RESUMEN
(S)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide (ZD6169) is a novel ATP-sensitive potassium channel opener. Bladder activity and selectivity after oral dosing were studied in conscious, normotensive rats and dogs by monitoring cystometric and cardiovascular (CV) parameters. The reference ATP-sensitive K+ channel opener cromakalim was also evaluated in this study. ZD6169 significantly reduced micturition frequency in rats (ED50 = 0.16 mg/kg), but its effect on CV parameters was minimal (ED20 = 30 mg/kg), yielding a selectivity dose ratio of 187. The duration of action was between 7 and 24 hr at doses of 0.3 and 3 mg/kg, but it was more than 24 hr at 10 mg/kg. The ED50 value for bladder activity in dogs was less than 1.0 mg/kg, and the ED20 value for CV activity was slightly greater than 15 mg/kg but less than 20 mg/kg; the selectivity ratio was greater than 15. A significant improvement in bladder compliance was noted in dogs with ZD6169, and the bladder activity in rats was blocked by i.v. glibenclamide (3 mg/kg). Cromakalim had a bladder profile similar to that of ZD6169 but appeared to be more selective for CV parameters. In conclusion, ZENECA ZD6169 is a unique ATP-sensitive K+ channel opener with in vivo selectivity of relaxing bladder smooth muscle. This agent has the potential for treating patients with urge incontinence.
Asunto(s)
Adenosina Trifosfato/farmacología , Amidas/farmacología , Benzofenonas/farmacología , Canales de Potasio/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Animales , Benzopiranos/farmacología , Presión Sanguínea/efectos de los fármacos , Cromakalim , Relación Dosis-Respuesta a Droga , Gliburida/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Pirroles/farmacología , Ratas , Ratas WistarRESUMEN
ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin-1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, the blood pressure-lowering effect was not observed with ZENECA ZM181,037 in spontaneously hypertensive rats. ZENECA ZM181,037 demonstrated a K+ channel-blocker profile. In the isolated rat aorta stimulated with 20 mmol/l KCl, both the d- and l-enantiomer of ZENECA ZM181,037 antagonized the relaxation of cromakalim with mean pKB values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 mumol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in 86Rb+ by cromakalim in both portal vein and detrusor muscle strips; however, ZENECA ZM181,037, dissimilar to glibenclamide and tolbutamide, did not increase plasma glucose when given orally to dogs. Thus, ZENECA ZM181,037 is a blocker of the ATP-sensitive K+ channel (KATP) in vascular and nonvascular tissues. In view of the profound saluresis produced by ZENECA ZM181,037, the lack of antihypertensive effect appears to result from its blocking activity on KATP in vascular tissues.
Asunto(s)
Acetamidas/farmacología , Diuréticos/farmacología , Bloqueadores de los Canales de Potasio , Acetamidas/administración & dosificación , Acetamidas/uso terapéutico , Adenosina Trifosfato/farmacología , Administración Oral , Animales , Benzopiranos/farmacología , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Cromakalim , Diuréticos/administración & dosificación , Diuréticos/uso terapéutico , Perros , Relación Dosis-Respuesta a Droga , Electrofisiología , Gliburida/administración & dosificación , Gliburida/farmacología , Cobayas , Hipertensión/tratamiento farmacológico , Técnicas In Vitro , Inyecciones Intravenosas , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Pirroles/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Estereoisomerismo , Tolbutamida/administración & dosificación , Tolbutamida/farmacologíaRESUMEN
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.
Asunto(s)
Antihipertensivos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Diuréticos/farmacología , Pirazinas/farmacología , Animales , Aorta , Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Perros , Hipertensión/tratamiento farmacológico , Masculino , Músculo Liso Vascular/efectos de los fármacos , Nefrectomía , Potasio/sangre , Potasio/orina , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Ratas , Ratas Endogámicas SHRRESUMEN
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.