RETRACTED ARTICLE: Direct renin inhibition: clinical pharmacology

Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors such as aliskiren. Aliskiren has a low bioavailality (2.6% to 5%) compensated by its high potency to inhibit renin and a long plasma half-life (24 to 40 h), which makes it suitable for once-daily dosing. The once-daily administration of aliskiren to hypertensive patients lowers blood pressure as strongly as standard doses of established AT1 receptor blockers (losartan, valsartan, and irbesartan), angiotensin-converting enzyme inhibitors (ramipril and lisnopril), hydrochlorothiazide, or long-acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, valsartan, irbesartan, or ramipril. However, the biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme inhibition and angiotensin II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-NO-cGMP pathway. Blockade of the renin–angiotensin system with angiotensin I-converting enzyme inhibitors, AT1 receptor blockers, or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize renin–angiotensin system blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the renin–angiotensin system fully quiescent is a new possibility requiring further study. Preliminary results show that short-term administration of aliskiren has beneficial antialbuminuric effects in diabetic patients with chronic nephropathy and favorable neurohormonal effects in patients with chronic heart failure.     

A case of losartan induced angioedema

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) target the renin-angiotensin system and are used in the management of hypertension. Both classes of drugs have similar side effects. ARBs are considered to be much better tolerated than ACE inhibitors with lesser incidence of side effects. Angioedema is a very rare side effect associated with ACE inhibitors (ACEI) and even rarer so with ARBs. The cause for angioedema in ACE inhibitors is said to be the rise in bradykinin levels. It has been postulated that angiotensin II receptor activates the bradykinin-prostaglandin-nitric oxide cascade, resulting in bradykinin-mediated side effects of ARBs such as angioedema, but the true mechanism remains largely unknown. We present here a rare case of late onset angioedema associated with losartan (an ARB) in a female patient. She had been started on an ARB as a first line treatment for uncomplicated mild to moderate hypertension. She had no prior exposure to ACE inhibitors and did not have any other significant medical history. Though rare angioedema is a serious recognized side effect of ARB therapy and the patients started on them should be warned to look for the early signs so as to take corrective action.     

Renin inhibitors,clinical experience

The inhibition of the renin–angiotensin system is one of the most commonly utilized ways to lower blood pressure in patients with arterial hypertension. Up till now, angiotensin-converting enzyme inhibitors as well as angiotensin receptor blockers are the established inhibitors of this system, and both classes are used in clinical routine. There is a wealth of information about those classes, which are known not only to lower blood pressure, but also to prevent end-organ damage and, ultimately, reduce mortality in patients. Direct renin inhibition was already targeted 30 years ago to inhibit the renin–angiotensin system, but low bioavailability and short duration of action of the first generations of renin inhibitors withheld their clinical success. With the new generation of non-peptide orally available renin inhibitors, a third substance to inhibit the renin–angiotensin system is on the market, and the prototype of this class, aliskiren, has now been tested in various clinical trials in arterial hypertension. We review the studies of aliskiren and discuss its current role in the contemporary treatment of arterial hypertension as well as the possible new fields of action for aliskiren in treating heart failure and diabetic nephropathy.     

Cyclooxygenase-2 and the renal renin-angiotensin system

In the kidney, cyclooxygenase-2 (COX-2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na(+)/K(+)/2Cl(-) cotransport, and administration of non-specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX-2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX-2 expression. In AT1 receptor knockout mice, COX-2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX-2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX-2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX-2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX-2 inhibitor but not a COX-1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low-salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX-2-selective inhibitors. In mice with genetic deletion of COX-2, ACE inhibitors or low-salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX-1 null mice there were no significant differences in either the basal or ACE inhibitor-stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX-2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX-2 derived prostaglandins and the renin-angiotensin system may underlie physiological and pathophysiological regulation of renal function.     

Cyclooxygenase‐2 and the renal renin–angiotensin system

In the kidney, cyclooxygenase‐2 (COX‐2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na⁺/K⁺/2Cl^? cotransport, and administration of non‐specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX‐2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX‐2 expression. In AT1 receptor knockout mice, COX‐2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX‐2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX‐2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX‐2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX‐2 inhibitor but not a COX‐1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low‐salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX‐2‐selective inhibitors. In mice with genetic deletion of COX‐2, ACE inhibitors or low‐salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX‐1 null mice there were no significant differences in either the basal or ACE inhibitor‐stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX‐2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX‐2 derived prostaglandins and the renin–angiotensin system may underlie physiological and pathophysiological regulation of renal function.     

Aliskiren—mode of action and preclinical data

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin–angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.     

Aliskiren attenuates oxidative stress and improves tubular status in non-diabetic patients with chronic kidney disease-Placebo controlled,randomized, cross-over study

PurposePharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) may have a beneficial impact on proteinuria and chronic kidney diseases (CKD) progression. Despite recent progress by means of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), there is still no optimal therapy which can stop progression of the nephropathy. Recently introduced aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. The purpose was to evaluate the extent of oxidative stress and tubular injury after the direct renin inhibitor, aliskiren compared with placebo and perindopril in patients with non-diabetic chronic kidney disease (NDCKD).Material/methodsA randomized, double-blind, cross-over trial was performed in 14 patients receiving 300 mg aliskiren, 10 mg perindopril and placebo in random order. The end point was a change in the urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and α1-microglobulin (α1m) and 15-F_2α-isoprostane.ResultsAliskiren reduced excretion of 15-F_2α-isoprostane (p = 0.03) and α1m (p = 0.01) as compared to placebo. There were no differences between aliskiren and perindopril in this regard. NAG urine excretion did not change after aliskiren and perindopril.ConclusionsAliskiren attenuates oxidative stress and may improve functional status of tubules in patients with NDCKD.     

Hypertension in type II diabetes mellitus

Treatment of hypertension in patients with NIDDM should be administered with special attention not to increase insulin resistance nor to impair insulin secretion capacity. The coexisting risk for coronary artery disease and myocardial infarction should not be increased by undesired drug effects on the plasma lipoprotein profile. Late lesions of diabetes mellitus (nephropathy, neuropathy) have also to be taken into account. Consequently angiotensin converting enzyme inhibitors, if necessary combined with calcium channel blockers, should be administered first. If blood pressure is thus not sufficiently controlled, alpha-adrenergic blockers, vasodilating agents or sympatholytics may be added. Once insulin treatment is installed, or if required for other reasons (nephropathy, congestive heart failure, cardiac arrhythmia), also diuretics and beta-adrenergic blockers are indicated in antihypertensive treatment of diabetic patients.     

Treatment of hypertension in black patients with angiotensin-converting enzyme inhibitors

The prevalence of hypertension and the incidence of complications from uncontrolled elevated blood pressure in blacks is much greater than in the white population. In general, blacks have underlying differences in the factors relating to blood pressure level, including low plasma renin, and, in certain instances, a decreased ability to excrete sodium. The stepped-care approach in the management of the black hypertensive patient is similar to that taken with white patients, but racial differences in response to antihypertensive drugs exist that require careful consideration when choosing a treatment regimen. Thiazide diuretics are effective in blacks and are often used as initial therapy. Blacks tend to respond less well to β-blockers, but when combined with a diuretic, they are also effective. Encouraging data are available on the use of calcium channel blockers in blacks. When combined with a diuretic, the angiotensin-converting enzyme (ACE) inhibitors also provide an alternative to therapy for black patients. The use of low doses of ACE inhibitors has reduced the high incidence of adverse effects associated with this group of drugs in earlier studies.     

Renin inhibitors as possible antihypertensive agents

Summary The blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme has become an established principle in the treatment of hypertension. This has stimulated interest in the inhibition of renin, the enzyme which catalyzes the first and rate-limiting step in the formation of angiotensin II. During recent years, considerable progress has been made in the development of renin inhibitors. Several potent and selective compounds have been synthesized and studiedin vitro andin vivo. In experimental animals with a stimulated renin-angiotensin system the haemodynamic effects of renin inhibitors have been shown to be identical to those of angiotensin-converting enzyme inhibitors. The two classes of agents also have similar antihypertensive effects in various forms of experimental renal hypertension. However, it is not clear whether their efficacy will be comparable in patients with essential hypertension. The main shortcoming of the currently available renin inhibitors is their low bioavailabilty after oral administration and their short duration of action. The improvement of these pharmacokinetic properties is the main challenge for future research in this area.     

Role of potassium channels in the control of renin secretion from isolated perfused rat kidneys

This study aimed to assess the relevance of specific potassium channels, such as inwardly or outwardly rectifying and calcium-regulated potassium channels, to the control of renin secretion. For this purpose we examined the effects of the K+ channel blockers 4-aminopyridine (1 mmol/l), barium (100 micromol/l), tetraethylammonium (2 mmol/l) and apamin (200 nmol/l) on basal renin secretion, on renin secretion stimulated by isoproterenol (10 nmol/l) and on the inhibition of renin secretion by angiotensin II (100-300 pmol/l) in the isolated rat kidney perfused at constant pressure. Whilst all four K+ channel blockers increased renal vascular resistance, only 4-aminopyridine and barium attenuated isoproterenol-stimulated renin secretion in an additive fashion and augmented the inhibitory effect of angiotensin II. These effects of K+ channel blockers were not changed by the L-type calcium channel blocker amlodipine (5 pmol/l), indicating that their effects on renin secretion are not due to voltage-operated calcium influx. Our data, moreover, suggest that potassium efflux from renal juxtaglomerular cells is not important for the inhibitory action of angiotensin II on renin secretion. As a consequence it appears that the membrane potential of renal juxtaglomerular cells per se is relevant to renin secretion such that membrane depolarization inhibits the exocytosis of renin whilst hyperpolarization favors renin secretion. By their activity, potassium channels can contribute to membrane hyperpolarization and thus facilitate renin secretion.     

Does the ADMA/DDAH/NO pathway modulate early regression of left ventricular hypertrophy with esmolol?

Hypertensive left ventricular hypertrophy (LVH) is a maladaptive response to chronic pressure overload and a strong independent risk factor for cardiovascular disease. Regression of LVH is associated with improved prognosis. Regression of LVH with antihypertensive therapy (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, and diuretics) has been reported, although only after long-term treatment. Asymmetrical dimethylarginine (ADMA), the most potent endogenous NO synthase inhibitor, is emerging as an important cardiovascular risk factor in patients with arterial hypertension and LVH, and dimethylarginine dimethylaminohydrolase (DDAH) is the mechanism that most frequently leads to accumulation of ADMA (plasma ADMA is cleared in small part by renal excretion, although the bulk of ADMA is degraded by DDAH). Left ventricular mass is strongly modulated by the NO system. As an important inhibitor of the bioavailability of NO, ADMA is an underlying mechanism of LVH. Beta-blockers can induce regression of LVH and reduced plasma ADMA levels. Oxidative stress is increased in patients with LVH, and this in turn increases generation of ADMA. In a previous preclinical study of spontaneously hypertensive rats, we found that short-term treatment (48 h) with esmolol reverses early LVH, increases the bioavailability of NO, and improves antioxidant status in plasma. Therefore, we propose that the ADMA/DDAH/NO pathway could modulate early regression of LVH with esmolol.     

Anaphylaxis and cardiovascular disease: therapeutic dilemmas

Cardiovascular disease (CVD) increases the risk of severe or fatal anaphylaxis, and some medications for CVD treatment can exacerbate anaphylaxis. The aim of this article is to review the effect of anaphylaxis on the heart, the potential impact of medications for CVD on anaphylaxis and anaphylaxis treatment, and the cardiovascular effects of epinephrine. The therapeutic dilemmas arising from these issues are also discussed and management strategies proposed. PubMed searches were performed for the years 1990–2014 inclusive, using terms such as angiotensin‐converting enzyme (ACE) inhibitors, adrenaline, allergic myocardial infarction, anaphylaxis, angiotensin‐receptor blockers (ARBs), beta‐adrenergic blockers, epinephrine, and Kounis syndrome. Literature analysis indicated that: cardiac mast cells are key constituents of atherosclerotic plaques; mast cell mediators play an important role in acute coronary syndrome (ACS); patients with CVD are at increased risk of developing severe or fatal anaphylaxis; and medications for CVD treatment, including beta‐adrenergic blockers and ACE inhibitors, potentially exacerbate anaphylaxis or make it more difficult to treat. Epinephrine increases myocardial contractility, decreases the duration of systole relative to diastole, and enhances coronary blood flow. Its transient adverse effects include pallor, tremor, anxiety, and palpitations. Serious adverse effects (including ventricular arrhythmias and hypertension) are rare, and are significantly more likely after intravenous injection than after intramuscular injection. Epinephrine is life‐saving in anaphylaxis; second‐line medications (including antihistamines and glucocorticoids) are not. In CVD patients (especially those with ACS), the decision to administer epinephrine for anaphylaxis can be difficult, and its benefits and potential harms need to be carefully considered. Concerns about potential adverse effects need to be weighed against concerns about possible death from untreated anaphylaxis, but there is no absolute contraindication to epinephrine injection in anaphylaxis.     

Differential regulation of renin and Cox-2 expression in the renal cortex of C57Bl/6 mice

Based on the controversy about the relevance of cyclooxygenase-2 (Cox-2)-derived prostanoids from the macula densa for the control of the renin system, this study aimed to determine the interrelation between Cox-2 and renin expression in the mouse kidney. In control mice renin mRNA was readily detectable whilst renocortical Cox-2 mRNA abundance was at the detection limit of the RNase protection assay and no specific signals for Cox-2 were obtained by in situ hybridization or Western blot analysis. Experimental maneuvers such as low-salt diet, treatment with loop diuretics or angiotensin I converting enzyme inhibitors clearly increased renin mRNA abundance up to sevenfold, but under none of these conditions renocortical Cox-2 mRNA levels were significantly changed. Moreover, the strong stimulation of renin expression by angiotensin I-converting enzyme inhibition was not changed by the cyclooxygenase inhibitor ibuprofen, which in turn clearly lowered tissue prostanoid content. Our data suggest a marked divergence of renin and Cox-2 expression in the kidney cortex of C57Bl/6 mice with no clear evidence for a role of Cox-2-derived prostanoids from the macula densa in the regulation of renin expression.     

Role of insulin-sensitizing property of telmisartan, a commercially available angiotensin II type 1 receptor blocker in preventing the development of atrial fibrillation

Atrial fibrillation (Af) is the most common disorder of cardiac rhythm and is responsible for substantial morbidity and mortality in the general population. A recent community-based observational study revealed that diabetes and hypertension were associated with the development of Af. Since there is no definite evidence to show that type 1 diabetes is at increased risk for the development of Af, insulin resistance rather than hyperglycemia per se could explain the link between diabetes and Af. Several clinical trials suggest that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of insulin resistance. Indeed, interruption of the RAS with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been shown to prevent the onset of diabetes in hypertensive patients. Further, several experimental and clinical studies showed the beneficial role for the inhibition of the RAS in preventing Af as well. However, to what extent the insulin-sensitizing effects of ARBs could account for the prevention of Af remains to be clarified. Recently, telmisartan, an ARB, was found to act as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma influences the gene expression involved in carbohydrate metabolism. In animal study, telmisartan administration caused a significant attenuation of weight gain and reduced glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet, compared with treatments of losartan, another type of ARB. Furthermore, recently, some clinical papers also reported the insulin-sensitizing effects of telmisartan in hypertensive patients. In this paper, we would like to propose the possible ways of clarifying to what extent the insulin-sensitizing effects of ARBs could account for the prevention of Af. (1) Does telmisartan reduce the development of Af in insulin resistant hypertensive patients? (2) When adjusted for blood pressure, is the effect of telmisartan superior to other ARBs? (3) Does this beneficial effect of telmisartan correlate to its insulin-sensitizing properties? Ongoing clinical trial (ONTARGET) has been designed the efficacy of telmisartan with an ACEI, ramipril, alone or in combination. This randomized, double-blind, multicenter international studies will provide further information whether telmisartan can improve insulin resistance and subsequently reduce the development of Af in high-risk hypertensive patients.     

Physiology of local renin-angiotensin systems

Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.     

Neurohormonal influences on maintenance and reversal of two‐kidney one‐clip renal hypertension

The factors involved in maintenance and reversal of mean arterial blood pressure (MAP) in the chronic two‐kidney one‐clip hypertensive rat (2K1C‐RHR) are still debated. The reduction in MAP after reversal of 2K1C hypertension has been ascribed either to release of a renal medullary depressor hormone (RMDH) or suppression of the renin–angiotensin and/or sympathetic nervous system. We studied in conscious rats: (i) The effects of angiotensin II receptor blockade (ARB; candesartan), sympathetic blockade (propranolol and phentolamine) or a combination on MAP in 6‐week long 2K1C‐RHR; (ii) The effects of reversal of 2K1C hypertension by removal of the constricting clip (unclipping, UC) or nephrectomy (Nx) on MAP, plasma renin activity (PRA) and noradrenaline (NA) spillover rates. The results show that: (i) MAP in the 2K1C‐RHR was almost normalized by ARB but not significantly affected by the sympathetic blockade. The combination was not more effective than ARB alone; (ii) UC and Nx reduced MAP in 2K1C to similar levels as ARB. No significant changes in PRA or catecholamines could be detected in UC and Nx groups. We conclude that hypertension in 2K1C‐RHR is maintained by the renin–angiotensin system without much contribution from the sympathetic nervous system. Furthermore, we found no evidence that UC of our model of 2K1C was associated with a generalized decrease in sympathetic tone or substantial release of RMDH from the unclipped kidney. Thus, we conclude that in the present model of 2K1C, both maintenance and reversal of hypertension are controlled by the renin–angiotensin system.     

Augmented intrarenal and urinary angiotensinogen in hypertension and chronic kidney disease

Activated intrarenal renin–angiotensin system plays a cardinal role in the pathogenesis of hypertension and chronic kidney disease. Angiotensinogen is the only known substrate for renin, which is the rate-limiting enzyme of the renin–angiotensin system. Because the levels of angiotensinogen are close to the Michaelis–Menten constant values for renin, angiotensinogen levels as well as renin levels can control the renin–angiotensin system activity, and thus, upregulation of angiotensinogen leads to an increase in the angiotensin II levels and ultimately increases blood pressure. Recent studies using experimental animal models have documented the involvement of angiotensinogen in the intrarenal renin–angiotensin system activation and development of hypertension. Enhanced intrarenal angiotensinogen mRNA and/or protein levels were observed in experimental models of hypertension and chronic kidney disease, supporting the important roles of angiotensinogen in the development and the progression of hypertension and chronic kidney disease. Urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin–angiotensin system status in angiotensin II-infused rats. Also, a direct quantitative method has been developed recently to measure urinary angiotensinogen using human angiotensinogen enzyme-linked immunosorbent assay. These data prompted us to measure urinary angiotensinogen in patients with hypertension and chronic kidney disease, and investigate correlations with clinical parameters. This short article will focus on the role of the augmented intrarenal angiotensinogen in the pathophysiology of hypertension and chronic kidney disease. In addition, the potential of urinary angiotensinogen as a novel biomarker of the intrarenal renin–angiotensin system status in hypertension and chronic kidney disease will be also discussed.     

Use of an angiotensin II antagonist (saralasin) in the recognition of "angiotensinogenic" hypertension;.

The possibility has been explored of using a specific angiotensin ii antagonist, saralasin (P-113, 1-sar-8-ala-angiotensin ii) to recognize patients whose hypertension depends upon excessive angiotensin ii activity. Among 60 hypertensive patients, saralasin infusion reduced blood pressure in 16 "responders," but not in 44 "nonresponders." The "responders" had the following findings: elevated plasma renin activity in renal vein (or veins) or peripheral veins or both (16 of 16); reduced renal blood flow, shown by arteriography, isotopic studies or pyelography (15 or 16), or progressive azotemia (one of 16); and reduction in blood. These findings indicated that angiotensin ii probably caused hypertension in the "responders," One "nonresponder" had renal vein levels of plasma renin activity suggestive of angiotensinogenic hypertension. Since hypertension was invariably angiotensinogenic when it was reduced by saralasin and, with one possible exception, was never angiotensinogenic in "nonresponders," the antagonist appears to provide an efpressure to or toward normal after corrective operation (four of four) or propranolol therapy (eight of eight). fective means of recognizing angiotensinogenic hypertension.