Development of PKG Iα (Protein Kinase G Iα)–Dimerizing Antihypertensive Drugs
Are We Standing at the Shore of the Rubicon?
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See related article, pp 577–586
Blood pressure control is largely dependent on the vasodilator capacity of blood vessels, which for the major part requires the release of endothelium-derived relaxing factors, that is, NO and endothelium-derived hyperpolarizing factor (EDHF). In conduit vessels, NO is most relevant, whereas in resistance vessels, EDHF is believed to have a more prominent role.
NO interacts with sGC (soluble guanylyl cyclase) to convert GTP (guanosine-5′-triphosphate) to cGMP, which subsequently binds to PKG (protein kinase G). Two PKG genes (I and II) exist, and vascular smooth muscle cells express only PKG I. The PKGI gene expresses as 2 separate isoforms (α and β), which are splice variants of the same gene and differ only in sequence of their N-terminal leucine zipper (LZ) interaction domain.1 They occur as homodimers, and their LZ domains mediate PKG binding to specific substrates, via LZ–LZ cointeraction. For instance, cGMP-activated PKG Iα phosphorylates vasodilator-stimulated phosphoprotein (Figure). NO donors (nitrates), sGC activators/stimulators (riociguat, cinaciguat, and vericiguat), and phosphodiesterases 1 and 5 inhibitors (which block cGMP degradation by phosphodiesterases 1 and 5, eg, ITI-214 and sildenafil) target this pathway (Figure). Yet, their indications include angina pectoris, erectile dysfunction, pulmonary arterial hypertension, and neurological disorders, but not systemic hypertension. This might be because central blood pressure is mainly regulated through resistance vessels, requiring drugs to exclusively target EDHF.