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N K Hollenberg

Publications and source records attributed to N K Hollenberg.

At least 19 recordsLinked to original sources
PubMed1992

Evolution of the treatment of hypertension: what really matters in the 1990s?

Over the past decade we have seen a shift in the strategy for the treatment of hypertension, from stepped therapy--involving a highly structured, unvarying series of steps--to recommendations for more individualized treatment. How shall we accomplish that goal? Severe hypertension provides a clear indication to bypass earlier recommendations. Demographic data such as age, gender, and race, often cited, have proved less helpful. Concomitant medical problems, which are found in greater than 50% of hypertensive patients, are most often the crucial determinants in the selection of antihypertensive therapy. Concurrent coronary artery disease, diabetes mellitus, heart failure, azotemia, asthma, chronic obstructive pulmonary disease, borderline cognitive dysfunction, anxiety, and depression are all common. Each has implications for antihypertensive therapy. Moreover, blood pressure reduction is a surrogate for our real goal, which is reduction of cardiovascular risk. Thus, consideration of concomitant medical problems has extended to left ventricular hypertrophy, obesity, hyperlipidemia, and insulin resistance as additional risk factors in hypertension. Consideration of all of these factors makes it possible to individualize antihypertensive therapy in most patients.

Age Factors↗
PubMed1992

Renal and adrenal responsiveness to angiotensin II: influence of beta adrenergic blockade.

The increase in aldosterone secretion that occurs in response to Angiotensin II (AII) is enhanced when normal humans are in external balance on a low salt diet. The responsible mechanism has not been identified. Angiotensin converting enzyme inhibition reduces blood levels of AII and aldosterone, but does not decrease PRA or AI and does not modify adrenal responsiveness to AII in the sodium-depleted state. This study was designed to assess the possibility that the enhanced adrenal response reflects plasma renin activity (PRA), plasma AI concentration, or catecholamines acting via a beta adrenergic receptor. Nine healthy males were studied when in balance on a high sodium intake (200 mmol Na/day), a low sodium diet (10 mmol Na) and after 4 days of beta adrenergic blockade with either nadolol or propranolol. The adequacy of beta adrenergic blockade was assessed with a postural stimulus and significant blockade was achieved, somewhat more with nadolol (40 mg/day) than with propranolol (Inderal LA, 80 mg every 12 hrs). Beta blockade enhanced the renal vascular and pressor response to AII but did not modify the adrenal response to posture or to AII. This study confirms the role for AII levels in the modulation of renal vascular and pressor responses to AII and rules out a role for PRA, AI, or catecholamines acting via a beta adrenergic receptor in the modulation of adrenal responsiveness to AII.

Adrenal Glands↗
PubMed1992

Arterial response to ketanserin and aspirin in patients with advanced peripheral atherosclerosis.

BACKGROUND: In advanced atherosclerosis, endothelial lesions and turbulent flow in stenotic vessels result in platelet aggregation with the liberation of vasoactive factors, including thromboxane A2 and serotonin. This study was designed to assess the combined effect of these factors on arterial dimensions at the time of limb angiography in patients with advanced peripheral vascular disease. METHODS: Diameter changes of 53 segmental stenosis of large arteries were measured in digitized angiograms by a computerized objective method in response to either placebo (13 segments in 7 patients), ketanserin (23 segments in 23 patients), or ketanserin superimposed on aspirin (17 segments in 7 patients). Responses of arterial collaterals were evaluated by a coded assessment. Statistically significant vasodilatation was observed in both the stenotic and post-stenotic segments of the large arteries only when serotonin-2 receptor blockade with ketanserin and cyclo-oxygenase inhibition with aspirin were combined. RESULTS: In the area of the stenosis and in the post-stenotic segment diameter increased 8.2% +/- 2.3% (P = .032) and 7.3% +/- 1.3% (P less than .001), respectively, when aspirin was combined with ketanserin. Significant changes did not occur in either the placebo group or in the group receiving only ketanserin. In the area of stenosis, there was a good correlation between the relative baseline narrowing of the vessel and its vasodilatation after combined ketanserin and aspirin (r = .689; P = .002). Vasodilatation at the level of arterial collaterals also was significantly more pronounced when the combination was used (P less than .001). CONCLUSIONS: These findings suggest a component of vasoconstriction related to the deposition of activated platelets in stenotic segments of the large arteries in atherosclerosis.

Adult↗
PubMed1992

Treatment of hypertension: the place of angiotensin-converting enzyme inhibitors in the nineties.

The past decade has seen a shift in the strategy for hypertension treatment from stepped therapy--a highly structured monolithic series of steps--to recommendations for a more individualized selection of treatment. Severe hypertension is a clear indicator to bypass traditional steps. Demographic factors, such as age, gender, and race, are often cited, but have proved to be less helpful. Concomitant medical conditions and problems are very common and are more often the crucial determinants in the selection of antihypertensive therapy. Coronary artery disease, diabetes mellitus, heart failure, azotemia, asthma, and chronic obstructive pulmonary artery disease, anxiety, and depression are all common, and each has implications for the selection of antihypertensive therapy. Blood pressure reduction is a surrogate for reduction of cardiovascular risk, and therefore, consideration of concomitant medical problems has extended to left ventricular hypertrophy, obesity, mild hyperlipidemia, and insulin resistance, as additional risk factors in hypertension. Consideration of all these factors makes it possible to individualize antihypertensive therapy in most patients today.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Effect of CLS 2210 (calcium dobesilate) on survival and myocardial infarction size in the rat: influence of dose and duration of treatment.

CLS 2210 (calcium dobesilate) has been shown to reduce the volume of myocardium infarcted after coronary artery occlusion in the dog. This study, in rats, was designed to determine whether CLS 2210 would reduce mortality and infarct size after coronary occlusion. Another goal was to ascertain whether a duration of administration exceeding 6 h improves survival. Experiments were performed in rats with myocardial infarction induced by coronary artery ligation. In one series, rats were blindly randomized into four groups receiving, over a period of 6 h, either 200, 400 or 800 mg/kg of CLS 2210 or a placebo. In a second series, the animals were randomized to receive as initial dose a bolus of either 50 mg/kg of CLS 2210 by intravenous infusion or placebo followed by 25 mg/kg/h of the same drug or placebo over 24 h: mortality and infarct size were assessed after 24 h. A third series of rats received the same dosage schedule of CLS 2210 or placebo, but mortality was evaluated after 1 week, to ascertain whether CLS 2210 merely postponed death. Our first goal in this study was to ascertain whether CLS 2210 would improve survival after coronary artery occlusion in the rat. In the placebo group, death occurred in 61 of 112 rats (54.5%). In the CLS-2210-treated group, mortality was sharply reduced, to 68 of 182 (37.3%; p less than 0.01). Mortality in rats receiving CLS 2210 for 6 h was significantly lower, 35.6%, when compared to the placebo which was 51.9% (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Non-modulation as an intermediate phenotype in essential hypertension.

Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1992

"Tissue need" and limb collateral arterial growth. Skeletal contractile power and perfusion during collateral development in the rat.

Among the factors that might influence collateral arterial growth after arterial occlusion, the capacity to deliver blood flow in relation to metabolic need and work performance are obvious candidates. In this study in rats after superficial femoral artery ligation, we assessed collateral arterial growth (by arteriography), basal and peak limb blood flow during acetylcholine-induced vasodilation (by electronic drop counting), pressure-flow relations, and contractile power of the gastrocnemius muscle (force transduction during sciatic nerve stimulation) at intervals over 3 months after superficial femoral artery ligation. Basal and peak blood flow and muscle contractile power were clearly reduced 1 week after ligation but had returned to normal by 3 weeks. Major collateral arterial growth, however, progressed between 3 weeks and 3 months. The limb perfusion pressure-blood flow relation was still altered at 3 weeks, with blunting of the normal autoregulation, and became more normal by 3 months after superficial femoral artery ligation. Collateral arterial growth continues after blood flow adequate to maintain work performance has been restored and may reflect a response to more subtle abnormalities involving distal pressure delivery, evident in altered pressure-flow relations.

Angiography↗
PubMed1992

Abnormal norepinephrine and aldosterone responses to upright posture in nonmodulating hypertension.

The subgroup of patients with nonmodulating hypertension demonstrates a number of abnormalities of the renin-angiotensin-aldosterone axis. We previously identified abnormalities in plasma and urinary dopamine in nonmodulators and posited that this may be in part due to a generalized defect in sympathetic nervous system activity. In the present study we assessed the state of activation of the renin-angiotensin system and the sympathetic nervous system in normal subjects and patients with modulating, nonmodulating, and low renin essential hypertension during sodium depletion and change from supine to upright posture. Levels of plasma norepinephrine were higher in non-modulators during the posture study (P < 0.05). PRA rose with upright posture in all groups, but low renin subjects had a blunted response. Nonmodulators and low renin subjects had lower aldosterone levels both supine (P< 0.05) and upright (P< 0.01). However, the aldosterone/PRA increment ratio was increased in low renin subjects (P< 0.01), whereas it was decreased in nonmodulators. Twenty-four-hour urine collections for catecholamine determinations were obtained in a subgroup of the subjects, with nonmodulators showing higher levels of norepinephrine excretion which approached significance (P = 0.08). In vitro experiments using rat and human adrenal glomerulosa cells showed that norepinephrine does not affect aldosterone secretion per se. These observations extend the series of abnormalities observed in nonmodulating hypertension. However, it is likely that the alterations in norepinephrine levels during sodium depetion and upright posture are a secondary event and not linked to the altered aldosterone production in these patients.

Adult↗
PubMed1991

Management of hypertension and cardiovascular risk.

Blood pressure reduction in hypertensive patients is a surrogate for the real therapeutic goal of reducing the risks consequent to hypertension. This surrogate is convenient but its use may have important therapeutic implications. Results of treatment with new antihypertensive agents, data from clinical trials, and insights into underlying mechanisms are reviewed. The overall success of antihypertensive therapy has been undeniable, but has reduced minimally the frequency of atherosclerosis and coronary events; metabolic disarray resulting from the agents used, especially thiazides and beta blockers, may have contributed to this. Electrolyte abnormalities predispose to malignant arrhythmias and sudden death during myocardial infarction. Left ventricular hypertrophy, a chief risk factor for coronary events, arrhythmias, and heart failure, responds selectively to antihypertensive agents. Similarly, progression of renal injury may be sensitive to the agents used. Obesity and hypertension frequently coexist. Evidence is growing that atherogenic abnormalities common in obese patients, such as insulin resistance, also occur in the nonobese patient and are sensitive to the antihypertensive agent selected.

Adrenergic beta-Antagonists↗
PubMed1991

Variation in apparent serum digitalis-like factor levels with different digoxin antibodies. The "immunochemical fingerprint".

Increased levels of a circulating digoxin-like factor (DLF) occur in a number of physiologic states in which sodium homeostasis is altered, and may contribute to the pathogenesis of hypertension. We exploited the different affinities for DLF of seven antisera directed at digoxin to develop an immunochemical profile, and then employed this index to address two questions: does the same DLF species exist in several conditions associated with increased DLF levels, including pregnancy, renal failure, hepatic failure, and neonatal cord blood? Will this approach prove useful in assessing candidates proposed to be DLF? An identical profile was identified in serum from pregnant women and patients with renal or hepatic failure, and a highly significant correlation existed between DLF levels measured with antisera of high and intermediate affinity in 42 subjects with increased levels (r = 0.93; P less than .001). In patients with renal failure, when endogenous DLF levels were too low to assess the profile, concentration of the serum resulted in measurable DLF levels that had an identical profile. The profile was somewhat altered in umbilical cord blood, perhaps reflecting an influence of increased steroid hormone levels. Among agents suggested as candidates for DLF, neither lysophosphatidylcholine nor ouabain showed a profile resembling DLF. Progesterone, 17-OH-progesterone, and bufalin, on the other hand, did show substantial similarity, perhaps providing a clue to the structure of DLF. The normal plasma levels of progesterone and 17-OH-progesterone are 100- to 1000-fold too low to be candidates for DLF and bufalin was sufficiently dissimilar not to be a candidate. DLF in at least three different patient populations probably represents identical chemical species.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed1991

Embolization of platelets after endothelial injury to the aorta in rabbits. Assessment with 111indium-labeled platelets and angiography.

This study exploits the ability of a collateral arterial network to trap platelet aggregates in order to document the frequency of macroembolization in rabbits after endothelial damage. Two weeks after ligation of the right superficial femoral artery, endothelial injury was induced in the distal aorta; within 3 hours the rabbits were studied using either angiography or 111indium-labeled (111In) platelet scintigraphy. Angiography indicated visible aggregates in the thigh region in eight of 19 and arterial occlusion in three of 19 rabbits. The collateral-dependent thigh also showed more 111In-labeled platelet activity than the contralateral side (P less than .001), whether platelets were injected before or 2 hours after injury. Radioactivity in the limbs of rabbits with no injury was distributed symmetrically. Blood pool volume, assessed with technetium-99m-labeled red blood cells, was the same in both thighs, and could not account for these observations. The findings indicate that platelet activation and aggregation after endothelial injury lead to microembolization much more frequently than it leads to macroaggregate formation and visible artery occlusion.

Animals↗
PubMed1991

Constrictive effect of serotonin on visible renal arteries: a pharmacoangiographic study in anesthetized dogs.

Serotonin (5HT) has been implicated in the pathogenesis of several arterial disorders. Experimental intrarenal infusion of 5HT has produced initial decreases, and later sustained increases in total renal blood flow in the dog, and flow limiting renal artery spasm in other species. We assessed renal angiographic responses to 5HT infused into one renal artery of nine dogs before and after treatment with indomethacin (I). On blinded assessment of arteriograms, 5HT-induced narrowing was detected (p less than 0.001), and the effect was accentuated by I (p less than 0.001). Ketanserin (K), a 5HT-2 receptor antagonist, reversed the arteriographic vasoconstrictor effect of 5HT in five I-treated dogs (p less than 0.05). Linear cortical defects and decreased contrast intensity were seen in the nephrogram phase during 5HT infusion after I. This appearance resembled the arteriographic findings in hemorrhagic shock, suggesting profound impairment of renal cortical perfusion. This study suggests that 5HT constricts visible renal arteries via interaction with the 5HT-2 receptor, and that this in vivo effect is modified by arterial synthesis of vasodilator prostaglandins in the anesthetized dog.

Angiography↗
PubMed1991

Hypercholesterolemia enhances macrophage recruitment and dysfunction of regenerated endothelium after balloon injury of the rabbit iliac artery.

BACKGROUND: We studied the effects on and possible interaction of balloon denudation and hypercholesterolemia on large arteries in the rabbit with special regard to structure and vascular reactivity. METHODS AND RESULTS: New Zealand White rabbits fed a 1% cholesterol diet or a standard diet for 14 weeks underwent balloon denudation of the left iliac artery 4 weeks before death. Both the balloon-injured and the control iliac arteries were harvested for in vitro studies of vascular reactivity, for immunohistochemical staining with monoclonal antibodies directed at smooth muscle cells and macrophages, and for scanning electron microscopy. Balloon injury caused intimal smooth muscle proliferation with little macrophage infiltration and was followed by recovery of endothelium-dependent vasodilator function within 4 weeks. Hypercholesterolemia caused macrophage-rich lesions confined to the intima with moderate impairment of endothelial vasodilator function. Balloon injury in the setting of hypercholesterolemia caused intimal smooth muscle cell proliferation and intense macrophage infiltration throughout the arterial wall and severe impairment of endothelial vasodilator function. Scanning electron microscopy confirmed regrowth of the endothelium in all balloon-injured vessels. In the balloon-injured arteries of hypercholesterolemic animals, the regenerated endothelium exhibited areas of atypical morphology not seen after balloon injury or hypercholesterolemia alone. CONCLUSIONS: The present study shows that balloon injury, hypercholesterolemia, and their combination cause distinct lesions and functional disturbances. An arterial balloon injury in the setting of hypercholesterolemia produces a diffuse inflammatory response that is accompanied by a sustained impairment of endothelial function and a marked proliferative response.

Animals↗
PubMed1991

Functional derangements in the regulation of aldosterone secretion in hypertension.

Excess production of aldosterone secondary to an adrenal tumor or bilateral hyperplasia is a known, but infrequent, cause of hypertension. A more frequent adrenal abnormality, observed in 30-40% of hypertensive patients, is a functional derangement in aldosterone secretion. Two such conditions have been described: low renin essential hypertension and non-modulating essential hypertension. Both have in common 1) an abnormality in the interaction of angiotensin II (Ang II) with the adrenal and 2) sodium sensitivity of the blood pressure. However, the pathophysiological mechanisms for the sodium sensitivity and hypertension are different. In normal subjects, the response of the adrenal glomerulosa cell to Ang II varies with the level of sodium intake, with sodium restriction enhancing the response. In one group of hypertensive patients with low plasma renin levels, the normally reduced aldosterone responses to Ang II on the high salt diet do not occur. Thus, these individuals have an enhanced adrenal response to Ang II under circumstances in which it should be reduced, thereby leading to lower renin levels and a tendency toward sodium retention. The second group has the opposite defect; that is, on a low sodium diet, they have a reduced adrenal response to Ang II. This results in a normal or high plasma renin level. The sodium sensitivity of their blood pressure arises not from the adrenal abnormality but from the associated defect in sodium-dependent, Ang II-mediated changes in renal blood flow. Thus, on a high salt diet, these patients, who are termed "non-modulators," fail to increase renal blood flow, thereby leading to a sodium-retaining state.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1991

Implications of thrombosis and vasospasm in peripheral vascular disease.

Platelet activation releases not only thromboxane A2 but also serotonin, another vasoconstrictor agent that acts on blood vessels through a specific, 5-HT2 receptor. The development of ketanserin, the selective 5-HT2-receptor blocker, has made it possible to explore the role of serotonin in animal models and patients with endothelial injury and atherosclerotic disease. In animals models, growing collateral arterial vessels are exquisitely sensitive to the vasoconstrictor effects of serotonin, which are reversed by ketanserin. When endogenous platelet activation is induced by endothelial injury, a combination of ketanserin and a thromboxane synthesis inhibitor or antagonist is more effective at reversing collateral arterial vasoconstriction than either agent alone. More recently, studies at the time of angiography in humans with advanced atherosclerosis have shown that more than 50% display a dilator response to ketanserin in low doses: the response primarily involves dilatation of collateral arterial vessels, which is associated with a significant increase in calf blood flow. These findings support existing evidence that platelet products contribute to the ischemia syndromes due to atherosclerosis, and provide a promising approach to improved management.

Animals↗
PubMed1991

The kidney in hypertension: treatment strategies.

As in any patient with hypertension, the first goal in the hypertensive patient with renal disease is to control the hypertension. The second goal is to reduce overall cardiovascular risk, which includes an increased likelihood of coronary events. The third goal is to minimize the likelihood that renal disease will progress, or minimize the rate of progression. There is substantial evidence to indicate that control of hypertension, however achieved, will slow the rate of progression of renal injury and destruction. Studies in animal models have indicated that angiotensin-converting enzyme inhibitors are more consistent in preventing progressive renal injury, and perhaps have a more sustained action than standard agents employed hitherto. In the patient with a clear indication for beta-adrenergic blockade, such as a prior coronary event or angina pectoris, a beta-adrenergic blocking agent should be employed. Preliminary, but intriguing, evidence is available to suggest that a beta-adrenergic blocking agent that incorporates a vasodilator action may enjoy special benefits in terms of achieving the three goals. In the case of renal injury, completion of the studies required to prove this point will improve our ability to deal with the problem of hypertension in the patient with renal disease.

Adrenergic beta-Antagonists↗