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Biomedical subjects

N K Hollenberg

Publications and source records attributed to N K Hollenberg.

At least 19 recordsLinked to original sources
PubMed2002

AT(1)-receptor blockade and the kidney: importance of non-ACE pathways in health and disease.

Large-scale trials with angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT(1))-receptor blockers have clearly shown that blockade of the renin-angiotensin system reduces the deterioration in renal function associated with diabetes. AT(1)-receptor blockers represent a more rational approach to blockade of this system than ACE inhibitors, due to the presence of non-ACE pathways of angiotensin II formation. Studies in healthy volunteers maintained on a low-salt diet indicate that such pathways account for approximately 30-40% of total angiotensin II formation, and this figure increases to 60-70% in individuals maintained on a high-salt diet (resembling the situation in most human populations). Activation of the renin-angiotensin system is increased in diabetic patients, and comparison of the renal vascular responses to captopril and candesartan shows a strong correlation between the effects of ACE inhibition and AT(1)-receptor blockade, indicating that the deleterious effects of renin-angiotensin system activation in diabetes are mediated largely through angiotensin II. The presence of multiple risk factors, such as genetic predisposition, hyperglycaemia, obesity and tissue damage, places diabetic patients at high risk of disease related to activation of the renin-angiotensin system. Effective and early blockade of this system is therefore an important aspect of management.

Angiotensin Receptor Antagonists↗
PubMed2002

Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan.

AIM: Our recent studies revealed a striking but variable enhancement of renal vasodilator responses to blockers of the renin-angiotensin system in subjects with diabetes mellitus, possibly reflecting the level of intrarenal activation of the renin-angiotensin system, and thus a risk of nephropathy. As obesity is a common finding in diabetic individuals, and obesity has been linked to an increase in plasma angiotensinogen levels, we enrolled diabetic subjects with a wide range of body mass index (BMI) for this study. METHODS: Twelve Type 2 diabetic subjects in balance on a low sodium diet participated after baseline renal plasma flow and glomerular filtration measurements were made. Each subject then received 150 mg irbesartan, and renal function was measured every 45 min for 4 h. RESULTS: The average vasodilator response to irbesartan was 174 +/- 33 ml/min. No correlation was found between renal plasma flow response to irbesartan and duration of diabetes, baseline glucose, or HbA1c level. BMI, our measure of obesity, was highly correlated to the renal response to irbesartan (r = 0.7; P = 0.01). CONCLUSIONS: Our findings suggest an important role for obesity in activating the intrarenal renin system, perhaps via production of angiotensinogen. BMI may be an indicator of risk of nephropathy.

Adult↗
PubMed2001

Angiotensin receptor blockers in diabetic nephropathy.

Where shall we place angiotensin receptor blockers in the scheme of the prevention of diabetic nephropathy? Only the results of a large, randomized double-blind trial with a comparable and appropriate alternative would prove therapeutic efficacy. The results of several trials with angiotensin-converting enzyme (ACE) inhibitors have proven them to be the standard of care for diabetics and their kidneys. As reviewed in this article, the results of three large such clinical trials have recently been completed with angiotensin receptor blockers in patients with type 2 diabetes mellitus. Initial results appear favorable. However, whether angiotensin blockers have more to offer than ACE inhibitors is still speculative. The renin-angiotensin system plays an important role in the pathogenesis of diabetic nephropathy. Since alternative pathways to ACE have been uncovered in the formation of angiotensin II, inhibition at the final end point would provide favored blockade. Because angiotensin receptor blockers do provide this specific blockade, they offer far more promise than ACE inhibitors.

Angiotensin II↗
PubMed2001

Familial factors in the antihypertensive response to lisinopril.

BACKGROUND: Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS: This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS: Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION: Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.

Adolescent↗
PubMed2001

Renal implications of angiotensin receptor blockers.

The role of the renin-angiotensin system (RAS) in the regulation of blood pressure and the pathogenesis of both hypertension and renal complications involves an intricate interplay of genetic and environmental factors. In the case of diabetic nephropathy, the genes governing the RAS are an obvious choice in the search for contributing factors. These genetic components can reflect polygenetic mechanisms or a major gene effect. During recent years, polymorphisms of the genes governing both angiotensin converting enzyme (ACE) and angiotensinogen have been studied, with varying outcomes. Investigation of the interaction between ACE inhibition and the glycemic state yields equally interesting results. In healthy subjects on a high salt diet, the hyperglycemic state produced significant increases in renal plasma flow (RPF) in response to administration of the ACE inhibitor captopril. A similar study using the angiotensin receptor blocker (ARB) eprosartan demonstrated again that the agent had little effect on RPF in subjects in a normal glycemic state; however, when administered during a hyperglycemic state, a marked increase in RPF occurred. Implications for the prevention of nephropathy and endstage renal disease (ESRD) in diabetics with hypertension are significant. Until recently, pharmacologic intervention in the RAS has focused on the ACE step, with documented success being reported in the prevention of diabetic nephropathy and ESRD using ACE inhibitors. Despite this success, data suggest that greater therapeutic benefit might be accomplished by blocking the deleterious effects of angiotensin II at the receptor site. From a renoprotective perspective, the ARB appear to have tremendous potential in the management of hypertension.

Angiotensin Receptor Antagonists↗
PubMed2001

Renal perfusion and function in healthy African Americans.

BACKGROUND: Despite their increased risk of nephropathy, remarkably little is known about renal perfusion and function in healthy African Americans. METHODS: We enrolled 32 healthy African Americans and compared renal perfusion and function in 82 age-matched healthy Caucasians. Studies were performed on a diet containing 200 mmol of sodium and 100 mmol of potassium per day. In a separate study of 28 subjects, 10 African American and 18 Caucasians, the contribution of the renin-angiotensin system was assessed by measuring renal hemodynamic responses to angiotension II (Ang II) and captopril. RESULTS: Although glomerular filtration rate (GFR) was similar, renal plasma flow (RPF) was significantly less in age-matched African Americans (568 +/- 18) than Caucasians (620 +/- 13 mL/min/1.73 m(2), P = 0.0063). After captopril, African Americans had a sevenfold greater vasodilator response and a rise in RPF (35.3 +/- 4.9 vs. 4.9 +/- 12.4 mL/min/1.73 m(2) in African Americans and Caucasians, respectively, P < 0.028). Ang II administration caused a significantly smaller vasoconstrictor response in African Americans (Ang II-induced fall in RPF, -97 +/- 18 vs. -150 +/- 9 mL/min/1.73 m(2), P = 0.05), and angiotensin-converting enzyme (ACE) inhibition enhanced the response to Ang II in African Americans significantly. CONCLUSIONS: A reduction in RPF, blunting of the renal vascular response to Ang II, and an accentuated renal vasodilator response to captopril, which in turn corrects the blunting of responsiveness to Ang II, all suggest activation of the renin system in apparently healthy African Americans. As PRA was identical in Caucasians and African Americans, the findings suggest that it is the intrarenal-renin system that is activated in African Americans. This difference in normal control mechanisms could predispose to nephropathy.

Adult↗
PubMed2001

Renal vascular responses to captopril and to candesartan in patients with type 1 diabetes mellitus.

BACKGROUND: Enhanced renal vasodilator responses to angiotensin-converting enzyme (ACE) inhibition in diabetes mellitus despite a normal or low plasma renin activity level have suggested intrarenal activation of the renin-angiotensin system in this disease. There is, however, a continuing debate as to the mediators of the renal hemodynamic response to ACE inhibition-reduced angiotensin II formation or pathways involving kinins, prostaglandins, and nitric oxide. METHODS: Twelve patients with type 1 diabetes mellitus of 18 +/- 3.2 (SEM) years of duration (7 females and 5 males, ages 17 to 50, 32 +/- 4.0 years) who were free of sustained microalbuminuria and on a high-salt diet were given the ACE inhibitor captopril (25 mg orally) on one day and the AT1 receptor blocker candesartan (16 mg orally) on another day. Renal plasma flow (RPF) and glomerular filtration rate were measured before and for four hours after administration. RESULTS: Both drugs caused a significant increase in RPF (captopril 574 +/- 26 to 625 +/- 37 mL/min/1.73 m2, P = 0.008; candesartan 577 +/- 26 to 643 +/- 37, P = 0.004). There was a highly significant correlation between the responses to captopril and to candesartan (r = 0.86, P < 0.001). Seven subjects had an RPF response to captopril that was accentuated (90 +/- 13 mL/min/1.73 m2), while five had a response that was normal (-4 +/- 9). There was no significant change in glomerular filtration rate on either drug. CONCLUSION: The remarkable rise in RPF in response to captopril and candesartan despite high-salt balance suggests the intrarenal activation of the renin-angiotensin system in diabetes that is not reflected in plasma renin levels. The high correlation between the renal hemodynamic response to captopril and to candesartan indicates that reduced angiotensin II formation is the main mechanism of action of the ACE inhibitor.

Adult↗
PubMed2001

Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake.

OBJECTIVE: Homeostasis Model Assessment (HOMA index) is predictive of insulin sensitivity in normal and diabetic patients. This study was designed to see if insulin resistance in hypertensives, measured using the HOMA index, differs, based on salt sensitivity, renin status and sodium intake. METHODS: Fasting insulin and glucose were determined in subsets of 426 essential hypertensives, and normotensives. HOMA was calculated as fasting glucose (mmol) x fasting insulin (muU/ml)/22.5. RESULTS: Four hundred and twenty-six essential hypertensives and normotensives from four HERMES centers form the basis of this report. There was no difference in the HOMA index between hypertensives and normotensives (P= 0.291) or between hypertensives grouped according to blood pressure salt sensitivity (P = 0.153). However, when essential hypertensives were subgrouped by renin status, the low-renin group had significantly lower (P< 0.01) HOMA index than the normal/high-renin group. When normal/high-renin group was divided into modulators and non-modulators, the nonmodulators had significantly higher HOMA index (P< 0.001) than other hypertensive subsets. The effect of sodium intake on the HOMA index was significant only for non-modulators (P< 0.002), with salt restriction increasing insulin resistance. CONCLUSION: Insulin sensitivity differs among subsets of essential hypertension, non-modulators being most insulin resistant and the low-renin subset insulin sensitive. Salt restriction might have an adverse effect on insulin sensitivity in non-modulators. The reduction in cardiovascular risk seen in low-renin hypertensives may be related to their increased insulin sensitivity; in contrast, the clustering of cardiovascular risk factors seen in nonmodulators may be due to increased insulin resistance.

Adult↗
PubMed2001

Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism.

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na(+) intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (P=0.0001). Blacks, on the other hand, showed no gender difference (P=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.

Adrenal Glands↗
PubMed2001

Is there a future for renin inhibitors?

Pharmacological interruption of the renin-angiotensin system is possible at three major sites, the angiotensin-converting enzyme (ACE), the AT1 receptor and at the interaction of renin with its substrate, angiotensinogen. Skeggs and his associates in 1957 argued logically but without prognostic accuracy that 'since renin is the initial and rate-limiting substance in the renin-angiotensin system, it would seem that the renin inhibition approach would be the most likely to succeed'. In fact, the development of agents that act at all three levels has enjoyed substantial success, yet renin inhibition, which showed early progress in studies in humans, has languished. Our task in this essay is to review the reasons for the slow evolution of renin inhibition and to discuss the potential of such agents in modern pharmacotherapy. All of the structure-action relationships have involved variation on the original peptide structure. The possibility that alternative approaches based on x-ray crystallography and reconstruction of the structure of the active site would lead to novel agents, appears not to have been explored systematically. This opportunity is all the more attractive because renin is one of the few targets that is actually soluble and amenable to x-ray crystallographic studies. At the moment, it appears that all renin inhibitor development programs have been closed, although hints periodically reappear to indicate that one company or another is pursuing a novel agent. The decision to close programs seems to have reflected not the therapeutic potential of renin inhibitors, but rather the cost of their synthesis, continuing problems with bioavailability and the remarkable success of the competitor class--the AngII antagonists. We believe that the potential of renin inhibition in human therapy has been under estimated and still shows substantial promise.

Angiotensin Receptor Antagonists↗
PubMed2001

Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man.

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30-40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165+/-14 mL/min/1.73 m2) significantly exceeded the response to captopril (118+/-12 mL/min/1.73 m2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97+/-20 mL/min/1.73 m2) also significantly exceeded the response to captopril on the same diet(30+/-15 mL/min/1.73 m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet,when compared with the response to captopril,suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60-70% range.

Adult↗
PubMed2001

Potential of the angiotensin II receptor 1 blocker eprosartan in the management of patients with hypertension or heart failure.

When angiotensin-converting enzyme (ACE) inhibition first became available to block the renin system, few could have predicted the evolution that would occur in this field. The advent of angiotensin II receptor 1 (AT(1)) blockers has created new opportunities. These agents, including eprosartan, are extraordinarily well tolerated, not only when compared with antihypertensive agents but also in comparison with the ACE inhibitors, which are rather well tolerated. The AT(1) blocker class is growing rapidly, at least in part because many believe that these drugs will share with the ACE inhibitors the special ability to reduce morbidity and mortality. Does eprosartan have a special role within this class? Eprosartan differs structurally from the other AT(1) blockers in that it is not a biphenyl tetrazole. It differs functionally in vitro in being a pure competitive antagonist, as opposed to the nonequilibrium, insurmountable characteristics of the other blockers. This feature may prove to be useful for titration in the fragile patient. The reduction in catecholamine release induced by eprosartan that has been observed in animal models may account for some special examples of increased efficacy. One such example pertains to the difference in the dose-response relationship for the action of eprosartan on the renal blood supply in comparison with other AT(1) blockers. Eprosartan doses well below those required for control of blood pressure have a pronounced effect on the kidney. If research already under way supports these early suggestions, then eprosartan will be an important addition to our therapeutic armamentarium.

Acrylates↗
PubMed2000

Medical therapy, symptoms, and the distress the cause: relation to quality of life in patients with angina pectoris and/or hypertension.

BACKGROUND: Adverse events during drug therapy can be assessed through measurement of 2 features: their frequency and their severity. Their severity, in turn, can be measured by assessing the distress that they cause. Our goal was to relate the magnitude of the distress induced by treatment with calcium-channel blocking agents to the change in quality of life assessed through psychosocial instruments in patients treated with calcium-channel blocking agents, either for hypertension or for angina pectoris. METHODS: Four hundred seventy-five patients with angina pectoris were randomized to double-blind treatment with PPR (physiological pattern release) verapamil hydrochloride, amlodipine besylate, amlodipineatenolol combination, or placebo. In addition, 557 hypertensive patients were randomized either to PPR verapamil or nifedipine GITS (gastrointestinal system). Both studies were double-blind. RESULTS: Significant differences in treatment of angina pectoris or hypertension, were not found between the regimens. Overall quality of life also failed to show a significant difference in either group. In both groups, however, remarkable concordance was found between the degree of distress associated with specific symptoms and a change in quality of life. An unchanged, stable symptom distress was associated with a significant improvement in the quality of life of about 0.1 SD. Improvement or erosion of symptom distress represented by 1 step was associated with a 0.1- to 0.2-SD change. The extreme change in symptom distress was associated with a substantially larger change in global quality of life. CONCLUSIONS: The magnitude of symptom distress or relief associated with symptoms in 2 patient populations correlated strongly with a shift in quality of life. The assessment of distress associated with symptoms provides valuable additional information on drug therapy.

Adult↗