Vol. 293, Issue 3, 1040-1047, June 2000

Inhibitory Effects of AE0047, a New Dihydropyridine Ca²⁺ Channel Blocker, on Renal Nerve Stimulation-Induced Renal Actions in Anesthetized Dogs

Tomoyuki Yamasaki, Masaji Ohmagari, Isao Tamai, Kazutaka Hayashi and Yasuo Matsumura

Department of Pharmacology (T.Y., M.O., I.T., Y.M.), Osaka University of Pharmaceutical Sciences; and Pharmaceutical Research Division (K.H), Yoshitomi Pharmaceutical Industries Ltd., Osaka, Japan

The effects of AE0047, a newly developed dihydropyridine Ca²⁺ channel blocker, and nicardipine on changes in the renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS at a low frequency (0.5-2.0 Hz) caused significant decreases in the urine flow, urinary excretion of sodium, and fractional excretion of sodium, while also inducing increases in the NE secretion rate (NESR), without affecting the renal hemodynamics. RNS at a high frequency (2.5-5.0 Hz), which diminishes the renal blood flow, glomerular filtration rate, and filtrate fraction, elicited more potent decreases in urine formation and increases in NESR than those seen for the low-frequency RNS. When AE0047 (10 and 50 ng/kg/min) was administered intrarenally, increases in the basal renal blood flow and urine formation were observed. During AE0047 (50 ng/kg/min) infusion, low-frequency RNS-induced antidiuretic action and increase in NESR were markedly attenuated. Qualitatively similar results were observed for high-frequency RNS. In addition, high-frequency RNS-induced renal vasoconstriction was significantly suppressed by AE0047 infusion at higher doses. Lower doses of AE0047 (10 ng/kg/min) tended to attenuate the low- and high-frequency RNS-induced antidiuretic actions, although neither of the RNS-induced increases in NESR were suppressed by lower doses of AE0047. Nicardipine (50 ng/kg/min) also increased the level of basal urine formation, but the RNS-induced changes in renal function and increases in NESR were not affected by this drug. These results suggest that AE0047 suppresses the RNS-induced NE overflow from renal nerve endings, which is probably involved in the inhibitory effects of the drug on the antidiuretic action elicited by RNS.