Determinants of angiotensin II generation during converting enzyme inhibition (original) (raw)
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Need for plasma angiotensin measurements to investigate converting-enzyme inhibition in humans
American Heart Journal, 1989
Since only a minute proportion of total angiotenaln-converting enzyme (ACE) is present in plasma, the reliability of conventional in vitro measurements of ACE actlvlty has been queatloned. Data presented here demonstrate that the definition of ACE .inhibltion depends on the methodology used, with different results obtained with different substrates. We have developed a method that provides accurate and precise determinations of "true" angiotenain levels and in viva ACE activity was estimated by measuring the plasma angiotenain Il/angiotenain I ratio. Since the initial interruption of angiotensin II production by an ACE Inhibitor stimulates renal renln release, the response can be quantitated by meaaurin,g changes in plasma levels of angiotenaln I. The actual state of the renin-anglotenain system during ACE inhibltlon is represented by the plasma anglotenain II level. When ACE inhibItion is no longer complete, increased angiotenaln I levels bring the system back toward initial angiotenaln II concentrations. (AM HEART J 1989;117:717.)
Pharmacology & Toxicology, 1992
Over the past several years, angiotensin I converting enzyme (ACE) inhibitors, compounds that block the formation of angiotensin I1 (ANG II), have become widely used in the treatment of cardiovascular disease. Recently, a new class of orally active, non-peptide inhibitors of the renin-angiotensin system, the ANG I1 receptor antagonists have also become available. Since both classes of compounds block the renin-angiotensin system, although at different sites, it remains to be determined whether blockade of ANG I1 receptors will have any specific advantage over inhibition of ACE. The following review assesses the actions of ANG I1 antagonists and suggests ways in which blockade of ANG I1 receptors may differ both pharmacologically and clinically from inhibition of ACE. Abbreviations: ACEangiotensin I converting enzyme; ANGangiotensin. Renin-angiotensin system. The enzyme renin is secreted by the kidney into the blood in response to a number of stimuli, including a reduction in blood pressure and a reduction in extracellular fluid volume. Renin cleaves 10 amino acids from its a-2 globulin substrate angiotensinogen to form the decapeptide ANG I. ANG I is rapidly converted to the biologically active octapeptide upon circulation through organs, by the action of the endothelial enzyme, angiotensin I converting enzyme (ACE). ANG I1 inhibits renal renin synthesis and release. Thus, a negative feedback mechanism exists, controlling the formation of ANG 11. Classically, ANG I1 has been viewed as a hormone synthesized solely within plasma. The discovery of components of the reninangiotensin system in many tissues of the body has led to the hypothesis that, in addition to being a circulating hormone, ANG I1 may be formed locally and therefore possess additional autocrine or paracrine actions (Levens et al. 1981; Dzau et al. 1987; Sealey & Laragh 1990). While ANG I1 may be formed within cells and tissues, the contribution of locally generated ANG I1 to the overall reponse of the renin-angiotensin system has not yet been clearly elucidated. The renin-angiotensin system can be inhibited, both by blocking the actions of ACE and renin, and by preventing the interaction of ANG I1 with cellular receptors. The biochemistry of the renin-angiotensin system is outlined in fig. 1. The renin-angiotensin system and kallikrein-kinin system. The enzyme kininase 11, which degrades bradykinin, is identical with ACE, the enzyme that converts ANG I to ANG I1 (Erdos & Skidgel 1986). Thus, following inhibition of ACE, not only is the formation of ANG I1 prevented, but the potential exists for bradykinin levels to increase in plasma and in tissues. Bradykinin stimulates prostaglandin formation (Hsueth et al. 1977) and, although at the present time controversial, there is some evidence suggesting a role for bradykinin and prostaglandins in many of the actions and side-effects of ACE inhibitors. An outline of the interaction between the renin-angiotensin and kallikrein-kinin systems is shown in fig. 1. Actions of ANG II. ANG I1 directly constricts vascular smooth muscle, causes the release of noradrenaline and adrenaline from the adrenal medulla and inhibits the reuptake and facilitates the depolarisation-evoked release of noradrenaline from prejunctional sympathetic nerve endings. ANG I1 also promotes the synthesis and the release of aldosterone from the adrenal cortex, pituitary vasopressin release and thirst. ANG I1 exerts direct effects upon the kidney, increasing sodium reabsorption and lowers renal blood flow and glomerular filtration rate. Although these actions of ANG I1 are many and varied, all serve to main
Clinical Pharmacology and Therapeutics, 1981
Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin 1 and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin 1 and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.
The American Journal of Cardiology, 1987
Local tissue renin-angiotensin systems have recently been discovered in various organs, and evidence is accumulating that inhibition of these local reninangiotensin systems may contribute to the actions of converting enzyme (CE) inhibitors. Measurements of CE activity and angiotensin II concentrations revealed that after oral administration of CE inhibitors, CE was inhibited not only in lung vascular endothelium and blood, but also in the heart, kidney, vascular wall, brain and other organs. The functional significance of tissue CE inhibition is suggested first by the antihypertensive effect of brain CE inhibition in spontaneously hypertensive rats, A lthough converting enzyme (CE) inhibitors have become established antihypertensive drugs and are currently under investigation for therapeutic use in such cardiac diseases as congestive heart failure and arrhythmias, their mechanisms of action are still not fully understood. Originally, a reduction of the vasoconstrictor peptide angiotensin II circulating in the blood, and possibly an accumulation of the vasodilator peptide bradykinin, were believed to be solely responsible for the actions of these drugs. However, doubts about this concept were raised early, based on various experimental and clinical findings.' For instance, it was shown that blood pressure could be reduced in forms of hypertension that were not associated with a stimulated plasma renin-angiotensin system.2r3 Further, the inhibition of the plasma renin-angiotensin system could often not be directly correlated with the antihypertensive effects of these drugs.3-5 Moreover,
Hypertension, 1984
The antihypertensive, hemodynamic, and humoral effects of the new convertingenzyme inhibitor enalapril (MK-421) were assessed by sequential studies during 3 months of uninterrupted treatment (20 mg twice daily) in 10 hypertensive patients. Six achieved good blood pressure (mean arterial pressure) control with enalapril alone (from 126 ± 7.0 mm Hg pretreatment to 105 ± 1.6 mm Hg at 3 months, p < 0.05). The other four required the addition of diuretics (hydrochlorothiazide 25 mg orally twice daily) at different stages of follow-up, with resultant blood pressure control (128 ± 9.6 mm Hg pretreatment to 113 ± 1.9 mm Hg at 2 months after the addition of diuretics). Neither the acute nor long-term blood pressure response could be predicted from the pretreatment levels of plasma renin activity. The blood pressure reduction during enalapril therapy was characterized by a decrease in total peripheral resistance (53 ± 2.5 U-M 2 pretreatment to 38 ± 3.0 U-M 2 at 3 months, p < 0.05) with no significant change in cardiac output or heart rate. This lack of reflex tachycardia could not be ascribed to baroceptor dysfunction since the response to head-up tilt (the increase in diastolic blood pressure, in heart rate, and in plasma catecholamines) was normal and not significantly different from pretreatment response. Average blood volume did not change (91% ± 4.3% of normal in the pretreatment period to 93% ± 2.9% after 3 months of therapy, p = NS) despite the significant lowering of arterial pressure with enalapril alone (n = 6). This could have been possibly related to the reduction in plasma aldosterone (12.6 ± 2.3 to 8 ± 0.9 ng/dl, p < 9.95) induced by treatment. In conclusion, the hemodynamic consequences of blood pressure reduction by enalapril were similar to those produced by other converting-enzyme inhibitors and angiotensin II antagonists. These findings suggest that the hemodynamic effects of enalapril were related to interference with the generation of angiotensin II rather than a direct action of the drug.
Clinical and Experimental Pharmacology and Physiology, 1992
1. The effects of angiotensin-converting enzyme (ACE) inhibitors on the tissue ACE were assessed by quantitative in vitro autoradiography after acute and chronic administrations of the drugs. 2. Following acute administration of lisinopril, perindopril or benazepril, ACE was markedly inhibited in the lung, kidney and blood vessels but not in the testis. In the brain, ACE was inhibited mainly in structures with a deficient blood brain barrier. 3. High doses of perindopril progressively inhibited ACE in other brain structures. Tissue ACE inhibition persisted after serum levels of the enzyme had returned to control levels. In the case of perindopril, the time course of tissue ACE inhibition correlated with the inhibition of the pressor responses to exogenous angiotensin I. 4. After chronic administration of lisinopril or perindopril for 14 days, a similar pattern of ACE inhibition was observed in the kidney, lung and blood vessels. In the lung, however, lisinopril was found to increase total ACE by 30%, while plasma ACE was increased two-threefold by both lisinopril and perindopril. Testicular ACE remained unaltered by chronic lisinopril treatment. 5. Overall, the changes in tissue ACE after the administration of inhibitors more closely parallel the drugs' biological effects than changes in plasma ACE or drug levels. ACE in the testis and brain is protected by permeability barriers that limit access of the drugs.
Clinical and Experimental Pharmacology and Physiology, 1990
I . Serum angiotensin converting enzyme activity (ACEA) and plasma renin activity ( P R A ) were determined in rats under different experimental conditions such as: nephrotic syndrome (NS), bilateral nephrectomy (BN), renovascular hypertension (RH), dehydration (DEH). anaesthesia (AN), low sodium diet (LSD) and high sodium diet (HSD), and injection with propranolol (PRO) and isoprenaline (ISO).
2015
SUMMARY The role of the renin-angiotensin system in the regulation of blood pressure in normal human subjects was investigated by administering to them the converting enzyme inhibitor (SQ 20881) during sodium-replete and sodium-depleted states. In the sodium-replete state (150 m£q sodium intake for 5 days) in eight normal subjects, converting enzyme inhibitor decreased the average mean arterial pressure from 75 ± 4 to 65 ± 5 mm Hg (P < 0.005) because of a decrease in peripheral resistance from 17 ± 1 to 14 ± 1 U (P < 0.025). Cardiac output did not change because of a simultaneous decrease in venous return. Sodium depletion (10 mEq sodium intake for 5 days) in six subjects resulted in an insignificant decrease in blood pressure (from 7 5 ± 4 t o 6 9 ± 2 mm Hg), whereas cardiac output decreased from 5.15 ± 0.29 to 3.91 ± 0.22 liters/min (P < 0.05). Plasma renin activity increased with sodium depletion from 2.13 ± 0.38 to 7.3 ± 1.3 ng/ml per hour (P< 0.005). Converting enzy...