Pharmacokinetics and pharmacodynamics of a nitric oxide-releasing derivative of enalapril in male beagles.

1. Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO-releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin-converting enzyme. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect. 5. In conclusion, the present results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.

The effects of isradipine and spirapril as monotherapy and combined therapy on blood pressure, renal hemodynamics, natriuresis, and urinary kallikrein in hypertensive nephropathy.

In this cross-over, double-blind study, 12 essential hypertensive patients (stage I, II, and III) with glomerular filtration rate (GFR) between 50 to 80 mL/min/1.73 m2, were submitted to 4 weeks of placebo followed by 12 weeks with isradipine SRO (IS) 5 mg, spirapril (SP) 6 mg, and isradipine plus spirapril (IS + SP). The study evaluated the effects of these drugs on GFR ((99m)Tc DTPA), effective renal plasma flow (ERPF) ((131)I-orthoiodohippurate), urinary sodium excretion (UNaV), urinary kallikrein excretion (UKal), urinary albumin excretion (UAE), and plasma renin activity (PRA). The three protocols significantly reduced mean blood pressure (128 v 107 mm Hg; 126 v 112 mm Hg; 129 v 104 mm Hg with IS, SP and IS + SP, respectively). ERPF and GFR did not change. UNaV increased significantly after IS (0.17 v 0.22 mEq/min) and IS + SP (0.18 v 0.24 mEq/min). UKal increased significantly after IS (58.6%) and IS + SP (53.6%). UAE decreased significantly only after SP. PRA increased significantly after IS (1.31 v 2.84 ng/mL/h), SP (1.10 v 2.15 ng/mL/h), and after IS + SP (1.23 v 3.21 ng/mL/min). In conclusion, IS, SP and IS + SP were effective in reducing blood pressure while keeping renal function stable. Only SP significantly decreased UAE. Enhanced UKal may have played a role in natriuresis observed after IS and IS + SP.

Preventive effect of chronic converting enzyme inhibition on aortic stiffening induced by renovascular hypertension in conscious dogs.

OBJECTIVE: The aim was to assess the influence of the renin-angiotensin system on the geometrical and elastic properties of the aorta in conscious dogs, using a model of renovascular hypertension, and to examine the effects of inhibition of the system by the angiotensin converting enzyme inhibitor spirapril. METHODS: The aortic elastic behaviour in response to renovascular hypertension was studied in 15 conscious dogs instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. Renovascular hypertension was induced by surgical occlusion of one renal artery and stenosis of the other. One day after renal surgery, dogs were randomly assigned to two groups receiving for two months either the new angiotensin converting enzyme inhibitor spirapril (n = 8) or a placebo capsule (n = 7). The two groups of dogs were compared to a control group of normotensive dogs (n = 7). After two months of treatment the elastic properties of the aorta were studied by computation of the beat to beat pressure-diameter hysteresis loops obtained during transient increase of pressure induced by bolus doses of angiotensin. The aortic pressure-diameter (P-D) relationship, obtained over a wide range, was fitted by an exponential fit (P = alpha.e beta D), where beta is the stiffness index. A decomposition of the P-D curve according to a biphasic model of the parallel arrangement of elastin and collagen enabled two pressure-diameter elastic moduli to be obtained, one representing the resistance to stretch at low pressure levels (elastic fibres and smooth muscle), and the other representing the resistance to stretch at the highest pressures (collagen fibres). RESULTS: The pressure-diameter curve of the placebo group was shifted to the left compared to the curves of the control and spirapril groups, showing that renovascular hypertension was associated with isobaric reduction of aortic diameter. The stiffness index beta was higher (p < 0.05) in the placebo group [0.605(SD 0.304) mm-1] than in either the control group [0.362(0.126) mm-1] or the spirapril group [0.348(0.083) mm-1], suggesting that renovascular hypertension was associated with aortic stiffening. The biphasic analysis showed that the collagen pressure-diameter elastic modulus was unaffected by spirapril, whereas the elastin pressure-diameter elastic modulus was significantly reduced by converting enzyme inhibitor with respect to the placebo (p < 0.05). CONCLUSIONS: Chronic converting enzyme inhibition by spirapril prevents the isobaric aortic diameter reduction induced by renovascular hypertension in conscious dogs and decreases aortic stiffness, in particular by changing the elastic behaviour of the elastin fibres rather than of the collagen fibres.

Alterations in the water intake caused by central inhibition of angiotensin-converting enzyme in the rat.

In the present study we investigated the effects of central (i.c.v.) and subcutaneous (s.c.) injections of a 2 micrograms dose of lisinopryl, an inhibitor of angiotensin I(ANGI)-converting enzyme (CE), on water intake. I.c.v. but not s.c. injection of lisinopryl abolished drinking in response to s.c. isoprenaline (100 micrograms/kg) and significantly reduced drinking in response to 24 h water deprivation or s.c. polyethylene glycol (30% w/v, 10 ml/kg). Lisinopryl had no effect on water intake induced by cellular dehydration (s.c. injection of hypertonic saline (2 M NaCl)). These results are consistent with the hypothesis that lisinopryl acts as a CE blocking agent in the brain. The thrist challenge induced by hypotension using isoprenaline acts primarily by generating ANGII systemically and centrally. The other thirst challenges such as cellular dehydration are independent of the ANGII in the brain. This conclusion was made possible by utilizing a new CE blocking agent at a smaller dose than normally used for other ANG I-CE inhibitors.

Estudio comparativo entre el lisinopril y la metildopa en el tratamiento de la hipertensión arterial esencial / A comparative study between lisinopril vs methyl-dopa in essencial hypertension

Se estudiaron 60 pacientes con hipertensión arterial esencial sostenida, sin complicaciones cardiorrenales. siquiendo un diseño doble ciego, aleatorio y paralelo para valorar la respuesta antihipertensiva de dos fármacos: lisinopril y metildopa. Después de un periodo de dos semanas en el que al total de pacientes se les administró placebo, la muestra se dividió en forma aleatoria para recibir tratamiento activo durante 12 meses (grupo uno: lisinipril; grupo dos: metildopa). Se consideró significativo cualquier cambio en la prueba t de Student con una p<0.02. No se observaron diferencias entre grupos al inicio del tratamiento activo. Al final del estudio, la presión arterial sistólica y diastólica descendieron en ambos grupos; para el uno de 160 + - 10 a 135 + - 6 y de 112 + - 7 a 84 + - 4; para el dos de 168 + - 11 a 143 + - 10 y de 111 + - 5 a 89 + - 7 mm/Hg. El descenso entre grupos fue de mayor magnitud en el grupo uno, comprobándose la eficacia del lisinopril en dosis única cada 24 horas. En tres pacientes del grupo uno (10 por ciento) se presentaron como efectos colaterales tos y estreñimiento, mientras que con metildopa se observó cansancio fácil en cinco (17 por ciento), depresión en cuatro (13 por ciento), diarrea en tres(10 por ciento) e impotencia en tres de nueve varones (33 por ciento); la magnitud de los mismos no obligó de acuerdo con los pacientes a suspender el tratamiento en ninguna instancia. De los resultados se concluye que ambos fármacos son eficaces para abatir la presión arterial, pero la eficiencia del lisinopril es mayor.

Effect of pH on the inhibition of angiotensin converting activity by enalaprilat in the rat perfused mesenteric vascular bed.

The previous finding that converting enzyme inhibitors (CEIs) potentiate bradykinin (BK), but do not inhibit conversion of angiotensin (ANG) I in isolated vessels, was explored further in the rat perfused mesenteric vascular bed. To investigate whether other peptidases besides angiotensin converting enzyme (ACE) might be involved in CEI-resistant ANG I conversion, synthetic angiotensinogen fragments (1-14, 1-11 and 2-14) were studied. Their vasoconstrictor activities were found to be about 80 times less than that of ANG I, and were not altered by the CEI enalaprilat, indicating that tonin-like enzymes do not play a role in the generation of ANG II by the arterial wall. The hypothesis that BK potentiation by CEI in arteries might be due to a direct effect on the receptors was not supported by the lack of potentiation, by enalaprilat, of the vasorelaxant effect of Lys-Lys-BK (an ACE-resistant BK homologue). Finally, the effect of pH in the perfusing solution on ACE inhibition by enalaprilat was studied. Whereas converting activity decreased with increasing pH in the range 6.8 to 8.1, enalaprilat did not affect the responses to ANG I at pH 7.5 or 7.8, but blocked them at pH 7.1. Our results indicate that arterial ACE shows substrate-specific inhibition and that, at physiological pH, converting activity is resistant to inhibition by CEIs, whose hypotensive action would be due mainly to inhibition of arterial wall kininase activity.

Effects of teprotide, captopril and enalaprilat on arterial wall kininase and angiotensin converting activity.

We have previously shown that the hypotensive action of angiotensin I (ANG I) converting enzyme (ACE) inhibitors is temporally related to a long-lasting inhibition of kininase activity in the arterial wall. More recently, we showed that conversion of ANG I in the perfused mesenteric vascular bed was not inhibited by enalaprilat at concentrations above those which maximally inhibited kininase activity. The present study extends these observations to two other ACE inhibitors and to another vascular bed, the rat hindlimb preparation. Like enalaprilat, captopril (0.06-1.5 mumol/l) or teprotide (0.4-10 mumol/l) did not inhibit the conversion of ANG I in the perfused mesenteric bed, although the response to bradykinin was substantially potentiated, indicating that the ACE inhibitor decreased kininase activity. In the perfused hindlimb preparations, enalaprilat reduced kininase activity without altering the conversion of ANG I. Enalaprilat or captopril administered to rats caused a decrease in mean arterial blood pressure that lasted for over 24 h. In mesenteric preparations taken from animals 24 h after treatment with ACE inhibitors, kininase activity was inhibited whereas converting activity was unchanged. Therefore, the long-lasting hypotensive effect of ACE inhibition is apparently related to a prolonged inhibition of kininase activity in the arterial wall, which is believed to be the target for ACE inhibitor activity.