Differential effect of acute baroreceptor unloading on cardiac and systemic sympathetic tone in congestive heart failure.

OBJECTIVES: The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF). BACKGROUND: We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF. METHODS: We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [+/-SEM] pulmonary artery pressure 46 +/- 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP). RESULTS: SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 +/- 1.7 to 11.2 +/- 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 +/- 86 to 409 +/- 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 +/- 1.3 to 4.9 +/- 0.9%, p < 0.001). CONCLUSIONS: There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.

Antiadrenergic effect of chronic amiodarone therapy in human heart failure.

OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.

Dietary supplementation with L-arginine fails to restore endothelial function in forearm resistance arteries of patients with severe heart failure.

OBJECTIVES: We sought to examine the efficacy of dietary supplementation of L-arginine on endothelium-dependent vasodilation in patients with congestive heart failure. BACKGROUND: Endothelial dysfunction, as evidenced by a diminished response to such vasodilators as acetylcholine, is well defined in patients with heart failure. These responses are improved by intraarterial infusion with L-arginine. Because L-arginine is a semi-essential amino acid, we investigated the effects of dietary L-arginine on endothelium-dependent vasodilation in these patients. METHODS: Twenty patients with heart failure (New York Heart Association functional class III/IV, mean [+/- SE] age 51.3 +/- 1.7 years) and seven healthy control subjects (mean age 52.6 +/- 3.3 years) were studied. All patients continued taking their usual treatment. Responses to acetylcholine and sodium nitroprusside were determined using forearm plethysmography. Patients with heart failure received either L-arginine (20 g/day every day for 28 days) or placebo (vehicle syrup in equal amounts) in a double-blind protocol. The calculated power of the study was between 62% and 80% to detect a 30% to 40% change in area under the dose-response (forearm vascular resistance) curve. RESULTS: Responses to acetylcholine, but not to sodium nitroprusside, were significantly attenuated in patients with heart failure compared with control subjects (mean area under curve [AUC], control subjects vs. patients with heart failure: 1,125.4 +/- 164.5 vs. 617.3 +/- 116.6 U, p < 0.05, by Student t test). A significant increase in urea and aspartate transaminase levels in patients receiving active L-arginine treatment was observed. Responses to acetylcholine (AUC; before vs. after L-arginine: 641.5 +/- 126.7 vs. 695.9 +/- 151.9 U) and sodium nitroprusside were not affected by either L-arginine or placebo. CONCLUSIONS: Endothelial dysfunction was apparent in patients with heart failure despite rigorous vasoactive treatment. Oral administration with L-arginine was ineffective in influencing endothelial function in these patients.

Adverse consequences of high sympathetic nervous activity in the failing human heart.

OBJECTIVES: In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. BACKGROUND: Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. METHODS: Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. RESULTS: The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study. CONCLUSIONS: These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.

Hormonal therapy increases arterial compliance in postmenopausal women.

OBJECTIVES: This study investigated the effects of hormonal therapy on large arterial properties. BACKGROUND: Arterial stiffness is an emerging risk marker for coronary heart disease and is potentially modifiable. Postmenopausal use of hormonal therapy is associated with a lower risk of coronary heart disease. METHODS: Total systemic arterial compliance (SAC) and pulse wave velocity (PWV) were determined in 26 premenopausal and 52 postmenopausal women, 26 of whom were taking hormonal therapy. RESULTS: Arterial compliance was greater in the premenopausal group (mean +/- SEM 0.57 +/- 0.04 arbitrary compliance units [ACU]) than in the postmenopausal group not taking hormonal therapy (0.26 +/- 0.02 ACU, p = 0.001). Postmenopausal women taking hormonal therapy had a significantly increased total SAC compared with women not taking hormonal therapy (0.43 +/- 0.02 vs. 0.26 +/- 0.02 ACU, p = 0.001). PWV in the aortofemoral region in the premenopausal women was 6.0 +/- 0.2 vs. 8.9 +/- 0.3 m/s (p < 0.001) in untreated postmenopausal women. However, postmenopausal women taking hormonal therapy had a significantly lower PWV than those not taking hormonal therapy (7.9 +/- 0.2 vs. 8.9 +/- 0.3 m/s, p = 0.01). Eleven postmenopausal women had their hormone replacement therapy withdrawn for 4 weeks, resulting in a significant decrease in SAC and a significant increase in aortofemoral PWV. CONCLUSIONS: The increased SAC and decreased PWV in women receiving hormonal therapy suggest that such therapy may decrease stiffness of the aorta and large arteries in postmenopausal women, with potential benefit for age-related cardiovascular disorders. The reduction of arterial compliance with age appears to be altered with hormonal therapy.

Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks.

BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.

Low blood flow after angioplasty augments mechanisms of restenosis: inward vessel remodeling, cell migration, and activity of genes regulating migration.

-The predominant cause of restenosis after angioplasty is now thought to be inward remodeling, but the mechanisms responsible are unknown. Remodeling in normal vessels is regulated by the endothelium in response to altered shear stress. Although the endothelium is often damaged by angioplasty, restenosis rates after angioplasty have been correlated with impaired coronary flow. Thus, we examined how increases or decreases in blood flow through balloon catheter-injured rat carotid arteries affect vessel morphometry (4, 10, and 28 days), cell migration (4 days), and levels of promigratory mRNAs (2 and 10 days). After 28 days, the luminal area in vessels with low blood flow was significantly less than in those with normal and high blood flow (0.17+/-0.01 [low] versus 0.24+/-0.06 [normal] versus 0.30+/-0.02 [high] mm(2), P:<0.01), predominantly because of accentuated inward remodeling (or reduced area within the external elastic lamina; 0.42+/-0.02 [low] versus 0.54+/-0.07 [normal] versus 0.53+/-0.04 [high] mm(2), P:<0.05). Low flow also enhanced smooth muscle cell migration 4 days after injury by 90% above normal and high flows (P:<0.01). Two days after injury, low flow significantly increased levels of mRNAs encoding promigratory peptides (integrin alpha(v)ss(3), transforming growth factor-ss(1), CD44v6, MDC9, urokinase plasminogen activator receptor, and ss-inducible gene h3); these changes persisted 10 days after injury and were localized to the neointima. Low blood flow may promote restenosis after angioplasty because of its adverse effect on vessel remodeling, and it is associated with the augmented expression of multiple genes central to cell migration and restenosis.

Impaired contraction and relaxation in skin resistance arteries from patients with congestive heart failure.

OBJECTIVE: The aim was to determine the pharmacological reactivity of human small resistance arteries in patients with cardiac failure. METHODS: Small arteries (< 300 microns internal diameter) were removed from gluteal skin biopsy specimens and mounted in a double myograph for isometric force recording. RESULTS: Arteries from six patients with congestive heart failure contracted to only 65% of the maximum response recorded in nine arteries from normal volunteers when activated by potassium chloride (124 mM), noradrenaline (1 microM), or both. The lesser contraction in congestive heart failure vessels with no significant shift in sensitivity (EC50) was also observed in concentration-response studies with noradrenaline, angiotensin I, and angiotensin II. The concentration-contraction curves for serotonin showed only 40% of the maximum contractility to K+ in normal arteries, and this ratio was similar in congestive heart failure arteries. Normal arteries precontracted with noradrenaline (1 microM) relaxed in response to sodium nitroprusside, calcitonin gene related peptide, and the endothelium dependent agonist acetylcholine; in congestive heart failure vessels there was a marked loss of the relaxation response only to acetylcholine. CONCLUSIONS: These results suggest that in chronic congestive heart failure skin resistance arteries have impaired contraction responses probably independent of any receptor down regulation. The loss of endothelium dependent vasodilatation to acetylcholine suggests that EDRF release is impaired. These changes may well play an important role in the disturbances of peripheral vascular function associated with heart failure.

Spontaneous running increases aortic compliance in Wistar-Kyoto rats.

OBJECTIVE: Previous studies in humans have found, using non-invasive methodology, that arterial compliance is elevated with exercise training. Forced exercise in animals has corroborated these findings, but the association of this type of exercise with psychological stressors limits its relevance to humans. We have investigated the effects of spontaneous running exercise from 4-20 weeks of age on aortic and mesenteric compliance and vascular reactivity in Wistar-Kyoto (WKY) rats. METHODS: Animals were killed using CO2 asphyxia and the aorta, mesentery and heart rapidly removed. The heart was dissected and weighed. The aorta was separated into 3 4-mm rings which were mounted on wires in organ baths for determination of compliance and vascular reactivity to noradrenaline, acetylcholine and sodium nitroprusside. The slope of diameter-pressure relationship derived using Laplace's equation was used as an index of compliance. RESULTS: During the final 2 weeks of training WKY rats ran an average of 7.9 +/- 1.0 km/24 h. Body weight was not affected by training. Training significantly increased the weight of the atria, left and right ventricles as well as total heart weight and left ventricular/body weight ratio. Aortic compliance was increased from 12.3 +/- 0.4 to 14.2 +/- 0.5 microns/mmHg (P < 0.05) after training. There was no effect of training on aortic reactivity to noradrenaline, acetylcholine or sodium nitroprusside. CONCLUSION: Exercise training increased intrinsic aortic compliance in WKY rats which provides evidence for a structural basis for the elevated compliance reported previously with 4 weeks of aerobic exercise in man.

Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)-adrenergic receptors in the heart.

OBJECTIVE: To explore long-term cardiac phenotype in transgenic (TG) mice with 300-fold overexpression of beta(2)-adrenergic receptors (AR). METHODS: Echocardiography was performed serially on a cohort of wild-type and TG mice (n=26 each) between 4 and 15 months of age. Survival was monitored and autopsy and histological examinations were performed. RESULTS: Heart rate was higher in TG than in wild-type mice throughout the study period. The left ventricular dimensions and fractional shortening were similar between TG and wild-type groups during 4-6 months. Starting at 9 months, however, TG mice showed progressive reduction in fractional shortening and systolic wall thickening, and increase in left ventricular dimensions and left ventricular mass, indicating onset of heart failure, left ventricular hypertrophy and remodeling. Abnormal waveforms in the electrocardiogram and episodes of ventricular ectopic beats were also observed in TG mice. Death of TG mice started at 8.5 months, and the cumulative mortality was 81% by 15 months (P<0.0001 vs. 4% in wild-type mice). The majority of deaths were due to severe heart failure, indicated by cardiac dilatation, lung congestion, pleural effusion and atrial thrombus. Left ventricular sections showed widespread interstitial fibrosis, loss of myocytes and myocyte hypertrophy in TG mice. CONCLUSIONS: A high level of beta(2)AR overexpression results in cardiomyopathy and heart failure. The onset was slower and the expression levels of receptors required are much higher than previously described for the beta(1)AR overexpression.

Prevalence of cardiac structural and functional abnormalities in untreated primary hypertension.

We examined the prevalence of left ventricular structural and functional abnormalities in previously untreated subjects by performing echocardiography in 89 normal volunteers, 57 patients with established hypertension, and 38 patients with mild or borderline hypertension. We measured left ventricular mass, wall thickness, internal diameter, and wall thickness/radius ratio. Because of intergroup differences in body size, we used covariance analysis to index these variables to a common value of 1.8 m2. No adjustment was needed for the wall thickness/radius ratio. Functional variables determined were fractional shortening and transmitral early/late flow velocity ratio (the latter was standardized by analysis of covariance to age 40 years). The prevalence of left ventricular mass index values more than 2 SD above the mean of the normal group was 30% in the patients with established hypertension and 12-15% in the patients with mild hypertension. Corresponding figures for wall thickness index were 65% and 32% and for the wall thickness/radius ratio 60% and 40%. The prevalence of abnormality in the transmitral flow velocity was 28% in the patients with established hypertension and 12% in the patients with mild hypertension. A multivariate discriminant function that used combined anatomic and functional variables provided the most reliable classification; it was correct in 82% of normal subjects, 65% of patients with established hypertension, and 61% of patients with mild hypertension. The majority of patients with hypertension have cardiac structural or functional abnormalities, or both.

Estrogen enhances basal nitric oxide release in the forearm vasculature in perimenopausal women.

The mechanisms of estrogen-induced cardiovascular protection are incompletely understood. Acute estrogen administration enhances acetylcholine-induced vasorelaxation, suggesting that endothelium-dependent factors may be important. The effect of long-term estrogen supplementation on endothelial function has not been well defined. In this double-blind, randomized study, we examined endothelial function in forearm resistance arteries in 11 perimenopausal women before and after 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n = 6) or placebo (n = 5). Forearm blood flow was measured by venous-occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not influence blood pressure or heart rate. Estrogen supplementation significantly reduced systolic and diastolic pressures but had no effect on plasma lipoproteins. Estrogen did not alter the vasodilator responses to acetylcholine at doses of 9.25, 18.5, and 37 micrograms/min (rise in forearm blood flow before estrogen: 263 +/- 72%, 288 +/- 66%, and 383 +/- 84%, respectively; after estrogen: 205 +/- 34%, 260 +/- 44%, and 359 +/- 54%, P > .05.). Vasodilator responses to the endothelium-independent agent sodium nitroprusside (1.6 micrograms/min) were also unchanged after estrogen supplementation. However, estrogen enhanced vasoconstrictor responses to the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine at doses of 1, 2, and 4 mumol/min (fall in fore-arm blood flow before estrogen: 13 +/- 9%, 20 +/- 7%, and 26 +/- 8%, respectively; after estrogen: 18 +/- 9%, 36 +/- 7%, and 47 +/- 7%, P = .04). Responses to vasoactive agents were unchanged after administration of placebo. Thus, in perimenopausal women, estrogen supplementation reduces blood pressure and enhances basal but not acetylcholine-induced nitric oxide release in fore-arm resistance arteries.

Estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover in perimenopausal women.

Estrogens are reported to provide protection against the development of cardiovascular disease in women, but the mechanisms underlying these effects are not well defined. We hypothesized that estrogen might reduce neural cardiovascular tone. We therefore studied responses to exogenous norepinephrine and norepinephrine spillover in 12 perimenopausal women randomized to 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n=7) or placebo (n=5). Forearm blood flow was measured by venous occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not influence blood pressure or heart rate. Total body and forearm norepinephrine spillover were measured by radiotracer methodology. Forearm vasoconstrictor responses to norepinephrine (25, 50, and 100 ng/min) were attenuated after estrogen supplementation (P=.002). Vasoconstrictor responses to angiotensin II (8, 16, and 32 ng/min) were unchanged postestrogen. There was a significant reduction in total body spillover of norepinephrine after estrogen supplementation (pre-estrogen, 700+/-152; postestrogen, 439+/-150 ng/min; P<.05), but there was no change after placebo. Total body clearance and forearm spillover of norepinephrine were unchanged by either estrogen or placebo. Estrogen supplementation also significantly decreased both systolic and diastolic blood pressures. Therefore, estrogen supplementation in perimenopausal women selectively attenuates vasoconstrictor responses to norepinephrine and reduces total body norepinephrine spillover, which is an index of sympathetic neural activity.

Plasma norepinephrine responses to head-up tilt are misleading in autonomic failure.

The failure of plasma norepinephrine to rise during upright posture is accepted as a diagnostic sign of autonomic nervous failure in patients with postural hypotension. Our clinical experience has been that this test is misleading, with an increase in plasma norepinephrine commonly occurring. To test whether this might result from absent reflex postural venous constriction lowering cardiac output and plasma norepinephrine clearance, we measured norepinephrine plasma kinetics during recumbency and 30 degrees head-up tilting in six patients with pure autonomic failure and eight healthy subjects. Mean arterial pressure fell by 54 +/- 8 mm Hg with head-up tilt in the patients with pure autonomic failure. The plasma norepinephrine concentration (arterial sampling) increased 73 +/- 29 pg/ml (mean difference +/- SED, p less than 0.02), solely because of a 36% reduction in the clearance of norepinephrine from plasma (0.78 +/- 0.09 l/min, p less than 0.0001). In normal subjects, plasma norepinephrine concentration rose by 112 +/- 20 pg/ml (p less than 0.001), largely because of a 24% increase in norepinephrine spillover to plasma (190 +/- 20 ng/min, p less than 0.005). When the postural fall in blood pressure and cardiac output in the pure autonomic failure patients was prevented by the selective venoconstrictor dihydroergotamine (10 micrograms/kg i.v.), no fall in plasma clearance or rise in plasma concentration of norepinephrine occurred. Measurement of the change in plasma norepinephrine with postural stimulation in patients with orthostatic hypotension is not a reliable diagnostic test for autonomic failure because elevations can occur in the plasma concentration that are entirely attributable to reduced plasma norepinephrine clearance.

Exercise training lowers resting renal but not cardiac sympathetic activity in humans.

Endurance exercise training has previously been shown to reduce the plasma concentration of norepinephrine. Whether reduction in sympathetic activity is responsible for the blood pressure-lowering effects of exercise training is unknown. Using a radiotracer technique, we measured resting total, cardiac, and renal norepinephrine spillover to plasma in eight habitually sedentary healthy normotensive men (aged 36 +/- 3 years, mean +/- SEM) after 1 month of regular exercise and 1 month of sedentary activity, performed in a randomized order. One month of bicycle exercise 3 times/wk (40 minutes at 60-70% maximum work capacity) reduced resting blood pressure by 8/5 mm Hg (p less than 0.01) and increased maximum oxygen consumption by 15% (p less than 0.05). The fall in blood pressure was attributable to a 12.1% increase in total peripheral conductance. Total norepinephrine spillover to plasma was reduced by 24% from a mean of 438.8 ng/min (p less than 0.05). Renal norepinephrine spillover fell by an average of 41% from 169.4 ng/min with bicycle training (p less than 0.05), accounting for the majority (66%) of the fall in total norepinephrine spillover. Renal vascular conductance was increased by 10% (p less than 0.05), but this constituted only 18% of the increase in total peripheral conductance. There was no change in cardiac norepinephrine spillover. The reduction in resting sympathetic activity with regular endurance exercise is largely confined to the kidney. The magnitude of the fall in renal vascular resistance, however, is insufficient to directly account for the blood pressure-lowering effect of exercise, although other effects of inhibition of the renal sympathetic outflow may be important.

Increased norepinephrine spillover into the jugular veins in essential hypertension.

In essential hypertension sympathetic nerve firing is commonly increased. A central nervous system origin has been presumed but not tested directly. To estimate cerebral norepinephrine release in essential hypertension, spillover of norepinephrine into the cerebrovascular circulation was measured by isotope dilution, with high internal jugular venous sampling. Norepinephrine was released into the cerebrovascular circulation in both hypertensive patients and healthy volunteers and was present after administration of the ganglion blocker trimethaphan and in patients with sympathetic nervous failure, indicating that brain neurons and not cerebrovascular sympathetic nerves were the probable source. Although differing among hypertensive patients, norepinephrine spillover on average was higher in the hypertensive patients (153 +/- 41 pmol/min) than in healthy subjects (59 +/- 12 pmol/min; p less than 0.05), and was elevated in six of 17 patients, in whom the accompanying whole body norepinephrine spillover rate was higher than in the remaining 11 patients (p less than 0.01). To test for a possible link between brain norepinephrine release and human sympathetic nervous function, the effect of the tricyclic antidepressant desipramine (0.3 mg/kg i.v.) on both brain and whole body norepinephrine spillover was measured in healthy volunteers. Desipramine lowered the cerebrovascular spillover of norepinephrine, its precursor dihydroxyphenylalanine, and its metabolite dihydroxyphenylglycol by 50-80% and produced a mean fall of 35% in whole body norepinephrine spillover. One interpretation of these results is that human sympathetic nerve firing is dependent on norepinephrine release within the brain and that increased cerebral norepinephrine release may possibly be present in some patients with essential hypertension, underlying their higher sympathetic nerve firing rates.

Region-specific neuropeptide Y overflows at rest and during sympathetic activation in humans.

Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y-like immunoreactivity and norepinephrine concentrations in samples taken from the brachial artery; coronary sinus; and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [3H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous sample neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119 +/- 5% of arterial, n = 7) and after a meal (132 +/- 12%, n = 7), with neuropeptide Y overflows of 6 +/- 2 and 11 +/- 2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norepinephrine concentrations as an index for quantifying sympathetic neural responses regulating the systemic circulation.

Differences in the neuronal removal of circulating epinephrine and norepinephrine.

Neuronal uptake is an important mechanism for the removal of norepinephrine, but its contribution to the removal of epinephrine is unknown. This study compared the neuronal removal of circulating epinephrine and norepinephrine by examination of the cardiac extractions or plasma clearances of [3H]norepinephrine and endogenous or 3H-labeled epinephrine in healthy subjects, patients with cardiovascular disorders, and subjects administered desipramine to block neuronal uptake. In rabbits the plasma clearances of [3H]epinephrine and [3H] norepinephrine by neuronal uptake and the formation of dihydroxyphenylglycol (DHPG) from simultaneously infused [3H] norepinephrine and epinephrine were compared. In normal patients 51 +/- 3% of plasma epinephrine was extracted during one pass through the coronary circulation, significantly less than the cardiac extraction of [3H]norepinephrine (78 +/- 1%). In patients with cardiovascular disorders extractions of epinephrine (34 +/- 3%) remained lower than those of [3H]norepinephrine (63 +/- 2%). After desipramine, cardiac extraction of epinephrine was reduced to 12 +/- 2% and [3H]norepinephrine to 20 +/- 3%. In subjects infused simultaneously with [3H]epinephrine and [3H] norepinephrine, desipramine reduced the cardiac extraction of [3H]epinephrine by 28 +/- 6%, significantly less than the 49 +/- 7% reduction in [3H]epinephrine extraction; the plasma clearance of [3H]epinephrine was reduced by 4 +/- 5%, significantly less than the 20 +/- 6% reduction in [3H]norepinephrine clearance. In rabbits desipramine reduced the plasma clearance of [3H] epinephrine by 18%, significantly less than the 42% reduction in [3H]norepinephrine clearance; production of DHPG from epinephrine was less than half the production of [3H]DHPG from [3H]norepinephrine. The above differences indicated that epinephrine was removed 44-64% less avidly than norepinephrine by uptake into and metabolism within sympathetic neurons.

Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)

No stereoselective first-pass hepatic extraction of propranolol.

The plasma level: time profile for l-propranolol and total propranolol concentrations were examined in normotensive subjects after intravenous and oral dl-propranolol. l-Propranolol concentrations in plasma accounted for about 60% of total propranolol. This was attributed to lower volume of distribution for the isomer. Mean plasma clearance of 1-propranolol was similarly affected while apparent plasma half-life for the l-isomer and total propranolol were of the same order. Oral bioavailability of 1- and total propranolol averaged 40.7 +/- 8.5% and 42.4 +/- 12.9%. Food and hydralazine increased oral bioavailability of total and l-propranolol by similar magnitudes. We conclude that difference in the kinetics of l- and total propranolol concentrations in plasma are small and probably of no clinical significance. Presystemic clearance of propranolol in man does not appear to be stereospecific.