Antihypertensive properties of a new long-acting angiotensin converting enzyme inhibitor in renin-dependent and independent hypertensive models.
The antihypertensive properties of a new long-acting, angiotensin-I-converting enzyme (ACE) inhibiting agent, (2S,3aS,7aS)-1-(N2-nicotinoyl-L-lysyl-gamma-D-glutamyl) octahydro-1H-indole-2-carboxylic acid (CAS 116662-73-8, DU-1777), were investigated orally in various experimental models of hypertension in comparison to a standard ACE inhibitor, lisinopril. The hypotensive potency of DU-1777 was not as marked as that of lisinopril in renin-dependent hypertensive models, i.e., two-kidney one-clip renal hypertensive rats (2K-1C RHR) (ED-20mmHg: 3.1 versus 1.0 mg/kg) or two-kidney two-clip renal hypertensive dogs (2K-2C RHD) (ED-20 mmHg: 2.5 versus 1.0 mg/kg), though the actions of the two drugs were both long-lasting and dose-related. When spontaneously hypertensive rats (SHR) were used, however, DU-1777 was as active as lisinopril (ED-20 mmHg: 17.9 versus 13.6 mg/kg). The most distinguishing results with DU-1777 were its hypotensive effects in renin-independent hypertensive models. In contrast to lisinopril, the drug produced a sustained and dose-related hypotensive effect in DOCA salt hypertensive rats (DOCA-HR) and one-kidney one-clip renal hypertensive rats (1K-1C RHR). There exists an inconsistency between the long duration of the agent's hypotensive action in all tested hypertensive models and its short duration of ACE inhibiting activity as demonstrated both in vivo and ex vivo. The sustained antihypertensive action of DU-1777 cannot be reasoned solely with respect to ACE inhibition, suggesting some additional mechanisms of action yet to be defined.
Nagata
S
S
Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Suita, Osaka, Japan.
Takeyama
K
K
Fukuya
F
F
Nagai
R
R
Hosoki
K
K
Nishimura
K
K
Deguchi
T
T
Karasawa
T
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D004151:Dipeptides / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D006978:Hypertension, Renovascular / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology*; D017706:Lisinopril / Q000627:therapeutic use; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012083:Renin / Q000502:physiology*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004151:Dipeptides; D007211:Indoles; C096049:DU 1777; D003900:Desoxycorticosterone; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D012083:Renin