Chronic Angiotensin-converting Enzyme Inhibitor Treatment Research Articles

Ventricular arrhythmia susceptibility in a new porcine model of heart failure (HF) with reduced ejection fraction

Abstract Introduction Sudden death secondary to ventricular arrhythmias is common in HF patients, with no effective treatment available outside of implantable cardiac defibrillators. While animal models are essential for the discovery of anti-arrhythmic drugs, no reliable large animal HF models with associated ventricular arrhythmias have been described so far. Objectives We aimed at evaluating ventricular remodeling and arrhythmia susceptibility in an HF pig model with reduced ejection fraction (EF) following myocardial infarction (MI). Methods MI was induced in 53 male Göttingen minipigs (12–15 months, 20–25 kg) by coronary embolization in mid-left anterior descending and mid-left circumflex coronary arteries using endovascular coils. Seven other pigs underwent sham operation and were used as control. Two weeks after surgery, cardiac function was assessed by echocardiography, and animals were included based on EF<50% (n=15/53), assigned either to 12 weeks of vehicle (n=9) or perindopril (n=6, 1 mg/kg/d, per os) group. At the end of the study, their left ventricular (LV) electrical remodeling was studied by echocardiography/electrocardiography and a programmed-electrical stimulation protocol was performed to evaluate the susceptibility to develop ventricular arrhythmias. Results At the end of the study, animals in the vehicle group had a significant LV remodeling associated with a reduced EF (p<0.05 vs. sham, see table). This remodeling was associated with cardio-pulmonary congestion, significant increases in LV end-diastolic pressure, left atrial volume, and lung mass (all p<0.05 vs. sham, see table), fully prevented by perindopril treatment. They had also an electrical remodeling as evidenced by an increase in PR, QRS, and QTc intervals, as well as LV effective refractory period (+18%, 14%, 33%, and 13%, respectively, p<0.05, compared to sham animals). Electrical changes were mitigated by perindopril treatment (p=NS vs. sham). LV mechanical dispersion measured with speckle-tracking echocardiography was significantly increased in vehicle group (58±5 vs. 22±1 ms in sham group, respectively) as well as in perindopril group. Programmed-electrical stimulations induced in 6/8 vehicle animals either non-sustained (n=3) or sustained (n=2) ventricular tachycardia, or ventricular fibrillation (n=1). In sham group only 1/7 animal had a ventricular fibrillation. No inducible ventricular arrhythmia was observed in animals treated with Perindopril. Conclusion In this new pig model of congestive HF with reduced EF, LV remodeling was associated with electrical remodeling and susceptibility to develop arrhythmias. Chronic angiotensin-converting enzyme inhibitor treatment prevented congestion, mitigated electrical remodeling, and suppressed arrhythmia susceptibility. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Servier Research Institute - CardioVascular & Metabolic Diseases Center for Therapeutic Innovation Table 1

The one-two punch: knocking out angiotensin II in the heart

Ang II plays an important role in the pathophysiology of cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors lower Ang II levels by inhibiting conversion of Ang I to Ang II, but Ang II levels have been shown to return to normal with chronic ACE inhibitor treatment. In this issue of the JCI, Wei et al. show that ACE inhibition induces an increase in chymase activity in cardiac interstitial fluid, providing an alternate pathway for Ang II generation.

Chronic pretreatment of ACEI reduces no‐reflow in patients with acute myocardial infarction treated with primary angioplasty

In animal models, pretreatment with angiotensin-converting enzyme inhibitor (ACEI) can reduce no-reflow. In the present study, we investigated whether pretreatment with ACEI may prevent no-reflow in patients who underwent primary coronary intervention for AMI. A total of 259 consecutive patients who underwent primary angioplasty for a first AMI were studied. No-reflow was defined as a TIMI flow grade < 3. The no-reflow phenomenon was found in 33 of 259 patients. There were no significant differences in clinical characteristics between the patients with and without ACEI pretreatment. However, the 47 patients receiving chronic ACEI treatment before admission had lower incidence of the no-reflow than those without it (4.2 and 14.6%, p<0.05). Multivariable logistic regression analysis revealed that absence of ACEI pretreatment was a significant predictor of the no-reflow along with absence of preinfarction angina, complete occlusion of the culprit lesion, high-burden thrombus, ejection fraction on admission, number of Q-waves, absence of statin pretreatment, and anterior AMI. Pretreatment with ACEI could preserve the microvascular integrity after acute myocardial infarction in humans.

P2794 Rebound after withdrawing chronic angiotensin-converting enzyme inhibitor treatment post-myocardial infarction

P2794 Rebound after withdrawing chronic angiotensin-converting enzyme inhibitor treatment post-myocardial infarction

The chronic inhibition of angiotensin-converting enzyme impairs postoperative renal function.

Postoperative renal impairment can increase postoperative mortality and morbidity. We sought to identify preoperative risk factors responsible for postoperative renal impairment in patients undergoing aortic surgery. This prospective study included 249 patients admitted for aortic surgery. Preoperative and postoperative glomerular filtration rates (GFRs) were assessed with pre- and postoperative creatinine clearance measurements. Postoperative renal impairment was defined as a 20% decrease in GFR between Day 0 (before surgery) and Day 7 +/-1 day (after surgery). Preoperative and intraoperative variables considered as potentially responsible for postoperative renal impairment were tested. Chronic treatment with angiotensin-converting enzyme inhibitors (ACEIs) was the only factor significantly associated with postoperative renal impairment (odds ratio [95% confidence interval] = 2.01 [1.05-3.83]). Chronic preoperative ACEI treatment is significantly associated with postoperative renal impairment. Inhibition of renal compensatory mechanisms caused by renin angiotensin system blockade might be responsible for the observed decrease in renal function in patients chronically treated with ACEIs undergoing aortic surgery. However, age and preoperative renal dysfunction were not associated with a postoperative decrease in GFR, but they were associated with a postoperative creatinine clearance <60 mL/min. The aim of this study was to identify preoperative risk factors responsible for postoperative renal impairment in vascular surgery. Chronic angiotensin-converting enzyme inhibitor treatment was the only factor significantly associated with postoperative renal impairment. Inhibition of renal compensatory mechanisms caused by renin angiotensin system blockade might be responsible for the observed decreased renal function.

How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure?

OBJECTIVEAngiotensin II (AII) and aldosterone are not always fully suppressed during chronic angiotensin converting enzyme (ACE) inhibitor treatment. In congestive heart failure (CHF) such failure of hormonal suppression is associated...

Differential Expression of Angiotensin-converting Enzyme and Chymase in Dogs with Chronic Mitral Regurgitation

The current study tested the hypothesis that angiotensin-converting enzyme (ACE) and chymase expression are subject to different regulatory processes in the heart, as well as the lungs and kidneys and, as a result, have an important effect on the efficacy of ACE inhibitor treatment in modulating tissue angiotensin II (ANG II) levels in heart failure. A total of 18 dogs underwent the induction of mitral regurgitation and were followed for 5 months. Eleven dogs were untreated and seven received the ACE-inhibitor ramipril at a dose of 10 mg PO BID. Seventeen dogs underwent a sham-operation: six of these dogs were treated with ramipril for 3 months (10 mg PO BID) and 11 were untreated and followed for 3 months prior to sacrifice. In mitral regurgitation dogs, ANG II levels were increased >2-fold in left ventricle, lungs, and kidney, but were normalized with ACE inhibitor-treatment only in the left ventricle. In the left ventricle and lungs steady state ACE mRNA levels and ACE activities were increased 2-fold in treated and untreated mitral regurgitation dogs compared to shams (P<0.05, ANOVA). In contrast, chymase mRNA levels were decreased by >50% and chymase activity was increased in left ventricle (LV) of mitral regurgitation dogs (P<0.05). Neither chymase mRNA nor chymase activity could be detected in the kidney; however, kidney ACE mRNA and ACE activity were significantly upregulated in treated and untreated mitral regurgitation dogs (P<0.05). These results suggest that ACE and chymase expression are regulated differentially in the dog in response to chronic mitral regurgitation and ACE inhibitor treatment. Further, these responses, as well as regulation of ANG II formation, are organ specific.

High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition.

The acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril to healthy subjects transiently increases 5.5-fold the plasma levels of a natural stem-cell regulator, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The aim of this study was to measure plasma Ac-SDKP levels during chronic treatment with all types of ACE inhibitors and to assess its relevance as a marker of ACE inhibition. Plasma levels of Ac-SDKP were blindly determined in age- and sex-matched hypertensive patients either treated (ACEI group, n=27) or not (non-ACEI group, n=23) with an ACE inhibitor for more than 1 month. Geometric mean [range] of plasma Ac-SDKP levels were significantly higher in the ACEI group (3.78 [1.48 to 14.5] pmol/mL) than in the non-ACEI group, with no overlap between the groups (0.75 [0.36 to 1.22] pmol/mL, P<.0001). The measurement of Ac-SDKP in plasma discriminated all the patients of the ACEI group, whereas the simultaneous determination of either in vitro (using hippuryl-histidine-leucine as substrate) or in vivo (angiotensin II/angiotensin I ratio) ACE activity failed to identify nine and five cases, respectively. We conclude that Ac-SDKP accumulates in plasma during chronic ACE inhibitor treatment. The long-term consequences of Ac-SDKP accumulation are unknown. The reliability of plasma Ac-SDKP measurement makes it the best marker of chronic ACE inhibition, which can help to verify patients' compliance to ACE inhibitor treatment.

The Effect of the Angiotensin Converting Enzyme (ACE) Inhibitors Captopril and Enalapril on the Development of Oxygen Induced Lung Injury in the Rat.† 1563

Certain ACE inhibitors can decrease pulmonary and renal fibrosis resulting from exposure to ionizing radiation, possibly related to their intrinsic free radical scavenging properties. This study was designed to determine if ACE inhibitors can alter the pattern of lung injury and fibrosis induced by prolonged hyperoxia. Sixty male Sprague-Dawley rats were randomized into four groups: control (receiving neither oxygen nor drug), oxygen exposed controls(receiving no drug), oxygen exposed Captopril treated (a thiol containing ACE inhibitor), and oxygen exposed Enalapril treated (a non-thiol containing ACE inhibitor). Rats were exposed to 98-100% oxygen for 36 hours; 90% oxygen for 36 hours then maintained in 80% oxygen until their sacrifice on study day 5, 25, or 48. Captopril (400mg/L) and Enalapril (260mg/L) were provided continuously via drinking water. Samples of blood, lung and liver were examined for histologic and biochemical evidence of injury. Weight gain was decreased in all oxygen exposed animals regardless of drug treatment. Histologic evidence of acute oxygen toxicity (pulmonary edema) was present in all oxygen exposed animals regardless of therapy. Intensity of immunostaining for α-SMA (a marker of transformed myofibroblasts) seen around respiratory bronchioles, in alveolar walls and at septal tips was decreased with chronic ACE inhibitor treatment. Immunostaining of lipocytes and type II alveolar epithelial cells with PCNA (a marker of the S1 phase of cellular division) was prominent in all oxygen exposed animals on day five, but decreased at later time points. Intensity and distribution of immunostaining for PDGF and fibronectin was not altered by drug treatment. Immunostaining of liver and lung lipocytes and large airway epithelium with TGFβ decreased with chronic ACE inhibitor treatment. Staining for collagen deposition and elastic fibers around respiratory bronchioles, in alveolar walls and at septal tips was less prominent in ACE inhibitor treated animals at 45 days. We suggest that ACE inhibitors may decrease the long term effects of hyperoxia in rats through their effect on TGFβ production.

Blockade of bradykinin B2 receptors prevents the increase in capillary density induced by chronic angiotensin-converting enzyme inhibitor treatment in stroke-prone spontaneously hypertensive rats.

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B2-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B2-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577 +/- 279, n = 11 and 3988 +/- 300 mm/mm3; n = 10; P < .05) compared with vehicle-treated animals (2935 +/- 137 mm/mm3; n = 13). These effects were abolished by chronic bradykinin B2-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429 +/- 309 mm/mm3; n = 7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B2-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.

Chronic low-dose treatment with perindopril improves cardiac function in stroke-prone spontaneously hypertensive rats by potentiation of endogenous bradykinin

We investigated the effect of chronic angiotensinconverting enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2receptor antagonist, icatibant (500 μg/kg/day s.c), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic highdose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, lowdose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dP/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacyclin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin. We investigated the effect of chronic angiotensinconverting enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2receptor antagonist, icatibant (500 μg/kg/day s.c), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic highdose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, lowdose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dP/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacyclin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.

Effect of low-dose treatment with perindopril on cardiac function in stroke-prone spontaneously hypertensive rats: role of bradykinin.

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of chronic ANG I-converting enzyme inhibition on aging processes. II. Large arteries

The consequences of hypertension and aging on cardiovascular structure and function are reputed to be similar, suggesting that blood pressure plays a role in the aging process. However, the exact relationship between aging, blood pressure, and the arterial structure-function relationship has not been demonstrated. To test the effects of aging, renin-angiotensin system, and pressure on the arterial wall, 20 normotensive male WAG/Rij rats were killed at 6, 12, 24, and 30 mo of age and compared with similar groups treated with an angiotensin (ANG)-converting enzyme inhibitor (ACEI), perindopril. Arterial function was determined by a systemic hemodynamic study and by in situ measurement of carotid compliance. Arterial wall structure was determined by histomorphometric and biochemical methods. Aging did not significantly modify blood pressure, but ACE inhibition decreased blood pressure significantly from 6 to 30 mo. Plasma renin activity decreased with age and increased with ACEI. Plasma atrial natriuretic factor increased with age and was significantly decreased with ACEI. Absolute and relative left ventricular weight increased with age, and ACEI delayed these increases. Arterial wall stiffness increased with age, as shown by a significant decrease in systemic and local arterial compliance and by an increase in aortic characteristic impedance. The increase in carotid wall compliance after poisoning of smooth muscle contractile function (KCN) was greater in young (6- and 12-mo old) than in old (24- and 30-mo old) rats. Chronic ACEI treatment increased basal carotid compliance values slightly and did not change KCN carotid compliance. The aortic and carotid luminal size increased regularly with age. Aging was associated without any change in absolute elastin content. In contrast, collagen content increased with aging. Aging was also associated with an increase in medial thickness. Medial thickening was mainly due to smooth muscle hypertrophy. Aging was associated with intimal proliferation, which became progressively thicker and collagen rich. ACEI treatment did not prevent aortic lumen enlargement but significantly postponed the increase in medial and intimal thickening. Biochemical determinations of the aortic wall components confirmed the morphometric data. In conclusion, the age-dependent large artery enlargement and stiffening were observed both in normotensive rats and in those rats whose blood pressure was lowered by ACEI. This suggests that aging and blood pressure affect arterial wall structure and function by different mechanisms.

Angiotensin-converting enzyme inhibition improves cardiac function. Role of bradykinin.

The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists

To compare the effects of angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II (Ang II) antagonists. Survey of data from recent studies. DISCREPANCY BETWEEN BLOOD PRESSURE REDUCTION INDUCED BY ACE INHIBITORS AND PLASMA ANG II LEVELS: Studies on the effects of ACE inhibition in hypertensive subjects have suggested that with chronic ACE inhibitor treatment, blood pressure remains lowered even when plasma Ang II returns to normal. However, this discrepancy may be largely an artefact related to difficulties in measuring low Ang II levels in the presence of high angiotensin I (Ang I) levels. Even with modern sensitive and specific Ang II assays it can be difficult to monitor in vivo ACE inhibition (Ang II:I ratio in plasma) because of ex vivo Ang II formation. Recently, in measuring 24-h blood pressure responses to ACE inhibitor treatment, we have obtained good correlations between the time-course of the blood pressure response and the change in circulating Ang II. PROBLEMS IN MEASURING RENIN ACTIVITY: Routine assays of renin activity in plasma can lead to an overestimate of the degree of in vivo inhibition during renin inhibitor treatment, because some protease inhibitors that are used in these assays can cause an ex vivo displacement of protein-bound renin inhibitor, thereby increasing its free concentration. This must be taken into account when using the ratio of enzymatically active renin to immunoreactive renin as an index of in vivo renin inhibition. BLOOD PRESSURE RESPONSE AND ANG II LEVELS WITH RENIN INHIBITORS AND ANG II ANTAGONISTS: Results published so far seem to indicate that with these drugs, as with the ACE inhibitors, the magnitude of the blood pressure effect is correlated with the decrease in the 'effective' Ang II concentration at the receptor sites. However, the time-course of the two effects may be different; with the renin inhibitors, the maximum effect on pressure was delayed compared with the effect on Ang II. Further studies are needed to establish the exact time-course of renin and Ang II changes and their relationship to blood pressure. Only with rigorously controlled assays will it be possible to answer the question whether, for a given change in 'effective' Ang II concentration at the receptor sites, the effect on blood pressure is different with the three classes of anti-renin-angiotensin drugs.

Activation of DNA synthesis and inositol-phosphate turnover in coronary venular endothelial cells exposed to bradykinin

Kinins are potent bioactive peptides formed by the enzymatic action of kallikrein on kininogens. The discovery that angiotensin-converting enzyme, which generates angiotensin II, is also a major degrading enzyme of kinins, gave rise to the hypothesis that kinin potentiation, in addition to angiotensin II reduction, may be involved in the therapeutic actions of angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitors have become important drugs in the treatment of hypertension, congestive heart failure, postmyocardial infarction, and diabetic nephropathy. Although angiotensin II reduction appears to be the predominant mechanism of the antihypertensive effect of chronic angiotensin-converting enzyme inhibitor treatment, the role of kinins in the antihypertensive effects of angiotensin-converting enzyme inhibitors seems to be renin dependent and cannot be generalized for all models of hypertension. On the other hand, at least under experimental conditions, various cardioprotective effects of angiotensin-converting enzyme inhibitors appear to be due to the potentiation of endogenous kinins, including improved cardiac function, structural changes following myocardial ischemia, and induction of capillary growth in hypertension-induced left ventricular hypertrophy.

Neuronal angiotensin-converting enzyme (ACE) gene expression is increased by converting enzyme inhibitors (CEI)

Exposure to angiotensin-converting enzyme (ACE) inhibitors has been associated with increased ACE activity in vivo and in vitro. In the current study, we examined the effects of ACE inhibitors on ACE gene expression and activity in brain and primary neuronal cultures prepared from brains of neonatal spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls. ACE mRNA levels were increased in brain and neuronal cultures following ACE inhibitor exposure. A concomitant increase in ACE activity was evident in brain, but ACE activity was decreased in neuronal cultures following ACE inhibitor exposure. Since ACE has been localized to several cell types in the brain, including endothelial cells and glia, as well as neurons, the differences in ACE activity between whole brain and neuronal cultures following exposure to ACE inhibitors may be related to differential regulation of the ACE gene in these cell types. These findings and the observation that ACE mRNA levels are >20-fold higher in cultured neurons from neonatal SHR than in those from WKY support the conclusions that the activity of the brain renin angiotensin system is enhanced in SHR and that blockade of this system by chronic ACE inhibitor treatment contributes to the sustained antihypertensive effect of ACE inhibitors in this model.