Angiotensin II type 1 receptor blockade: high hopes sent back to reality?

Chronic activation of the renin-angiotensin system (RAS) plays a crucial role in the development of various cardiovascular diseases (CVD). Thus, effective RAS inhibition has been a major achievement to improve the treatment of patients at risk for CVDs, such as myocardial infarction, heart failure and stroke. Three substance classes that block RAS-activation are currently available, angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockade (ARB) and renin inhibitors. Although the overall goal of these drugs remains the blockade of RAS activation, their individual targets in this system vary and may substantially influence the clinical benefit derived from the long term use of these substances. Here, we summarize the evidence available for the use of ARBs in different cardiovascular pathologies and the impact of this evidence on current treatment guidelines for patients at risk for CVD. Today, ARBs represent a good alternative in case of ACE-inhibitor intolerance due to their outstanding tolerability. ARBs in comparison to ACE-inhibitors have been proven to exert similar effective in the treatment of systolic heart failure, primary prevention of stroke, new onset of diabetes mellitus (DM) type 2 and DM type 2 dependent macroalbuminuria. ARBs should be considered as alternatives to ACE-inhibitors in subjects post-myocardial infarction. Overall however, there is no profound proof for a specific cardiovascular protection by blockade of the angiotensin II Type 1 (AT1) receptor that exceeds the impact of ACE-inhibition or synergises with ACE-blockade. In fact, combination of ARBs and ACE-inhibitor result in an increased rate of adverse effects and, therefore, this combination should not be encouraged. To summarize, the initial hope for a more specific impact on cardiovascular diseases by inhibition of the AT1-receptor in comparison to ACE-inhibition has not come true. However, ARBs have been proven to be equally effective as ACE-blockade in a large variety of clinical settings.

Saralasin, a nonspecific angiotensin II receptor antagonist, attenuates oxidative stress and tissue injury in cerulein-induced acute pancreatitis.

INTRODUCTION: Free radical-mediated pancreatic injury is believed to play a key role in the pathogenesis of acute pancreatitis. Most of these studies have focused on the effects of antioxidant enzymes and free radical scavengers on improving the pancreatic injury. Recent findings showed that cerulein-induced acute pancreatitis was associated with an upregulation of a local pancreatic renin-angiotensin system in the pancreas. In the current study we hypothesized that inhibition of this renin-angiotensin system by saralasin, a nonspecific antagonist for angiotensin II receptor, could attenuate the severity of cerulein-induced pancreatitis. METHODOLOGY: The effects of saralasin on oxidative stress and tissue injury in cerulein-induced pancreatitis were assessed by histopathologic analysis and on the basis of biochemical changes of plasma alpha-amylase level, pancreatic glutathione status, oxidative modification of protein, and lipid peroxidation. RESULTS: Data from the biochemical analysis showed that intravenous injections of saralasin at doses of 10 microg/kg to 50 microg/kg 30 minutes before the induction of acute pancreatitis significantly reduced pancreatic injury, as indicated by a decrease in plasma alpha-amylase activity in comparison with the cerulein-treated control. The effect of saralasin was further manifested by significant suppressions of glutathione depletion, oxidative modification of proteins, and lipid peroxidation in cerulein-treated rat pancreas. Histopathologic examination findings were in agreement with the biochemical data. CONCLUSIONS: These data suggest that prophylactic administration of saralasin can ameliorate the oxidative stress and tissue injury in cerulein-induced pancreatitis. Such a protective effect may provide new insight into the potential value of angiotensin II receptor antagonists in the clinical therapy for acute pancreatitis.

Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure.

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.

Selective blockade of AT1 angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts.

The aim of the present study was to assess the participation of angiotensin II receptors in the triggering mechanism of ischemic preconditioning. Isolated buffer-perfused rabbit hearts were subjected to 40 min of regional ischemia (37 degrees C) followed by 60 min of reperfusion. Ischemic preconditioning was induced with three cycles of 5-min ischemia and 10-min reperfusion given prior to the 40-min ischemic period. Infarct size and ventricular function were assessed. Ischemic preconditioning reduced infarct size to 5.2 +/- 1.2% of the area at risk (mean +/- S.E.M., P<0.001) when compared to controls (26.4 +/- 3.0%), but did not protect against ventricular dysfunction. Activation of angiotensin II receptors with angiotensin II (100 nM) also limited infarct size (9.6 +/- 2.2%, P

Effects of U-97018 on pressor responses to intracerebroventricularly administered angiotensin II in conscious normotensive rats.

We examined the effects of U-97018, an AT1 receptor antagonist, on the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin II (AII) in conscious normotensive rats in comparison to losartan, EXP 3174, EXP 655, and saralasin. In an i.c.v. study, U-97018, losartan, and EXP 3174 reduced the pressor response. EXP 655, an AT2 selective antagonist, also inhibited the pressor response to i.c.v. AII. U-97018 combined with EXP 655 did not fully eliminate the pressor response to i.c.v. AII. Moreover, saralasin, a nonselective peptide AII antagonist, also failed to abolish the pressor response to i.c.v. AII. Therefore, both AT1- and AT2-receptors probably are functional in inhibiting the pressor response to i.c.v. AII and that a part of the i.c.v. AII-induced pressor response occurs through non-AT1- and non-AT2-receptors. In an intravenous (i.v.) study, U-97018, losartan, and EXP 3174 reduced the pressor response to i.c.v. AII. At 10 mg/kg orally (p.o.), which is an antihypertensive dose in spontaneously hypertensive rats (SHR), neither U-97018 nor losartan reduced the pressor response to i.c.v. AII even at 180 min after administration. This result indicates that neither U-97018 nor losartan, at the oral antihypertensive dose, reaches the brain in sufficient amount to affect the pressor response to i.c.v. AII.

Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy.

Through the multiple actions of angiotensin II (AII), the renin-angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane-bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G-protein-linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK-954). Losartan was demonstrated to be an effective antagonist of many AII-induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin-converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.

Inhibition of injury induced intimal hyperplasia by saralasin in rats.

Increasing evidence points toward local production of renin and angiotensinogen in the artery wall. Because angiotensin converting enzyme (ACE) inhibitors have been shown to block intimal hyperplasia after arterial injury in the rat, it has been suggested that angiotensin II is an important mediator of the proliferative response to vascular injury. To prove that previous observations with use of ACE inhibitors are a result of effects on local angiotensin levels versus nonspecific drug effects, we tested the ability of an unrelated drug, the angiotensin II receptor antagonist saralasin, to similarly block intimal hyperplasia after aortic injury in the rat. Balloon catheter aortic denudation was performed in 28 rats pharmacologically treated for 14 days after surgery and split into four groups: group 1, saralasin 360 micrograms/kg/hr intravenously; group two, normal saline 0.5 mm3/hr intravenously; group 3, captopril 100 mg/kg/day orally; and group 4, heparin 50 U/kg/hr intravenously. Animals were killed and aortas were perfusion fixed at physiologic pressure 14 days after denudation. Cross-sectional intima-to-media ratios were calculated by computerized planimetry. Compared with saline controls, saralasin inhibited intimal hyperplasia 45% (p less than 0.001), captopril 59% (p less than 0.001), and heparin 68% (p less than 0.001). A reduction in total intimal area was also evident in animals treated with saralasin (p less than 0.01). Blood pressure in the group treated with captopril decreased from 107.4 +/- 3.9 to 96.3 +/- 4.3 mm Hg (p less than 0.01) after 6 days, whereas saralasin and heparin had no effect on blood pressure. Weight gain during the study was reduced in groups treated with captopril and heparin but not in the group treated with saralasin.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of acute saralasin to reverse chronic hypertension in fetal lambs.

Upper body arterial hypertension developed in 12 fetal lambs after chronic suprarenal aortic blood flow reduction. Sixty minutes after blood flow reduction, intravenous saralasin infusion was able to reduce upper body mean arterial blood pressure to control levels. Although saralasin infusion was able to decrease upper body arterial blood pressure after 1 day of hypertension, it was not able to return blood pressure to control levels. Three or more days later, saralasin was unable to cause a significant reduction in upper body arterial blood pressure. We conclude that, although the renin-angiotensin system has a role in maintaining the elevated blood pressure after greater than or equal to 1 day of suprarenal aortic blood flow reduction, some other mechanism also participates. We have ruled out a role for changing blood volume, and our results suggest that an elevation of plasma catecholamines is not responsible. Some other pathway for fluid regulation available to the fetus may be responsible.

Antidotes to lethal cocaine toxicity in the rat.

Cocaine, like catecholamines or angiotensin II, may induce lethal cardiac or cerebral damage. Restrained rats were fitted with a caudal arterial catheter for on-line cardiovascular monitoring and antidote administration. They were given 60 mg/kg of cocaine i.p., a dose which produces behavioral and cardiovascular effects, convulsions and death in an average time of 10 min. Selected antidotes were administered 5 min after the lethal dose of cocaine. Incidence of lethality was not changed by propranolol, prazosin, labetalol, diazepam or enalaprilat, a converting enzyme inhibitor. Animals treated with any one of the following agents, alpha- or beta-blockers, diazepam or competitive inhibitors of angiotensin II [Sar-1-ile-8] and [Sar-1-thr-8] angiotensin II, presented myocardial infarction. All animals treated with calcium channel antagonists or enalaprilat, whether they survived or not, did not present myocardial infarction. Treatment with nitrendipine, flunarizine or diltiazem, resulted in survival of the animals with no observable aftereffects. Similar results were observed when enalaprilat was administered, with diazepam as an antidote, to a lethal dose of cocaine. Antagonists to the sympatho-adrenal system and to the renin angiotensin system appear to be effective antidotes to cocaine toxicity in the present experimental model.

[Effect of the angiotensin II analog saralasin before donor nephrectomy on primary transplant function]. / Einfluss des Angiotensin II-Analogons-Saralasin bei Spendernierenentnahme auf die primäre Transplantatfunktion.

Cadaver kidney donors were treated with Angiotensin II-Analogon-Saralasin before nephrectomy in order to reduce the rate of acute renal failure. Eighteen (64.3%) of the recipients of the 30 donor kidneys pretreated with Saralasin were primarily free from dialysis. Six recipients showed acute renal failure. Two donor kidneys never resumed their function and no reports could be obtained on two organs. In the control-group with no pre-treatment, acute renal failure appeared significantly more often (67.3%). Thus only 32.7% of the recipients needed no further dialysis. This difference is statistically significant.

[Therapy of chronic heart failure with vasodilators]. / Therapie der chronischen Herzinsuffizienz mit Vasodilatatoren.

The chronic heart insufficiency is essentially characterized by a disturbed regulative function of the peripheral circulation. These processes taking place within efforts for compensation close the chain of the vicious circle. The vasodilators with their different principles of effect affect in various places of the vegetative nervous system up to the smooth musculature of the vessels and modulate the peripheral part of the cardiovascular system. Via a changed behaviour of the impedance also with the arterial vasodilation the ejection behaviour of the insufficed hearts changes. With the increase of the ejection fraction the filling pressure can decrease, also when only the arterial branch of the periphery of the vessels is influenced. In case of an additional vasodilation of the capacity vessels greater influences of the preload are present. As a rule after the full use of the conventional therapy with digitalis and saluretics is resorted to the adjuvant therapy with vasodilators. Good experiences in the therapy of chronic heart insufficiency are present above all for hydralazine and prazosin as well as increasingly also for captopril, when vasodilating and at the same time positively inotropic medicaments are disregarded. In future, depending upon haemodynamic and neurohumoral (PNA, PRAA) findings in problematic cases and aimed additional adjuvant therapy will be aspired to.

Congestive heart failure, hypertension, and hyperreninemia in bilateral Wilms' tumor: successful medical management.

Congestive heart failure is an unusual complication of the hyperreninemia of Wilms' tumors. Cases with bilateral tumors present a difficult management problem. This is a report of the successful medical management of a child with congestive heart failure secondary to hyperreninemia from bilateral Wilms' tumor. Hypertension and hyperreninemia were extensively documented. Their etiologic relation to the congestive heart failure was supported by the patient's improved cardiac function following specific renin-angiotensin blockade. With unilateral tumors, surgical excision corrects the hypertension; however, with large bilateral tumors, excision is out of the question. A unique feature of this case is the ability to control the blood pressure with saralasin. With subsequent antitumor therapy, renin concentrations decreased proportional to tumor size, and renin angiotensin blocking therapy could be discontinued.

Conceptual and therapeutic approaches to inhibition of the renin-angiotensin system in chronic heart failure.

The renin-angiotensin system is activated in the majority of patients with chronic congestive heart failure. This may be part of the pathophysiology of the disease, a secondary phenomenon, or the result of intense diuretic therapy. Irrespective of the mechanism of renin-angiotensin activation, converting enzyme inhibitors are an effective form of therapy as well as a means to evaluate pathophysiologic mechanisms of congestive heart failure. Because of the activation of the renin-angiotensin system, angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention can be suppressed and, in some individuals, completely blocked by converting enzyme inhibitors. Improved forward cardiac flow and reduction of pulmonary congestion occur with reversal of vasoconstriction, so that relief of edema, due to enhanced sodium and water excretion, will occur. While it is easy to identify a close correlation between markers of renin-angiotensin activity and the initial response to converting enzyme inhibitors, it is more difficult to identify this response long-term. This may be due to changes in dietary sodium intake, intensity of diuretic therapy, or alteration in renal blood flow and function. Clinically, however, the response to converting enzyme inhibitors is favorable in the majority of people.

[Experimental studies on the modifiability of ischemic acute renal failure by saralasin]. / Experimentelle Untersuchungen über die Beeinflussbarkeit des ischämischen akuten Nierenversagens durch Saralasin.

To estimate the renal ischemia-protective effect of saralasin, model studies were performed on rats and dogs. Acute ischemic renal failure was induced in rats by clamping off the vascular pedicle for 90 minutes. When the drug was prophylactically administered before the ischemia episode, a premature increase in post-ischemic plasma urea level and a shortening of survival time of the animals were observed compared with the untreated control. Following auto-transplantation of 24-hour cold-stored dog kidneys, the infusion of saralasin failed to improve renal blood flow (MRBF), glomerular filtration rate (KrCl) and fractional sodium excretion (FENa). On the other hand, the angiotensin blockade with captopril led to an increase in MRBF which was associated, however, with significant decreases in KrCl and FENa. This discrepancy was suggested to be due to a predominant postglomerular vasodilation. The results show that the application of saralasin before renal ischemia may aggravate the loss of renal function whilst the post-ischemic administration of the drug has no substantial effect on the acute failure of transplanted kidneys.

[The antihypertensive effect of saralasin in rabbits with neurogenic interoreceptive hypertension]. / Der antihypertensive Saralasin-Effekt bei Kaninchen mit neurogen-interorezeptiver Hypertonie.

The renal nerve activity plays an essential role in the stimulation of plasma renin activity (PRA), which may be involved in the pathomechanism of neurogenic hypertension after sino-aortic denervation (SAD). Therefore, studies were conducted on unanesthetized rabbits (10 animals; 3-4 kg) after bilateral carotid sinus denervation plus section of cervical aortic nerves and the patterns of blood pressure (BP), heart rate (HR), and PRA were measured after a single injection-dosis of Saralasin (i.v., 10 micrograms/kg). After SAD the BP increased rapidly to 190 mm Hg within one week and remained at this high level (190-220 mm Hg) throughout the whole experiment (120 weeks). No change in BP of control rabbits (100-110 mm Hg) could be observed. Two weeks after SAD, the PRA showed a short elevation (approx. 25 ng) which subsequently returned to the levels of control rabbits (approx. 19 ng). Only in hypertensive rabbits Saralasin produced a short decrease of BP during both the initial and the whole chronic phases of hypertension, which was associated with a larger decrease of HR (1st to 5th min). Surprisingly, Saralasin induced a drop of HR also in the control rabbits. Our results suggest that also the normalized renin-angiotensin system is involved in the pathomechanism of sympathetic induced SAD-hypertension and probable permanently support the chronic state of hypertension by a relative "reninism".

Role of renin-angiotensin system in cardiopulmonary bypass hypertension.

The role of the renin-angiotensin system in the aetiology of perioperative hypertension was studied in 15 previously normotensive patients undergoing coronary artery surgery and anaesthetized with fentanyl. Measurements of plasma renin activity were made at intervals before and during cardiopulmonary bypass (CPB). In addition, angiotensin II blockade with saralasin was used in an attempt to treat hypertension during CPB. Nine of the patients became hypertensive (increase in systemic pressure of more than 20 per cent) before CPB and although the mean plasma renin activity was higher in this group than in the normotensive patients it was within normal limits for each group. Hypertension during CPB (mean blood pressure greater than 100 mmHg at 1.8 l X m-2 flow), occurred in seven patients but was not associated with increased renin activity and did not respond to saralasin in doses up to 20 micrograms X kg-1 X min-1. It is concluded that cardiopulmonary bypass associated hypertension is not mediated by activation of the renin-angiotensin system.