Cardiovascular activities of the new potent and long-lasting antihypertensive calcium entry blocker (+-)-3-ethyl,5-methyl,2- ([2-(formylamino)-ethyl]- thiomethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicar box ylate.
BBR 2160 ((+-)3-ethyl,5-methyl,2-([2-(formylamino)-ethyl]- thiomethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxy late, CAS 118587-22-7) is a new calcium entry blocker (CEB) which completely displaces 3H-nitrendipine from binding sites, is 10 times more potent than amlodipine (A) and equiactive with nifedipine (N). On the rat aorta contracted by 10 mmol/l Ca++, or 45 mmol/l K+, BBR 2160 shows higher CEB activity than N and A, achieving the maximum effect on voltage operated channels-induced contractions in 6 h, while N takes about 2 h. BBR 2160, N and A negatively affect the chronotropism on spontaneously beating, and inotropism on electrically driven guinea pig atria, respectively. In vitro BBR 2160 has marked vasoselectivity. Administered orally to conscious hypertensive rats (SHR) and renal hypertensive dogs (RHD), it caused a dose-dependent reduction in systolic blood pressure with a relatively slow onset, peak effect at 3-6 h and duration over 6 h. BBR 2160 and A have more pronounced activity on SHR than on normotensive rats (NR) (ED20 NR/SHR 3.3 for both compounds), while the antihypertensive and hypotensive activities of N are in the same dose-range (ED20 NR/SHR 1.3). No tolerance develops to the antihypertensive effects of BBR 2160 after five days' dosing up to 3.2 mg/kg in SHR and 1 mg/kg in RHD. In instrumented conscious normotensive dogs BBR 2160, N and A mostly lower diastolic blood pressure and total peripheral resistance, and do not increase total oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
Germini
M
M
Boehringer Mannheim Italia S.p.A., Research Center, Monza, Italy.
Passoni
A
A
Casciarri
I
I
Bosetti
P
P
Piazzoni
L
L
Cazzulani
P
P
Gandolfi
C A
CA
Tofanetti
O
O
Ceserani
R
R
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001784:Blood Gas Analysis; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D004095:Dihydropyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C069279:BBR 2160