Studies on Hypotensive Mechanism of Slow-released Nifedipine in Patients with Essential Hypertension

In order to clarify the hypotensive mechanism of Ca2+ antagonist, the effects of slow-released nifedipine （Nif） on water-sodium balance, the renin-angiotensin-aldosterone （RAA） system, sympathetic nerve activity, plasma ionized calcium （pCa2+）, and pressor response to infused noradrenaline （NA-R） and angiotensin II （ATII-R） were investigated following single dose （20mg） and 4 week administration of Nif （60mg/day） in 12 in-patients with essential hypertension （EHT）. After the single dose administration of Nif, mean arterial pressure （MAP） decreased significantly. Heart rate （HR）, urine volume （UV）, urinary excretion of sodium （UNa V）, fractional excretion of sodium （FENa）, and inorganic phosphorus （FEP）, plasma renin activity （PRA） and plasma noradrenaline concentration （pNA） were increased, while creatinine clearance （Ccr） and plasma aldosterone concentration （PAC） did not change. The percentage of change in MAP correlated negatively with basal MAP and positively with pretreatment logarithm PRA （logPRA）. The percentage of reduction of MAP was significantly greater in low renin EHT （LRH） than in normal renin EHT （NRH）. On the other hand, change in UNa V correlated positively with the change in FENa （ΔFENa） and in FEP （ΔFEP）, but not with that in Ccr. ΔFENa correlated positively with ΔFEP and negatively with pretreatment logPRA. Following 4 weeks of the therapy, in spite of progressive and significant reduction in MAP, HR returned to the pretreatment level. UV, UNa V, FENa, FEP and pNA were increased or tended to increase one week after the beginning of therapy. However, these values returned to pretreatment levels during the 4 weeks of treatment. Similar changes were observed in 24 hour urine volume and urinary excretion of sodium. Sustained reductions in plasma volume, body weight, NA-R and ATII-R were demonstrated. While a sustained increase in PRA was found, PAC slightly decreased during the 4 weeks of the treatment. PCa2+ and Ccr did not change significantly throughout the treatment ?period. The change in NA-R （ΔNA-R） correlated positively with pretreatment levels of pNA and pCa 2+, and negatively with pretreatment NA-R. The regression line between NA-R and pNA shifted to a lower NA-R level after the Nif therapy. The percentage of change in MAP （%ΔMAP） after 4 weeks showed a significant positive correlation with pretreatment pCa2+, logPRA and pNA levels. A reduction of MAP （%ΔMAP） in the chronic phase of the treatment was significantly greater in LRH with lower values of pCa2+ than in NRH. These findings led us to suppose that in addition to its direct vasodilative effect, suppression of sympathetic nerve activity, aldosterone secretion and pressor responses to NA and ATII, reduction in body fluid volume and sodium due to diuresis and natriuresis may contribute to the hypotensive mechanism of long-term treatment by Nif. It was also suggested that the abnormal calcium metabolism relating to RAA system, sympathetic nerve activity, NA-R and to volume status may play an important role in the hypertensive mechanism in EHT, particularly in LRH.