Budralazine

Abstract: We studied the effect of chronic antihypertensive treatment with budralazine on the lower blood pressure limit of cerebral blood flow autoregulation using spontaneously hypertensive rats. Cerebral blood flow in the parietal cortex and caudate nucleus was measured to determine the lower limit using the hydrogen clearance method. The lower limit in both cerebral regions was significantly higher in 10 untreated spontaneously hypertensive rats than in 10 Wistar-Kyoto rats. The upward-shifted lower limit was restored to close to normal in the caudate nucleus and was partially restored in the parietal cortex of nine rats by 9 weeks of treatment with the high dose (50-68 mg/kg/day) of budralazine, which kept blood pressure constant at approximately normotension during the treatment period; the lower limit was slightly restored in both cerebral regions of seven rats by 4 weeks of treatment with the high dose. However, 9 weeks of treatment with the low dose (19-27 mg/kg/day) of budralazine, which produced moderate continuous hypotension in nine rats, did not apparently influence the lower limit. Our results suggest that long-term antihypertensive therapy with budralazine reduces the upward-shifted lower blood pressure limit of cerebral blood flow autoregulation toward normal and that the restoration induced by budralazine depends on the degree of blood pressure reduction as well as on the duration of the therapeutic period.

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Abstract: Antihypertensive and pharmacological properties of budralazine were examined in comparison with other antihypertensive drugs. Budralazine was orally effective against various types of hypertension in rats and it, like reserpine but unlike hydralazine, produced a much greater pressure reduction in hypertensive than in normotensive rats. The drug was similar to reserpine and alpha-methyldopa but not to hydralazine in showing a gradually progressive action. At equihypotensive oral doses, budralazine was less potent than hydralazine in producing tachycardia in unrestrained SHR. After long-term therapy, it effectively prevented the development of hypertension in SHR to almost the same extent as did hydralazine. Budralazine failed to produce diuresis in SHR at antihypertensive doses but antagonized isolated rabbit aortic contractions induced by vasoconstrictors and decreased femoral arterial resistance in dogs. Thus, the antihypertensive budralazine is characterized by the ability to produce vasodilator, non-diuretic and weak cardiac stimulant effects.

Abstract: 高血圧自然発症ラット(SHR)を用いて，budralazine の大脳皮質頭頂部および尾状核の局所脳血流量(rCBF)に対する作用を水素クリアランス法によって検討し，以下の成績を得た．1)SHR に各種抗高血圧薬を経口投与し，平均血圧が 110～120mmHgのレベルに下降した時点で rCBF を測定した．対照は，脱血によって同じレベルまで血圧を下降させた群を用いた．2) budralazine (40mg/kg)投与によって，大脳皮質頭頂部および尾状核のいずれの部位の rCBF も脱血対照群に比べ有意に増加し，それぞれの部位の脳血管抵抗(CVR)は有意に低下した．3) hydralazine (9mg/kg)は，budralazine と類似した有意な rCBF の増加および CVR の低下を示した．4) nifedipine (7mg/kg)は，rCBF をそれぞれの部位で有意に増加したが，その程度は budralazine に比べて軽度であり，CVR は低下傾向を示すにとどまった．5) prazosin (6mg/kg)および α-methyldopa (1，000mg/kg)は rCBF および CVR に対してほとんど影響を及ぼさなかった．6) budralazine (3～10mg/kg)を静脈内投与した時，血圧を下降することなく大脳皮質頭頂部および尾状核のいずれの部位でも用量依存的かつ持続的な rCBF の増加を示した．7) reserpine (2mg/kg，i．P．)前処置によって，budralazine の rCBF 増加作用は尾状核で有意に抑制され，大脳皮質頭頂部では抑制傾向を示した．8) 6-hydroxydopamine(250μg/head，i．c．v．)前処置によって，budralazine の rCBF 増加作用は大脳皮質頭頂部で有意に抑制され，尾状核では抑制傾向にあった．以上の成績は，脳血流に対する作用に関して budralazine は prazosin および α-methyldopaと明らかに相違しており，budralazine による降圧効果発現時に脳血流が増加する可能性を示している．また，budralazine の rCBF 増加作用の一部にカテコールアミン神経系の関与が示唆された．