Table 2. Experimental pharmacological studies addressing RV dysfunction (indirectly, directly).

Target/mode of action	Model/species	Molecule	Main phenotypic findings	Benefit for RV contractile function	Absence of benefit for RV contractile function	Ref.
Using approved PAH therapeutics
PDE-5, inhibition	PAB, AC-shunt, rat	Sildenafil	PAB: ↑RV systolic function, exercise capacity, RV fibrosis	x		(38)
			No effect: RVH, RV diastolic function
			No effect in AC-shunt
PDE-5, inhibition	PAB, rat	Sildenafil	↓RV fibrosis		x	(34)
			↑RV diastolic function
			No effect: RV systolic function, exercise capacity
PDE-5, inhibition	PAB, mouse	Sildenafil	↑RV systolic function	x		(36)
			No effect: RVH, RV fibrosis
Prostacyclin, analogue	SuHx, PAB, rat	Iloprost	↓RV fibrosis	x		(35)
			↑Exercise capacity (SuHx), RV systolic function (SuHx)
			No effect: PA remodeling, RV systolic function (PAB)
Soluble guanylate cyclase, activator	PAB, mouse	Riociguat	↓RV fibrosis	x		(36)
			↑RV systolic function
			No effect: RVH
Targeting adrenoceptors
β-adrenoceptor, blockade	MCT, rat	Arotinolol	↓RVH, RVSP			(39)
β-adrenoceptor, blockade	MCT, rat	Bisoprolol	↓RV fibrosis	x		(40)
			↑RV systolic function
β-adrenoceptor, blockade	MCT, SuHx, rat	Carvedilol, metoprolol	↓RVH	x		(41)
			↑ RV systolic function, exercise capacity (SuHx), survival (MCT)
			No effect: RVSP, PA remodeling
β-adrenoceptor, blockade	MCT, rat	Nebivolol	↓PA remodeling	x		(42)
			↑RV systolic function
β-adrenoceptor, enhancement of signaling	MCT, PAB, rat	Gallein	↑ RV systolic function (MCT), exercise capacity (PAB)	x		(43)
α1A-adrenoceptor, agonism	Bleomycin, mouse	A61603	↓RV fibrosis	x		(44)
			↑RV systolic function
			No effect: PA remodeling
α1A-adrenoceptor, agonism	PAB, mouse	A61603	↓Liver weight	x		(45)
			↑RV systolic function, exercise capacity
			No effect: RVH, RV fibrosis, RV diastolic function
Targeting the renin-angiotensin-aldosterone system
AT1 receptor, antagonism	MCT, rat	Losartan	↓PVR, PA remodeling		x	(46)
			↑RV diastolic function
			No effect: RV contractility
AT1 receptor, antagonism	PAB, rabbit	Losartan	No effect: RVH, RV systolic function		x	(47)
Neprilysin, inhibition; AT1 receptor, antagonism	PAB, rat	Sacubitril/valsartan	↓RVH	x		(48)
			↑RV systolic and diastolic function
ACE, inhibition	PAB, rabbit	Ramipril	No effect: RVH, RV systolic function		x	(47)
AT1 receptor + mineralocorticoid receptor, antagonism	PAB, rat	Losartan + eplerenone	No effect: RV systolic function, RV remodeling, survival		x	(49)
ACE2	PAB, mouse	ACE2	↓RVH	x		(50)
			↑RV systolic function
			No effect: RV fibrosis
ACE2	MCT, rat	ACE2	↓RVH, PA remodeling	x		(51)
			↑RV systolic function
ACE2, activation	MCT, HOX, bleomycin, rat	Diminazene aceturate	↓RVH, RV fibrosis, PA remodeling	x		(52)
			↑RV systolic function
Mineralocorticoid receptor, antagonism	HOX, mouse, MCT, rat	Spironolactone	HOX: ↓RVSP, RV fibrosis, PA remodeling			(53)
			MCT: ↓RVSP, PA remodeling, PVR
			No effect: RV fibrosis, RV remodeling
Mineralocorticoid receptor, antagonism	MCT, rat	Spironolactone	↓RVSP, PA remodeling, PVR			(54)
Mineralocorticoid receptor, antagonism	SuHx, rat	Eplerenone	↓PA remodeling, PVR			(54,55)
Mineralocorticoid receptor, antagonism	SuHx, rat	Spironolactone	↓RVH, RVSP, PVR			(55)
AT1 receptor + mineralocorticoid receptor	PAB rats	Losartan + eplerenone	No effect: RV function, RV remodeling, survival		x	(49)
Mineralocorticoid receptor, antagonism	SuHx, PAB, mouse	Eplerenone	↓RVH, RVSP, PA remodeling			(56)
			PAB: No effect: RVH, RV fibrosis, RV systolic function
Targeting inflammation and oxidative stress
Nrf2, stimulation of activity and expression	HOX, SuHx, mouse	Dimethyl-fumarate	↓RVSP, RVH, PA remodeling			(57)
Nrf2, stimulation of activity and expression	HOX, mouse	Oltipraz	↓RVH, PA remodeling			(58)
SOD, SOD mimetic	MCT, rat	EUK 134	↓RV fibrosis, RVH	x		(59)
			↑ RV systolic function
NADPH-oxidase, decrease of expression and activity	HOX, mouse	Rosiglitazone	↓RVSP, PA remodeling			(60)
Vascular ROS release, reduction; PASMCs proliferation, decrease	HOX, mouse	OA-NO2	↓RVSP, RVH, PA remodeling			(61)
MPO, inhibition	SuHx, rat	AZM198	↓RVSP, RVH, PA remodeling			(62)
NF-κB, inhibition	PAB, rat	E6446, Pyrrolidine dithiocarbamate	↓ RV fibrosis	x		(63)
			↑ RV systolic function
			No effect: RVH
ASK1, inhibition	PAB, mouse; SuHx, MCT, rat	GS-444217	↓RV fibrosis, RVH, PA remodeling (in MCT and SuHx)	x		(64)
			↑RV systolic function
p38MAPK, inhibition	PAB, HOX, mouse	PH797804	↓RV fibrosis Increased: RV systolic function	x		(65)
TNF-alpha, antagonism	MCT, rat	Etanercept	↓RVSP, PA remodeling			(66)
TNF-alpha, antagonism	Endotoxin-induced, pig	Etanercept	↓RVSP, PVR			(67)
			↑RV diastolic function
IL-6, IL6R/sIL6R antagonism	MCT, SuHx, rat	ERBF	↓RVSP, RVH, PA remodeling	x		(68)
			↑RV systolic function
IL-1, receptor antagonism	MCT, HOX, rat	IL-1 receptor antagonist	MCT: ↓RVH, RVSP, PA remodeling			(69)
			HOX: no effect
Targeting energy metabolism
PDK, inhibition	PAB, MCT rat	Dichloroacetate	↓RVH	x		(70)
			↑RV systolic function
PDK, inhibition	HOX, rat	Dichloroacetate	↓RVH, PVR, RVSP, PA constriction and remodeling			(71)
			↑RV CO
PDK, inhibition	MCT, rat	Dichloroacetate	↓PA remodeling, RVH, mortality			(72)
PDK, inhibition	RV volume overload, pig	Dichloroacetate	↓RVH	x		(73)
			↑RV contractile reserve
FAO, partial inhibition	PAB, rat	Trimetazidine, ranolazine	↓RVH, RV fibrosis	x		(74)
			↑RV systolic function, exercise capacity
FAO, partial inhibition	MCT, HOX rat	Trimetazidine	↓RVSP, RVH, PA remodeling			(75)
RV lipid deposition, reduction	BMPR2 R899X, mouse	Metformin	↓RV lipid accumulation		x	(76)
			No effect: RV systolic and diastolic function
RV lipid deposition, reduction	Western diet + PAB, mouse	Metformin	↓RVSP, RVH		x	(77)
			↑RV diastolic function
PPARγ activation, reduction of RV intramyocardial lipid deposition	SuHx, rat	Pioglitazone	↓RVSP, RVEDP, RVH, RV fibrosis, PA remodeling	x		(78)
			↑RV systolic function, RV diastolic function
PPARγ, activation	ApoE-ko + HFD, mouse	Rosiglitazone	↓RVSP, RVH, PA remodeling		x	(79)
PPARγ, activation	HOX, rat	Rosiglitazone	↓RVSP, RVH, PA remodeling			(80)
PPARγ, activation	MCT, rat	Pioglitazone	↓RVSP, RVH, RV fibrosis, PA remodeling			(81)
			↑Survival
Targeting tyrosine kinases
Tyrosine kinase, inhibition	MCT, rat, HOX, mouse	Imatinib	↓RVH, RVSP, PA remodeling			(82)
Targeting extracellular matrix remodeling
Galectin-3, inhibition	PAB, mouse	N-acetyllactosamine	↓RV fibrosis		x	(83)
			No effect: RV systolic function
Targeting HDACs
HDAC class I, II, IV, inhibition	HOX, rat	Valproic acid, suberoylanilide	↓RVH, RVSP, PA remodeling			(84)
HDAC class I, inhibition	HOX, rat	MGCD0103	↓RVSP, PA remodeling		x	(85)
			No effect: RV systolic function
HDAC class I, II, inhibition	PAB, rat	Trichostatin A, valproic acid	↓RV systolic function			(86)
			↑RV fibrosis
HDAC class I, inhibition	MCT, rat	Valproic acid	↓PA remodeling, RVH			(87)
HDAC class I, II, inhibition	SuHx, rat	Trichostatin A	No effect: PA remodeling, RV systolic function, RVSP, RVH		x	(88)
HDAC class VI, inhibition	SuHx, MCT, rat	Tubastatin A	↓PA remodeling, RVH, RVSP, PVR			(89)

ACE, angiotensin-converting enzyme; ApoE-ko, apolipoprotein E-knockout; AT1, angiotensin II receptor type 1; HDAC, histone deacetylase; HFD, high fat diet; HOX, hypoxia; MCT, monocrotaline; Nrf2, nuclear factor erythroid 2-related factor 2; PDE-5, phosphodiesterase-5; PA, pulmonary artery; PAB, pulmonary artery banding; PVR, pulmonary vascular resistance; RV, right ventricle; RVH, right ventricular hypertrophy; RVSP, right ventricular systolic pressure; SuHx, Sugen5416/hypoxia.