Antihypertensive effect of the novel water-soluble calcium antagonist (+/-)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate dihydrochloride in rats.
The antihypertensive effect of (+/-)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate dihydrochloride (NKY-722, CAS 117241-46-0) was examined in conscious spontaneously hypertensive rats (SHR), normotensive Wistar rats (NWR) and anesthetized NWR, and its vasodilatory effect was investigated in the perfused NWR mesenteric vascular bed. NKY-722 and nicardipine administered intravenously (10-100 micrograms/kg) and orally (0.3-10 mg/kg) lowered blood pressure dose-dependently with an increase in heart rate in conscious SHR and NWR. The effects of NKY-722 were slower in onset and longer-lasting than those of nicardipine, and were more marked in SHR than in NWR. The effect of NKY-722 was roughly the same as that of nicardipine on intravenous administration. However, NKY-722 was 4-8 times more potent than nicardipine on oral administration. In anesthetized NWR, the hypotensive effects of NKY-722 administered via the femoral vein, portal vein and duodenum were examined in comparison with those of nicardipine. The findings suggest that NKY-722 is more efficiently absorbed from the gastro-intestinal tract and more resistant to the hepatic first pass effect than nicardipine. In the perfused NWR vascular bed, NKY-722 and nicardipine (0.01-1.0 microgram) attenuated the pressor response to KCl dose-dependently. The effect of NKY-722 was slower in onset and longer-lasting than that of nicardipine. In conclusion; NKY-722 has a potent, slow-onset and long-lasting antihypertensive activity, which is mainly attributed to its slow-onset and long-lasting vasodilatory action. NKY-722 is expected to be a useful antihypertensive drug.
Wada
K
K
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
Nakamura
S
S
Morishita
S
S
Kanda
M
M
Matsui
H
H
Fukata
F
F
Shirahase
H
H
D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D004095:Dihydropyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009529:Nicardipine / Q000493:pharmacokinetics / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013152:Splanchnic Circulation / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C058351:NKY 722; D011189:Potassium Chloride; D009529:Nicardipine