Effects Of NKH477 Research Articles

Effects of NKH477 on endothelin-1-induced renal responses in anaesthetized dogs.

1. Intrarenal arterial infusion of a direct adenylate cyclase activator (NKH477; 300 ng/kg per min) increased renal blood flow, urine flow rate and urinary sodium excretion in anaesthetized dogs. 2. Intrarenal arterial infusion of endothelin (ET)-1 (2 ng/kg per min) reduced basal values of these parameters and glomerular filtration rate, which were recovered by the addition of NKH477 during ET-1 infusion. 3. These results demonstrate that NKH477 can counteract ET-1-induced antinatriuresis, mainly by restoring glomerular filtration.

Effects of NKH477 on renal nerve stimulation-induced responses in anesthetized dogs

We evaluated the effects of an adenylate cyclase activator, N, N-dimetyl-β-alanine[3 R-(3α,4αβ,5β,6β,6 aα,10α,10 aβ,10 bα)]-5(acetyloxy)-3-ethenyldodecahydro-10,10 b-dihydroxy-3,4 a,7,7,10 a-pentamethyl-1-oxo-1 H-naphtho[2,1-b]pyran-6-yl ester hydrochloride (NKH477), on neural control of renal functions in anesthetized dogs. Renal nerve stimulation (2 Hz) increased renal norepinephrine efflux and reduced renal blood flow, glomerular filtration rate, urine flow rate, urinary Na + excretion and fractional Na + excretion. Intrarenal arterial infusion of NKH477 (300 ng/kg/min) suppressed the stimulation-induced reductions in renal blood flow and glomerular filtration rate and attenuated the reductions in urine flow rate and urinary Na + excretion but not the changes in renal norepinephrine efflux and fractional Na + excretion. Infusion of NKH477 did not affect the urinary responses induced by renal nerve stimulation at a lower frequency (0.5–1 Hz) which had little influence on renal blood flow and glomerular filtration rate. The present results demonstrate that NKH477 inhibits renal vasoconstriction and hypofiltration but not the enhanced tubular Na + reabsorption during activation of the renal sympathetic nervous system.

Metabolic Fate of NKH477. (2). Blood Concentration, Distribution, Excretion and Effects on Drug-Metabolizing Enzyme System in Rats after Repeated Intravenous Administration.

The blood concentration, distribution and excretion of radioactivity were investigated in male rats after daily intravenous administration of 14C-NKH477 for 21 days. The effects of NKH477 on hepatic drug metabolizing enzyme system were also investigated in male rats. 1. The radioactivity in the blood at 24 hr after daily administration rose as number of dose increased, the elimination of radioactivity from the blood after the last dosing was slower than that after a single dosing. 2. In most tissues, the radioactivity accumulated during the period of repeated administration, especially in the spleen, blood, kidney and mesenteric lymph node that rose markedly. Disappearance of radioactivity from most tissues after the last dosing was slower compared with that after a single dosing. 3. Within 168 hr after a repeated administration for 21 days, urinary and fecal excretion amounted to 7.8% and 88.9% of cumulative dose, respectively. The ratio of excretion between urine and feces was approximately the same as after a single dosing. 4. Repeated administration of NKH477 at doses of 0.3 and 1.0 mg/kg/day for 7 days had no effect on liver weight, microsomal cytochrome P-450 contents and hepatic drug-metabolizing enzyme system.

Effects of NKH477, a forskolin derivative, and dibutyryl-cyclic AMP on adrenal catecholamine release in response to splanchnic nerve stimulation, acetylcholine, DMPP and muscarine in anesthetized dogs.

The effects of NKH477, a water-soluble forskolin derivative, and dibutyryl-cyclic adenosine monophosphate (dbcAMP) on the release of adrenal catecholamines (CAs) in response to splanchnic nerve stimulation (SNS), acetylcholine (ACh), the nicotinic receptor stimulant 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) and muscarine were examined in anesthetized dogs. NKH477, dbcAMP and the cholinergic agonists were infused and injected, respectively, into the adrenal gland intra-arterially. SNS (3 Hz) or injections of ACh (3 micrograms), DMPP (2 micrograms) and muscarine (2 micrograms) produced increases in CA output determined from adrenal venous blood. Both NKH477 infusion (0.3, 1 and 3 micrograms/min) and dbcAMP infusion (0.1, 0.3 and 1 mg/min) caused dose-dependent enhancement of the SNS-, ACh- and DMPP-induced increases in CA output, whereas they failed to affect the muscarine-induced increases in CA output. Neither NKH477 nor dbcAMP affected basal CA output. Cyclic AMP (cAMP) overflow determined from adrenal venous blood increased during NKH477 infusion. These results indicate that NKH477 and dbcAMP have facilitatory effects on adrenal CA release mediated by nicotinic receptors, but not by muscarinic receptors in the dog, and suggest the selective action of cAMP on nicotinic mechanism.

P-553 - Effects of NKH477 on renal hemodynamics and function in anesthetized dogs.

P-553 - Effects of NKH477 on renal hemodynamics and function in anesthetized dogs.

P-276 - Effects of NKH477, a novel water-soluble forskolin derivative, on contractile force and adenylate cyclase activity in isolated guinea-pig ventricular muscles

P-276 - Effects of NKH477, a novel water-soluble forskolin derivative, on contractile force and adenylate cyclase activity in isolated guinea-pig ventricular muscles