in our animal model.
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