Evaluation of a long-acting converting enzyme inhibitor (enalapril) for the treatment of chronic congestive heart failure

Converting enzyme inhibition of the renin-angiotensin system has proved a valuable therapeutic approach in patients with severe chronic congestive heart failure. In the present study, a new long-acting converting enzyme inhibitor (enalapril) was evaluated with acute single dose testing (10, 20 or 40 mg) in nine patients with severe chronic congestive heart failure. Four hours after administration, there was a significant reduction of systemic vascular resistance (-19%) and pulmonary wedge pressure (-19%); in addition, there were related increases of cardiac index (+16%) and stroke index (+19%) (probability [p] less than or equal to 0.05 for all changes). This was associated with an increase of plasma renin activity (9 +/- 3 to 35 +/- 11 ng/ml per hour) and a decrease of plasma aldosterone (19 +/- 4 to 9 +/- 2 ng/100 ml) (p less than 0.02 for both). With long-term therapy (1 month), there was improvement of exercise tolerance time and lessening of symptoms based on the New York Heart Association classification. Hemodynamic improvement was maintained in most, but not all, patients. There was no orthostatic hypotension during head-up tilt and hemodynamic values in the upright position were associated with normalization of intracardiac pressures. Long-term converting enzyme inhibition was indicated by a persistent increase of plasma renin activity (16 +/- 2 ng/ml per hour) and a decrease of plasma aldosterone (8 +/- 3 ng/100 ml). In addition, relative angiotensin II receptor occupancy was decreased as judged by the pharmacodynamic response to infusion of the angiotensin II analog saralasin. In conclusion, the long-acting converting enzyme inhibitor, enalapril, was effective in patients with chronic congestive heart failure; however, additional studies will be necessary to further delineate the optimal dose range and identify those patients who are most likely to respond to the drug.     

Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin.

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.     

The contributions of sympathetic tone and the renin-angiotensin system to severe chronic congestive heart failure: Response to specific inhibitors (prazosin and captopril)

The contribution of sympathetic tone and the renin-angiotensin system to the pathogenesis of chronic heart failure was evaluated. In 20 paired studies of the same 10 patients, the baseline hemodynamic and humoral correlates of congestive heart failure, and the response to alpha adrenergic blockade (prazosin) and angiotensin converting enzyme inhibition (captopril) were assessed. Despite the extent of failure, baseline plasma renin activity ranged from normal to very high. In contrast, baseline plasma catecholamlne levels were always elevated. Baseline plasma norepinephrine reflected the severity of heart failure, correlating inversely with baseline cardiac index before administration of both drugs. Comparable improvement in left ventricular function was noted after acute therapy. Baseline renin and norepinephrine did not predict the response to prazosin, but baseline renin did predict the response to captopril: pulmonary wedge pressure (r = ?0.776, p < 0.01), stroke index (r = 0.752, p < 0.02), systemic vascular resistance (r = ?0.673, p < 0.05).In summary, elevated levels of plasma norepinephrine were inversely correlated with baseline cardiac function, but norepinephrine levels did not change despite improved hemodynamics with specific prazosin therapy. The renin-angiotensin system exhibited a wide spectrum of activity and hemodynamic improvement with captopril was related to this activity. Absence of a correlation between plasma norepinephrine and plasma renin activity suggested that their contributions to vasoconstriction were not interdependent. Increased sympathetic tone was consistent in severe heart failure, whereas renin-angiotensin activity differed widely. The response to captopril can be used to identify a subset of patients with severe heart failure and adverse angiotensin-mediated vasoconstriction.     

Circulatory autoregulation in chronic congestive heart failure: responses to head-up tilt in 41 patients

To evaluate mechanisms that regulate the response to postural change in patients with chronic congestive heart failure (CHF), the hemodynamic and vasoactive hormonal responses to head-up tilt were examined in 41 patients. Peripheral venous pooling was present in only 18 patients and was inversely correlated with baseline pulmonary wedge pressure. Baseline supine hemodynamic indexes of these 18 patients indicated less severe CHF compared with those of the 23 patients who did not demonstrate venous pooling. The 18 patients with intact afferent pooling also had lower levels of plasma renin activity and demonstrated increases in both plasma renin activity and norepinephrine on tilt; these reflex increases in vasoactive hormones were not seen in the 23 patients with severe CHF. Overall, 3 patterns could be identified. Of the 18 patients with venous pooling, 12 maintained many of the elements of normal postural response, with increases in systemic vascular resistance and circulating norepinephrine that maintain blood pressure constant. Six patients did not increase resistance in response to peripheral venous pooling and had major decreases in blood pressure analogous to idiopathic orthostatic hypotension. The larger group of 23 patients with more severe CHF did not have peripheral venous pooling and, hence, no afferent stimulus for reflex changes. Thus, the hemodynamic and neurohormonal responses to head-up tilt in CHF are heterogeneous and may be influenced by the severity of disease. The abnormalities of response may reflect the progression of vascular adaptation with loss of myocardial pump function and are important in terms of the pathophysiology and treatment of chronic heart failure.     

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.     

Role of renin and aldosterone suppression in the antihypertensive mechanism of clonidine

The hypothesis that clonidine decreases blood pressure by suppression of the renin-angiotensin II-aldosterone system was investigated in 20 hypertensive patients during a constant sodium and potassium intake. A significant decrease in mean arterial pressure (MAP), from 123 ± 3 to 102 ± 3 mm Hg (P < 0.001) was observed in 15 patients (responders) during treatment with clonidine. In these patients, plasma renin activity (PRA) was decreased by clonidine from 9.9 ± 3.9 to 5.4 ± 1.6 ng/ml/hour (P < 0.05). The decrease in MAP correlated with the decrease in PRA (r = 0.685, P < 0.02) and with the pretreatment PRA (R = 0.596, P < 0.05). The aldosterone excretion was decreased by clonidine by 29 per cent (from 16 ±4 to 11 ± 2 μg/24 hours), but not significantly. However, the changes in PRA were significantly correlated with the changes in aldosterone (r = 0.645, P < 0.05). Among the responders to clonidine, those with the higher pretreatment PRA levels showed the greatest fall in blood pressure. A common characteristic of the nonresponders to clonidine (five patients) was the presence of moderate to severe renal insufficiency. Moreover, in the nonresponders, PRA and urinary aldosterone were not significantly suppressed by clonidine.In order to evaluate further the role of renin suppression as an antihypertensive mechanism during clonidine treatment, the renin (angiotensin II) dependency of hypertension was tested prior to the administration of clonidine by giving an infusion of the angiotensin II competitive antagonist, saralasln to eight patients. In four of the eight patients blood pressure was decreased by both clonidine and saralasin, whereas in three patients clonidine decreased MAP, but saralasin elicited a pressor response. Finally one nonresponder to clonidine exhibited a depressor response to saralasin. Thus, clonidine decreased blood pressure in patients with nonrenin-dependent hypertension.Over-all results indicate that although the decrease in blood pressure is related to renin suppression during treatment with clonidine, another antihypertensive mechanism (or mechanisms) still exists in hypertension without renin dependency.     

Hemodynamic characteristics of hypertension after coronary bypass surgery and effects of the converting enzyme inhibitor.

In 13 patients with hypertension after coronary bypass surgery, the underlying hemodynamic mechanism was an increased systemic vascular resistance. To elucidate the role of the renin-angiotensin system in left ventricular function, plasma renin activity and hemodynamic measurements were performed during the peak of the hypertensive episode and 15 to 30 minutes after the administration of the converting enzyme inhibitor SQ20881 (1 mg/kg body weight). Eight of the 13 patients responded to the inhibitor; in these patients control plasma renin activity was 8.78 ± 2.3 ng/ml per hour, and mean arterial pressure decreased markedly from 123 ± 6 to 101 ± 5 mm Hg (P < 0.005), due to a decrease in systemic vascular resistance from 22 ± 2 to 14 ± 1 units (P < 0.005). The decrease in systemic vascular resistance induced by the inhibitor correlated with the control plasma renin activity (r = 0.825, P < 0.05). In the responders, administration of the inhibitor also increased cardiac output from 5.26 ± 0.36 to 7.39 ± 0.61 liters/min (P < 0.005) because of an increase in stroke volume from 61 ± 3 to 78 ± 5 ml/beat (P < 0.005), although left ventricular filling pressure decreased from 8.5 ± 1 to 6.0 ± 1 mm Hg (P < 0.005). In the remaining five patients (nonresponders to the inhibitor), control plasma renin activity was 1.8 ± 0.3 ng/ml per hour (P < 0.05 compared with the responders), but the control hemodynamic data did not differ from those of the responders. In the nonresponders the small decrease in mean arterial pressure (from 128 ± 5 to 123 ± 4 mm Hg, P < 0.025) was due to a decrease in stroke volume and cardiac output, but systemic vascular resistance did not change. As in the responders, administration of the inhibitor decreased left ventricular filling pressure in this group from 8 ± 1 to 6 ± 0.8 mm Hg (P < 0.025).These results indicate that the renin-angiotensin system is often involved in postcoronary artery bypass hypertension. In patients with increased renin, blockade of angiotensin II improved left ventricular function by reducing afterload rather than preload, thus indicating that angiotensin II acts on the heart and veins.     

Angiotensin-converting enzyme inhibition in congestive heart failure: the concept

Plasma renin activity frequently is increased in patients with congestive heart failure. This increase in inversely related to serum sodium concentration, but is not correlated with hemodynamic measurements. Nonetheless, inhibition of converting enzyme activity by administration of teprotide or captopril results in a decrease in systemic vascular resistance that is directly related to the control plasma renin activity. These data suggest that angiotensin II contributes to the systemic vasoconstriction of heart failure and that chronic inhibition of the renin-angiotensin system may have a salutary effect on left ventricular performance in patients with heart failure.     

Combined vasodilator therapy for chronic congestive heart failure

There are few data to support the potential efficacy of combined vasodilator therapy for severe congestive heart failure. For documentation of the feasibility of such an approach, a short-term hemodynamic study utilizing captopril, an oral converting enzyme inhibitor, followed by the addition of nitroprusside infusion, was made of 11 patients with severe chronic congestive heart failure. Captopril alone resulted in reduction of mean arterial pressure (84 +/- 7 to 70 +/- 3 mm Hg), associated with increase of cardiac index and stroke index. There was also a significant reduction of systemic resistance and pulmonary wedge pressure. The initial hemodynamic response to captopril was correlated with initial plasma renin activity (all values at least p less than 0.05). The addition of nitroprusside to captopril resulted in further hemodynamic improvement. Reduction of mean arterial pressure, systemic vascular resistance, and pulmonary wedge pressure were all significant, as were increases of cardiac index and stroke index. The degree of hemodynamic improvement with this sequence of vasodilator therapy was linearly related to the reduction of mean arterial pressure. Therefore vasodilators with dissimilar mechanisms of action may have an additive effect. These data support the potential feasibility of combined, long-term oral vasodilator therapy in selected subgroups of patients with congestive heart failure.     

Centrally administered inhibitors of the generation and action of angiotensin II do not attenuate the increase in ACTH secretion produced by ether stress in rats

The role of the brain renin-angiotensin system in the ACTH response to ether stress in rats was investigated by injecting the angiotensin II receptor blocking drug saralasin, the angiotensin II converting enzyme inhibitors enalaprilat and captopril, and the renin inhibitor L 363714 intraventricularly and measuring the ACTH and corticosterone concentration in plasma 10 min after ether stress. ACTH and corticosterone were elevated to at least the same level in rats treated with the inhibitors as they were in rats treated with the corresponding vehicles; indeed, ACTH values were somewhat greater in stressed rats treated with the converting enzyme inhibitors and the renin inhibitor. ACTH values in the absence of ether were not affected by saralasin, enalaprilat, and captopril and were increased by L 363714. The data do not support the hypothesis that the brain renin-angiotensin system is involved in the maintenance of ACTH secretion or that it mediates the increase produced by ether stress.     

ACE-Inhibition and Angiotensin II Receptor Blockers in Chronic Heart Failure: Pathophysiological Consideration of the Unresolved Battle

Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.     

Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt.

OBJECTIVE: In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system. METHODS: We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function. RESULTS: ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response. CONCLUSIONS: Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.     

Rationale for Combining a Direct Renin Inhibitor with other Renin- Angiotensin System Blockers. Focus on Aliskiren and Combinations

Inhibition of the renin-angiotensin system has been a highly successful therapeutic approach for the prevention of hypertension-related end organ damage. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers lower blood pressure and reduce morbidity and mortality in patients with cardiovascular and kidney disease. However, progression to end-stage disease remains common in these patient populations. A compensatory increase in plasma renin activity occurs with the use of either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, thus causing increased levels of angiotensin II, which may limit the therapeutic effectiveness of these agents. The direct renin inhibitor, aliskiren, suppresses the renin-angiotensin system by inhibiting its first and rate-limiting step. This early inhibition reduces the production of all downstream components of the system. In this review, recent clinically relevant advances in the understanding of renin-angiotensin system biology are explored as a rationale for combining aliskiren with other blockers of the renin-angiotensin system. These combinations more fully inhibit the renin-angiotensin system, with the goal of providing additional therapeutic benefits in diseases associated with chronic activation of the renin-angiotensin system.     

Immediate converting-enzyme inhibition with intravenous enalapril in chronic congestive heart failure

To test the hypothesis that intravenous enalapril is a useful pharmacologic probe of the renin angiotensin system, intravenous enalapril was administered to 9 patients with severe congestive heart failure (CHF). This produced abrupt and complete blockade of converting enzyme, with peak effect occurring at 30 minutes, as reflected by increases of plasma renin activity (from 16.8 +/- 6 to 86.6 +/- 23 ng/ml/hour) and decreases of plasma aldosterone levels (from 46 +/- 14 to 25 +/- 6 ng%) (both p less than 0.05). With reduction of angiotensin II--mediated vasoconstriction, systemic vascular resistance decreased markedly (from 1,974 +/- 233 to 1,400 +/- 136 dyne s cm-5) and cardiac index was improved (from 1.88 +/- 0.9 to 2.20 +/- 0.21 liters/min/m2) (both p less than 0.05). The time course of angiotensin II levels suggested that the lack of a cumulative effect from additive doses of intravenous enalapril was a reflection of complete inhibition of converting enzyme. One patient did not respond to enalapril; despite comparable hemodynamic severity of CHF, the renin-angiotensin system was not activated in this patient. Thus, intravenous enalapril is capable of rapid and complete inhibition of converting enzyme for the accurate assessment of angiotensin II--mediated vasoconstriction in patients with severe CHF.     

Adrenal responses to pharmacological interruption of the renin-angiotensin system in sodium-restricted normal man.

We assessed the role of the renin-angiotensin system in the control of aldosterone secretion in response to sodium restriction in 62 normal subjects. Both saralasin, an angiotensin II antagonist, and SQ 20881, a converting enzyme inhibitor, induced a dose-related decrease in plasma aldosterone levels when the renin-angiotensin system was activated by restriction of sodium intake. Two types of experiments were performed with saralasin. In the first set, a dose-response relationship was established 20 min after beginning infusions ranging from 0.03-1.0 microgram/kg/min. The optimal dose was 0.1 microgram/kg/min, with a reduction in aldosterone levels of -10.1 +/- 3.8 ng/dl (P less than 0.025). Higher doses induced smaller reductions in aldosterone levels. In the second set, a 3-h infusion was given. The results were qualitatively similar but the magnitude was greater (-15 +/- 4 ng/dl; P less than 0.01). The aldosterone response 20 min after administration of SQ 20881 paralleled the angiotensin II response, with the first significant decrement (-6.5 +/- 1.5 ng/dl; P less than 0.01) occurring at 0.1 mg/kg and maximum (-10 +/- 3 ng/dl) occurring at 0.3 mg/kg. Thus, both agents produced qualitatively similar changes in aldosterone secretion in sodium-restricted normal subjects. However, neither reduced sodium restricted aldosterone levels to that measured in sodium-loaded subjects because of the intrinsic limitation of each agent. Saralasin is a partial agonist. SQ 20881 induces an increase in plasma renin activity via interruption of the short feedback loop, which probably limits its action. Yet, these data do support the hypothesis that angiotensin mediates the adrenal's response to sodium restriction in normal man.     

Converting enzyme inhibition during chronic angiotensin II infusion in rats. Evidence against a nonangiotensin mechanism

Interpretation of results obtained with angiotensin-converting enzyme inhibition in hypertensive patients has been obscured by the possibility of nonangiotensin-mediated mechanisms, particularly rats, we have compared the effects of converting enzyme inhibition (CEI) by oral captopril administration to those of dextrose. In this setting of constant angiotensin II levels, any apparent effects of CEI must be mediated by a nonangiotensin-related mechanism. Angiotensin II infusion at 30 ng/min increased mean blood pressure by an average of 22 mm Hg. Following 7 days of CEI, effective blockade of converting enzyme was established both by a 10-fold elevation of vasodepressor sensitivity to exogenous bradykinin and a markedly decreased plasma converting enzyme activity. On the ninth day of angiotensin II infusion, mean arterial pressure, heart rate, and plasma renin activity were not different between CEI and dextrose-treated groups. Similarly, blockade of angiotensin II by saralasin induced a comparable fall in blood pressure in both groups. Metabolic studies also revealed no long-term differences in water and food intake, weight change, or sodium and potassium metabolisms. These findings suggest that, in the continued presence of angiotensin II, there is no detectable hemodynamic or metabolic effect of chronic converting enzyme inhibition, and therefore that bradykinin plays little or no role in its long-term antihypertensive action.     

The brain renin-angiotensin system and prolactin secretion in the male rat

The present studies investigated the role of the brain renin-angiotensin system in the regulation of PRL secretion in the male rat. Blood samples were taken from conscious rats before, during, and after administration of test substances into the third cerebral ventricle. In the first series of experiments, we determined the sensitivity of the PRL response to intracerebroventricular (icv) administration of angiotensin II (Ang II) and found that PRL levels were significantly suppressed in a dose-related manner (10-500 ng). A dose of 1 ng did not significantly affect PRL values, compared to those from vehicle-injected animals. Ang II elicited water intake at doses of 50 and 500 ng, but not at the 10- or 1-ng doses. In the second series of experiments, we investigated the role of endogenous brain Ang II in the regulation of PRL secretion under basal and stimulated conditions. The endogenous system was manipulated by icv infusion of saralasin, an Ang II receptor antagonist, or icv injection of enalaprilat, a converting enzyme inhibitor, to prevent synthesis of Ang II. Neither saralasin nor enalaprilat administration produced an increase in PRL levels under basal, nonstressed conditions. However, during immobilization stress, when PRL levels increased 3-fold during icv vehicle infusion, saralasin infusion resulted in a 7-fold rise in plasma PRL titers relative to prestress baseline values. These results demonstrate that, in male rats, the inhibitory effects of icv administration of Ang II on PRL secretion are very sensitive and are observed at doses which do not affect water intake. The endogenous brain Ang II system appears not to be involved in the maintenance of the low plasma PRL levels observed under basal, nonstressed conditions. However, the system does appear to affect the magnitude of the PRL response to immobilization stress.     

Angiotensin II Antagonists

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin I1 inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin 11. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.     

Das Renin-Angiotensin-System

The renin-angiotensin system is among the most important endogenous regulators of blood pressure. Angiotensin peptides are generated locally in the kidneys as well as in blood vessels. The major effects of the system are caused by the binding of angiotensin II to its type 1 cell surface receptor. This receptor mediates increased blood pressure and glomerular filtration pressure, as well as stimulation of inflammation and fibrosis. Three classes of inhibitors of the renin-angiotensin system are available: renin inhibitors, ACE inhibitors and angiotensin receptor blockers. ACE inhibitors have been studied most extensively. Blockers of the renin-angiotensin system exert a unique combination of beneficial effects in patients with hypertension and chronic kidney disease. These drugs lower blood pressure, ameliorate the systemic sequelae of hypertension (e.g. left ventricular hypertrophy), prevent cardiovascular events, decrease proteinuria and retard the progression of chronic kidney failure.     

Vascular angiotensin receptors and their role in blood pressure control.

The renin angiotensin system has an important role in regulating arterial blood pressure in homeostasis and disease. A reciprocal relationship exists between sodium balance and the circulating levels of renin and angiotensin II. The vascular responsiveness to angiotensin II, the major vasconstrictor component of the renal pressor system, can be impaired by numerous factors including sodium depletion or a reduction in effective plasma volume. In situations in which the renin-angiotensin system is activated, a negative relationship between the angiotensin II pressor response and the circulating angiotensin II level is observed. This effect seems to involve a change of the angiotensin II receptor interaction in the vascular smooth muscle. The prevention of angiotensin II generation by the inhibition of converting enzyme causes an immediate increase in the pressor response to angiotensin; after bilateral nephrectomy, it takes much longer to develop. In addition, the depressor response to angiotensin antagnoists and converting enzyme inhibitor is preserved after bilateral nephrectomy for much longer periods than can be accounted for by the disappearance of circulating renin. These observations support the view that the decrease in vascular response to angiotensin II during sodium deprivation or when body fluid volumes are reduced is the result of prior occupancy of the receptor sites by endogenous hormone generated both in the plasma and locally within blood vessel walls. Therefore, a change in the number or affinity of receptors consequent to a change in sodium balance or as a modulating function of the renin-angiotensin system need not be postulated to explain changes in angiotensin vascular responsiveness.