Antihypertensive treatment in diabetic patients. Review of current data

Thirty to 50% of diabetic patients suffer from hypertension, exhibiting increased cardiovascular risk. In the present article we review key studies regarding the current knowledge for blood pressure (BP) goals in people with diabetes, the treatment used and the possible diabetogenic effects of antihypertensive drugs, as well as the beneficial and non-beneficial combinations of antihypertensive drugs in diabetic patients. Early placebo controlled trials proved the beneficial outcome of BP lowering in diabetic patients with initially high BP levels. More recent trials examined the impact of intensive compared to less intensive BP goals in diabetic populations. However, initial BP goals had significant differences from final achieved BP levels. Accordingly, current data support initiation of antihypertensive drug treatment in all patients with diabetes and systolic BP ≥140 mmHg, with the aim to lower it consistently <140 mmHg, although how far below 140 mmHg the systolic BP goal should be is not clear. Available literature indicates that more than one drug is commonly used to achieve target BP. Drugs acting on the renin–angiotensin–aldosterone axis have been shown to act protectively on diabetic nephropathy, while β-blockers and diuretics seem to have a diabetogenic effect. Interestingly, recent studies examining the role of combined use of available renin–angiotensin–aldosterone axis blockers versus its separate use exhibited an increased incidence of adverse outcome in diabetic patients who used combinations of drugs that act against renin–angiotensin–aldosterone system. More studies need to be conducted in order to establish the best combination therapy to reduce diabetic complications.     

Education,literacy, and health: Mediating effects on hypertension knowledge and control

Objective

To determine whether literacy mediates the association between education, hypertension knowledge and control.

Methods

In-person interviews with a literacy assessment and chart review were conducted with 330 hypertensive patients from six primary care safety net clinics. Mediational analysis was used to test the role of literacy skills in explaining the relationship between education and hypertension knowledge and control.

Results

In multivariate analyses that did not make an adjustment for the other variable, both lower educational attainment and more limited literacy were found to be significant independent predictors of poorer hypertension knowledge and control. When literacy was entered into models that included education only, the association between education and knowledge was fully attenuated and no longer significant (Grades 1–8: β = −0.30, 95% CI = −1.44–0.83), while the relationship between education and blood pressure control was only minimally reduced (AOR 2.46, 95% CI 2.10–2.88). More limited literacy skills also was associated with hypertension control in the final model (AOR 2.68, 95% CI 1.54–4.70).

Conclusion

Patient literacy mediated the relationship between education and hypertension knowledge. Literacy was a significant independent predictor of blood pressure control, but only minimally explained the relationship between education and blood pressure.

Practice implications

Health literacy is critical to the design of educational tools to improve knowledge acquisition. However, in order to impact health outcome, future health literacy studies should also address other psychosocial factors that impact motivation and capability to manage disease.     

AT1-receptor autoantibodies and uteroplacental RAS in pregnancy and pre-eclampsia

Pre-eclampsia is a common, pregnancy-induced disorder, consisting of hypertension and proteinuria. The condition is one of the leading causes for maternal and perinatal morbidity and mortality. Nonetheless, the underlying molecular mechanisms remain unclear. Immunological mechanisms and the renin–angiotensin system have been implicated in the development of pre-eclampsia. Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) have been identified in pre-eclamptic patients, unifying the two hypothesis. Evidence has also accumulated for the existence and importance of a local, utroplacental renin–angiotensin system. We summarize recent data emphasizing the pathophysiological role for the autoantibodies and the uteroplacental renin–angiotensin system.     

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.     

Hypotensive Effect of Potentiated Antibodies to Angiotensin II and AT1 Receptors

Hypotensive activity of ultralow doses of antibodies to angiotensin II and its receptors was studied on adult NISAG rats with hereditary stress-induced arterial hypertension. Antibodies to C-terminal fragment of angiotensin II receptors produced the most pronounced hypotensive effect, which was reproducible after repeated administration. These antibodies decreased systolic blood pressure by 16.40±0.62 mm Hg. The most rapid hypotensive effect was produced by affinity purified antibodies to angiotensin II: 2 h after administration of these antibodies systolic blood pressure decreased by 12.80±5.49 mm Hg. Our results indicate that combination treatment with ultralow doses of antibodies to angiotensin II and its receptors hold much promise for the use in clinical practice.     

The role of the brain renin–angiotensin system in hypertension: Implications for new treatment

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin–angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine–vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150 — the prototype of a new class of centrally acting antihypertensive agents.     

Role of the renin-angiotensin system in post-transplantation hypertension in patients with multiple kidneys.

To define the role of the renin-angiotensin system in post-transplantation hypertension we studied 12 hypertensive recipients of renal transplants. The patients received saralasin acetate, an angiotensin II antagonist, while on a normal sodium diet and again after seven days of sodium restriction. In six patients with only one kidney, saralasin did not lower blood pressure on either diet; salt depletion did not lower systolic or diastolic blood pressures. In six patients with more than one kidney, salt depletion also did not lower blood pressure; however, salt depletion plus saralasin lowered their systolic pressures from a mean (+/- S.E.M.) of 146 +/- 9 to 128 +/- 8 mm Hg, and mean diastolic pressures fell from 103 +/- 5 to 89 +/- 5 (P less than 0.001). In four of five patients renal-vein renin activity was greater in one or more host kidneys than in the transplant kidney (or kidneys). Although pre-transplant blood pressure was the same in both groups, post-transplantation hypertension is more likely to be angiotensin II-dependent in patients with more than one kidney.     

An age effect on the association of common variants of ACE with Alzheimer's disease

It is now well established that vascular risk factors are associated with cognitive performances. The renin–angiotensin system (RAS) components, major determinants of the cardiovascular system, are expressed in the brain and were shown to play a role on amyloid metabolism, learning and memory. The angiotensin-converting enzyme (ACE), a pivotal RAS protein, is encoded by a huge gene containing many variants, one of them, the I/D variant (rs1799752), being associated with Alzheimer's disease (AD). Other variants, such as SNPs rs4291A>T located −240 bp from the initiation codon, and rs4343G>A encoding a silent mutation in exon 16, were inconsistently associated with the risk of AD. In a case–control study including 376 late-onset AD patients and 444 control subjects, we showed a statistically significant effect on the risk of AD of two variants (rs4343 and rs1799752) and of the haplotype ATI (rs4343/rs4291/rs1799752) in subjects aged 73 years and above.     

Morgendlicher Blutdruckanstieg: vor oder nach dem Aufwachen?

Summary The coincidence of the circadian peak of cardiovascular events with the morning blood pressure rise suggests causal connections. Rapidly acting antihypertensives taken before getting up may attenuate the increase early enough, if the onset does not occur before awakening.In 111 normotensives and in 109 subjects with untreated essential hypertension ambulatory blood pressure monitoring was performed to study whether the onset of the blood pressure rise occurs before or after waking up. The individual 24 h blood pressure profiles obtained by intermittent readings at intervals of 15 minutes were synchronized by the time of waking up.The resulting blood pressure curves showed no substantial blood pressure rise during sleep, but steep increases after awakening: Within the first hour after waking up blood pressure increased from 107.3+11.4/62.3±9.6 mm Hg (mean+sd) to 121.4±16.0/75.3+12.6 mm Hg in normotension and from 124.7+16.0/72.7+12.2 mm Hg to 140.3+17.2/84.5+13.3 mm Hg in hypertension. The velocity of this increase was dependent on the lag between waking up and getting up. There was no phase difference between early morning blood pressure and heart rate rises.Thus to attenuate the morning blood pressure increase, rapidly acting drugs after awakening may be considered instead of long acting antihypertensives administered prior to sleep.

     

Accentuated vascular and endocrine response to SQ 20881 in hypertension.

We assessed vascular and hormonal responses to inhibition of peptidyldipeptide hydrolase, which converts angiotensin I to angiotensin II (converting enzyme) and degrades bradykinin (kininase II), in subjects given 10 meq of sodium to activate both systems. In nine normal subjects a threshold dose of 30 MICROgram per kilogram of the inhibitor, SQ 20881, modestly influenced mean blood pressure (-5 +/- 1 mm Hg, P less than 0.05), and renal blood flow (+50+/-8 ml per 100 g per minute), plasma renin activity (+ 2.3 +/- 0.6 ng per milliliter per hour), and angiotensin II (-11 +/- 3 pg per milliliter) more strikingly (P less than 0.01). In six patients with essential hypertension the threshold inhibitor dose was reduced to 10 microgram per kilogram; 30 kilogram per kilogram had an enhanced (P less than 0.01) effect on mean blood pressure (-11 +/- 2 mm Hg), renal blood flow (137 +/- 20 ml per 100 g per minute), and angiotensin II concentration (-29 +/- 12 pg per milliliter). SQ 20881 elevated plasma bradykinin concentration (7.4 +/- 2.6 ng per milliliter, P less than 0.02) only in the hypertensive patients. Because both renin-angiotensin and kallikrein-bradykinin systems are influenced, vascular responses to SQ 20881 must be interpreted cautiously, but this agent has excellent antihypertensive characteristics.     

Influence and implications of the renin–angiotensin–aldosterone system in obstructive sleep apnea: An updated systematic review and meta-analysis

Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin–angiotensin–aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin–angiotensin–aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04–0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05–60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11–7.27], p < 0.001), systolic (pooled wmd+ 5.87 [95% confidence interval 1.42–10.32], p = 0.0098) and diastolic (pooled wmd+ 3.40 [95% confidence interval 0.86–5.94], p = 0.0086) blood pressure, and heart rate (pooled wmd+ 3.83 [95% confidence interval 1.57–6.01], p = 0.0009) compared with those without obstructive sleep apnea. The elevation remained significant (except for renin levels) when studies involving patients with resistant hypertension were removed. Sub-group analysis demonstrated that levels of angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin–angiotensin–aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin–angiotensin–aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.     

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.     

Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: A randomised controlled trial

Objective

To assess the effect, tolerability and acceptability of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with treated, but uncontrolled, hypertension.

Design

A double-blind parallel randomised placebo-controlled trial involving 50 patients whose routine clinical records in general practice documented treated but uncontrolled hypertension. The active treatment group received four capsules of aged garlic extract (960 mg containing 2.4 mg S-allylcysteine) daily for 12 weeks, and the control group received matching placebos. The primary outcome measures were systolic and diastolic blood pressure at baseline, 4, 8 and 12 weeks, and change over time. We also assessed tolerability during the trial and acceptability at 12 weeks.

Results

In patients with uncontrolled hypertension (SBP ≥ 140 mm Hg at baseline), systolic blood pressure was on average 10.2 ± 4.3 mm Hg (p = 0.03) lower in the garlic group compared with controls over the 12-week treatment period. Changes in blood pressure between the groups were not significant in patients with SBP < 140 mm Hg at baseline. Aged garlic extract was generally well tolerated and acceptability of trial treatment was high (92%).

Conclusion

Our trial suggests that aged garlic extract is superior to placebo in lowering systolic blood pressure similarly to current first line medications in patients with treated but uncontrolled hypertension.     

Impaired autoregulation of cerebral blood flow in long-term type I (insulin-dependent) diabetic patients with nephropathy and retinopathy

Autoregulation of cerebral blood flow, i.e., the maintenance of cerebral blood flow within narrow limits during changes in arterial perfusion pressure, was studied in nine healthy control subjects and in 12 long-term Type I (insulin-dependent) diabetic patients with clinical microangiopathy. Cerebral blood flow was measured by the intravenous 133Xenon method. Mean arterial blood pressure was elevated approximately 30 mmHg by intravenous infusion of angiotensin amide II and lowered about 10 mmHg by intravenous infusion of trimethaphan camsylate. In the control subjects the flow/pressure curve was horizontal indicating perfect autoregulation. In the diabetic patients the flow/pressure curve showed a significant slope with a 1.9% change in CBF per 10 mmHg change in mean arterial blood pressure as compared to a slope value of -0.4% in the control subjects (P less than 0.05). Our results confirm the previous findings suggesting that autoregulation of cerebral blood flow is impaired in some long-term Type I diabetic patients with clinical microangiopathy (arteriolar hyalinosis).     

Effects of the nonapeptide SQ 20.881 on the blood pressure of conscious normotensive and chronic hypertensive mice

Prevention of conversion of angiotensin I to angiotensin II by means of a converting enzyme inhibitor, the nonapeptide SQ 20.881, in chronic hypertensive mice was followed by a drop in blood pressure in all mice independent of the ethiology of hypertension; in conscious normotensive mice was observed a significant decrease in blood pressure, which, however, was less than that observed in the hypertensive mice.     

The role of angiotensin-converting enzyme gene insertion/deletion polymorphism for blood pressure regulation in areca nut chewers

Areca tannin has been suggested as having a blood pressure regulatory effect through its ability to inhibit the pressor response to both angiotensin I and II. As genetic and environmental factors determine the susceptibility and development of diseases and no report has been published concerning the genetic interaction of metabolic effects in areca nut/betel quid (BQ) chewers, it is proposed that the cardiovascular effects of chronic BQ usage can be affected by the polymorphism of the angiotensin converting enzyme (ACE) gene. This is a cross-sectional community-based study. A total of 189 BQ chewing subjects and 256 non-chewing controls were studied. BQ chewing status was determined by using a structured questionnaire, and insertion/deletion (I/D) polymorphisms were determined by a polymerase chain reaction. BQ chewers with the DD genotype had significantly lower blood pressure, pulse pressure, and prevalence of hypertension compared with those of chewers with II or ID genotypes. Multiple stepwise regression analysis confirmed that the ACE I/D genotype was independently associated with systolic blood pressure (SBP). BQ chewers with the DD genotype accounted for a significant age, sex, and waist-to-hip ratio adjusted decrease in SBP (-5.9 mm Hg, P=0.021). This finding suggests that BQ chewing may be related to blood pressure regulation, which supports the hypothesis that concomitant genetic susceptibility and environmental factors determine the level of blood pressure.     

Central antihypertensive effects of inhibitors of the renin-angiotensin system in rats.

The possibility that mean arterial pressure (MA) might be maintained by an effect of angiotensin II or its precursors on the central nervous system in rats made hypertensive by occluding the aorta between the renal arteries was investigated. Aortic coarctation produced severe hypertension (MAP greater than 150 mmHg) and plasma renin activity values (radioimmunoassay) at least 10 times normal within 2-6 days after surgery. [Sar1, IIe8]angiotensin II, an angiotensin II antagonist administered centrally via an intracerebroventricular (icv) injection (10-100 mug), lowered the MAP in a dose-dependent manner. Peripheral administration of [Sar1, IIe8]angiotensin II (bolus injection) at 100 mug intra-arterially was ineffective, but the antagonist did lower arterial pressure when infused intravenously for 1 h at 4 times this dose. Less than Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, a converting enzyme inhibitor, and pepstatin, a renin inhibitor, were ineffective via an icv injection. These results suggest that angiotensin II is in part responsible for the elevation in blood pressure following aortic coarctation in rats. Both central and peripheral administration of [Sar1, Ile8]-angiotensin II lowered mean arterial pressure but the antagonist lowered arterial pressure at lower doses and produced a more rapid decline in arterial pressure when administered into the central nervous system then when administered intra-arterially or intravenously.     

RAAS polymorphisms alter the acute blood pressure response to aerobic exercise among men with hypertension

Limited evidence suggests renin–angiotensin–aldosterone system (RAAS) polymorphisms alter the blood pressure (BP) response to aerobic exercise training. We examined if RAAS polymorphisms influenced postexercise hypotension in men with high normal to Stage 1 hypertension. Forty-seven men (44.2±1.4 years, 145.1±1.6/85.5±1.1 mmHg) randomly completed three experiments: seated rest (control) and two cycle exercise bouts at 40% (LITE) and 60% (MOD) of maximal oxygen consumption. Ambulating BP was measured for 14 h after each experiment. RAAS polymorphisms associated with hypertension (i.e. angiotensin converting I enzyme, ACE I/D; angiotensin II type 1 receptor, AT₁R A/C; and intron 2 of aldosterone synthase, Int2 W/C) were analyzed using polymerase chain reaction and restriction enzyme digestion. Repeated measure ANOVA tested if BP differed between experimental conditions by RAAS genotypes. Compared to men with 0–2 variant alleles, men with ≥3 combined RAAS variant alleles had lower average systolic BP (SBP) (P=0.030) and lower average diastolic BP (DBP) (P=0.009) for 14 h only after LITE. In contrast, average BP was not different for MOD and control between RAAS variant allele groups over this time period (P≥0.05). LITE reduced BP in men with ≥3 variant RAAS alleles for 14 h, whereas MOD had no influence on BP in these men. In order to optimally prescribe exercise for its BP lowering benefits in those with hypertension, additional knowledge of how genetic variation affects the BP response to exercise is needed.Sources of Support: Supported by an American Heart Association Grant-in-Aid # 0150507N     

Are we poised to target ACE2 for the next generation of antihypertensives?

Antihypertensive drugs based on the blockade of the renin–angiotensin system (RAS) target classical components of this system, i.e., angiotensin-converting enzyme (ACE) and angiotensin (Ang) II type 1 receptor. These antihypertensives are well-recognized and successful, if prescribed properly, in reducing high blood pressure, but much less effective in preventing and reverting end-organ damage induced by cardiovascular disease (CVD) and hypertension. Thus, new strategies and new drug targets that are more effective must be discovered. Recent identification of a counterregulatory axis of the RAS [ACE2, Ang-(1–7), and Mas receptor] that is potentially important in promoting vasoprotective effects offers a novel target for CVD therapeutics. In this brief review, we will highlight the functional characteristics of this axis with special emphasis on ACE2 and its possible involvement in the pathophysiology of the CVD. In addition, we will present our views on the potential of ACE2 as a new target for the development of innovative antihypertensives by highlighting the development and functional findings obtained with small molecules ACE2 activators.     

Chronic low-dose isotretinoin treatment limits renal damage in subtotally nephrectomized rats

Retinoids are anti-proliferative and anti-inflammatory compounds. We had previously shown that retinoids alleviate kidney damage in acute models of renal disease. We now examined whether retinoids are also effective in a chronic renal ablation model. Subtotally nephrectomized rats (SNx; two-third ablation) were compared to sham-operated controls (sham). SNx rats were administered either 10 mg/kg b.w. (low dose, LD) or 40 mg/kg b.w. (high dose, HD) isotretinoin or vehicle (n = 10 per group). The experiment was terminated after 16 weeks. Systolic blood pressure was significantly higher after SNx compared to sham but lower in SNx with LD isotretinoin (vs. SNx + vehicle). Compared to SNx + vehicle, SNx + LD isotretinoin had lower glomerular cell numbers, less glomerular hypertrophy and sclerosis, and less interstitial expansion. Morphological improvement in SNx + LD isotretinoin was accompanied by improvement in creatinine clearance and reduced urinary albumin excretion. In contrast, HD isotretinoin caused aggravation of renal damage with fibrinoid necroses of vessels and elevated urinary albumin excretion despite lower blood pressure. The dichotomous effects of isotretinoin are at least in part due to time- and dose-dependent alterations of transforming growth factor β1 and collagen IV gene expression as also suggested by cell-culture studies in vascular smooth muscle cells. In addition, isotretinoin affected the systemic and the renal renin–angiotensin system (which was further analyzed in a model of angiotensin II infusion of the rat). Isotretinoin failed to cumulate at LD but cumulated at HD in SNx. We conclude that LD isotretinoin attenuates progressive renal damage, whereas HD isotretinoin cumulates and aggravates renal damage independent of blood pressure reduction. C. Morath and K. Ratzlaff contributed equally to the study.