Specific inhibition of the renin-angiotensin system: A key to understanding blood pressure regulation

The availability of specific inhibitors of the renin-angiotensin system has made it possible to evaluate precisely the contribution of this system to the maintenance of normal blood pressure and of various hypertensive situations encountered in animal models and in man. Furthermore, by combining the blockade of the renin system with accurate measurements of sodium balance, it is possible to expose and quantify latent or manifest abnormalities in renal sodium handling that operate directly or by interacting with the renin system.Experimental and clinical observations made with these inhibitors support the hypothesis that the level of blood pressure, normal or abnormal, is largely determined by two components: (1) the renin system (i.e., the angiotensin II-vasoconstrictor factor) and (2) the sodium extracellular and intravascular volume factor, which in the longer term may be indirectly supported by the renin system via angiotensin-induced aldosterone secretion.Normally, without threat to the homeostasis, the sodium volume component appears to be the main factor determining blood pressure and sustaining renal perfusion via adequate or—if necessary—increased blood pressure. However, whenever renal perfusion is compromised due to such events as hemorrhage, sodium depletion, upright posture, exercise, cardiac failure, cirrhosis, or renal vascular impairment, renin is secreted by the kidney. It seems that the renin-angiotensin system is the main vasoconstrictor system used by the body to support the sodium volume component to maintain or restore adequuate renal perfusion. There is little evidence that the catecholamines and the nervous system play any major or direct role in sustaining blood pressure, although indirectly they may be critically involved in monitoring renal renin release.Two models of renal hypertension have served as the experimental basis for development of this concept. Established two-kidney Goldblatt hypertension (one renal artery clipped, contralateral kidney intact) was found to be renin-dependent, since angiotensin II blockade induced a marked fall in blood pressure. Clinical counterparts to this predominantly “vasoconstrictor” type of hypertension are renovascular hypertension with unilateral renal artery stenosis, malignant and essential hypertension with high renin levels, and possibly normotensive situations with reduced “effective” blood volume such as cirrhosis and congestive heart failure.Chronic one-kidney Goldblatt hypertension (one renal artery clipped, contralateral nephrectomy) under conditions of unrestricted sodium intake appeared on the other hand to be predominantly sodium-volume-dependent, so that angiotensin II blockade did not alter the pressure level. However, sodium (and volume) depletion did not lower the blood pressure either in this model but resulted instead in a compensatory rise of renin release, and thus in a transition from a sodium-volume to vasoconstrictor-maintained type of hypertension. Accordingly, under conditions of sodium depletion, angiotensin II blockade did markedly reduce the blood pressure. Clinical counterparts to this model in which simultaneous sodium depletion plus blockade of the renin system are necessary to reduce blood pressure appear to be most patients with normal renin essential hypertension, chronic renal failure with normal or low renin levels, renovascular hypertension with bilateral renal artery stenoses, and possibly coarctation of the aorta.In contrast to these two model situations, low-renin essential hypertension as well as the hypertension induced by an excess of various mineralocorticoids appears to represent a pure volume type of hypertension, in which a diuretic-induced volume reduction does not result in a compensatory rise in renin release and a shift to vasoconstrictor support but instead results in a parallel reduction of blood pressure.     

The Clinical use of Angiotensin Converting Enzyme Inhibitors in Hypertension and Cardiac Failure

The renin-angiotensin system has a range of physiological actions concerned with the control of the circulation. Angiotensin II has both an immediate and a delayed pressor effect, it stimulates the secretion of aldosterone and antidiuretic hormone, promotes thirst, stimulates the sympathetic nervous system at various sites while inhibiting vagal tone, and has a range of direct effects on the kidney. Several aspects of this range of actions can become deranged in a number of forms of hypertension as well as in congestive cardiac failure. Hence much effort has been directed in recent years to the development of agents designed to interfere with the renin-angiotensin system and to apply these clinically in the treatment of hypertension and congestive cardiac failure. Orally active converting enzyme inhibitors are of proven benefit not only in renovascular hypertension, but also, when combined with loop diuretics, in the treatment of intractable hypertension as well as, both alone and in combination with thiazide diuretics, in the treatment of essential hypertension. In congestive cardiac failure controlled trials have shown that converting enzyme inhibitors can improve exercise tolerance while diminishing lassitude, correct potassium deficiency and limit ventricular arrhythmias. Energetic efforts are being made to develop orally active inhibitors of the enzyme renin itself, since these would be more specific in action than the presently available and very successful converting enzyme inhibitors.     

Successful treatment of severe hypertension with the combination of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker.

Three patients who suffered from congestive heart failure caused by severe hypertension were treated with a combination therapy consisting of angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Before initiation of treatment, all three patients showed elevations of serum creatinine concentration (sCr), plasma renin activity (PRA), and plasma aldosterone concentration (PAC), which indicated insufficient blood supply to the kidney during exacerbation of hypertension. All three cases successfully recovered from hypertensive heart failure with the combination therapy. sCr gradually decreased during continuation of the therapy, although one patient showed an increase in sCr at an early stage of the combination therapy. Blockade of the renin-angiotensin-aldosterone system (RAAS) by the combination of ACEI and ARB was well tolerated in patients with severe hypertension with renal damage and showed a beneficial effect in protecting against further renal damage. This result suggests that combination therapy with ACEI and ARB should be considered as a candidate treatment in cases of severe hypertension.     

Mechanisms in human renovascular hypertension

To clarify the pathophysiology of renovascular hypertension, we monitored intraarterial pressure continuously and measured hourly hormone levels for 24 hours under carefully controlled conditions in two hypertensive patients with unilateral renal artery occlusion. Comparison of the results with those obtained when the patients were normotensive 3 months after uninephrectomy indicated that, while the renin-angiotensin system played a central role in maintaining the hypertension, the sympathetic nervous system also contributed and, in addition, modulated short-term arterial pressure fluctuations. In the untreated state, the sympathetic regulation of renin secretion was heightened, and angiotensin II/aldosterone dose-responsiveness was augmented. It is suggested that these adaptive changes might serve to offset the tendency to severe sodium depletion and thence exacerbation of the hypertension.     

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.     

Association between activation of the renin-angiotensin system and secondary erythrocytosis in patients with chronic obstructive pulmonary disease

PURPOSE: An association between activation of the renin-angiotensin system and enhanced erythropoiesis has been observed in patients with several diseases, including congestive heart failure and hypertension. Our goal was to examine whether the renin-angiotensin system is associated with secondary erythrocytosis in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: Plasma renin activity, plasma aldosterone concentration, serum erythropoietin level, and serum angiotensin converting enzyme (ACE) activity were measured in 12 patients with COPD and secondary erythrocytosis [mean (+/-SD) hematocrit of 53% +/- 3%] and in 12 matched controls with COPD who did not have erythrocytosis (hematocrit 45% +/- 5%). All patients had chronic hypoxemia (PaO2 <60 mm Hg). RESULTS: Both plasma renin and aldosterone levels were threefold greater in patients with secondary erythrocytosis compared to controls. No difference in erythropoietin levels was observed between patients with or without secondary erythrocytosis. Renin levels (r = 0.45; P = 0.02) but not erythropoietin levels (r = 0.15; P = 0.47) were correlated with hematocrit in the entire sample. Renin levels and PaO2 were the only variables independently and significantly associated with hematocrit values in a multiple linear regression model. CONCLUSION: Activation of the renin-angiotensin system is associated with the development of secondary erythrocytosis in chronically hypoxemic patients with COPD. The exact mechanism is not yet fully understood, but angiotensin II may be responsible for inappropriately sustained erythropoietin secretion or direct stimulation of erythroid progenitors.     

Adenosine in renin-dependent renovascular hypertension

Our previous studies support the hypothesis that activation of the renin-angiotensin system by renal ischemia elevates adenosine levels and that adenosine acts in a negative feedback loop to limit renin release and to mitigate some of the hypertension-producing effects of angiotensin II. To further test this hypothesis, we compared the time course of caffeine-induced increases in plasma renin activity with the time course of changes in plasma levels of adenosine in two models of renin-dependent renovascular hypertension. Also, we compared the effects of caffeine on plasma renin activity and arterial blood pressure in renin-dependent versus renin-independent renovascular hypertension. In comparison to sham-operated rats, plasma levels of adenosine in the left and right renal veins and aorta were elevated severalfold in two-kidney, one clip rats (2K1C) 1 week after left renal artery clipping. However, adenosine levels declined during the second and third weeks after clipping. In 2K1C rats treated chronically with caffeine, plasma renin activity was markedly elevated during the first week after operation as compared to non-caffeine-treated 2K1C rats. However, during the second and third weeks after clipping, caffeine had lesser effects on plasma renin activity. A temporal relationship between plasma adenosine levels and caffeine-induced hyperreninemia was also observed in rats with aortic ligation. Caffeine accelerated hypertension in 2K1C rats and rats with aortic ligation (renin-dependent renovascular hypertension), but it had no effect on plasma renin activity or blood pressure in one-kidney, one clip rats (renin-independent renovascular hypertension). These results lend further support to the hypothesis that adenosine functions to mitigate the renin-angiotensin system in renin-dependent renovascular hypertension.     

Arterial hypertension and chronic heart failure

Arterial hypertension, alone or in combination with ischemic heart disease, precedes the development of heart failure. The Framingham study demonstrated that hypertension was the major risk factor in the development of heart failure. Arterial hypertension is not a sole factor contributing to the development of heart failure. The syndrome of heart failure is a consequence of multiple systemic responses and the development of heart failure is a complex and progressive process associated with cardiovascular disease resulting from risk factors: hypertension, obesity, smoking and dyslipidaemia. Arterial hypertension is the main precursor of left ventricular hypertrophy. Initially, this process causes diastolic dysfunction in the early stages of primary hypertension. Systolic dysfunction is rarely observed in those subjects. Left ventricular hypertrophy is also an important risk factor for myocardial infarction and ventricular arrhythmias. Asymptomatic systolic and diastolic left ventricular dysfunction may both progress to overt HFThe primary prevention of heart failure patients should be based upon strategies providing tight and sustained blood pressure control. This therapy should include an agent that inhibits the renin–angiotensin–aldosterone system. Treatment of arterial hypertension in patients with HF must take into account the prevalent type of cardiac dysfunction—diastolic or systolic.     

Role of the renin-angiotensin system in the development of congestive heart failure in the dog as assessed by chronic converting-enzyme blockade

Hormonal factors may be important in the regulation of peripheral vascular resistance (PVR) in congestive heart failure (CHF). The role of the renin-angiotensin system in the development of CHF was studied in 16 unanesthetized dogs. CHF was induced by rapid right ventricular pacing, with and without chronic converting-enzyme inhibition (CEI) by captopril. The hemodynamic changes and the activity of renin, aldosterone, norepinephrine and vasopressin were studied. The control dogs showed a greater decrease in cardiac output and a greater increase of mean pulmonary artery pressure than the captopril-treated group. In the group with CEI, only a small, transient increase in PVR was observed during the development of CHF; in the control group, there was an increase of 94% of basal values. The control group showed a continual increase of renin, aldosterone and norepinephrine. Four control dogs showed an inappropriately high secretion of arginine vasopressin. The increase of sympathetic nervous activity was only insignificantly attenuated by angiotensin II inhibition and was without a considerable influence on PVR except for an early transient increase in vascular tone. In our animal model, the renin-angiotensin system plays an important role in the regulation of PVR in CHF. In this kind of CHF the sympathetic nervous system appears to be of minor importance for the long-term regulation of PVR. Plasma arginine vasopressin levels were increased in control dogs; this increase may contribute to the increased vascular tone.     

The biochemistry of the renin-angiotensin system and its role in hypertension.

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.     

Acute effects of the calcium antagonist, nifedipine, on blood pressure, pulse rate, and the renin-angiotensin-aldosterone system in patients with essential hypertension

Ten milligrams nifedipine was administered orally to young and old persons with or without hypertension, and the acute effects of nifedipine on the renin-angiotensin-aldosterone system were studied one half to 3 hours later. Nifedipine reduced blood pressure and increased pulse rate in young and old persons with or without hypertension. Simultaneously, nifedipine produced a significant increase of plasma renin activity in young persons with or without hypertension but failed to do so in old persons with or without hypertension. As a result, angiotensin I and II increased significantly in young persons but not in old persons. Hydralazine elevated aldosterone concentration by stimulating the renin-angiotensin system but nifedipine failed to do so despite its effect on the renin-angiotensin system in young individuals. Since calcium is required to secrete aldosterone, it is suggested that nifedipine blocked aldosterone secretion by the agent's calcium antagonizing action.     

Oral calcium treatment lowers blood pressure in renovascular hypertensive rats by suppressing the renin-angiotensin system

The effects of calcium supplementation on blood pressure and its mechanisms were investigated in two-kidney, one clip renovascular hypertensive rats. Two series of experiments were performed: one was begun just after renal artery constriction, the other after the onset of hypertension. Calcium supplementation significantly attenuated the development of hypertension (systolic blood pressure: 183 +/- 8 vs 130 +/- 2 mm Hg) and was found to abate existing renovascular hypertension (systolic blood pressure: from 183 +/- 8 to 151 +/- 4 mm Hg). Calcium treatment did not cause significant alterations in fluid intake, urine volume, or urinary sodium excretion in either study. However, increased plasma renin activity and plasma aldosterone concentration were suppressed to the basal levels at the end of 3 weeks of calcium treatment (14 +/- 3 vs 8 +/- 2 ng angiotensin I/ml/hr; 530 +/- 50 vs 380 +/- 40 pg/ml). Blood pressure of calcium-treated renovascular hypertensive rats responded poorly to blockade of the renin-angiotensin system with captopril injection and angiotensin II analogue (saralasin) infusion. Further, in rats with chronic established renovascular hypertension, calcium treatment attenuated the enhanced pressor response to norepinephrine, but not to angiotensin II. These results suggest that the blood pressure-lowering actions of calcium supplementation are related primarily to suppression of renin secretion and secondarily to alteration of pressor response to norepinephrine in two-kidney, one clip renovascular hypertensive rats.     

The activated immune system and the renin–angiotensin–aldosterone system in congestive heart failure

Samsonov M, Lopatin J, Tilz G, Artner-Dworzak E, Nassonov E, Mareev V, Belenkov J, Wachter H, Fuchs D, (Cardiology Research Centre, Moscow, Russia; University of Graz, and the University of Innsbruck, Austria). Activated immune system and the renin–angiotensin–aldosterone system in congestive heart failure. J Intern Med 1998; 243 : 93–98.

Objects

The aim of the study was to investigate a possible relationship between plasma renin activity, angiotensin II, serum levels of angiotensin-converting enzyme, aldosterone and markers of immune activation in congestive heart failure (CHF).

Patients and Methods

Fifty-three patients (50 male, three female, mean age 46 ± 16 years) with congestive heart failure were studied. Twenty-eight patients had I or II NYHA class of CHF and 25 patients had III or IV NYHA class (NYHA class, mean ± SD : 2.3 ± 0.9). Serum neopterin concentration and hormones were measured by commercial radioimmunoassays. Serum soluble receptors of tumour necrosis factor and interleukin-2 were determined by ELISA.

Results

All analytes significantly correlated with NYHA classes (P < 0.05). There existed correlations between neopterin and angiotensin-converting enzyme or aldosterone (rs= 0.35 and rs= 0.36, P < 0.05). The soluble tumour necrosis factor receptor concentrations correlated with plasma renin activity (rs= 0.38, P < 0.05).

Conclusion

The result of our study suggest that there exists some relationship between the renin–angiotensin–aldosterone system and immune activation in severe congestive heart failure, however, the associations found are rather weak.

     

国产米力农治疗严重心力衰竭患者的血液动力学和肾素—血管紧张素—醛固酮系统变化

本文报告国产米力农治疗15例严重心力衰竭患者的血液动力学变化及其对肾素—血管紧张素—醛固酮(RAA)系统的影响。结果表明,用药后心指数、每搏指数增加(P<0.01),平均动脉压、平均右房压、平均肺动脉压和肺毛细血管嵌压下降(P<0.05或0.01);血浆肾素活性无变化(P>0.05),血管紧张素Ⅱ和醛固酮降低(P<0.05)。这提示国产米力农可明显改善严重心衰患者的血液动力学紊乱和抑制RAA系统激活。     

Atrial natriuretic factor in patients with cardiac decompensation before and after chronic therapy with an angiotensin-converting enzyme inhibitor]

BACKGROUND. Patients with severe congestive heart failure often have high plasma Atrial Natriuretic Factor (ANF) and neurohormonal activation. Ace inhibitors give clinical and hemodynamic benefits and lower plasma angiotensin and norepinephrine levels. The interactions between ANF and the Ace inhibitors are mainly modulated via the renin angiotensin system. METHODS. Plasma ANF, renin activity, urinary aldosterone and catecholamine levels were evaluated in 10 patients with congestive heart failure (at baseline, after 15 days of adequate treatment with digoxin and diuretics, and after 45 days of enalapril) in order to assess the changes of ANF and vasoconstrictor neurohormones with chronic Ace inhibitor therapy. RESULTS. ANF increased significantly in the congestive heart failure group compared to a normal subject control group (P < 0.001). After digoxin and diuretic therapy NHYA class improved significantly, but no significant hormonal changes were found. On the contrary, the addition of enalapril caused a significant decrease of plasma ANF and urinary aldosterone and catecholamines (P < 0.05). CONCLUSIONS. The relationship between the renin angiotensin system and catecholamines is complex but our findings indicate that: 1) Traditional therapy is effective in improving symptoms, but cannot induce a decrease of vasoconstrictive neurohormones; 2) ACE inhibitor therapy reduces ANF and neurohormonal activation. 3) ANF is a useful marker in evaluating the response to treatment.     

Effect of converting enzyme inhibitors on tissue converting enzyme and angiotensin II: therapeutic implications

Local tissue renin-angiotensin systems have recently been discovered in various organs, and evidence is accumulating that inhibition of these local renin-angiotensin 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, second by the concomitant persistence of blood pressure decrease and CE inhibition in vascular wall and kidney after long-term oral CE inhibitor treatment and third by ex vivo experiments demonstrating marked effects of oral CE inhibitor pretreatment on cardiac function in isolated rat hearts. Local inhibition of tissue renin-angiotensin systems may be an important factor involved in the beneficial effects of CE inhibitors in such cardiovascular diseases as arterial hypertension, congestive heart failure and cardiac arrhythmias.     

Atrial natriuretic factor: Physiologic actions and implications in congestive heart failure

Summary Atrial natriuretic factor (ANF) represents a newly recognized hormone of cardiac origin. This peptide is synthesized by the myocardial cells of both atria and released by atrial stretch. The hormone promotes sodium and water excretion by the kidney, inhibits the renin-angiotensin-aldosterone system, and reduces systemic arterial pressure. Specific receptors for ANF are present in the kidney, adrenal glands, vascular smooth muscle, platelets and central nervous system. Congrestive heart failure is characterized by increased circulating levels of ANF; however, there appears to be an attenuation in the renal response to the hormone.Recent investigations have reported the effect of systemic administration of synthetic ANF to normal individuals and those with congestive heart failure. The hormone may promote a significant natriuresis and diuresis in addition to reducing arterial pressure and inhibiting renin and aldosterone secretion. Substantial questions remain as to the full physiologic significance and therapeutic potential of this hormone.     

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.     

Neurohormonal activation in congestive heart failure: does it normalize after heart transplantation?

INTRODUCTION AND OBJECTIVE: In patients with congestive heart failure, neurohormonal activation plays an important role in disease progression and prognosis. The aim of this study was to document the evolution of neurohormonal activation after heart transplantation. PATIENTS AND METHOD: Thirty-seven patients on the waiting list for heart transplantation were included in the study. Plasma levels of angiotensin II, aldosterone, endothelin, atrial natriuretic peptide and adrenomedullin were measured before heart transplantation and again 1, 4, 9 and 12 months afterwards. Plasma levels of norepinephrine and renin were measured before and 1 month after heart transplantation. RESULTS: The levels of angiotensin II, norepinephrine and renin showed a nonsignificant trend towards reduction. The levels of aldosterone were unchanged, and an increase in endothelin levels was seen 9 and 12 months after transplantation. Plasma levels of atrial natriuretic peptide and adrenomedullin were significantly lower 1, 4, 9 and 12 months after heart transplantation compared to pretransplant levels. CONCLUSIONS: During the first several months after heart transplantation there were no significant reductions in plasma levels of angiotensin II, aldosterone and endothelin, and there were significant reductions soon after surgery in peptides with a predominantly vasodilator effect (atrial natriuretic peptide and adrenomedullin). This unfavorable neurohormonal profile may contribute to the development of posttransplant complications such as edema, arterial hypertension and endothelial dysfunction.     

The Renin-Angiotensin System in Essential Hypertension: Associations with Cardiovascular Risk

The importance of the renin-angiotensin system (RAS) in blood pressure regulation is well established. High RAS activity has also been implicated in connection with elevated cardiovascular risk in patients with essential hypertension. Data from epidemiological studies have related high plasma renin levels in essential hypertensive patients to cardiovascular complications. However, whether renin itself is a risk factor of cardiovascular events or just acts as a marker for other risk factors still remains to be elucidated. Several possible mechanisms that could be responsible for the association between elevated RAS activity and cardiovascular risk are reviewed. The concept of high RAS activity being a cardiovascular risk factor is strongly supported by results from large clinical studies showing the beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure and hypertension. Knowing more about the exact mechanisms of the association between high RAS activity and cardiovascular complications would enable us to profile the treatment of high blood pressure more specifically to improve outcome in individuals or groups of patients.