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N K Hollenberg

Publications and source records attributed to N K Hollenberg.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of ACE inhibition on pressor, renal vascular, and adrenal responses to infusion of angiotensin I in normal subjects eating a low-salt diet.

To examine the influence of angiotensin-converting enzyme (ACE) on pressor, renal vascular, and adrenal responses during angiotensin I (Ang I) infusion, we studied 10 normotensive, healthy men. Each was in balance with a 10-mEq sodium, 100-mEq potassium intake and was studied before and during ACE inhibition with enalapril. Ang I (3, 10, and 30 ng/kg/min) was infused in each subject. Then ACE inhibition was instituted with enalapril for 3 days, which induced the anticipated fall in blood pressure, plasma Ang II, and aldosterone concentration, and rise in renal plasma flow. During ACE inhibition only the 30-ng/kg/min Ang I dose raised plasma Ang II levels. There was a spectrum, however, in the end-organ response to Ang I during ACE inhibition. Responses of plasma aldosterone concentration and blood pressure were in excellent accord with the reduction in Ang II formation. On the other hand, responses of the renal blood supply were substantially less inhibited than anticipated. Under the conditions of this study, ACE inhibition led to nonuniform changes in the response to exogenous Ang I, suggesting intrarenal conversion of Ang I to Ang II.

Adolescent↗
PubMed2000

Effects of gender and genotype on the phenotypic expression of nonmodulating essential hypertension.

Nonmodulation describes a subset of the normal/high renin essential hypertensive population. It is an inherited trait. This report reviews the genetic and gender data recently available that discuss the modification of the expression of the nonmodulating phenotype. Both the adrenal and the renal blood flow markers for nonmodulation are associated with a single nucleotide polymorphism (SNP) in the coding region of the angiotensinogen gene at codon 235. Even though the nonmodulating phenotype is associated with a somatic gene, gender modifies its expression. In women, the expression of the nonmodulating phenotype is approximately half of that in men. Additional analysis suggests that this gender difference is almost entirely explained by a difference in the frequency of nonmodulation in younger premenopausal women. In older, likely postmenopausal women, there is no gender difference. This suggests that the expression of the nonmodulating phenotype, presumably secondary to changes in the expression of the angiotensinogen gene, is modulated by female sex hormones.

Female↗
PubMed2000

Impact of angiotensin II on the kidney: does an angiotensin II receptor blocker make sense?

The renin-angiotensin system (RAS) regulates blood pressure, volume, and electrolyte balance. Derangements of the RAS may contribute to hypertension and renal injury, particularly in patients with types 1 or 2 diabetes. Angiotensin-converting enzyme (ACE) inhibitors have been proven to be beneficial in patients with hypertension and diabetes by preventing or delaying the development and progression of proteinuria and glomerulosclerosis. Comparisons with other drug classes demonstrate renoprotective effects for ACE inhibitors that are independent of-and additive to-their systemic antihypertensive actions. These renal effects may derive from their preferential dilation of renal efferent arterioles, which further reduces intraglomerular pressure. Inhibition of angiotensin II (Ang II) synthesis is subtotal, however, because local non-ACE enzymes also convert Ang I to Ang II. The existence of alternative pathways for Ang II generation that are unaffected by ACE inhibitors raises questions about whether ACE is the optimal target for RAS suppression. Ang II receptor blockers (ARBs), which interrupt the RAS at the target-organ receptor level, will block the effect of angiotensin whether its production involved ACE or a non-ACE pathway. ARBs are currently undergoing clinical trials to assess their efficacy in hypertensive patients with nephropathy.

Angiotensin II↗
PubMed2000

What does the future hold? ACE inhibition, angiotensin II receptor blockade, and diabetic nephropathy.

The influence that ACE inhibition has had on the natural history of cardiovascular and renal disease is remarkable, exceeding the expectations of even the most optimistic adherents. With the development of AngII antagonists, the mechanism by which ACE inhibitors reduce tissue injury has become an important problem. If the ACE inhibitors had their useful action through non-angiotensin-dependent mechanisms such as reduced kinin degradation, then AngII antagonist will not prove as useful. Conversely, if the major influence of the ACE inhibitors reflected a reduction in AngII formation, then the AngII antagonists will show real promise not only in matching the influence of the ACE inhibitors, but perhaps exceeding their ability to influence natural history, because the AngII antagonists will block non-ACE pathway-dependent AngII generation.

Angiotensin Receptor Antagonists↗
PubMed2000

Implications of species difference for clinical investigation: studies on the renin-angiotensin system.

The justification for clinical investigation has its roots in the fact that physiological mechanisms and disease pathogenesis in animal models replicate mechanisms and pathogenesis in humans only in part. In the case of the renin-angiotensin system, there is species variation in the anatomic distribution of the renin-angiotensin system, in the active site of the renin enzyme, and in the structure of angiotensin and the AT(1) receptor. The conversion of angiotensin I (Ang I) to angiotensin II (Ang II) may prove to be the most important aspect of species variation. In plasma, all the conversion occurs through a single enzyme, angiotensin-converting enzyme (ACE), and species variation in structure and function have not been reported. Non-ACE-dependent pathways, which occur only at the tissue level, show unambiguous, striking species variation. Specifically, chymase, the most important enzyme responsible for non-ACE conversion of Ang I to Ang II, shows striking species variation. In humans and a number of species, including the hamster, quantitatively important chymase-independent Ang II formation from Ang I occurs in the heart, arteries, and kidney. In rats and rabbits, on the other hand, chymase differs, is not active in the conversion of Ang I to Ang II, and indeed is involved in Ang II degradation. Consequently, one would anticipate that blockade of the system at the ACE step would be equivalent to that at the Ang II receptor in the rat. This has been widely reported. In humans, on the other hand, one would anticipate that the AT(1) receptor blockers will be more effective than ACE inhibitors. Again, preliminary evidence favors this possibility. The implications for therapeutics are clear.

Animals↗
PubMed2000

Effect of angiotensin II antagonist eprosartan on hyperglycemia-induced activation of intrarenal renin-angiotensin system in healthy humans.

We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria ( approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1. 73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.

Acrylates↗
PubMed2000

Renal hemodynamic and hormonal responses to the angiotensin II antagonist candesartan.

The development of very specific blockers for the angiotensin II type 1 (AT(1)) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT(1) receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33+/-2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142+/-13 mL. min(-1). 1.73 m(-2)) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3+/-1.6 ng. L(-1). s(-1); 55.0+/-5.6 ng angiotensin I. mL(-1). h(-1)) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non-ACE-dependent angiotensin II generation in the kidney.

Adult↗
PubMed2000

Application of supercritical fluid chromatography to characterize a labile digitalis-like factor.

A sodium pump inhibitor (digitalis-like factor), isolated from the peritoneal dialysate of volume-expanded, hypertensive patients with kidney failure who were treated with this dialysis modality, was further purified and characterized by means of supercritical fluid chromatography, a separation technique whose application to very-low-concentration biomolecules is new. Previous studies suggested that after high-performance liquid chromatography (HPLC) purification, this inhibitor was the only factor correlated with volume status and blood pressure in these patients. When this same HPLC fraction was furthered purified on 2-dimensional supercritical fluid chromatography, a single peak coeluted with [Na,K]ATPase inhibitory activity. When split specimens were used, there was a strict correlation between the peak area, measured by flame ionization detection, and activity (n=10, R=0.98, P=0.00001). Inhibitory activity after supercritical fluid chromatography was still correlated with the degree of volume expansion of donor patients (P=0.01). After HPLC purification, this volume-sensitive inhibitor was chemically labile. With further purification on supercritical fluid chromatography, the active peak was still labile with comparable half-life. Supercritical fluid chromatography coupled with flame ionization detection provided an estimate of the amount of the inhibitor present. Again using split specimens, we determined that the labile digitalis-like factor was approximately 30-fold more effective than ouabain in inhibiting renal [Na,K]ATPase activity and >/=500 times more effective than ouabain in causing vascular smooth muscle contraction. The data suggest that we have purified to homogeneity a labile digitalis-like factor that is readily distinguished from ouabain or bufalin, based on chromatographic characteristics, chemical lability, and a much lower effective concentration for its biological activity.

Cardenolides↗
PubMed2000

Sodium-dependent calcium release from vascular smooth muscle mitochondria.

Interest in mitochondrial calcium (Ca2+) uptake and release waned as it became apparent that sarcoplasmic reticulum calcium stores dominate the control of cytoplasmic calcium concentration. Our recent demonstration of a very large rise in vascular smooth muscle (VSM) cytoplasmic sodium (Na+) concentration after inhibition of the sodium, potassium-ATPase (sodium pump) led us to several questions. Do VSM mitochondria show Na(+)-dependent Ca2+ release? Are the documented changes in cytoplasmic Na+ concentration sufficient to cause Ca2+ release? Do features of the cardiac mitochondrial exchange system, including differential sensitivity to a number of calcium antagonists and cation specificity, apply to VSM? We isolated mitochondria from bovine aorta and mesenteric arteries and employed arsenazo III as the Ca2+ indicator. Mitochondria from arterial vessels accumulated added calcium (up to 50 nmol Ca2+/mg protein) and released Ca2+ on exposure to Na+. This concentration-dependent relationship was linear from 0 to 10 mM of Na+, and it plateaued between 20 mM and 40 mM of Na+. VSM mitochondria exposed to 20 mM Na+ released 118 +/- 25 nmol Ca2+ per mg mitochondrial protein in 20 min, when a new equilibrium was reached. Lithium (Li+), in contrast to Na+, produced much smaller amounts of Ca2+ release from the VSM mitochondria. Na+-dependent Ca2+ release was antagonized in a concentration-dependent manner by diltiazem (0-320 microM) with a Ki of 10.2 microM. Nifedipine had a lesser effect, and verapamil produced almost no inhibition. VSM mitochondria responses resemble those from heart mitochondria in that Na+-dependent Ca2+ release is present with a similar range of sensitivity to Na+ and a similar pattern of influence of diltiazem, nifedipine and verapamil. However, the influence of Li+ on Ca2+ release was much smaller and the amount of the Ca2+ released was much greater for VSM mitochondria compared with that reported for heart mitochondria. The large amount of Ca2+ released and the range of Na+ concentration that provoked Ca2+ release being within the physiologically achievable range raise the interesting possibility that these mechanisms may modify intramitochondrial cytosolic Ca2+ concentration, and hence could potentially contribute to the contractile response that follows inhibition of the sodium pump.

Animals↗
PubMed2000

The past, present and future of hypertension management: a potential role for AT(1)-receptor antagonists.

The benefits of effective antihypertensive treatment were established at least 40 years ago, but despite the availability of more reliable and better-tolerated antihypertensive drugs, the control of blood pressure remains poor in most patients. Long-term antihypertensive efficacy requires treatment that combines reliable 24-hour reduction of blood pressure with good tolerability to facilitate patient compliance. Treatment should also protect against target-organ damage. As the majority of negative cardiovascular effects of angiotensin II are mediated through the angiotensin II type 1 (AT(1)) receptor, specific blockade of this receptor is a rational approach for achieving these ideals. Several AT(1)-receptor blockers have been developed that combine antihypertensive efficacy and placebo-like tolerability - the latter being unique in the history of antihypertensive therapy. In experimental animals these drugs prevent or reverse target organ damage in the heart, the vasculature and the kidney. Ongoing large-scale outcome studies are now underway to establish the benefits of AT(1)-receptor blockade beyond blood pressure control.

Angiotensin Receptor Antagonists↗
PubMed2000

Blunted suppression of plasma renin activity in diabetes.

We have documented, contrary to expectation, that the renin-angiotensin-aldosterone system (RAAS) is stimulated normally by restriction of sodium intake inpatients with Type 2 diabetes mellitus (DM) and hypertension. Conversely, plasma renin activity (PRA)is suppressed less than in normal subjects by a high-salt diet in these patients. Increasing plasma angiotensin II (Ang II) concentration through intravenous Ang II infusion also suppresses renin release, via the short feedback loop. In this study, we sought to ascertain whether the limited renin suppression in Type 2 diabetes mellitus via high-salt intake is a unique defect or part of a more generalised abnormality of PRA suppression. We studied 38 patients with Type 2 DM and hypertension, 158 hypertensive control patients, and 61 normotensive controls. All patients were studied while in metabolic balance on a 10 mEq sodium (Na) diet. The response to the Ang II infusion at 3 ng/kg/min for 45 minutes was measured. We found that PRA fell significantly in normal subjects, from 4.0 +/- 0.33 to 2.5 +/- 0.23 ngAngI/ml/hr (p=0.0056). In patients with essential hypertension, the Ang II infusion also led to a fall in PRA from 3.51 +/- 0.23 to 2.76 +/- 0.17 ng Angl/ml/hr(p=0.014). In patients with DM, despite a similar basal PRA (3.7 +/- 0.40 ng AngI/ml/hr), the infusion of Ang II did nor influence PRA significantly (3.43 +/- 0.42ng AngI/ml/hr; p > 0.77), though these patients had the most robust mean arterial pressure response. Our data are in complete accord with the concept of high intrarenal Ang II in DM and suggest lower systemic Ang II despite comparable PRA.

Adult↗
PubMed2000

The renin-angiotensin system and cardiovascular disease.

Suppression of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors is an established method for controlling blood pressure and reducing the risk of cardiovascular disease. In addition to reducing blood pressure, suppression of the RAS is able to protect against the target-organ damage that results from hypertension. Unfortunately, despite the use of ACE inhibitors and agents from the other classes of conventional antihypertensives, effective control of blood pressure remains poor. A major contribution to this failure to control blood pressure appears to be lack of compliance with the prescribed medication, arising from the presence of unacceptable side effects. Angiotensin II type 1 (AT1) receptor blockers, such as candesartan, are the latest class of antihypertensive agent to be developed. They target the AT1-receptor - the final common pathway for all the known negative cardiovascular effects of angiotensin II - and provide pronounced antihypertensive efficacy without the side effects of cough and angioneurotic oedema that are associated with the use of ACE inhibitors.

Angiotensin Receptor Antagonists↗
PubMed1999

Physical Symptoms Distress Index: a sensitive tool to evaluate the impact of pharmacological agents on quality of life.

OBJECTIVES: To examine whether the degree of stress associated with adverse physical side effects correlates with overall quality of life (QOL) and compliance rates. To determine if instruments used to assess QOL can detect differences between treatments that have no known central nervous system effects. PATIENTS AND METHODS: This randomized, double-blind, parallel group study evaluated 180 to 480 mg of controlled onset, extended release (COER)-verapamil (n = 259) or 30 to 120 mg/d of nifedipine gastrointestinal therapeutic system (GITS) (n = 269) in men and women between 21 and 80 years of age with stages 1 to 3 hypertension. A battery of questions evaluating psychological well-being and a physical symptom distress index was administered after a 4-week placebo washout (baseline) and after 10 weeks of treatment or at dropout. RESULTS: Both treatments effectively lowered blood pressure, and there were no significant between-group differences in psychosocial QOL. A difference in the level of physical symptom distress was detected between treatments (P = .002; multivariate analysis of variance), with 7 significant univariate treatment effects, all favoring COER-verapamil, being noted-pedal edema, polyuria, rapid heart beat or palpitations, hives, muscle cramps, abdominal cramps, and headaches. Constipation-related distress increased significantly (P = .001) but to a similar extent with both treatments. The difference in symptom distress tended to predict compliance as there were more withdrawals in the nifedipine GITS group (n = 85) vs COER-verapamil group (n = 64) (P = .08). CONCLUSIONS: Patient-assessed physical symptom distress is a sensitive, simple technique to evaluate the effect of antihypertensive medications on QOL and tolerability, as shown by its ability to detect the improvement associated with COER-verapamil. Depending on the agents involved, the Physical Symptom Distress Index may more closely predict dropout rates than the traditional psychosocial instruments, as suggested by the lower dropout rate in the COER-verapamil group. Thus, in studying treatment effects on QOL, both the distress of physical symptoms and the impact of psychosocial factors should be evaluated.

Adult↗
PubMed1999

Renal response to captopril reflects state of local renin system in healthy humans.

BACKGROUND: Heightened activity of the renin-angiotensin system has been linked to the development of both essential hypertension and diabetic nephropathy. Blunting of the renal vasoconstrictor response to Ang II, specifically when it is corrected by angiotensin converting enzyme (ACE) inhibition, is a feature which we have employed as a marker for activation of the intrarenal RAS. In this study we tested the hypothesis that variation in the renal vasodilator response to ACE inhibition in healthy humans reflected the variation in angiotensin-mediated renal vasoconstriction provoked by a low-salt diet. METHODS: We studied 20 healthy people (ages 19 to 57; 15 males) who were in balance on a low sodium diet. Ang II was infused for 45 minutes (3 ng/kg/min), followed by 25 mg captopril and a repeat Ang II infusion; PAH clearance was measured at the end of each interval. RESULTS: All subjects responded to captopril with a rise in renal plasma flow (range 43 to 242, mean 118 + 12 ml/min/1.73 m2). Individual vasodilator response to captopril was a strong inverse predictor of the precaptopril vasoconstrictor response to Ang II (P = 0.006, r = -0.59). There was a stronger, positive correlation of the vasodilator response to captopril and enhancement of Ang II responsiveness after captopril (r = 0.57). Plasma renin activity was significantly correlated with captopril response among the large responders (P = 0.003; r = 0.83), but not at all among those with little response. CONCLUSION: These results suggest substantial variation in angiotensin-mediated control of the renal circulation in healthy individuals on a low sodium intake. Variation in the vasodilator response to captopril, correlated with responses to Ang II, provides a measure of that control.

Adult↗
PubMed1999

Age, renal perfusion and function in island-dwelling indigenous Kuna Amerinds of Panama.

BACKGROUND/AIMS: Among possible contributors to a progressive fall in renal perfusion and function with increasing age, some hypotheses have invoked the rise in blood pressure that occurs with age, and a high-protein diet typical of urban cultures. Kuna Amerinds residing in isolated islands off the Panamanian Coast have a very low protein intake and show no tendency for blood pressure to rise with age, thus providing an opportunity to test these hypotheses. METHODS: We measured renal plasma flow and glomerular filtration rate (PAH and inulin clearance) in 16 Kuna Indians ranging in age from 18 to 86 years (51 +/- 6 years) who have resided on Ailigandi, an isolated Panamanian island for all of their lives. Inulin and PAH were infused with a battery-driven pump for 60 min, and a metabolic clearance rate used to calculate inulin and PAH clearance. For comparison, we employed identical techniques in 29 residents of Boston, ranging in age from 19 to 79 years (52 +/- 4 years), all normotensive and free of disease or medication use. Twenty-four were Caucasian. RESULTS: The Bostonian controls showed the anticipated fall in PAH clearance with age (y = 806 - 4.9 x; r = -0.82; f = 38.0; p < 0.0001). Our hypothesis was that the absence of a blood pressure rise with age and the low protein intake would flatten the slope relating renal perfusion to Kuna age. Our finding was a numerically steeper slope relating age and renal plasma flow in the Kuna (y = 936 - 6.48x; r = -0.81; p < 0.001). Filtration fraction rose with age in both populations, and again the rise was steeper in the Kuna. GFR in the Kuna, on the other hand, was very much higher at any age (139 +/- 4 ml/min/1.73 m2) than in Bostonians (112 +/- 3 ml/min/1.73 m2; p < 0.001). CONCLUSION: The findings are not in accord with the hypothesis that age-related changes in renal perfusion and glomerular filtration rate reflect an important contribution from blood pressure rise and a high protein intake, typical of modern, urban life.

Adolescent↗
PubMed1999

Hyperglycemia and angiotensin-mediated control of the renal circulation in healthy humans.

Type 1 and type 2 diabetics have an enhanced renal vasodilator response to angiotensin-converting enzyme (ACE) inhibition despite suppressed plasma renin activity (PRA), indicating possible activation of the intrarenal renin angiotensin system. To investigate the role of hyperglycemia, we evaluated the renal hemodynamic response to ACE inhibition in 9 healthy subjects in high-salt balance after steady-state hyperglycemia (8.4+/-1 mmol/L) was achieved via intravenous glucose administration. Renal plasma flow (RPF) and glomerular filtration rate (GFR) responses to captopril and to angiotensin II (Ang II) were measured as paraminohippuric acid and inulin clearances. Hyperglycemia produced a significant increase in RPF of 117 mL. min-1. 1.73 m-2 after 90 minutes but not GFR. Administration of captopril at a dose of 25 mg during glucose infusion led to an increase in RPF of 173+/-24 mL. min-1. 1.73 m-2 (P<0.01) but did not significantly change RPF in the absence of hyperglycemia (7+/-21 mL. min-1. 1.73 m-2). Captopril did not alter GFR in the presence or absence of hyperglycemia. Ang II infusion during hyperglycemia decreased RPF by 45+/-16 mL. min-1. 1. 73 m-2, and this was significantly enhanced by captopril (-98+/-26 mL. min-1. 1.73 m-2, P<0.05). In contrast, there was no enhancement of the vasoconstrictor response to Ang II in the absence of hyperglycemia. PRA did not change with hyperglycemia. Enhancement of renal vasodilation during hyperglycemia by captopril without alteration of PRA suggests activation of the intrarenal renin angiotensin system.

Adult↗