Table 2: Drug
inhibitors for the 5 different mechanisms of action.
Drug Name |
Type of Drug |
Working Mechanism |
References |
Adrenomedullin |
Guanylate cyclase
activators |
This
peptide elicits potent hypertensive and vasorelaxant
effects in vivo and in vitro through an autocrine
and paracrine fashion. In the arteries, it works through protein kinase A
phosphorylation and increased cAMP and NO
production, promoting vasodilation. |
|
SAR7334 |
TRPC6
Inhibitor |
TRPC
family members play a role in the pathogenesis of familial PAH and IPAH.
TRPC6 upregulation plays a role in PASMC
proliferation. They regulate cellular Ca2+ flux either by acting
as Ca2+ entry channels or by changing membrane potentials. SAR7334
works by blocking the Ca2+ channel thereby reducing the
hypoxia-induced increases in pulmonary arterial hypertension. |
|
Fluoxetine |
Serotonin
Inhibitor |
Plasma serotonin is increased in IPAH
patients. Fluoxetine reduces
hypoxic PH in rats, and targeted improvements in humans. The
5-hydroxytryptamine 2A (5-HT2A) receptor
mediates serotonin-induced proliferation in rat pulmonary artery fibroblasts. Genetic deficiency of the 5-HT2B serotonin
receptor reduces hypoxic PH in mice. SERT and the 5-HT receptors act
coherently to mediate the proliferative effects of serotonin on PASMCs. |
[55] |
NFAT |
Transcription
factor Inhibitor |
Ca2+ regulated transcription factor nuclear
factor of activated T cells isoform c3 (NFAT c3) is required for chronic
hypoxia-induced PH in mice. NFAT c3 activation leads to proliferative
response followed by recovery of contractile phenotype and hypertrophy of
PASMC. It was recently demonstrated that RhoA/Rho
kinase-dependent actin cytoskeleton remodeling is required for ET-1-mediated
NFATc3 activation in PASMC from chronically hypoxic PH mice. |
[56] |
Imatinib |
PDGF
Inhibitor |
Imatinib was found to block the PDGFR and
improve experimental PH. Administration of imatinib
and other PH drugs and suppression of GCC-proliferation by TS-1 resulted in
normalization of hemodynamics, the lung perfusion scintigram,
and arterial oxygen saturation. |
[57] |
Rho kinase
inhibitors |
Rho
Kinase Inhibitors |
In the
vascular wall, ROCK mediates vascular smooth muscle contraction, actin
cytoskeleton organization, cell adhesion, and motility. ROCK is also involved
in vascular inflammation and remodeling, through Rock inhibitors have the ability produce endothelian-1, inhibition of
downstream GPCR, and function in the cGMP
pathway/NO pathway. |
[40] |