Differential systemic and regional hemodynamic profiles of four angiotensin-I converting-enzyme inhibitors in the rat

Summary Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure by reducing systemic vascular resistance. That the peripheral vasodilating properties of ACE inhibitors might not be homogeneously distributed in all vascular beds and might differ from one drug to another has been investigated in the normotensive rat by the pulsed Doppler technique using the active components of four different ACE inhibitors: captopril, enalapril, perindopril, and ramipril.Systemic (cardiac output and blood pressure) and regional (kidney, mesentery, hindquarter) hemodynamic responses to saline or to cumulative bolus injections (0.01–1 mg/kg) of captopril, enalaprilat, perindoprilat, or ramiprilat were continuously monitored. The effects of successive bolus injections (0.3–300 ng/kg) of angiotensinII were also investigated. The four ACE inhibitors produced an almost complete blockade of plasma angiotensin-II converting-enzyme activity (83%, 100%, 100%, and 100%, respectively), induced dose-dependent decreases in mean blood pressure, did not significantly affect cardiac output, and reduced total peripheral and mesenteric vascular resistances to the same extent. Hindlimb vascular resistance was identically decreased, but to a lower extent than total peripheral resistance by enalaprilat, perindoprilat, and ramiprilat, whereas it was increased by captopril at low doses only. Renal resistance was markedly decreased by the four drugs, and éspecially by captopril. The decreasing rank order for ACE-inhibitor-induced vasodilation is exactly the same (renal>total peripheral=mesenteric >hindlimb vascular resistances) as that of angiotensin-II-induced regional vasoconstriction, indicating that the vasodilator properties of ACE inhibitors are mainly due to angiotensin-II vasomotor tone suppression. None of the investigated compounds significantly affected mesenteric and hindlimb blood flows, except captopril, which lowered the latter significantly. Finally, the four drugs increased renal blood flow markedly.Thus, the four drugs exhibited different regional vasodilating patterns, those of enalaprilat, perindoprilat, and ramiprilat being almost similar, while that of captopril was different.     

Cardiac arrhythmias are ameliorated by local inhibition of angiotensin formation and bradykinin degradation with the converting-enzyme inhibitor ramipril

Summary We investigated the influence of the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac arrhythmias in guinea pigs and rats. Ramiprilat, the active moiety of ramipril, did not influence action potentials of isolated guinea-pig papillary muscle or rabbit sinus node, thereby excluding cellular electrophysiological evidence of anti-arrhythmic properties. Ramipril protected against cardiac arrhythmias induced by digoxin infusion in guinea pigs. This effect was comparable with that of lidocaine. In isolated perfused ischemic working rat hearts, angiotensin (ANG) I (3×10^–9 M/l) and ANG II (1×10^–9 M/l) aggravated reperfusion arrhythmias, accompanied by deterioration of cardiodynamic and metabolic events. Bradykinin (BK) (1×10^–10–1×10^–8 M/l), in contrast, protected against reperfusion arrhythmias, which corresponded to an increase in energy-rich phosphates and glycogen stores and a decrease in lactate levels in myocardial tissue. Identical changes were seen in hearts from rats pretreated with ramipril (1 mg/kg PO) or perfused with ramiprilat (2.58 ×10^–7–2.58×10^–5 M/l). Local ACE inhibition in these ischemic hearts antagonized ANG I but not ANG II effects and enhanced BK effects. The BK antagonist D-Arg-(Hyp², Thi^5,8, D-Phe⁷) BK abolished the beneficial effects of BK, ramipril, and ramiprilat. Increased concentrations of BK or ramiprilat were able to reverse the antagonism.The antiarrhythmic agent nicainoprol, a fast-sodiumchannel blocking drug (class Ib), also protected isolated rat hearts against reperfusion arrhythmias, but was without beneficial effects on cardiac hemodynamics and biochemical parameters, in contrast to the ACE inhibitor.These results suggest that the beneficial effects of the ACE inhibitor ramipril on digoxin and reperfusion arrhythmias are not mediated by their direct actions on ionic channels in the cell membrane. It seems that other factors are responsible for its beneficial effects on reperfusion arrhythmias, cardiac function, and metabolism, which are associated with a reduction in ANG II generation and BK degradation by local ACE inhibition in the heart.     

ACE-inhibition induces NO-formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts.

The role of NO-formation induced by accumulated endogenous bradykinin (BK) via local ACE-inhibition with ramiprilat (RT) or by adding BK exogenously was evaluated in cultured bovine aortic endothelial cells (BAEC) and in isolated rat hearts with post-ischaemic reperfusion injuries. Furthermore we used the n-octyl-ester of ramipril (RA-octil) which was shown to have no ACE-inhibitory action. In BAEC, ACE-inhibition by RT (1 x 10(-8)-1 x 10(-6) mol/l) or addition of BK (1 x 10(-8)-1 x 10(-6) mol/l) stimulated the formation of NO and prostacyclin (PGI2) as assessed by endothelial cyclic GMP- and 6-keto-PGF1a formation. Cyclic GMP and PGI2 synthesis was completely suppressed by the NO synthase inhibitor NG-nitro-L-arginine (L-NNA, 1 x 10(-5) mol/l) and by the B2 kinin receptor antagonist HOE 140 (1 x 10(-7) mol/l). RA-octil (1 x 10(-8)-1 x 10(-4) mol/l) did not affect endothelial cyclic GMP production in BAEC. In isolated working rat hearts subjected to local ischemia with reperfusion both RT (1 x 10(-8) mol/l) and BK (1 x 10(-9) mol/l) reduced the incidence and duration of ventricular fibrillation. In parallel myocardial function (left ventricular pressure, coronary flow) and metabolism (high energy rich phosphates) were improved showing a comparable fingerprint for RT and BK. Addition of L-NNA (1 x 10(-6) mol/l) or HOE 140 (1 x 10(-9) mol/l) abolished these protective effects of RT and BK. As in the BAEC studies RA-octil was without beneficial effects on the isolated ischaemic rat heart. The findings on BAEC show that inhibition of ACE localized on the luminal side of the vascular endothelium results in increased synthesis of NO and prostacyclin by local accumulation of endothelium-derived BK. Similar mechanisms may occur in the ischaemic rat heart leading to cardioprotection.     

KATP channel opening does not contribute significantly to the vasodilatory effect of SH-group-containing ACE inhibitors

Summary Angiotensin-converting enzyme (ACE) inhibitors are widely used in the management of hypertension, heart failure, and nephropathy. It has been suggested that ACE inhibitors containing the sulfhydryl group (SH) have an additional effect on K_ATP channels. To prove this hypothesis, we studied the effects of the SH-containing ACE inhibitors, captopril and zofenopril, on K_ATP channel opening of bovine coronary arteries and guinea pig thoracic aortas. Bovine coronary arteries were precontracted with the thromboxane A2 analogue, U46619, and guinea pig thoracic aortas were precontracted with phenylephrine and then relaxed with either captopril or zofenopril (n=8). Inhibition of K_ATP channel opening with glibenclamide moderately attenuated the zofenopril-induced relaxation of guinea pig thoracic aorta. However, in the bovine coronary arteries, the relaxing effect of both captopril and zofenopril remained uneffected by glibenclamide. In experiments with enalapril (a non SH-containing ACE inhibitor:n=6) on guinea pig thoracic aortas, no effect on K_ATP channels could be seen. From our experiments, we conclude that the postulated opening of K_ATP channels by SH-group-containing ACE inhibitors contributes little to the vasodilation of guinea pig thoracic aortas caused by ACE inhibitors, and that SH groups have no influence upon K_ATP channels of bovine coronary arteries.     

Local corticosterone production and angiotensin-I?converting enzyme shedding in a mouse model of intestinal inflammation

AIM: To investigate local corticosterone production and angiotensin-I converting enzyme (ACE) protein expression and their interaction in healthy and inflamed intestine.METHODS: Acute intestinal inflammation was induced to six weeks old male Balb/c mice by administration of either 3% or 5% dextran sodium sulfate (DSS) in drinking water for 7 d (n = 12 in each group). Healthy controls (n = 12) were given tap water. Corticosterone production and ACE protein shedding were measured from ex vivo incubates of the small and large intestine using EIA and ELISA, respectively. Morphological changes of the intestinal wall were assessed in hematoxylin-eosin stained tissue preparations of jejunum and distal colon. Effects of angiotensin II, captopril and metyrapone on corticosterone production was assessed by incubating pieces of small intestine of healthy mice in the presence of 0.1, 1 or 10 μmol/L angiotensin II, 1, 10 or 100 μmol/L captopril or 1, 10 or 100 μmol/L metyrapone solutions and measuring corticosterone released to the incubation buffer after 90 min (n = 5 in each group).RESULTS: Both concentrations of DSS induced inflammation and morphological changes in large intestines but not in small intestines. Changes were observed as distortions of the crypt structure, mucosal erosion, immune cell infiltration to the mucosa and submucosal edema. Ex vivo corticosterone production (2.9 ± 1.0 ng/mL vs 2.0 ± 0.8 ng/mL, P = 0.034) and ACE shedding (269.2 ± 97.1 ng/mL vs 175.7 ± 52.2 ng/mL, P = 0.016) were increased in small intestines in 3% DSS group compared to the controls. In large intestine, corticosterone production was increased compared to the controls in both 3% DSS (229 ± 81 pg/mL vs 158 ± 30 pg/mL, P = 0.017) and 5% DSS groups (366 ± 163 pg/mL vs 158 ± 30 pg/mL, P = 0.002). Large intestine ACE shedding was increased in 5% DSS group (41.5 ± 9.0 ng/mL vs 20.9 ± 5.2 ng/mL, P = 0.034). Angiotensin II treatment augmented corticosterone production in small intestine at concentration of 10 μmol/L (0.97 ± 0.21 ng/mg protein vs 0.40 ± 0.09 ng/mg protein, P = 0.036).CONCLUSION: Intestinal ACE shedding is increased by DSS-induced intestinal inflammation and parallels local corticosterone production. ACE product angiotensin II stimulates corticosterone formation in healthy intestine.     

Renal and neurohormonal changes following simultaneous administration of systemic vasoconstrictors and dopamine or prostacyclin in cirrhotic patients with hepatorenal syndrome

Background/Aims: Intravenous ornipressin in cirrhotic patients with hepatorenal syndrome causes marked improvement of systemic hemodynamics and suppression of plasma renin and norepinephrine but only moderate improvement of renal function. This study was designed to investigate whether these beneficial effects could be enhanced by the simultaneous administration of dopamine. The renal effects of the i.v. infusion of norepinephrine plus prostacyclin in patients with hepatorenal syndrome were also assessed.Methods: Renal plasma flow, glomerula filtration rate, free water clearance, sodium excretion and the plasma levels of renin and norepinephrine were measured in baseline conditions and during the administration of ornipressin (6 IU/h) and ornipressin (6 IU/h) plus dopamine (2 μg/kg·min) in nine patients with hepatorenal syndrome. Five additional patients with hepatorenal syndrome were studied prior to and following the administration of norepinephrine (0.45±0.1 μg/kg·min) and norepinephrine (0.85±0.2 μg/kg·min) plus prostacyclin (5 ng/kg·min).Results: Despite a significant increase in arterial pressure and marked suppression of plasma renin activity during ornipressin and ornipressin plus dopamine administration, no significant improvement in renal function was observed. Norepinephrine and norepinephrine plus prostacyclin also failed to increase renal perfusion and glomerular filtration rate.Conclusions: The combined administration of systemic vasoconstrictors (ornipressin or norepinephrine) and vasodilators (dopamine or prostacyclin), at the doses used in the current study and for a short period of time, does not improve renal function in cirrhotic patients with hepatorenal syndrome. The current study does not confirm a potential role for ornipressin in the treatment of hepatorenal syndrome.     

Early intervention with angiotensin-converting enzyme inhibitors during thrombolytic therapy in acute myocardial infarction: rationale and design of captopril and thrombolysis study. CATS investigators group.

The adjunctive use of angiotensin-converting enzyme (ACE) inhibitors with thrombolytic therapy early during acute myocardial infarction offers theoretic advantages. In the acute phase, captopril may scavenge free radicals, blunt the catecholamine response, elicit coronary vasodilation, and increase prostacyclin and bradykinin levels. In the chronic phase, ventricular remodeling may be attenuated. At present, a large number of controlled clinical trials mainly focusing on the effects of ACE inhibition in the chronic phase are underway. Only a few studies concentrate on the effect of acute intervention with ACE inhibitors in ischemia-reperfusion, i.e., thrombolysis in myocardial infarction. In April 1990 under auspices of the Interuniversity Cardiology Institute of the Netherlands, a large nationwide acute intervention trial with captopril in 280 patients receiving thrombolytic therapy was started, the Captopril and Thrombolysis Study (CATS). The primary hypothesis of CATS supposes a very early effect of ACE inhibition on evolving myocardial damage due to ischemia and the consequences of early reperfusion. This will be evaluated by serial echocardiography, Holter monitoring and neurohumoral measurements immediately on thrombolysis and during the first year after myocardial infarction.     

Comparison of captopril with enalapril in the treatment of heart failure: Influence on hemodynamics and measures of renal function

Summary Twenty-nine patients with severe heart failure (NYHA III) were randomly assigned to receive therapy with an angiotensin converting enzyme inhibitor (ACE inhibitor), either captopril or enalapril. The mean daily dosage of captopril was 56±5 mg and of enalapril 9.5±0.4 mg. After a mean of 8±1 days, the influence of both ACE inhibitors on hemodynamics and renal function was compared. The mean arterial pressure in the group treated with captopril (Group A) fell by 9±3 mmHg (p<0.01), and in the group treated with enalapril (Group B) it fell by 12±3 mmHg (p<0.001). The difference between the groups was not significant. Heart rate decreased in both groups; however, the change was significant (p<0.05) only in patients treated with enalapril (–11±3 bpm in Group B vs. –7±4 bpm in Group A). Stroke volume index increased by 6±3 ml/m² in Group A (p<0.05) vs. 10±2 ml/m² in Group B (p<0.01). The increase in stroke volume index was not significantly different between the two groups. Mean decreases in pulmonary artery and right atrial pressure were also comparable in both groups. Thus, hemodynamic improvements were similar during therapy with either captopril or enalapril. Serum sodium and potassium before therapy were 137±1 mmol/l and 4.1±0.1 mmol/l, respectively, in group A and 139±1 mmol/l and 4.0±0.1 mmol/l, respectively, in group B. Neither serum electrolytes nor serum creatinine were changed significantly by therapy with captopril or enalapril. These results suggest that despite differences in duration of action the effects on hemodynamics, serum electrolytes, and renal function are similar when comparable dosages of ACE inhibitors are used.     

Attenuation of myocardial reperfusion injury by sulfhydryl-containing angiotensin converting enzyme inhibitors

Summary Recent studies have suggested the beneficial effects of angiotensin converting enzyme (ACE) inhibitors against myocardial ischemic-reperfusion injury. This study was designed to compare the cardioprotective effects of two sulfhydryl ACE inhibitors, captopril and zofenopril, with those of a nonsulfhydryl ACE inhibitor, fosinopril. The efficacy of these ACE inhibitors to scavenge oxygen radicals in vitro were also examined. Isolated rat hearts perfused by the Langendorff technique were preperfused in the presence or absence of ACE inhibitors (50 m for 15 minutes), and the hearts were then subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion. Zofenopril and captopril, but not fosinopril, improved postischemic left ventricular functions and reduced myocardial cellular injury, as evidenced by improved recovery of the first derivative of left ventricular pressure development and reduced creatine kinase release compared with control (p<.05). Coronary flow was significantly increased by captopril and zofenopril only. The same two drugs also inhibited the enhanced lipid peroxidation during reperfusion. Although significant differences were not noticed in the postischemic myocardial membrane phospholipid composition, captopril and zofenopril reduced nonesterified fatty acid contents, including palmitic, linoleic, oleic, and arachidonic acids. In vitro studies demonstrated that captopril and zofenopril were able to scavenge hydroxyl radicals. These results indicate that among three ACE inhibitors, two sulfhydryl-containing drugs, captopril and zofenopril, possess cardioprotective as well as free-radical scavenging abilites. Attenuation of phospholipid degradation and lipid peroxidation may be contributory to the protective effects observed in this study.     

Comparison of effects of combined ACE inhibitor and low-dose thiazide diuretic with ACE inhibitor alone on insulin action in patients with hypertension and Type 2 diabetes: a double-blind crossover study

Aims To establish the safety in terms of insulin sensitivity of a low dose thiazide/ACE inhibitor combination. Methods We examined the effects on insulin sensitivity of captopril either alone or in combination with low-dose bendroflumethiazide (1.25 mg) in 15 hypertensive Type 2 diabetic patients. Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomised, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendroflumethiazide (CB) (1.25 mg). Results Blood pressure was lower following CB compare to C (138/83 vs. 144/85 mmHg; P < 0.05) and both were lower than baseline (153/92 mmHg; P < 0.01). CB resulted in a significant increase in fasting plasma glucose compared to C (9.6 ± 2.6 vs. 8.5 ± 1.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (25.1 ± 13.3 vs. 34.2 ± 16.8 µmol/kg/min; P < 0.01) as were isotopically determined glucose utilisation rates (29.0 ± 12.4 vs. 36.6 ± 17.3 µmol/kg/min; P < 0.05). There was no significant difference in fasting endogenous glucose production between treatments (CB 9.3 ± 3.3 vs. C 8.6 ± 1.6 µmol/kg/min), nor between suppression following insulin (CB 4.0 ± 2.1 vs. C 4.3 ± 3.1 µmol/kg/min). Conclusions Combination of low-dose bendroflumethiazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.     

Effects of the calcium antagonist diltiazem on action potentials, slow response and force of contraction in different cardiac tissues

Action potential duration in human and guinea-pig ventricular myocardium is reduced by diltiazem ≥10 μmol/l. A reduction of action potential amplitude and maximum upstroke velocity is observed only at high concentrations of diltiazem (30 μmol/l). In depolarized myocardium (rabbit SA- and AV-node, guinea-pig papillary muscle depolarized by (K⁺)₀ = 27 mmol/l) diltiazem ≥ 0.3 μmol/l reduces amplitude and maximum upstroke velocity of the calcium-dependent action potentials. The decrease in maximum upstroke velocity of the slow response in depolarized guinea-pig papillary muscle is enhanced by elevation of the stimulation frequency, as are the negative inotropic effects (use-dependence). In contrast to nifedipine diltiazem also delays the recovery of the maximum upstroke velocity of the slow response after stimulus-induced inactivation. The reduction of maximum upstroke velocity induced by nifedipine is independent of the rate of activation whereas the blockade induced by diltiazem consists of a small blockade during rest and a profound use-dependent blockade.     

Protective effect of rhubarb on the intestinal mucosal barrier

AIM: To investigate the mechanism of rhubarb protection of the gut barrier.METHODS: The gut barrier damage models caused by hemorrhagic shock and intraperitoneal endotoxin were used to study the protective effect of rhubarb on the intestinal mucosal barrier. Rats were randomly divided into four groups, as follows: treatment (rhubarb) group; Positive control group; Negative control group; Placebo treatment group. Plasma endotoxin, tissue superoxidedismutase (SOD) and lipoperoxide (LPO) concentrations were measured and histological analysis was performed. Rhubarb was observed to have a protective effect on the gut.RESULTS: Rhubarb decreased intestinal permeability, attenuated endotoxin absorption (endotoxin serum levels: shock group 0.557 EU/mL ± 0.069 EU/mL vs rhubarb group 0.345 EU/mL ± 0.055 EU/mL), and decreased tissue SOD and tissue LPO levels (SOD serum, intestine and liver levels: endotoxin group 122.92 NU/mL ± 43.19 NU/mL, 292.24 NU/mL ± 88.76 NU/mL, 272.70 NU/mL ± 85.79 NU/mL vs rhubarb group 312.23 NU/mL ± 54.93 NU/mL, 391.09 NU/mg ± 98.16 NU/mg, 542.86 NU/mg ± 119.93 NU/mg; LPO content in the intestine and liver: endotoxin group 8.57 μmol/L ± 2.58 μmol/L, 86.97 μmol/L ± 46.54 μmol/L vs rhubarb group 3.05 μmol/L ± 1.13 μmol/L, 13.18 μmol/L ± 19.64 μmol/L). Gut histopathology revealed that rhubarb promoted goblet cell proliferation, increased mucus secretion and protected intestinal mucosa in the hemorrhagic shock model.CONCLUSION: Rhubarb may protect the gut barrier by decreasing intestinal permeability, scavenging oxygen free radicals, and promoting goblet cell proliferation within the intestinal mucosa.     

Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine

OBJECTIVES: Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. METHODS: Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline. RESULTS: Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice. CONCLUSIONS: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.     

Angiotensin converting enzyme inhibition by captopril influences cardiac work in healthy hearts

Although beneficial effects of angiotensin converting enzyme (ACE) inhibition have been demonstrated in ill (ischemic, failing) hearts, it has not been proved that ACE inhibition induces changes in healthy hearts. The question is of clinical relevance, as many hypertensive patients do not display cardiac damage at the onset of treatment with ACE inhibitors, and possible changes in cardiac work might turn out more or less advantageous in the development of hypertensive heart disease. In a refined working heart preparation allowing measurement of cardiac work, including the contribution of atrial work and paracrine cardiac regulation, effects of captopril on cardiac dynamics were assessed. Coronary overflow of bradykinin, norepinephrine, and lactate was measured. Hearts were perfused for 20 min with vehicle or captopril at 3 × 10⁻⁸, 3 × 10⁻⁷, 3 × 10⁻⁶, and 3 × 10⁻⁵ mol/L. At the highest concentration, captopril increased coronary flow. Extending previous studies, the present study demonstrates that, in a concentration-dependent manner, captopril decreased oxygen consumption and maximal left ventricular pressure although the bradykinin outflow was not affected. From these influences of the drug on cardiac work and metabolism in healthy hearts, a protective influence of captopril in acute, critical situations of cardiac malnourishment or cardiac overload may be derived.     

Kinins, nitric oxide, and the hypotensive effect of captopril and ramiprilat in hypertension.

We investigated the role of kinins in the acute depressor effect of captopril and ramiprilat in spontaneously hypertensive rats. Since the vasodepressor action of kinins may be linked to the generation of prostaglandins and endothelium-derived relaxing factors, we also investigated the role of prostaglandins and nitric oxide in the blood pressure reduction caused by angiotensin converting enzyme inhibitors. To this end, we contrasted the hypotensive effects of captopril (10 mg/kg i.v.), ramiprilat (2 mg/kg i.v.), and the angiotensin II antagonist DuP 753 (30 mg/kg i.v.) in spontaneously hypertensive rats with and without pretreatment with a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) (200 micrograms/kg/min i.v.), an inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine) (15 mg/kg + 10 mg/kg/hr i.v.), or an inhibitor of prostaglandin synthesis (indomethacin) (10 mg/kg i.v.). The kinin antagonist did not affect blood pressure in spontaneously hypertensive rats but did attenuate the hypotensive effect of captopril and ramiprilat; the kinin antagonist did not minimize the depressor action of DuP 753. The nitric oxide synthesis inhibitor increased blood pressure in spontaneously hypertensive rats and attenuated the hypotensive effect of captopril, ramiprilat, and DuP 753, but it did not impede the hypotensive effect of sodium nitroprusside. Pretreatment of hypertensive rats with indomethacin did not modify the acute hypotensive effect of ramiprilat or captopril. These data suggest a contribution of endogenous kinins and nitric oxide to the acute antihypertensive effect of captopril and ramiprilat in spontaneously hypertensive rats and of nitric oxide to the hypotensive effect of DuP 753.     

Cardioprotection with angiotensin-converting enzyme inhibitors: Redefined for the 1990s

The concept of “cardioprotection” with ACE inhibitors has evolved over the last decade. In the 1980s, protective benefits of ACE inhibitors in hypertension were established, regression of left ventricular hypertrophy was demonstrated, and improved ventricular function and survival in mild-to-moderate and severe congestive heart failure was documented. A further “protective” role of ACE inhibitors in coronary artery disease is emerging as more attention is focused on the concept of local tissue reninangiotensin systems. Recent contributions to the literature describe significant benefits of ACE-inhibitor therapy in acute myocardial infarction, including suppression of ventricular arrhythmias and reduction of both early and late ventricular dilation, preservation of left ventricular function, and improved survival. All of the above effects can be considered “cardioprotective.” However, as new benefits are reported in the 1990s, a broadened view of “cardiovascular protection” emerges from investigative studies in the literature. ACE inhibitors may reduce tolerance to nitrates, reduce angina in some but not all studies, and limit smooth muscle cell proliferation (and perhaps restenosis) induced by experimental balloon angioplasty. Local vascular effects may attenuate atherosclerotic changes in the arterial wall in experimental animals and may decrease the incidence of aneurysm formation in hypertensive animals. The effectiveness of ACE inhibitors in acute myocarditis, suggested by reports that captopril may reduce lesions of murine myocarditis when administered early after infection with coxsackievirus B3, requires clinical confirmation. Despite these apparently diverse “cardiovascular protective” consequences of ACE inhibitor therapy, the mechanism(s) of action of these agents remain to be elucidated. These agents affect not only the systemic renin-angiotensin systems, but local tissue systems as well. Debate continues as to the significance of the sulfhydryl group in certain ACE inhibitors: at the present time it is not clear whether the thiol group provides a treatment benefit. Finally, stimulation of other vasodilator systems by ACE inhibitors (bradykinin, prostacyclin) may play an important role in the “cardiovascular protective” effects of these agents.     

Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs

Objectives. This study was undertaken to examine whether nitric oxide released in ischemic myocardium decreases the coronary vascular resistance and attenuates the severity of contractile and metabolic dysfunction.Background. Endothelium-derived relaxing factor, recently identified as nitric oxide, is a potent relaxant of coronary smooth muscle.Methods. The left anrterior descending coronary artery was perfused through an extracorporeal bypass tube placed in the carotid artery in 56 open chest dogs. After hemodynamic stabilization, we occluded this bypass tube to decrease coronary blood flow to one third of the control flow. Thereafter, we maintained a constant coronary perfusion pressure(40.9 ± 3.1mm Hg).Results. Under ischemic conditions, the coronary arteriovenous differences in nitrate and nitrite (end products of nitric oxide) increased (from 3.5 ± 0.4 [mean ± SEM] to 12.9 ± 2.1 μmol/liter, p < 0.01). ⁰-Monomethyl -arginine (3 μg/kg body weight per min, intracoronary) decreased the coronary arteriovenous differences in nitrate and nitrite (5.0 ± 0.9 μmol/liter, p < 0.05) and coronary blood flow (from 29.8 ± 0.5 to 18.1 ± 1.1 ml/100 g per min, p < 0.001). Fractional shortening (from 3.7 ± 1.0 to −1.3 ± 0.7%, p < 0.001) and lactate extraction ration (from −44.0 ± 4.1 to −59.2 ± 4.9%, p < 0.005) of the perfused area also decreased. These values were restored by the concomitant administration of -arginine. Blood flow to the endomyocardium was decreased relative to the epimyocardium. A reduction in coronary blood flow and worsening of myocardial contractile and metabolic functions due to the administration of ^G-monomethyl -arginine during ischemia were observed in denervated hearts. A reduction in coronary blood flow in ischemic myocardium was observed with the administration of ^W-nitro- -arginene methyl ester as well, although neither ^W-nitro- -arginine methyl ester nor ^G-monomethyl -arginine changed coronary blood flow and myocardial contractile and metabolic functions in the nonischemic myocardium. The cyclic guanosine monophosphate content of epicardial coronary artery increased due to myocardial ischemia; this increased was attenuated with ^G-monomethyl -arginine treatment.Conclusions. We conclude that endogenous nitric oxide predominantly decreases the coronary vascular resistance of ischemic endomyocardium, thereby improving myocardial contractility and metabolic function.     

Cardioprotection by Orotic Acid: Metabolism and Mechanism of Action

The pyrimidine base, orotic acid (OA), improves the function of recently infarcted hearts subjected to global ischemia but its mechanism of action is unclear. Our aims were to examine (i) in normal rats, the effect of OA on pyrimidine levels in plasma, liver and heart; (ii) in rats with normal or infarcted hearts, the effect of OA on adenine nucleotide metabolism and mechanical function, before and after global ischemia. To investigate the metabolism of OA, normal rats received 100 mg/kg OA, and changes in plasma and tissue concentrations of pyrimidines were examined. The effects of OA were also studied in rats receiving OA for 2 days after coronary ligation or sham operations, and plasma and tissue pyrimidine concentrations examined. Their hearts were isolated and perfused, then subjected to 30 min of global ischemia. Mechanical function and adenine nucleotide content were assessed pre- and post-ischemia. In normal, unoperated rats, administration of 100 mg/kg OA significantly increased hepatic uracil and cytosine nucleotide concentrations, then increased plasma uridine (+124%) and cytidine (+55%), and transiently increased myocardial uracil nucleotides (+21%). Infarction significantly reduced recovery of cardiac work after global ischemia (sham=62%; INFARCT=26%;P<0.05), and OA treatment in infarcted hearts increased post-ischemic work by 192% (P<0.05), but not in shams. Pre-ischemic ATP was reduced in the surviving myocardium of infarcted hearts from 21.7±0.8 to 14.7±0.7μmol/g dry weight (P<0.001) and total adenine nucleotides (TAN) from 30.3±0.8 to 22.4±1.1μmol/g dry weight (P<0.001). OA treatment prevented these reductions in infarcted hearts (ATP 20.7±0.5; TAN, 29.1±0.6μmol/g dry weight). We conclude that OA protects the infarcted heart against global ischemia by enhancing hepatic release of pyrimidine nucleosides into the plasma, which then prevent depletion of adenine nucleotides in the surviving myocardium.     

ACE-Inhibition plus Mineralocorticoid Antagonism versus ACE-inhibition alone in Patients with Anterior Myocardial Infarction

Background. Aldosterone exerts pro-fibrotic effects, acting via mineralo-corticoid reeptors in cardiovascular tissues. Aldosterone antagonism in combination with ACE inhibition may better protect against untoward effects of aldosterone than ACE inhibition alone. Methods. In a double blind, randomised study the tolerability and efficacy of canreonate (25 mg/day) plus captopril versus captopril alone were evaluated in 187 patients with an acute anterior myocardial infarction (MI) and a serum creatinine concentration <2.0 mg/dL and a serum K concentration <5.0 mmol/L. Ninety-four patients received captopril and 25 mg canreonate (group A). Group B (93 patients) received captopril and placebo. At baseline and at 10 and 90 days after admission Doppler echocardiography was performed. Results. Clinical and demographic aspects were similar in both groups. Also, baseline cardiac enzyme levels, left ventricular (LV) function and incidence of surgical interventions and angioplasty were comparable. Overall, creatinine, blood urea and serum K did not show significant differences between groups. However, in 9 patients in group A increases in serum K > 5.5 mmol/dL and creatinine >2.0 mg/L were observed after 10 days of treatment. At 90 days, the mitral E/A ratio was higher (p = 0.001) and LV end systolic volume smaller (p = 0.021) in patients treated with canreonate than in those receiving placebo. No further side effects were observed during the study period. Conclusions. Our data suggest that the combination of captopril plus canreonate is well tolerated following an acute myocardial infarction and has a beneficial effect on diastolic and systolic LV parameters and may decrease post-MI remodelling.     

NO-mediated vasodilation in the rat liver: Role of hepatocytes and liver endothelial cells

Background/Aims: Nitric oxide (NO) is a potent vasodilator. We investigated the mechanisms responsible for this effect in the liver.Methods: Isolated perfused rat liver and cultures of endothelial sinusoidal cells and hepatocytes were used.Results: L-arginine (10⁻³ M) and NO donor Sin-1 (10⁻⁵ M) respectively increased the liver flow by 52% (p<0.01) and 93% (p<0.01) vs controls. The NO synthase inhibitor N^w-nitro-L-arginine (10⁻³ M) and the guanylate cyclase inhibitor methylene blue (10⁻⁵ M) respectively decreased the basal liver flow by 26% and 16% (p<0.05) and inhibited the vasodilating effects of L-arginine. L-arginine (10⁻³ M) increased nitrite concentration in hepatocyte culture (77.25±7.40 μmol · 1⁻¹ vs 14.70±3.55 μmol · 1⁻¹ in controls; p<0.01) and in liver endothelial cell culture (0.36±0.09 μmol · 1⁻¹ vs 0.12±0.05 μmol · 1⁻¹ in controls; p<0.05). N^w-nitro-L-arginine inhibited the basal production and abolished the L-arginine-induced production of nitrites both in hepatocyte and in liver endothelial cell cultures. The concentration of nitrites in the hepatocyte supernatant rose from 14.70±3.55 μmol⁻¹ · 1⁻ to 150.50±45.55 μmol · 1⁻¹ in the presence of a combination of interleukin-1β, TNF a and interferon γ.Conclusions: Under basal conditions, NO regulates the vascular tone of liver circulation. Both liver endothelial cells and hepatocytes can be implicated. NO production by hepatocytes may increase during inflammation.