The angiotensin converting enzyme inhibitors captopril and enalapril inhibit apomorphine-induced oral stereotypy in the rat

The possible functional interaction between angiotensin and dopamine mechanisms in the rat was investigated by examining the effects of the angiotensin converting enzyme inhibitors captopril and enalapril on apomorphine-induced stereotypy. Apomorphine-induced behaviour was observed, and recorded using a keypad linked to a microcomputer. In agreement with previous findings, low doses of apomorphine induced a syndrome of vacuous mouth movements, penile grooming, yawning and immobility whereas at higher doses the yawning syndrome disappeared to be replaced with sniffing, licking and gnawing. Two antagonism studies were carried out. In the first the effects of captopril on apomorphine-induced behaviour were compared with those of the classical neuroleptic haloperidol, and in the second dose-response curves for the effects of captopril and enalapril on apomorphine-induced behaviour were determined. Captopril had no effect on the apomorphine-induced yawning syndrome whereas this was blocked by haloperidol. In contrast, both captopril and haloperidol blocked oral stereotypy (licking and gnawing) induced by apomorphine but had no effect on sniffing induced by the dopamine agonist. Selective blockade of apomorphine-induced oral stereotypy by angiotensin converting enzyme inhibition was confirmed in the second study in which both captopril and enalapril were observed to antagonize apomorphine-induced gnawing. The inhibition of apomorphine-induced gnawing by enalapril correlated with inhibition of brain angiotensin converting enzyme, but not lung angiotensin converting enzyme, by the drug as assessed by ex vivo penetration studies. These data suggest that angiotensin converting enzyme inhibition modulates the expression of apomorphine-induced oral stereotypy, a response that is thought to be mediated by postsynaptic dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme inhibitors can potentiate ozone-induced airway hyperresponsiveness

We investigated the effects of single and chronic oral administration of angiotensin-converting enzyme inhibitors on ozone-induced airway hyperresponsiveness in guinea pigs. Ozone exposure (3 ppm for 2 h) significantly increased airway responsiveness in vehicle-treated animals and in animals with either single or chronic administration (8 days) of drugs. Single administration of imidapril, enalapril and captopril significantly potentiated ozone-induced airway hyperresponsiveness at a dose of 100, 50 and 50 mg/kg, respectively, although these doses did not influence airway responsiveness in normal guinea pigs, i.e., the magnitude of potentiation was captopril > enalapril > imidapril. In the study of chronic administration of the drugs, imidapril (10-100 mg/kg per day) had no influence on airway responsiveness in both normal and ozone-treated animals. In contrast, captopril and enalapril (10-100 mg/kg per day) dose-dependently potentiated ozone-induced airway hyperresponsiveness, with no influence on airway responsiveness in normal animals. That is, the magnitude was enalapril > captopril. These results indicate that angiotensin-converting enzyme inhibitors potentiate airway responsiveness in ozone-treated guinea pigs but not in normal guinea pigs and that imidapril is less potent than enalapril and captopril in potentiating ozone-induced airway hyperresponsiveness in guinea pigs.     

Renin vs. angiotensin-converting enzyme inhibition in the rat: consequences for plasma and renal tissue angiotensin

To compare the effects of a potent rat renin inhibitor peptide (RIP) and angiotensin-converting enzyme (ACE) inhibitor on the intrarenal and plasma renin-angiotensin systems, anesthetized Sprague-Dawley rats were treated with an infusion of vehicle, ramipril or graded doses of the rat RIP (acetyl-His-Pro-Phe-Val-statine-Leu-he-NH2) for 30 min. Kidney and plasma samples were processed rapidly, and angiotensin peptides were separated by high-pressure liquid chromatography before measurement by a double-antibody radioimmunoassay. Blood pressure fell identically, by approximately 15 mm Hg, after either the RIP or ACE inhibitor. Plasma Ang II was 83 +/- 20 fmol/ml in vehicle-treated rats and fell to 28 +/- 3 fmol/ml with ramipril (10 mg/kg), the dose-response zenith. Plasma Ang II was significantly lower, 9 +/- 2 fmol/ml, with the highest RIP dose used. Control renal tissue Ang II was 183 +/- 18 fmol/g, fell with ramipril to 56 +/- 6 and then fell to a similar level (47 +/- 10 fmol/g) after RIP. Ang I/Ang II ratios indicated the expected sharp drop in Ang I conversion after ramipril in plasma and tissue. RIP did not influence conversion rate in plasma but was associated with an unanticipated fall in Ang I conversion in renal tissue, perhaps reflecting local aspartyl protease inhibition, which contributes to normal Ang II formation. Also unanticipated was a rise in tissue Ang I concentration during RIP administration. Renin inhibition is more effective than ACE inhibition in blocking systemic Ang II formation, supporting studies suggesting that quantitatively important non-ACE-dependent pathways participate in Ang II formation.     

Additional cases of ureteral obstruction associated with Henoch-Sch?nlein purpura

AIMS: There is controversy regarding the potential antioxidant effect of captopril, therefore this study was performed to compare the in vitro antioxidant power of captopril with other angiotensin-converting enzyme (ACE) inhibitors. METHODS: Antioxidant power of captopril, enalapril, fosinopril, perindopril, quinapril and ramipril in aqueous solution was measured using the ferric reducing (antioxidant) power (FRAP) assay; captopril was also measured in ethanolic solution. RESULTS: Only captopril showed significant antioxidant power, demonstrating a stoichiometric factor of 1.0 in this assay. Concentration-related antioxidant power was seen in both aqueous and ethanolic solutions. CONCLUSIONS: Captopril shows antioxidant activity in vitro. This property could be relevant in vivo if captopril is concentrated in membranes, lipoproteins or at other important sites.     

Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin in the potentiation

One adverse effect of the angiotensin-converting enzyme (ACE) inhibitors used for treatment of hypertension and congestive heart failure is the production of dry coughs. Imidapril is a new type of ACE inhibitor with a very low incidence of coughs. The magnitude and the mechanism of cough potentiation of imidapril and other ACE inhibitors has been studied in guinea-pigs. In normal guinea-pigs single and repeated dosing of imidapril at 0.1 to 100 mg kg-1 had no effect on capasaicin- or citric acid-induced coughs. Single and repeated dosing of enalapril and captopril at 10 to 30 mg kg-1, respectively, significantly increased the number of capsaicin-induced coughs. Repeated dosing of 1 mg kg-1 enalapril also significantly augmented the capsaicin cough. In bronchitic guinea-pigs imidapril also had no effect on the coughs induced by the two stimulants. Enalapril and captopril significantly increased the number of coughs induced not only by capsaicin but also by citric acid. Lower doses of enalapril were enough to augment the capsaicin-induced coughs, whereas medium to large doses failed to augment the cough irrespective of the protocol of administration. Bradykinin-induced discharges of the vegal afferents from the lower airway were significantly increased by enalaprilat but not by imidaprilat. Capsaicin-induced discharges of the afferents were, on the other hand, significantly depressed by enalaprilat, but not by imidaprilat. Interestingly, enalaprilat depression of the discharges was significantly reversed by Hoe-140, a bradykinin B2 receptor blocker. In guinea-pigs pretreated with a low dose of enalapril, arterial infusion of bradykinin significantly potentiated the coughs induced by capsaicin. The results indicated that imidapril was less potent than enalapril and captopril in potentiating cough responses induced by capsaicin and citric acid in guinea-pigs, and further suggest that bradykinin might be a key substance in the mechanism of the potentiation of coughs associated with ACE inhibitors.     

Comparison of blood pressure and angiotensin responses to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme inhibitor enalapril in essential hypertension

OBJECTIVE: To compare the responses of angiotensin II (Ang II) and blood pressure to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme (ACE) inhibitor enalapril. SUBJECTS: Eight non-sodium-restricted patients with mild-to-moderate essential hypertension. DESIGN: A single-blind crossover study. Ro 42-5892 (600 mg orally, once a day) and enalapril (20 mg orally, once a day) were given for 8 days before detailed investigations were carried out. METHODS: Ambulatory blood pressure was measured directly for 24 h by the Oxford technique on three occasions. Off-treatment and on day 8 of treatment with Ro 42-5892 and with enalapril. Ang II was measured by radioimmunoassay after separation by high-performance liquid chromatography. RESULTS: Plasma renin activity and Ang II were lowered by 83% [95% confidence interval (CI) 61-105] and 68% (95% CI 49-87), respectively, 0.5-1 h after Ro 42-5892, but after only 3 h values had returned to baseline. Unlike this rapid and short-term suppression of Ang II, the maximal antihypertensive response to Ro 42-5892 (fall in blood pressure 12.9/9.0 mmHg) occurred only after 6 h. Blood pressure returned to baseline after 8 h. In response to enalapril, Ang II was maximally suppressed by 63% (95% CI 32-94) after 2 h and by 83% (95% CI 76-90) after 8 h. Despite early maximal Ang II suppression, the maximal antihypertensive response to enalapril occurred only after 12 h (fall in blood pressure 25.3/16.3 mmHg). With this compound a significant antihypertensive effect was still present 24 h after dosing. CONCLUSIONS: Compared with enalapril at 20 mg once a day, repeated oral administration of a single dose of Ro 42-5892 at 600 mg caused only short-term suppression of Ang II and blood pressure. Suppression of Ang II and reduction in blood pressure were temporally dissociated, both with the ACE inhibitor and the renin inhibitor. This implies that the blood pressure lowering effect of these inhibitors is caused partly by Ang II suppression outside the circulation.     

Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats

BACKGROUND: Blockade of type 1 angiotensin (Ang) II receptors combined with ACE inhibition may amplify the efficacy of the renin-angiotensin system blockade because ACE inhibitors do not completely and permanently suppress Ang II production. METHODS AND RESULTS: Enalapril or losartan (1, 3, 10, and 30 mg/kg) or their combination was administered for 2 to 4 weeks to spontaneously hypertensive rats. The combination of low doses of each agent induced greater reductions in blood pressure (BP) and left ventricular weight/body weight (LVW/ BW) ratio than monotherapy with the same or higher doses. When approximately equipotent regimens of enalapril, losartan, and their combination, as judged by BP fall, were compared, there were similar increases in plasma and renal renin and in plasma Ang-(1-7) and Ang I and similar reductions in plasma angiotensinogen. Enalapril alone reduced plasma Ang II levels, and losartan alone increased Ang II levels. The combination of enalapril with losartan prevented or reduced the increase in Ang II levels observed with losartan alone. CONCLUSIONS: These findings show that the synergistic interaction between the effects of low doses of enalapril and losartan on BP and LVW/BW ratio is due to more effective inhibition of the renin-angiotensin system by their combination than by either agent alone. When both drugs are given together, the ACE inhibitor-induced fall in plasma Ang II results in modulation of the Ang II antagonist-induced reactive rise in Ang II, thereby lowering the plasma Ang II concentration, which competes with the antagonist for the Ang II receptors.     

Chronic sodium balance and blood pressure response to captopril in conscious mice

The influence of chronic administration of the converting enzyme inhibitor captopril on blood pressure and sodium balance was evaluated in conscious Swiss Webster mice. Arterial pressure was measured with chronic indwelling catheters, and sodium balance was determined by infusing sodium intravenously in isotonic saline and collecting urine 24 h/d. Experiments to validate sodium balance measurements in mice demonstrated recovery of 100+/-3% of sodium intake under steady-state conditions (n=20 mice on 70 individual days, sodium intake range 160 to 1000 micromol/d). It was further demonstrated that mean arterial pressure, heart rate, and body weight were unaltered from 115+/-7 mm Hg, 646+/-12 bpm, and 34+/-0.6 g, respectively, as sodium intake was increased stepwise from 150 to 900 micromol NaCl per day. An additional validation group (n=7) demonstrated that daily and cumulative sodium balance can be accurately determined during and after the intravenous administration of an agent known to alter renal sodium handling (furosemide 50 mg. kg-1. d-1). Experiments were then performed to examine the influence of intravenous captopril infusion (40 mg. kg-1. d-1, n=7) in mice in which the daily sodium intake was fixed at approximately 200 micromol/d. This dose of captopril was determined to significantly decrease the pressor response to a 10-ng bolus of angiotensin I (Ang I) from 24+/-5 in the control state to 6+/-2 mm Hg (n=5). After 5 days of infusion of the converting enzyme inhibitor, mean arterial pressure significantly fell from 114+/-3 to 58+/-2 mm Hg, body weight significantly decreased from 36+/-1 to 33+/-1 g, and cumulative sodium balance significantly decreased to -270+/-55 micromol. These parameters returned toward control during 5 postcontrol days. Results of this study demonstrate that accurate sodium balance measurements can be obtained from individual conscious mice over a 5-fold range of sodium intake. The experiments also indicate that converting enzyme inhibition has a potent influence to lower blood pressure in normal mice; the hypotensive response appears to be due in part to increased urinary sodium excretion.     

Targeting TGF-beta overexpression in renal disease: maximizing the antifibrotic action of angiotensin II blockade

BACKGROUND: Overproduction of transforming growth factor-beta (TGF-beta) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease. METHODS: One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated. RESULTS: Both enalapril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-beta expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-beta expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-beta expression. CONCLUSIONS: The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.     

Variability in PAH-DNA adduct measurements in peripheral mononuclear cells: implications for quantitative cancer risk assessment

We investigated the angiotensin II (Ang II)-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin J (Ang I), and tetradecapeptide (TDP) renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM). The angiotensin converting enzyme (ACE) inhibitor captopril (36 microM) completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 microM) significantly reduced (80-90%) the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95%) the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition.     

Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension

OBJECTIVE: To evaluate the contribution of angiotensin-(1-7) [Ang-(1-7)] and prostaglandins to the acute and long-term antihypertensive actions of captopril in mild-to-moderate essential hypertensive patients. DESIGN AND METHODS: Blood pressure, cardiac rate and the plasma concentrations of angiotensin I (Ang I), angiotensin II (Ang II), Ang-(1-7), prostaglandin E2 and 6-keto prostaglandin F1 alpha (the breakdown product of prostacyclin) were determined in the peripheral venous blood of 24 essential hypertensive subjects before and 3 h after administration of 50 mg captopril. Eleven of 24 patients completed a 6-month treatment period with captopril monotherapy (50 mg twice a day). The hemodynamic and hormonal response produced by a last 50 mg dose of captopril was determined once again in the 11 subjects who maintained blood pressure control with captopril monotherapy for 6 months. RESULTS: The fall in blood pressure produced 3 h after drug intake was comparable for the first and the last 50 mg captopril dose. Although the first response to captopril increased plasma levels of Ang I only, the response to the last dose of the drug (6 months after) caused significantly higher levels of Ang I and Ang-(1-7). Neither acute nor chronic therapy with captopril had a significant effect on plasma concentrations of Ang II. Although plasma levels of prostaglandin E2 and 6-keto prostaglandin F1 alpha were not modified by a first exposure to captopril, the concentrations of 6-keto prostaglandin F1 alpha but not prostaglandin E2 rose significantly in subjects treated with the inhibitor for 6 months. A negative correlation was also demonstrated between diastolic blood pressure and plasma Ang-(1-7) levels in the 11 essential hypertensive subjects in whom blood pressure was controlled with captopril monotherapy. CONCLUSIONS: Inhibition of angiotensin converting enzyme with captopril had a significant effect on blood pressure that was not directly accounted for by a suppression of plasma Ang II levels. Continuous therapy with captopril unmasked a contribution of Ang-(1-7) and prostacyclin to the antihypertensive actions of this drug.     

Inhibition of angiotensin converting enzyme from sheep tissues by captopril, lisinopril and enalapril

Inhibition of angiotensin converting enzyme(EC 3.4,15.1, ACE) in presence of captopril, lisinopril and enalapril were investigated in kidney, lung and serum of sheep using Hip-His-Leu(HHL) as substrate. The activity in kidney, lung and serum was inhibited at HHL concentration above 5 mM. The inhibitory constants (IC50) ranged between 5.6 nM for serum ACE with lisinopril and 70000 nM for renal ACE with enalapril while Ki ranged from 1.0 nM for serum ACE with lisinopril to 12000 nM for kidney ACE with enalapril. Differences in inhibition observed in different tissues suggest that the inhibitors may block function(s) of ACE to varying degrees in each tissue.     

Interruption of prolonged ramipril treatment in hypertensive patients: effects on the renin-angiotensin system

The increase in renin secretion and the induction of the converting enzyme (ACE) observed during treatment by ACE inhibitors (CEIs) could result in increased angiotensin II (ang II) synthesis when the treatment is stopped. The object of this study was to compare changes in the components of the renin-angiotensin system with changes in arterial pressure in hypertensives, following the cessation of long-term ramipril treatment. Twenty hypertensives, treated for at least three months with ramipril, in monotherapy for the last three weeks, were randomly allocated to two parallel groups and received for fifteen days, on a double-bind basis, either a placebo (withdrawal group W, n = 12) or ramipril at the previous doses (treated group T, n = 8). Blood pressure was measured using four different techniques. The active renin (AR), angiotensinogen, angiotensin I (ang I), angiotensin II (ang II) and aldosterone plasma concentrations were measured, as was plasma angiotensin I converting enzyme (ACE) activity in vitro (colorimetric and fluorimetric method) and in vivo (the ang II/ang I ratio). The biological effects of cessation of long-term ramipril treatment in hypertensives were a decline in AR and angiotensin I concentrations, an increase in ACE activity and no significant changes in angiotensinogen, angiotensin II and aldosterone levels. Fifteen days after withdrawal, the different parameters of the renin-angiotensin system appear to have returned to basal value. A slow rise in blood pressure was also observed but no rebound increase was noted during the 15 days neither in angiotensin II levels nor in blood pressure. Following the cessation of prolonged ramipril treatment, in vivo converting enzyme inhibition disappears slowly, probably on account of the slow tight binding inhibitor properties of ramiprilat, the active metabolite of this CEI. The gradual decline in AF, plasma levels, together with the prolonged ACE inhibition as measured in vivo by the ang II/ang I ratio, explains the absence of a rise in ang II synthesis.     

Centralized i.v. team provides inpatient and home-care treatment

AIM: The study of the effects of the inhibitor of angiotensin converting enzyme ramipril (tritace) on the 24-h profile of blood pressure (BP) in patients with mild and moderate arterial hypertension. MATERIALS AND METHODS: Ramipril was given to 21 males aged 45-68 years with essential hypertension stage II (WHO criteria) with stable elevated diastolic blood pressure (95-114 mm Hg) in a single dose 2.5-10 mg/day. Captopril controls received 100 mg twice a day. BP was monitored using "SpaceLabs Medical" unit (model 90207, USA). RESULTS: Compared to placebo, ramipril lowered systolic and diastolic blood pressure both for the 24-h period and in the day time; captopril lowered only diastolic BP in the day time. Side effects of long-term application of ramipril occurred 2 times less frequently than in application of captopril. CONCLUSION: Long-term treatment with ramipril in the above regimen provides more effective control of BP than captopril in the above doses in patients with mild and moderate hypertension.     

Metrological analysis of measuring systems in testing an anticipatory reaction to the position of a moving object

This study compared the effects of angiotensin converting enzyme (ACE) inhibitors captopril versus enalapril on left ventricular (LV) muscle mass and LV systolic and diastolic function in 58 patients with primary glomerulonephritis and moderate chronic renal failure. The design was a 6-8 week titration phase and 6-month maintenance phase. Mean myocardial mass calculated by M-mode echocardiography in the captopril group was 153 +/- 26 g/m2 before, and 130 +/- 14 g/m2 after 6 months of treatment, in enalapril group 147 +/- 22 g/m2 before, and 126 +/- 23 g/m2 after 6 months of treatment (p < 0.05). LV ejection fraction, early and late transmitral flow velocities and early to late LV inflow velocities ratio were not significantly affected by both ACE inhibitors.     

Effects of angiotensin II generated by an angiotensin converting enzyme-independent pathway on left ventricular performance in the conscious baboon

Human chymase is a serine proteinase that converts angiotensin (Ang) I to Ang II independent of angiotensin converting enzyme (ACE) in vitro. The effects of chymase on systemic hemodynamics and left ventricular function in vivo were studied in nine conscious baboons instrumented with a LV micromanometer and LV minor axis and wall thickness sonomicrometer crystal pairs. Measurements were made at baseline and after [Pro11DAla12] Ang I, a specific substrate for human chymase, was given in consecutive fashion as a 0.1 mg bolus, an hour-long intravenous infusion of 5 mg, a 3 mg bolus, and after 5 mg of an Ang II receptor antagonist. [Pro11DAla12]Ang I significantly increased LV systolic and diastolic pressure, LV end-diastolic and end systolic dimensions and the time constant of LV relaxation and significantly decreased LV fractional shortening and wall thickening. Administration of a specific Ang II receptor antagonist reversed all the hemodynamic changes. In separate studies, similar results were obtained in six of the baboons with ACE blockade (20 mg, intravenous captopril). Post-mortem studies indicated that chymase-like activity was widely distributed in multiple tissues. Thus, in primates, Ang I is converted into Ang II by an enzyme with chymase-like activity. This study provides the first in vivo evidence of an ACE-independent pathway for Ang II production.     

Renoprotective differences between perindopril and enalapril in the diabetic hypertensive rat do not reflect glomerular angiotensin-converting enzyme activity

1. The various angiotensin-converting enzyme inhibitors have structural differences which affect their affinities for the catalytic sites on converting enzyme. We postulated that such differences might result in differences in renoprotective efficacy. We investigated this in the diabetic spontaneous hypertensive rat. We also investigated whether these differences might reflect variations in glomerular or plasma angiotensin-converting enzyme activity. 2. One week after induction of diabetes, rats were started on antihypertensive therapy: enalapril, 10 mg.day-1.kg-1, or perindopril, 4 mg.day-1.kg-1, in the drinking water. After 3 months, the rats were killed, blood samples were taken and tissues were harvested. Angiotensin-converting enzyme activity in isolated glomeruli and plasma was measured by fluorimetric assay. Glomerular protein content was also determined. 3. Urinary protein excretion was significantly lower in perindopril-treated rats than in either controls (P < 0.0005) or enalapril-treated rats (P < 0.05). Glomerular protein content was also lower in perindopril-treated rats (P < 0.05 versus enalapril; P < 0.005 versus control). There was no difference in glomerular angiotensin-converting enzyme activity between the two inhibitors although both were lower than control values (enalapril P < 0.025; perindopril P < 0.025). Plasma angiotensin-converting enzyme activity was significantly lower in the perindopril group than in either control (P < 0.005) or the enalapril group (P < 0.01). 4. We conclude that in the spontaneous hypertensive rat with streptozotocin-induced diabetes, perindopril is more effective than enalapril in reducing proteinuria and glomerular protein accumulation. This difference does not result from differences in glomerular-converting enzyme activity.     

Investigations into the mechanism of vasoconstrictor action of the topical steroid betamethasone-17-valerate in the rat

1. The effect of topical betamethasone upon skin blood flow was investigated in the rat. Two types of vasodilator stimuli were used; local heating to the surface of the skin and intradermal application of inflammatory agents. Blood flow was measured by laser doppler velocimetry. 2. Topical betamethasone-17-valerate (1 g with an 18 h pretreatment) significantly inhibited the heat-induced vasodilatation in the rat skin, as also did systemically administered betamethasone (1 mg kg-1, 3 h pretreatment). 3. Angiotensin converting enzyme (ACE) inhibitors (captopril, 5 mg kg-1 and enalapril, 1 mg kg-1, 30 min pretreatments) were the only drugs out of several different types of systemically administered inhibitors and antagonists that were tested which also inhibited the heat-induced vasodilatation. Aprotinin (100,000 KIU kg-1, 5 min pretreatment) a serine protease inhibitor, significantly potentiated the heat-induced response. 4. Bradykinin (50 nmol per site), des-Arg9-bradykinin (5 nmol per site), substance P (0.1 nmol per site) and capsaicin (1 mumol per site) induced an increase in skin blood flow. 5. Topical betamethasone treatment resulted in a significant inhibition of the vasodilator response to des-Arg9-bradykinin, whereas captopril treatment inhibited the responses to substance P, capsaicin, bradykinin and des-Arg9-bradykinin. 6. Intradermal application of captopril (10-100 micrograms) also caused a dose-dependent inhibition of the heat-induced vasodilatation. 7. These results suggest that topical betamethasone may be acting in a manner similar to that of the ACE inhibitors to produce an inhibition of the flow responses in the skin and that this effect may be brought about by interfering with the action of vasodilator peptide(s) or protein(s).     

Induction of an appetite for sodium in rats that show no spontaneous preference for sodium chloride solution—The Fischer 344 strain.

Fischer 344 rats show no spontaneous preference for isotonic NaCl solution. These experiments indicate, however, that a strong appetite for this solution may be induced by various methods, including adrenalectomy, administration of a mineralocorticoid hormone, acute depletion of sodium, and treatment with inhibitors of the angiotensin I converting enzyme. These treatments were also shown to produce the expected changes in the renin-angiotensin-aldosterone system, which thus appears to be involved in the induction of an appetite for NaCl solution in this strain of rat. The intakes of NaCl induced in the Fischer 344 rats by these experimental paradigms are less than those that have been reported in either Sprague-Dawley or Wistar strains in similar paradigms. In the case of sodium depletion, the intake of NaCl solution by Fischer 344 rats appears to be more closely related to the deficit than in the other 2 strains. The Fischer 344 strain of rats may be a particularly good model for studies of need-related sodium appetite. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Angiotensin III-induced dipsogenic and pressor responses in rodents.

Three experiments examined responses to angiotensins in 64 male Sprague-Dawley rats, 64 male Mongolian gerbils, and 40 Octodon degus—a South American rodent. In Exp I, injections of [des-Asp–1]-angiotensin I ([des-Asp–1]-AI), angiotensin II (AII), and angiotensin III (AIII), at doses of .001–2 mg/kg (sc), induced drinking in the rat and degus, but not in the gerbil. In Exp II, pretreatment with captopril (50 mg/kg), an angiotensin converting enzyme inhibitor, prevented the endogenous conversion of sc injected [des-Asp–1]-AI to AIII and prevented drinking in rats and degus. The pharmacological artifact of hypovolemia caused by angiotensin-induced increases in vascular permeability was not observed in members of these species. In Exp III, blood pressure changes resulting from injections of AII and AIII in rats and gerbils were measured. Significant pressor elevations were seen following the administration of both analogs, although AII was more potent. Results demonstrate that AIII is dipsogenic in rats and degus and serves as a pressor agent in rats and gerbils. No explanation was found for the gerbil's relative lack of dipsogenicity to the presently tested angiotensins. (54 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)