VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension

Abstract

BackgroundPulmonary Arterial Hypertension (PAH) remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene caused the spontaneous expression of a PH phenotype that was fully corrected by VIP. The objectives of this investigation were to answer the questions: 1) Can VIP protect against PH in other experimental models? and 2) Does combining VIP with an endothelin (ET) receptor antagonist bosentan enhance its efficacy?MethodsWithin 3 weeks of a single injection of monocrotaline (MCT, s.c.) in Sprague Dawley rats, PAH developed, manifested by pulmonary vascular remodeling, lung inflammation, RV hypertrophy, and death within the next 2 weeks. MCT-injected animals were either untreated, treated with bosentan (p.o.) alone, with VIP (i.p.) alone, or with both together. We selected this particular combination upon finding that VIP down-regulates endothelin receptor expression which is further suppressed by bosentan. Therapeutic outcomes were compared as to hemodynamics, pulmonary vascular pathology, and survival.ResultsTreatment with VIP, every other day for 3 weeks, begun on the same day as MCT, almost totally prevented PAH pathology, and eliminated mortality for 45 days. Begun 3 weeks after MCT, however, VIP only partially reversed PAH pathology, though more effectively than bosentan. Combined therapy with both drugs fully reversed the pathology, while preventing mortality for at least 45 days.Conclusions1) VIP completely prevented and significantly reversed MCT-induced PAH; 2) VIP was more effective than bosentan, probably because it targets a wider range of pro-remodeling pathways; and 3) combination therapy with VIP plus bosentan was more effective than either drug alone, probably because both drugs synergistically suppressed ET-ET receptor pathway.

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…VIP was also shown to aid in therapy of PAH [188] and a VIP de�ciency was shown to produce an in�ammatory response [187]. VIP has been shown to stimulate the production of BH4, acting through the synthesis of the enzyme GTP cyclohydrolase I, the rate limiting step in the de novo production of BH4 [189].…”

Expresión de Endotelina-1 en pollos con hipertensión arterial pulmonar por hipoxia hipobárica

“…This endothelial dysfunction, vasoconstrictors predominate and vascular remodeling ensues, which entails thickening of the middle muscle and the adventitia layers in arterioles (5). ET-1 appears as the most potent vasoconstrictor in the pulmonary vasculature, and the use of ET-1 inhibitors of correspondent receptors, like bosentan and intestinal vasoactive peptide to control PH has been proposed (7,8).…”

“…En esta disfunción endotelial predominan los vasoconstrictores y ocurre una remodelación vascular, que incluye el engrosamiento de la media muscular y de la adventicia en arteriolas (5). ET-1 aparece como el vasoconstrictor más potente en las arterias pulmonares y el uso de los inhibidores de la ET-1; se ha propuesto el uso del bosentán y sus receptores, amén del péptido intestinal vasoactivo (7,8).…”

New horizons in pulmonary arterial hypertension therapies

“…Vasoactive intestinal peptide (VIP) is a molecule that acts to relax the vasculature and reduce the effects of vasoconstrictors [53]. The importance of VIP in PAH was demonstrated in mutant mice models, where deletion of the VIP gene led to significant increases in right ventricular (RV) systolic pressures, vascular remodelling and inflammation [54].…”

“…In these VIP knockout mice, both the vascular and right ventricular remodelling were attenuated by treatment with VIP. Further experiments in rat models with monocrotaline-induced PAH suggested that treatment with VIP may be more effective than treatment with bosentan and that combination therapy with bosentan could potentially give a greater efficacy than either VIP or bosentan therapy alone [53].…”