Myocardial Specific BNP Gene-Delivery Improves Diastolic Function and Ventricular Structure in Spontaneous Hypertensive Rodents

G-protein coupled receptors (GPCRs), in addition to signaling through heterotrimeric G proteins, also signal through b-arrestins. GPCR ‘‘biased ligands’’ preferentially engage a subset of receptor signals, for example activating either G-protein or b-arrestin mediated signals while limiting engagement of the other pathway, and thus elicit unique pharmacology compared to unbiased agonists or antagonists. TRV120027 is a potent, selective b-arrestin biased ligand of the angiotensin II type 1 receptor (AT1R). TRV120027 is a competitive antagonist of angiotensin II-stimulated G protein signaling, but stimulates b-arrestin recruitment and activates several kinase pathways, including p44/42 MAPK, Src, and eNOS phosphorylation via b-arrestin coupling. Consistent with this b-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increases cardiomyocyte contractility in vitro. Moreover, in rat hemodynamic studies, including pressure-volume loop analysis, TRV120027 produced unique and differential cardiovascular pharmacology in vivo, when compared to classical unbiased AT1R antagonists. Like the unbiased AT1R antagonist telmisartan, TRV120027 administered via continuous intravenous infusion had minimal effects on heart rate and reduced mean arterial pressure to a similar degree. TRV120027, however, increased cardiac performance, as measured by the slope of the end-systolic pressure volume relationship (ESPVR), and preserved cardiac stroke volume. The effects of TRV120027 on the slope of the ESPVR and blood pressure were rapidly reversible. In stark contrast, treatment with telmisartan led to a protracted decline in the ESPVR slope and a reduction in stroke volume. In toxicology studies in the rat, supra-therapeutic doses of TRV120027 were generally well-tolerated and without adverse effects on renal function. TRV120027 was rapidly cleared, with a half-life of less than 2 minutes. This distinct in vivo pharmacokinetic and pharmacodynamic profile, including a reduction of systemic blood pressure and improved cardiac performance, coupled with a short half-life and rapid reversibility, suggest that TRV120027 represents a potentially ground-breaking new therapy for patients with heart failure, and validates the continued exploration GPCR biased ligands to selectively target specific receptor functions in drug discovery.