The site of action of ICI 206,970, an aminomethylphenol pyrazine derivative, with effects on Na+ and water excretion similar to hydrochlorothazide, was determined using free-flow micropuncture and in vivo microperfusion techniques. Furosemide and ICI 206,970 were perfused into the loop of Henle, at a concentration of 10(-4) M. Furosemide reduced water, Na+ and K+ reabsorption by the loop, but ICI 206,970 had little effect. Amiloride and ICI 206,970 were perfused into the distal nephron at a concentration of 10(-4) M. Both compounds reduced the reabsorption of Na+ and secretion of K+, ICI 206,970 having a somewhat greater effect than amiloride at this dose. ICI 206,970 also reduced water reabsorption by the distal tubule. ICI 206,970 was infused i.v. at a dose of 10 mg/kg/hr into anesthetized rats, and its effect on reabsorption by various nephron segments was determined. This compound tended to reduce proximal reabsorption of Na+, K+ and water, but had little effect on reabsorption of electrolytes and water by the loop of Henle, or distal tubule reabsorption of Na+ and water. Distal K+ secretion decreased after administration of ICI 206,970. Reabsorption of electrolytes and water beyond the late distal nephron was not affected by the drug. Urinary excretion of Na+ and water was elevated, but K+ excretion remained unchanged after treatment with ICI 206,970. The sites of action of ICI 206,970 appear to be the proximal and distal nephron. Urinary excretion of Na+ and water was largely dependent on the effect of ICI 206,970 on proximal reabsorption, as this compound had little effect on loop of Henle or distal tubule reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

01 Jan 1993·PharmacologyQ4 · MEDICINE

ICI 206, 970: A Novel Calcium Channel Blocker with Eukalemic Diuretic Activity

Q4 · MEDICINE

Article

Author: Donahue, Jacqueline Y. ; Schwartz, Jack A. ; Howe, Burton B. ; Do, My Linh ; Keith, Richard A. ; Kau, Sen T. ; Halterman, Tracy J.

ICI 206,970 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which exhibited a calcium antagonist profile. The isolated rat aorta evaluation and dihydropyridine ligand [3H]-PN 200-110 binding studies demonstrated that ICI 206,970, like verapamil and nifedipine, inhibits vascular smooth muscle tone by inhibiting voltage-sensitive calcium channels. ICI 206,970 produced dose-related hypotensive, negative chronotropic, dromotropic, and coronary vasodilator responses after i.v. injection in anesthetized dogs. ICI 206,970, similar to calcium channel blockers and dissimilar to diuretics, produced an acute antihypertensive effect in spontaneously hypertensive rats (SHR), and significant protection against the development of myocardial hypertrophy in SHR after chronic oral treatment for 28 consecutive days. It is concluded that ICI 206,970 is a calcium channel blocker in addition to its novel eukalemic diuretic property.

Methods and findings in experimental and clinical pharmacology

ICI 206,970: a novel eukalemic diuretic with calcium channel blocking activity.

Article

Author: Leszczynska, K ; Johnston, P ; Zuzack, J ; Yochim, C ; Kau, S ; Schwartz, J ; Li, J ; Giles, R

ICI 206,970, an aminomethylphenol pyrazine derivative, produced diuretic and saluretic effects, but caused only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. ICI 206,970, unlike HCTZ, increased diuretic activity in a more clearly defined dose-related manner, and did not reach the plateau level even up to a dose of 100 mg/kg p.o. The diuretic and natriuretic response is believed to be a combination of a direct effect on tubule function and changes in GFR, particularly at higher doses. Based upon studies in in vitro amphibian models for mimicking mammalian nephron, ICI 206,970 appeared to possess a furosemide-like activity in toad cornea and amiloride-like activity in toad bladder. It is concluded that ICI 206,970 is a potent eukalemic diuretic with the potential of multiple sites of renal action.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Preclinical	US	AstraZeneca PLC	-
Hypertension	Preclinical	US	AstraZeneca PLC	-

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