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Biomedical subjects

Norman K Hollenberg

Publications and source records attributed to Norman K Hollenberg.

At least 19 recordsLinked to original sources
PubMed2006

Prorenin and angiotensin-dependent renal vasoconstriction in type 1 and type 2 diabetes.

Prorenin is a powerful marker for risk of nephropathy and retinopathy in diabetes, but the responsible mechanism remains unclear. Studied were 35 patients with diabetes (18 with type 1 and 17 with type 2) and 69 age-matched healthy subjects with para-aminohippurate and inulin clearances and their response to captopril. All patients with diabetes had normal renal function and no microalbuminuria. Prorenin was calculated as the difference between total renin and active renin. Active renin level in patients with diabetes (11.6 +/- 0.9 microU/ml) was significantly lower than in normal subjects (14.5 +/- 1.3 microU/ml; P < 0.05); despite this, the renal vascular response to captopril was much larger (82.9 +/- 11.5 versus 13.6 +/- 5.8 ml/min per 1.73 m(2); P < 0.01). Prorenin in both patients with type 1 and type 2 diabetes (175.7 +/- 15.1 microU/ml) also was significantly higher than in normal subjects (128 +/- 5.8 microU/ml; P < 0.01). Active renin correlated with prorenin in normal subjects (r = 0.44, P = 0.0002), and this correlation was much more striking in patients with diabetes (r = 0.72, P = 0.0001). The active renin and prorenin correlation was identical in type 1 and type 2 diabetes. There was a clear correlation between plasma prorenin and the renovascular response to captopril in patients with diabetes (P < 0.01) but not in normal subjects (P > 0.13). The strong correlation between plasma prorenin concentration and the renovascular response to captopril in diabetes supports the hypothesis of a direct effect of prorenin, but the unanticipated high degree of correlation between plasma prorenin and active renin limits the conclusions that can be drawn.

Adult↗
PubMed2006

(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans.

Epidemiological and medical anthropological investigations suggest that flavanol-rich foods exert cardiovascular health benefits. Endothelial dysfunction, a prognostically relevant key event in atherosclerosis, is characterized by a decreased bioactivity of nitric oxide (NO) and impaired flow-mediated vasodilation (FMD). We show in healthy male adults that the ingestion of flavanol-rich cocoa was associated with acute elevations in levels of circulating NO species, an enhanced FMD response of conduit arteries, and an augmented microcirculation. In addition, the concentrations and the chemical profiles of circulating flavanol metabolites were determined, and multivariate regression analyses identified (-)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as independent predictors of the vascular effects after flavanol-rich cocoa ingestion. A mixture of flavanols/metabolites, resembling the profile and concentration of circulating flavanol compounds in plasma after cocoa ingestion, induced a relaxation in preconstricted rabbit aortic rings ex vivo, thus mimicking acetylcholine-induced relaxations. Ex vivo flavanol-induced relaxation, as well as the in vivo increases in FMD, were abolished by inhibition of NO synthase. Oral administration of chemically pure (-)-epicatechin to humans closely emulated acute vascular effects of flavanol-rich cocoa. Finally, the concept that a chronic intake of high-flavanol diets is associated with prolonged, augmented NO synthesis is supported by data that indicate a correlation between the chronic consumption of a cocoa flavanol-rich diet and the augmented urinary excretion of NO metabolites. Collectively, our data demonstrate that the human ingestion of the flavanol (-)-epicatechin is, at least in part, causally linked to the reported vascular effects observed after the consumption of flavanol-rich cocoa.

Administration, Oral↗
PubMed2006

Nonmodulation and essential hypertension.

Nonmodulation is a process in which there is a disorder in angiotensin-dependent control of the renal circulation and adrenal aldosterone release. The abnormalities are associated with an inability to handle a sodium load and salt-sensitive hypertension. All of the features are corrected by angiotensin-converting enzyme inhibition. A striking family history of hypertension and concordance of responses to angiotensin II in sibling pairs have suggested a familial factor. Genes governing renin substrate (angiotensinogen) production showed gene polymorphisms in nonmodulators. As nonmodulation occurs in approximately 40% of patients with essential hypertension, clearly other genes must contribute.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

The influence of dietary sodium on blood pressure.

The goal of this essay is to examine the evidence relating salt intake to blood pressure in humans. Despite studies involving many thousands of subjects and patients performed in many hundreds of centers the issue remains controversial-indeed far more controversial than seems appropriate. There is little disagreement that in some animal models and in some patients with hypertension salt intake can exert a rather substantial influence. There is more controversy on the responsible mechanisms. The greatest controversy, by far, involves whether or not policy should involve a mandatory reduction in salt intake in all members of the community. The available evidence shows that the influence of salt intake is too inconsistent and generally too small to mandate policy decisions at the community level. At the level of the individual patient and that patient's physician, it is important to recognize that salt intake can make a substantial contribution to hypertension. That contribution is more likely if the patient is old rather than young, obese rather than lean, black rather than white, has diabetes mellitus with hypertension, or has evidence of renal injury. Unfortunately, tools for assessing the sodium and chloride intake in the individual and for assessing its contribution to BP in the individual are inadequate. On the bright side, prognosis is improved substantially by the array of antihypertensive drugs available today.

Animals↗
PubMed2006

Vascular action of cocoa flavanols in humans: the roots of the story.

Diet patterns are widely recognized as contributors to hypertension. Widely studied potential contributors include intake of sodium, potassium, magnesium, calcium, soluble fiber, omega-3 fatty acids, alcohol, protein, and calories. We add to that list the effect of dietary flavanols present in certain cocoas, which have sufficient activity on vascular nitric oxide to influence blood pressure control. Kuna Indians who live on islands near Panama have little age-related rise in blood pressure or hypertension. On migration to Panama City, blood pressure rises with age, and the frequency of essential hypertension matches urban levels elsewhere. We have identified a specific food that probably makes an important contribution to cardiovascular status. Island-dwelling Kuna drink more than 5 cups of flavanol-rich cocoa per day and incorporate that cocoa into many recipes. Mainland Kuna ingest little cocoa, and what they take is commercially available and flavanol-poor. The flavanol-rich cocoa activates nitric oxide synthase in vitro and in intact humans in the doses that the Kuna employ. Vasodilator responses to flavonoid-rich cocoa are prevented or reversed by the arginine analog, N-nitro-L-arginine methyl ester. Island-dwelling Kuna have a 3-fold larger urinary nitrate:nitrite than do Mainland dwellers. As endothelial dysfunction is central to current thinking on cardiovascular pathophysiology, a food that enhances endothelial function could have broad implications. The list of candidate conditions that might be influenced is impressive, ranging from atherosclerosis and diabetes mellitus to hypertension and preeclampsia, to vascular dementias and end-stage renal disease. The next decade will be interesting.

Aging↗
PubMed2006

Hypertension, the Kuna, and the epidemiology of flavanols.

A low sodium diet has often been implicated in the protection of low blood pressure populations from hypertension, but several other dietary factors, including those as yet unidentified, may also be involved. The Kuna Indians of Panama are free of hypertension and cardiovascular disease, but this is changing with migration to urban areas. We compared the indigenous diet of Kuna Indians living on remote islands in Panama (Ailigandi), whose lifestyle is largely hunter-gatherer, with those who have moved to a suburb of Panama City (Vera Cruz). Between April and October 1999, members of a Kuna research team administered a 118-item food frequency questionnaire to133 adult Kuna from Ailigandi and 183 from Vera Cruz. Single 24-hour urine collections and nonfasting blood samples were obtained. The Kuna in Ailigandi reported consuming a 10-fold higher amount of cocoa-containing beverages, 4 times the amount of fish, and twice the amount of fruit as urban Kuna (P<0.05 by t test). Salt added was ample among those living in Ailigandi and Vera Cruz according to both self-report (7.1+/-1.1 and 4.6+/-0.3 tsp weekly) and urinary sodium levels (177+/-9 and 160+/-7 mEq Na/g creatinine), respectively. The low blood pressure of island-dwelling Kuna does not seem to be related to a low salt diet. Among dietary factors that varied among migrating Kuna, the notably higher intake of flavanol-rich cocoa is a potential candidate for further study.

Acculturation↗
PubMed2006

Cocoa flavanols and brain perfusion.

Foods and beverages rich in flavonoids are being heralded as potential preventive agents for a range of pathologic conditions, ranging from hypertension to coronary heart disease to stroke and dementia. We and others have demonstrated that short-term ingestion of cocoa, particularly rich in the subclass of flavonoids known as flavanols, induced a consistent and striking peripheral vasodilation in healthy people, improving endothelial function in a nitric oxide-dependent manner. The vasodilator response was reversed by N-nitro-L-arginine methyl ester, an arginine analog that blocks nitric oxide synthesis. Flavanol-poor cocoa induced much smaller responses. Because impairment of endothelial function is a nearly universal accompaniment of the aging process, we examined the peripheral vasodilator response to flavanol-rich cocoa in healthy older subjects. Observations point to a favorable response among the older. Together with peripheral vascular disease, cerebrovascular disease is responsible for significant mortality with advancing age. An association of decreased cerebral perfusion with dementia has been recently highlighted. The prospect of increasing cerebral perfusion with cocoa flavanols is extremely promising. Our still preliminary data hold out the promise that the cerebral blood supply in the elderly participates in the vasodilator response. With the modalities of transcranial Doppler and MRI, we have the capabilities of analyzing the potential benefits of flavanols on brain perfusion and, subsequently, on cognition.

Aged↗
PubMed2006

Renin inhibition with aliskiren: where are we now, and where are we going?

With the development of aliskiren, blockade of the renin-angiotensin-aldosterone system (RAAS) at the level of the interaction of renin with a substrate has become a clinical reality. This review covers the specific features of the first agent likely to achieve widespread clinical exposure, aliskiren. The potential of renin inhibition must be viewed in the context of the remarkable efficacy of both angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockers (ARBs). The implications of blockade of the renin system at its rate-limiting step are reviewed, with the therapeutic implications for both the renin inhibitor employed alone or the renin inhibitor combined with an ACE inhibitor or ARB. The relevant and necessary studies are ongoing.

Amides↗
PubMed2006

Diabetes, nephropathy, and the renin system.

Blockade of the renin-angiotensin system has become crucial in the management of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, especially in patients who are at risk of nephropathy. In this review, we address the issue of why the renin system and its blockade are so important. As in many complex processes, diabetic nephropathy reflects an interaction between genetic factors and environmental factors. Recent research has uncovered a number of environmental factors; control of these factors should contribute to improved management. The renin system is important in patients with diabetes mellitus because so many relevant factors converge on the intrarenal renin system.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Aging and vascular responses to flavanol-rich cocoa.

OBJECTIVES: Strong evidence has secured aging as a powerful predictor of both cardiovascular risk and endothelial dysfunction, yet specific treatment is not available. We tested the hypothesis that vascular responsiveness to flavanol-rich cocoa increases with advancing age. We have previously shown that flavanol-rich cocoa induced peripheral vasodilation, improving endothelial function via a nitric oxide (NO)-dependent mechanism. METHODS: We studied blood pressure and peripheral arterial responses to several days of cocoa in 15 young (< 50 years) and 19 older (> 50) healthy subjects. RESULTS: The nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine-methyl-ester (L-NAME) induced significant pressor responses following cocoa administration only among the older subjects: systolic blood pressure (SBP) rose 13 +/- 4 mmHg, diastolic blood pressure (DBP) 6 +/- 2 mmHg (P = 0.008 and 0.047, respectively); SBP was significantly higher in the older subjects (P < 0.05). Flow-mediated vasodilation, measured by tonometry in the finger, was enhanced with flavanol-rich cocoa in both groups, but significantly more so among the old (P = 0.01). Finally, basal pulse wave amplitude (PWA) followed a similar pattern. Four to six days of flavanol-rich cocoa caused a rise in PWA in both groups. At peak vasodilation following acute cocoa intake on the final day, both groups showed a further, significant rise in PWA. The response in the older subjects was more robust; P < 0.05. L-NAME significantly reversed dilation in both groups. CONCLUSIONS: Flavanol-rich cocoa enhanced several measures of endothelial function to a greater degree among older than younger healthy subjects. Our data suggest that the NO-dependent vascular effects of flavanol-rich cocoa may be greater among older people, in whom endothelial function is more disturbed.

Adolescent↗
PubMed2006

Organ systems dependent on nitric oxide and the potential for nitric oxide-targeted therapies in related diseases.

Nitric oxide (NO) is a universal messenger molecule that plays diverse and essential physiologic roles in multiple organ systems, including the vasculature, bone, muscle, heart, kidney, liver, and central nervous system. NO is produced by 3 known isoforms-endothelial, neuronal, and inducible NO synthase-each of which perform distinct functions. Impairment of NO bioactivity may be an important factor in the pathogenesis of a wide range of conditions, including preeclampsia, osteoporosis, nephropathy, liver disease, and neurodegenerative diseases. Although increased levels of NO synthase or NO bioactivity have been associated with some of these disease states, research increasingly suggests that preservation or promotion of normal NO bioactivity may be beneficial in reducing the risks and perhaps reversing the underlying pathophysiology. Based on this rationale, studies investigating the use of NO-donating or NO-promoting agents in some of these diseases have produced positive results, at least to some degree, in either animal or human studies. Further investigation of NO-targeted therapies in these diverse diseases is clearly mandated.

Alzheimer Disease↗
PubMed2006

Effects of the PPAR-gamma agonist rosiglitazone on renal haemodynamics and the renin-angiotensin system in diabetes.

BACKGROUND: Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS. We aimed to determine if the TZD rosiglitazone could reduce RAS activation. METHODS: We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months. We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed. RESULTS: The RPF response to ACE inhibition was not altered. There was no change in GFR, PRA, active renin and aldosterone levels. Two patients developed oedema one had an elevated baseline active renin and another had an elevated baseline aldosterone level. CONCLUSION: The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.

Adult↗
PubMed2005

Body mass index and angiotensin-dependent control of the renal circulation in healthy humans.

Obesity is increasingly recognized as a risk factor for renal disease, but the mechanism is unclear. Renal plasma flow response to captopril, as an index of renin-angiotensin system activity, was measured by para-aminohippurate clearance technique in 100 healthy, normotensive subjects in balance on a high-salt diet. Of the 100 subjects, body mass index exceeded 25 in 56 and exceeded 30 in 22. The average vasodilator response to captopril was 27+/-7 mL/min per 1.73 m2 (P<0.0001). After adjustment for other predictors of the renal plasma flow response to captopril using a multivariate linear regression model, there was a highly significant relationship between age- and plasma renin activity-adjusted body mass index and the renal plasma flow response to captopril; however, a quadratic model provided a substantially better fit (r=0.55; P<0.0001; P=0.03 versus linear correlation). The strong association between increasing body mass index and angiotensin-dependent control of the renal circulation suggests that this may be a mechanism by which obesity contributes to renal disease. Weight loss should be considered in the overweight or obese patient for renal protection.

Adult↗
PubMed2005

Renin inhibition: what are the therapeutic opportunities?

Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has become a crucial element in cardiovascular and renal medicine. This review evaluates the potential of renin inhibition as an adjunct to therapies that depend on renin system interruption.

Dipeptides↗
PubMed2005

The role of beta-blockers as a cornerstone of cardiovascular therapy.

The beta-adrenergic blockade as a therapeutic approach first emerged in the 1950s. During the past five decades, the total number of indications that have been suggested, and the remarkable number approved by regulatory agencies, places beta-blockade far ahead of all competing treatments, not only in the cardiovascular area, but in all of therapeutics. Differentiation of beta-adrenergic blocking agents has been made on the basis of beta1 selectivity, duration of action, intrinsic sympathomimetic activity, lipophilicity, and whether or not the beta-adrenergic blocking action is accompanied by an alpha-adrenergic blocking action. With the development of nebivolol, a beta-adrenergic blocking agent that also activates nitric oxide synthase in blood vessels, comes a new therapeutic option. Endothelial dysfunction with loss of nitric oxide production is a common feature in many cardiovascular diseases. This fascinating class of drugs continues to provide us with new and important therapeutic opportunities.

Adrenergic beta-Antagonists↗