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ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.
This trial evaluated the effects of epoprostenol on patients with severe left ventricular failure. Patients with class IIIB/IV congestive heart failure and decreased left ventricular ejection fraction were eligible for enrollment if angiography documented severely compromised hemodynamics while the patient was receiving a regimen of digoxin, diuretics, and an angiotensin-converting enzyme inhibitor. We randomly assigned 471 patients to epoprostenol infusion or standard care. The primary end point was survival; secondary end points were clinical events, congestive heart failure symptoms, distance walked in 6 minutes, and quality-of-life measures. The median dose of epoprostenol was 4.0 ng/kg/min, resulting in a significant increase in cardiac index (1.81 to 2.61 L/min/m2), a decrease in pulmonary capillary wedge pressure (24.5 to 20.0 mm Hg), and a decrease in systemic vascular resistance (20.76 to 12.33 units). The trial was terminated early because of a strong trend toward decreased survival in the patients treated with epoprostenol. Chronic intravenous epoprostenol therapy is not associated with improvement in distance walked, quality of life, or morbid events and is associated with an increased risk of death.
CONTEXT - Angiotensin-converting enzyme (ACE) inhibitors are associated with an increased risk of angioedema, but the risk of recurrent angioedema if treatment is continued is not known.
OBJECTIVE - To test the hypothesis that the association between ACE inhibitor use and angioedema may not be recognized and to determine characteristics of angioedema associated with continued use of ACE inhibitors.
DESIGN - Retrospective cohort study.
SETTING - Tennessee Medicaid program.
PATIENTS - Medicaid enrollees aged 15 years or older who used an ACE inhibitor and had a first documented episode of angioedema between 1986 and 1992 were followed up for recurrent episodes through June 1993.
MEASUREMENTS AND MAIN RESULTS - We previously identified 82 patients with a first confirmed diagnosis of angioedema during 51 752 person-years of ACE inhibitor use in this population (1.6 per 1000 person-years). Among these 82 patients, there were 16 outpatient recurrences of angioedema among 13 patients during 189 patient-years of follow-up (8.5 per 100 patient-years). The rate of angioedema was much higher in users of ACE inhibitors with continued exposure (18.7 per 100 patient-years) than in those whose use of the drug was discontinued (1.8 per 100 patient-years) (P=.001). Review of the medical records for patients taking ACE inhibitors who had recurrent angioedema revealed that physicians attributed angioedema to a number of causes not related to ACE inhibitor use, even after multiple recurrences.
CONCLUSION - Continuing use of ACE inhibitors in spite of angioedema results in a markedly increased rate of angioedema recurrence with serious morbidity.
Effectiveness of antihypertensive agents is assessed not only by systemic blood pressure levels, but by multiple parameters that reflect specific organ functions. Among antihypertensive agents, those which inhibit angiotensin actions show particular efficacy in ameliorating end organ damage. This efficacy likely reflects the central role that angiotensin has in regulating renal function by its multifaceted actions. We will therefore focus on the renin angiotensin system, and compare its actions on parameters of renal injury with other antihypertensive treatment approaches.
Angiotensin converting inhibitors (ACEI) not only decrease angiotensin II (Ang II) but also potentiate the effects of bradykinin. Bradykinin is a potent stimulus to tissue type plasminogen activator (t-PA) secretion in animal models. In this study, we tested the hypothesis that bradykinin increase t-PA levels in humans. Bradykinin was infused in seventeen hypertensive patients randomized to treatment with the ACEIs captopril and quinapril or with placebo. Bradykinin caused a significant decrease in mean arterial pressure (MAP) (p = 0.014) and increase in pulse (p < 0.001). ACEI significantly potentiated the hemodynamic effect of bradykinin (p < 0.05). Although baseline t-PA antigen levels were similar in the ACEI-treated (6.85 +/- 0.85 ng/ml) and placebo-treated (7.85 +/- 0.68 ng/ml) subjects, bradykinin caused a significant (p < 0.01) increase in t-PA antigen levels (to 19.3 +/- 8.2) only in the ACEI-treated patients. This increase in t-PA was independent of activation of the sympathetic nervous system. Bradykinin had no effect on PAI-1 antigen levels. These in vivo data suggest that infusion of bradykinin results in an increase in circulating t-PA levels without an effect on PAI-1.
We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.
Angiotensin converting enzyme (ACE) inhibitors block degradation of bradykinin and bradykinin stimulates prostacyclin production. ACE inhibitors are reported to increase prostaglandins. Therefore, we set out to determine 1) the contribution of prostacyclin to the bradykinin-mediated vasodepressor effects of ACE inhibitors, 2) whether ACE inhibitors alter the effect of bradykinin on prostacyclin, and 3) whether the effects of ACE inhibitors on bradykinin and prostaglandins are class effects or dependent on ACE inhibitor structure. To address these questions, we compared the effects of captopril, quinapril and placebo on blood pressure, urinary excretion of 2,3-dinor-6-keto-PGF1 alpha, and the vasodepressor response to i.v. bradykinin in 21 salt-replete normal-to-high renin hypertensive patients. Captopril and quinapril doses were titrated to lower pressure similarly. Captopril, but not quinapril, increased excretion of prostacyclin metabolite (217 +/- 50 vs. 135 +/- 21 pg/mg Cr base line, P < .05). Both ACE inhibitors dramatically, equally potentiated the vasodepressor response to bradykinin; the bradykinin dose required to decrease mean arterial pressure 15 mm Hg or increase pulse 20 bpm was 50-fold lower in ACEI-treated than in placebo-treated subjects (10 +/- 0 and 12.1 +/- 2.1 ng/kg/min in captopril and quinapril groups vs. 567 +/- 109 ng/kg/min in the placebo group; P < .005). ACE inhibition significantly attenuated the prostacyclin response to bradykinin at any given level of hypotensive response. Indomethacin abolished the prostacyclin response to bradykinin but did not alter the vasodepressor response. These data demonstrate that ACE inhibitors potentiate bradykinin-mediated vasodepression through a prostaglandin-independent mechanism. They suggest that although ACE inhibitors increase prostaglandins by increasing bradykinin, ACE inhibitors may attenuate prostaglandin production through a second bradykinin-independent mechanism.
BACKGROUND - Angiotensin converting enzyme inhibitor (ACEi) therapy delays the onset of renal failure in diabetic nephropathy and inhibits or delays the onset of proteinuria in several animal models.
MATERIALS AND METHODS - We examined this question using a transgenic model of chronic glomerulosclerosis caused by an excess production of growth hormone (GH) in which there is progressive glomerular scarring leading to uremia. In addition, since GH mice do not have systemic hypertension or an elevated glomerular filtration rate, we could address the question of whether ACEi or angiotensin II receptor antagonists (AII RA) had an effect on the development of glomerulosclerosis under these conditions. Since excess matrix accumulates in glomerulosclerosis because of alterations in the balance between its synthesis and degradation, we examined the effect of ACEi and AII RA on these parameters.
RESULTS - Systemic blood pressure was unaffected by ACEi treatment, but the glomerular filtration rate decreased 85%. ACEi-treated mice had increased mesangial deposition of type I collagen and decreased 105 kD complex collagenase activity. In addition, ACEi-treated GH mice had increased glomerular alpha 1 type I collagen, alpha 1 type IV collagen, and alpha-smooth muscle cell actin mRNAs. No changes were noted in beta actin, or 72 kD metalloproteinase mRNAs. The result of these changes was a net increase in sclerosis. Surprisingly, GH mice treated with ACEi or AngII RA developed marked renal arteriolar lesions.
CONCLUSIONS - In some forms of glomerulosclerosis, the lesions develop independently of angiotensin II. Pharmacological inhibition of angiotensin II, in this circumstance, may aggravate the lesions through disregulation of the levels and the balance between glomerular matrix synthesis and degradation.
OBJECTIVE - To study the association of race and other patient characteristics associated with angiotensin converting enzyme (ACE) inhibitor-associated angioedema.
METHODS - This was a retrospective cohort study of participants in the Tennessee Medicaid Program ( >or= 15 years of age) to whom ACE inhibitors had been prescribed from 1986 through 1992.
RESULTS - We identified 82 patients with confirmed angioedema during 51,752 person-years of ACE inhibitor use, giving an overall rate of angioedema of 1.6 per 1000 person-years of ACE inhibitor use. After potential confounding factors were controlled for, the adjusted relative risk (RR) of angioedema among black American users of ACE inhibitors was 4.5 (95% confidence interval [CI] 2.9 to 6.8) compared with white subjects. In addition to race, other factors associated with a significantly increased relative risk in the entire population were the first 30 days of ACE inhibitor use (RR, 4.6; 95% CI, 2.5 to 8.5) compared to > 1 year of use, use of either lisinopril (RR, 2.2; 95% CI, 1.2 to 3.9) or enalapril (RR, 2.2; 95% CI, 1.4 to 3.5) compared to captopril, and previous hospitalization for any diagnosis within 30 days (RR, 2.0; 95% CI, 1.1 to 3.6). Neither ACE inhibitor dose nor concurrent diuretic use was associated with the risk of angioedema.
CONCLUSIONS - These data suggest that black Americans have a substantially increased risk of ACE inhibitor-associated angioedema compared with white subjects and that this increased risk cannot be attributed to an effect of dose, specific ACE inhibitor, or concurrent medications.
BACKGROUND - One suggested mechanism for the reduction in mortality rates resulting from the use of angiotensin converting enzyme inhibitors in congestive heart failure is the inhibition of the angiotensin II-mediated norepinephrine release. Direct evidence for this mechanism is lacking in humans.
SUBJECTS AND METHODS - We examined the effects of captopril, 25 mg three times a day, or matched placebo for 7 days on sympathetic activity during a 10 mEq/day sodium diet in seven healthy male subjects aged 30 +/- 3 (SEM) years. A tritiated norepinephrine radioisotope dilution technique was used to measure sympathetic activity, both at rest and during isometric handgrip exercise.
RESULTS - Captopril blunted the increase in mean arterial pressure during isometric handgrip exercise (placebo, from 81 +/- 4 to 112 +/- 2 mm Hg; captopril, from 78 +/- 3 to 101 +/- 2 mm Hg; p < 0.01). However, the increase in systemic norepinephrine spillover during isometric handgrip exercise was not blunted by captopril. Captopril had no effect on resting mean arterial pressure or systemic norepinephrine spillover.
CONCLUSIONS - Captopril did not attenuate baseline or static exercise-stimulated sympathetic activity in healthy subjects. These findings would indicate that angiotensin converting enzyme inhibition does not decrease sympathetic activity at rest or during the stimulus of isometric handgrip exercise.