title: Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat.
abstract: Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT1 receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT1). Target engagement in vivo (ACE, AT1, and NEP) was quantified by measuring inhibition of angiotensin-pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat-induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT1 receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile.
authors.affiliation: Department of Pharmacology, Theravance Inc., South San Francisco, CA 94080, USA. LHedge@theavance.com
authors.forename: Laxminarayan G
authors.initials: LG
authors.lastname: Hegde
authors.forename: Cecile
authors.initials: C
authors.lastname: Yu
authors.forename: Travis
authors.initials: T
authors.lastname: Renner
authors.forename: Harold
authors.initials: H
authors.lastname: Thibodeaux
authors.forename: Scott R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: Timothy
authors.initials: T
authors.lastname: Park
authors.forename: Madhavi
authors.initials: M
authors.lastname: Cheruvu
authors.forename: Rachael
authors.initials: R
authors.lastname: Olsufka
authors.forename: Erik R
authors.initials: ER
authors.lastname: Sandvik
authors.forename: Cassie E
authors.initials: CE
authors.lastname: Lane
authors.forename: Joe
authors.initials: J
authors.lastname: Budman
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hill
authors.forename: Uwe
authors.initials: U
authors.lastname: Klein
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
mesh_terms: D000799:Angioedema / Q000139:chemically induced; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013841:Thiazepines / Q000494:pharmacology* / Q000633:toxicity; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; D007189:Indans; D011422:Propionates; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013841:Thiazepines; C106266:omapatrilat; D000068756:Valsartan; C062766:candoxatril; D015260:Neprilysin; D014633:Valine