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.

The immediate pressor effect of saralasin in man.

An immediate pressor response to [Sar1-Ala8]-angiotensin II (saralasin) is described in all of 16 hypertensive subjects. Blood pressure rose within 1-3 min, peaked at 4-6 min, then returned toward baseline. Plasma norepinephrine and dopamine beta-hydroxylase activity were unchanged by saralasin, indicating that the pressor response is not mediated by saralasin-induced catecholamine release. Ten normal renin hypertensives had diastolic pressor responses of 19.4 +/- 3.3 mm Hg. After 5 weeks of diuretic therapy, the diastolic pressor responses to saralasin were decreased to 4.9 +/- 2.4 mm Hg. Six low renin hypertensives had diastolic pressor responses of 26.2 +/- 6.2 mm Hg, but 5 weeks of diuretic therapy did not decrease these pressor responses significantly. In two normal and two low renin hypertensives, the diastolic blood pressure rose to levels greater than 150 mm Hg. The amplitudes of the immediate pressor responses were inversely correlated with the base-line plasma renin activities, r = -0.46. The data support the concept that the agonist activity of saralasin occurs at the angiotensin II vascular receptor level with clinical expression mediated by sodium and/or volume changes.

The antihypertensive effect of captopril. Evidence for an influence of kinins.

The acute effect of the orally-active converting enzyme inhibitor, captopril, was compared to that of saralasin in 13 patients with various forms of hypertension on ad libitum sodium intake. A significant difference between the effects of the two drugs on mean arterial pressure (MAP) was found (-11 +/- 3 mm Hg with saralasin, -24 +/- 4.5 mm Hg after captopril). This difference was not correlated with control plasma renin activity (PRA). To determine the influence of the endogenous kallikrein-kinin system in the antihypertensive action of captopril, the effect of aprotinin (Apro), an inhibitor of kinin generation, on the MAP level achieved by captopril was assessed in five normal subjects and 15 patients with hypertension on ad libitum sodium intake. In normal subjects, captopril did not alter MAP, nor did Apro have any effect. In six patients with essential hypertension and normal PRA, MAP decreased by 5.5 +/- 2 mm Hg following captopril, and Apro did not modify this level. In nine patients with renovascular hypertension (RVH), MAP fell by 22 +/ 3 mm Hg after captopril administration, and Apro infusion induced a rise in MAP of 13 +/- 1.7 mm Hg. A positive correlation between log control PRA and the effect of aprotinin was obtained ( r = 0.63, p less than 0.005). Apro had no effect in two patients with RVH who experiences a large drop in MAP during salasin. These results suggest that endogenous kinins as well as other substances, the generation of which is inhibited by aprotinin, may participate to the antihypertensive effect of captopril in patients with angiotensin-dependent hypertension. The lack of an aprotinin effect on the MAP level achieved during saralasin infusion suggests that the influence of the kallikrein-kinin system is related to the effect of captopril rather than the fall in arterial pressure resulting from angiotensin blockade.

Angiotensin blockade: its clinical significance.

An understanding of the possible role of excessive angiotensin II activity in the pathogenesis of hypertension in every patient is therapeutically desirable, but it is frustrated by the lack of complete reliability of peripheral plasma measurements of renin activity. Observation of a clear-cut, supranormal decrease in blood pressure during the intravenous infusion of the angiotensin II antagonist, saralasin, has provided a far more reliable indication of the presence of an angiotensinogenic component in the hypertension. There is convincing evidence, however, that the presence of sodium-overload may prevent a decrease in blood pressure during saralasin infusion in persons known to have angiotensinogenic hypertension and that saralasin may cause a slight decrease in the blood pressure of normal subjects after natriuresis. For these reasons, it is important to study hypotensive responses to saralasin under standardized conditions after the administration of a potent diuretic and to compare the observations with those made on normal subjects under identical circumstances. This angiotensin antagonist may be used in the therapy of malignant or advanced hypertension and as an aid to therapeutic decisions in hypertensive patients who have known renal diseases, are taking oral contraceptives or have had severe trauma to the area of the kidneys. Side effects of saralasin are limited to excessive falls in blood pressure levels, mainly when vasodilators or ganglioplegic drugs are being taken at the time of the saralasin infusion, and excessive rises in blood pressure levels, especially in hypertensive subjects with "low renin" activity during high rates of saralasin infusion or after intravenous injections of large boluses. This safe and reliable drug is a valuable tool in the investigation and therapy of hypertension.

Antihypertensive effects of captopril and saralasin in essential and renal hypertension.

The antihypertensive effect of captopril and its mechanism of action were studied in patients with essential and renal hypertension. In mild essential hypertension (n = 12), during monotherapy with captopril (50 to 450 mg, 4 to 12 weeks) blood pressure was normalized in seven, improved in two and remained unchanged in three patients, plasma levels of active and acid-activatable inactive renin significantly increased and angiotensin II decreased, whereas no consistent changes in urinary kallikrein excretion occurred. In severe renal (n = 14) and essential (n = 9) hypertension, blood pressure was normalized in eight (seven with renal hypertension), improved in seven and unchanged in eight patients, when captopril (50 to 450 mg, 3 to 15 months) was added to the antihypertensive medication. In one patient with stenosis in a transplanted renal artery reversible renal failure occurred during captopril therapy possibly because of a steep initial decrease in blood pressure, although a toxic effect of the drug cannot be excluded. In another series of 12 renal and 8 essential hypertensive patients, a significant correlation between the acute effect of captopril (within 90 minutes) an saralasin on blood pressure was demonstrated (r=0.71, p less than 0.001). The change in blood pressure after either drug was significantly related to the initial plasma renin concentration. In conclusion, captopril seems to be an effective antihypertensive agent in essential and renal hypertension. Renal function should be monitored during captopril therapy. Our studies suggest that captopril decreases blood pressure by inhibiting the vasopressor action of the renin-angiotensin system.

Renal response to angiotensin-converting enzyme inhibition.

Angiotensin-converting enzyme inhibitors, both teprotide and captopril, induce a potentiated renal vascular response in patients with essential hypertension, and with that a consistent increase in sodium excretion and occasionally an increase in glomerular filtration rate. In patients with advanced congestive heart failure resistant to other vasodilators, a similar triad occurs. It is not yet clear in which settings the renal response to angiotensin-converting enzyme inhibition reflects a reduction in angiotensin II formation--thus implicating the renin-angiotensin system in the pathogenesis--or an additional action, such as a potentiation of the local actions of bradykinin or enhanced prostaglandin formation. Under some circumstances, especially where a qualitatively and quantitatively similar response occurs to angiotensin antagonists and angiotensin-converting enzyme inhibitors or where an angiotensin antagonist prevents an additional response to a converting enzyme inhibitor, it is clear that the specific action of the converting enzyme inhibitor on angiotensin II formation is responsible. Unfortunately, for most responses in animal models and all responses in patients, such rigorous evidence is not yet available.

Biological significance of active and inactive renin in man.

The biological significance of active and inactive renin was investigated by comparison of an in-vitro assay of active, total and inactive plasma renin concentration (PRC), plasma renin activity (PRA) and plasma concentrations of angiotensin I and II with an in-vivo change in mean arterial blood pressure (MAP) produced by antagonism of angiotensin with treatment with saralasin and by blockade of angiotensin-converting enzyme by treatment with captopril. A significant relationship between the changes in MAP during treatment with saralasin and captopril with the pretreatment levels of PRA, active and total PRC and angiotensin II were found; while the pre-existing level of inactive renin was not a predictor for the hypotensive effect of saralasin and captopril. During treatment with saralasin and captopril significant increases in PRA, plasma angiotensin I concentration and total and active PRC were found and no change in inactive PRC was observed.

Improvement in arterial oxygenation by saralasin infusion in man.

Simultaneous hemodynamic and blood gas measurements were performed in 26 hypertensive adults, who were cigarette smokers, before and after a 30-minute infusion of saralasin (5 microgram/kg/min) which is a highly specific competitive antagonist of angiotensin II (AII). The arterial pressure fell in nine, rose in seven and was unchanged in ten patients. The mean cardiac index for the entire group remained unchanged. Pulmonary arterial or wedge pressure, pulmonary vascular resistance, arterial PCO2 and pH did not change. Unrelated to the hemodynamic changes, the mean arterial oxygen pressure (PaO2) increased from 68.6 +/- 2.2 mm Hg to 73.9 +/- 2.1 mm Hg (P less than 0.001). In the absence of a significant increase in alveolar ventilation as indicated by an unchanged mean PCO2 and lacking a hemodynamic explanation, the mechanism for the rise in PaO2 is speculative at this stage. The possibility of an improvement in the distribution of ventilataion by saralasin infusion is under investigation.

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.

Failure of saralasin in preventing renal failure in ischemic transplanted kidneys.

Many potential cadaveric kidney donors have been exposed to shock or hypotension before or during organ donation. Renin-mediated vasoconstriction has been implied in the pathogenesis of acute renal failure. High renin levels have been associated with poor graft survival under hypothermic pulsatile perfusion. An attempt was made to block renin effect with Saralasin (1-Sar-8-ala-angiotensin II), a competitive blocker. Eight conditioned mongrel dogs had their renal arteries exposed, and Saralasin, 100 microgram, was injected intra-arterially. Warm ischemia was then induced for 30 min. Thereafter, the kidney was removed and placed under hypothermic pulsatile perfusion for 24 hours, during which time Saralasin was given continuously at a rate of 1 microgram/min. The kidneys were reimplanted in the same animal on the contralateral iliac fossa, Saralasin, 100 microgram, was given intraarterially after implantation, and a contralateral nephrectomy was performed. Four control animals were given saline solution instead of Saralasin. No significant differences were noted in perfusion characteristics and postoperative creatinine values between treated and control groups. This apparent lack of protective effect of angiotensin II competitive blocker suggests that in the pathophysiology of acute renal failure other factors could be involved besides renin release.

Relative significance of plasma renin activity and concentration in physiologic and pathophysiologic conditions.

Plasma renin activity (PRA) and concentration, measured after acid treatment of the plasma (PRC3.3), were determined on the same plasma samples in different conditions. Log PRA and log PRC3.3 were significantly (P less than 0.001) and similarly related to sodium intake, age, and plasma aldosterone concentration in normal subjects. The correlation coefficient between log PRA and log PRC3.3 was 0.49 in 80 sodium-replete and sodium-deplete normal subjects, and it was 0.84 in 84 hypertensive patients untreated or under treatment with thiazides. On the contrary, during beta adrenergic blockade, PRA decreased significantly (P less than 0.001) by 62% while the changes in PRC3.3 were not significant. At maximal exercise, PRA increased significantly by 168% while the PRC3.3 increase of 24% was not significant. In hypertensive patients with unilateral renal artery stenosis the ipsilateral renal vein/artery ratio was higher for PRA (2.46) than for PRC3.3 (1.56), whereas both ratios on the controlateral side were similar and close to one (1.14 and 1.06). The conditions in which PRA and PRC3.3 determinations are concordant or discordant are discussed.

[Arterial hypertension and maintenance hemodialysis: effects of specific inhibition of angiotensin II by saralasin acetate]. / Hypertension artérielle et hémodialyse de suppléance. Effets de l'inhibition spécifique de l'angiotensine II par l'acétate de saralasine.

The "effective" contribution of angiotensin II in blood pressure regulation was investigated in 6 patients on maintenance hemodialysis who were hypertensive at the time of the study (MAP 133 +/- 5 mmHg). Saralasin, a specific angiotensin II inhibitor, was infused at 0.5 and 2.5 microgram/kg/mn three hours before andone hour after hemodialysis. Before hemodialysis, a mean arterial pressure decrease of 13.2 to 19 p. 100 was obtained in 5 patients, arterial pressure being normalized in three of them. After hemodialysis, saralasin induced a normalization of arterial pressure in these 5 subjects. One patient, who was resistant to the saralasin infusion before and after the hemodialysis procedure, can be considered as purely volume-dependent. The renin-angiotensin system is probably one of the primary determinant of dialysis-resistant hypertension. However, a negative response to saralasin should encourage to control hypertension by more vigorous ultrafiltration during dialysis.

Hypertension screening and treatment with angiotensin inhibitors. Saralasin and captopril.

The number of studies in the literature on diagnostic and therapeutic uses of angiotensin antagonists has been increasing geometrically. Nearly 1,000 publishsd items deal with saralasin alone, although neither saralasin nor captopril is yet approved for general use or widely available. Reports to date represent only a fraction of the eventual situations in which these agents are likely to help the researcher and clinician. Food and Drug Administration approval of both agents is pending, and both are expected to be available soon. Consequently, the practitioner will want to become familiar with their usefulness, especially to screen for secondary forms of hypertension and to treat moderate to severe primary or secondary hypertension.

[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.

Propranolol and newer antihypertensive drugs in the management of hypertension.

Among the newer antihypertensive agents are the beta-blocking drugs, such as propranolol. These agents are useful as second-step drugs to be used if diuretic therapy alone is not effective. In mild to moderately severe hypertension, propranolol, in does of up to 480 mg/day in combination with a thiazide diuretic, has been found to be effective in over 80% of patients on long-term therapy. This degree of response is essentially similar to that noted with a combination of reserpine and a diuretic agent. Although some observers believe that propranolol produces many fewer side effects than the other step 2 drugs (reserpine and alpha-methyldopa), there are some patients who do experience restlessness, insomnia, and depression. Clonidine may be substituted for another step 2 drug, is of moderate potency, but may not be tolerated by a large number of patients because of the severe dry mouth and drowsiness that it produces. Prazosin appears to be a suitable substitute for hydralazine as an effective vasodialator if thiazides plus propranolol or thiazides plus reserpine or alpha-methyldopa are not effective. In some instances, it many be an acceptable second-step drug because of its alpha-adrenoreceptor-blocking properties. The angiotensin II competitive inhibitors or converting enzyme inhibitors may in the future have some place in the management of hypertension.

Newer antihypertensive agents.

There are very few areas of clinical pharmacology being pursued as vigorously as hypertension. Numerous new drugs are being discovered and tested both in United States and overseas. The most promising new antihypertensive drugs seem to fall into the angiotensin-renin blocker group and those affecting the sodium-volume axis in hypertensive patients. We can look forward to newer agents that are efficacious as monotherapy and on a daily or twice daily dosage regimen for the treatment of the vast majority of hypertensive patients. There is further hope that preoperative evaluation with angiotensin blockers in patients with renovascular hypertension may improve the predictability of successful renal bypass surgery.