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ZENECA ZM224,832 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which demonstrated a profile of calcium channel blockers. It produced diuretic and saluretic effects in animals but had only minimal alterations in kaliuresis after oral administration. In contrast to standard diuretics, the plasma K+ concentration was not altered in conscious dogs treated for 14 days with ZENECA ZM224,832 and the concurrent plasma renin activity was also minimally elevated. The isolated rat aorta evaluation indicated that ZENECA ZM224,832, like tiapamil and nifedipine, inhibited vascular smooth muscle tone by inhibiting voltage-dependent calcium channels. ZENECA ZM224,832 produced a dose-dependent decrease of blood pressure in spontaneously hypertensive rats (SHR) in which the antihypertensive activity was not noted with HCTZ. In addition, ZENECA ZM224,832, similar to diltiazem, produced an acute blood pressure lowering effect in nephrectomized SHR which was independent of its diuretic activity. It is concluded that ZENECA ZM224,832 is a potent eukalemic diuretic with calcium channel blocking properties.

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.