Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men.

BACKGROUND. Cardiac aging is characterized by a reduced heart rate response to beta-agonist stimulation with isoproterenol, but whether the ejection fraction and other cardiovascular responses are reduced in humans is largely unknown. In addition, whether reduced beta-agonist responses can be improved with exercise training has not been determined in humans. METHODS AND RESULTS. Cardiovascular responses to graded isoproterenol infusions (3.5, 7, 14, and 35 ng/kg/min for 14 minutes each) were assessed in 15 older (age, 60-82 years) and 17 young (age, 24-32 years) rigorously screened healthy men. Thirteen older and 11 young subjects completed 6 months of endurance training and were retested. At baseline, the older group had reduced responses to isoproterenol for heart rate (+65% older versus +92% young, p less than 0.001), systolic blood pressure (+9% versus +24%, p less than 0.001), diastolic blood pressure (-12% versus -24%, p less than 0.05), ejection fraction (+12 versus +20 ejection fraction units, p less than 0.001), and cardiac output (+70% versus +100%, p less than 0.001). The mean plasma isoproterenol concentrations achieved during the infusions were marginally higher (p = 0.07) in the older group (128 +/- 58, 227 +/- 64, 354 +/- 114, and 700 +/- 125 pg/ml) than in the young (79 +/- 20, 178 +/- 49, 273 +/- 79, and 571 +/- 139 pg/ml). Intensive training increased maximal oxygen consumption by 21% in the older group (28.9 +/- 4.6 to 35.1 +/- 3.8 ml/kg/min, p less than 0.001) and by 17% in the young (44.5 +/- 5.1 to 52.1 +/- 6.3 ml/kg/min, p less than 0.001), but training did not augment any of the cardiovascular responses to isoproterenol in either group. The mean plasma isoproterenol concentrations at the four infusion doses were unchanged after training in both groups. CONCLUSIONS. We conclude that there is an age-associated decline in heart rate, blood pressure, ejection fraction, and cardiac output responses to beta-adrenergic stimulation with isoproterenol in healthy men. Altered beta-adrenergic responses probably contribute to the reduced cardiac responses to maximal exercise that also occur with aging. Furthermore, intensive exercise training does not increase cardiac responses to beta-adrenergic stimulation with isoproterenol in either young or older men. The reduced beta-adrenergic response appears to be a primary age-associated change that is not caused by disease or inactivity.     

Myocardial noradrenaline content: a factor not considered up to now for the prognosis of patients with dilated cardiomyopathy

To evaluate the prognosis of patients with idiopathic dilated cardiomyopathy (EF less than 50%) in 55 patients the myocardial catecholamine concentration, plasma catecholamine concentration, and left ventricular ejection fraction were determined. The follow-up time ranged from 7 to 47 months. At the time of follow-up 10 of the 55 patients (group A) had died and three had undergone hearttransplantation. Group A patients had a significant lower EF (27 +/- 10 vs 36 +/- 9%, p less than 0.03), a lower myocardial norepinephrine (254 +/- 168 vs 579 +/- 416 pg/mg, p less than 0.007), higher plasma norepinephrine (640 +/- 333 vs 372 +/- 254 pg/ml, p less than 0.008) and plasma epinephrine (391 +/- 340 vs 116 +/- 81 pg/ml, p less than 0.006) in comparison to patients, who were still alive and not transplanted (group B). Survival was significantly lower in patients with an EF less than 30%, a plasma norepinephrine concentration greater than 350 pg/ml, a plasma epinephrine concentration greater than 125 pg/ml, and a myocardial norepinephrine content less than 400 pg/mg. Cox regression analysis revealed that the ratio of plasma vs myocardial norepinephrine was the best prognostic indicator for patients with an EF less than 30% and this ratio plus the plasma norepinephrine concentration were the best prognostic indicators for the whole group of patients. These data suggest that myocardial norepinephrine content is an important prognostic factor in patients with idiopathic dilated cardiomyopathy.     

Inhibition of sympathoadrenal activity by atrial natriuretic factor in dogs

In six conscious, trained dogs, maintained on a normal sodium intake of 2 to 4 mEq/kg/day, sympathetic activity was assessed as the release rate of norepinephrine and epinephrine during 15-minute i.v. infusions of human alpha-atrial natriuretic factor. Mean arterial pressure (as a percentage of control +/- SEM) during randomized infusions of 0.03, 0.1, 0.3, or 1.0 microgram/kg/min was 99 +/- 1, 95 +/- 1 (p less than 0.05), 93 +/- 1 (p less than 0.01), or 79 +/- 6% (p less than 0.001), respectively, but no tachycardia and no augmentation of the norepinephrine release rate (up to 0.3 microgram/kg/min) were observed, which is in contrast to comparable hypotension induced by hydralazine or nitroglycerin. The release rate of epinephrine (control, 6.7 +/- 0.6 ng/kg/min) declined immediately during infusions of atrial natriuretic factor to a minimum of 49 +/- 5% of control (p less than 0.001) during 0.1 microgram/kg/min and to 63 +/- 5% (0.1 greater than p greater than 0.05) or 95 +/- 13% (not significant) during 0.3 or 1.0 microgram/kg/min. Steady state arterial plasma concentrations of atrial natriuretic factor were 39 +/- 10 pg/ml (n = 6) during infusions of saline and 284 +/- 24 pg/ml (n = 6) and 1520 +/- 300 pg/ml (n = 9) during 0.03 and 0.1 microgram/kg/min infusions of the factor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of metoprolol on rest and exercise cardiac function and plasma catecholamines in chronic congestive heart failure secondary to ischemic or idiopathic cardiomyopathy

To define the effects of 2 months of metoprolol therapy on cardiac function, aerobic performance and sympathetic nervous system activity, metoprolol (75 to 100 mg/day) was administered to 10 patients with chronic congestive heart failure (CHF). Metoprolol was discontinued in 2 patients because of worsening CHF. In the remaining 8 patients, peak oxygen uptake increased significantly (14.8 +/- 3.0 to 16.1 +/- 2.5 ml/kg/min, p less than 0.05) as did the oxygen pulse (9.0 +/- 2.2 to 12.6 +/- 1.8 ml/beat, p less than 0.02). Resting heart rate (87 +/- 18 to 62 +/- 9 beats/min, p less than 0.05) and peak exercise heart rate (133 +/- 13 to 105 +/- 30 beats/min, p less than 0.02) were both reduced. Mean resting ejection fraction increased from 0.15 +/- 0.06 to 0.25 +/- 0.11 and peak exercise ejection fraction also tended to increase (0.19 +/- 0.11 to 0.28 +/- 0.15, difference not significant). Both resting plasma norepinephrine (613 +/- 706 to 303 +/- 142 pg/ml, p less than 0.05) and epinephrine (71 +/- 50 to 40 +/- 21 pg/ml, p less than 0.05) were reduced. Circulating lymphocyte beta-adrenergic receptor number was unchanged (1,334 +/- 292 to 1,344 +/- 456 receptors/cell, difference not significant). It is concluded that metoprolol therapy is associated with improvements in rest and exercise ventricular performance and maximal aerobic capacity. These improvements are associated with a decline in resting sympathetic nervous system activity.     

Adrenomedullary response to maximal stress in humans

The most important neuroendocrine response to stress is an increase in plasma epinephrine concentration. To investigate the clinical significance of this response, plasma catecholamine levels were measured (single-isotope derivative assay) in chronic stress (severe illness; n = 22) and acute maximal stress (cardiac arrest; n = 23). The results were then compared with the values from 60 normal resting subjects: epinephrine (mean +/- SEM) 0.034 +/- 0.002 ng/ml; norepinephrine 0.228 +/- 0.01 ng/ml. Chronic stress (intensive care unit patients) was associated with a fourfold elevation of epinephrine concentration (0.14 +/- 0.06 ng/ml; range 0.01 to 1.37; p less than 0.01 versus normal control subjects). Acute maximal stress (resuscitation following cardiac arrest) resulted in a greater than 300-fold increase in the plasma epinephrine level (10.3 +/- 2.9 ng/ml; range 0.36 to 35.9; n = 15; p less than 0.01). Peak plasma epinephrine levels in successfully resuscitated patients (n = 6) ranged from 0.36 to 273 ng/ml (three patients had received epinephrine therapy). The plasma norepinephrine level was increased twofold in intensive care unit patients (0.52 +/- 0.06 ng/ml; p less than 0.01) and 32-fold after cardiac arrest (7.37 +/- 1.8 ng/ml; p less than 0.01). During resuscitation, the correlation between the simultaneous epinephrine and norepinephrine levels was highly significant: r = 0.76; p less than 0.01. It is concluded that (1) chronic, severe stress produces only moderate elevations of plasma epinephrine levels (up to 1.37 ng/ml), whereas acute stress produces marked increases of plasma epinephrine that may reach the extraordinarily high level of 35.9 ng/ml, (2) the potential toxicity from the adrenomedullary response to acute stress is further exacerbated by the parallel release of norepinephrine, and (3) under close medical monitoring, it is possible to survive with plasma epinephrine concentrations as high as 273 ng/ml.     

Elevated levels of atrial natriuretic peptide and plasma catecholamines in arterial hypertension--indications for an interaction

In this study plasma levels of atrial natriuretic peptide and of the catecholamines epinephrine and norepinephrine were investigated in hypertensive patients (HT) (n = 30). 22 normotensive patients (NT) served as controls. Hypertensives showed an elevated ANP-level in comparison with controls (46.8 +/- 3.3 vs. 36.8 +/- 3.3 pg/ml, M +/- SEM, p less than 0.01). When patients with myocardial infarction or with reduced ejection fraction were excluded, the same relation was demonstrated (49.3 +/- 3.2 vs. 33.6 +/- 2.0 pg/ml, p less than 0.01). Plasma norepinephrine was 230.8 +/- 52.3 pg/ml in HT compared with 138.0 +/- 19.6 pg/ml in NT (p less than 0.05). Epinephrine was 70.8 +/- 10.5 vs. 54.8 +/- 9.7 pg/ml in HT and NT. To exclude an increased left ventricular enddiastolic - and hence left atrial - pressure as the cause for the elevation of ANP and norepinephrine, HT and NT were matched for the same levels of enddiastolic pressure (LVEDP) (n = 18). For each level of LVEDP ANP was higher in HT than in NT (p less than 0.01). The same held true for norepinephrine (p less than 0.05) and to a lesser extent for epinephrine (p = 0.09). Our results demonstrate that patients with essential hypertension exhibit markedly elevated levels for ANP and catecholamines which is not due to myocardial failure. We propose that the increased secretion of the vasodilatory hormone ANP serves as counterregulation against the vasoconstrictor norepinephrine. The endocrine function of the heart may play a pivotal role in the modulation of sympathetic activity.     

Acute hemodynamic effects of norepinephrine inhibition in patients with severe chronic congestive heart failure

The pathophysiologic role of high levels of circulating catecholamines in patients with congestive heart failure remains unclear. To assess the hemodynamic contribution of circulating catecholamines, metyrosine (alpha-methyl-p-tyrosine), an inhibitor of catecholamine synthesis, was administered to nine patients with acutely decompensated chronic congestive heart failure. Baseline left ventricular ejection fraction averaged 23.3 +/- 9.9%, whereas cardiac output averaged 3.69 +/- 1.03 liters/min, with a pulmonary wedge pressure of 27.4 +/- 8.5 mm Hg. After 48 h of metyrosine administration, plasma norepinephrine concentration decreased from 919.4 +/- 810.6 to 335.4 +/- 143.1 pg/ml (p less than 0.05). Plasma epinephrine concentration averaged 176.4 +/- 166.0 pg/ml at baseline, and was unchanged during metyrosine administration. Despite the significant decrease in circulating norepinephrine, no significant hemodynamic changes were observed during metyrosine administration. These results suggest that high levels of circulating norepinephrine may be more a marker of severe congestive heart failure than an important contributor to the underlying pathophysiology at this advanced stage of the disease process.     

Extraction of epinephrine and norepinephrine by the dog pancreas in vivo

This study determined the fractional extraction of epinephrine and norepinephrine by the in situ dog pancreas. Plasma samples for epinephrine measurements were taken simultaneously from the femoral artery and the superior pancreaticoduodenal vein. Pancreatic extraction of epinephrine was 73 +/- 5% when basal arterial epinephrine levels were 380 +/- 93 pg/mL, 76 +/- 4% when arterial levels were 896 +/- 123 pg/mL (epinephrine infused intravenously at 20 ng/kg/min), and 84 +/- 1% when arterial levels were 2,956 +/- 414 pg/mL (epinephrine infused intravenously at 80 ng/kg/min) suggesting that the process of epinephrine extraction by the pancreas is not saturable over this range. During a similar sampling protocol, norepinephrine was infused intravenously at 4 micrograms/kg/min; pancreatic extraction of norepinephrine was then 65 +/- 7% when arterial norepinephrine levels were 107,000 +/- 28,000 pg/mL. In separate experiments, lower rates of norepinephrine (12 to 1,200 ng/min) were infused directly into the pancreatic artery and pancreatic norepinephrine extraction was calculated; it ranged between 66% and 75%. Because the pancreas produces as well as extracts norepinephrine, a third technique was required to determine pancreatic norepinephrine extraction at the lower endogenous levels of norepinephrine; 3H-norepinephrine was infused intravenously and the arteriovenous difference of 3H-norepinephrine was measured. Fractional extraction of 3H-norepinephrine was 74 +/- 4% both in the basal state (arterial norepinephrine level = 202 +/- 44 pg/mL) and during systemic, glucopenic, stress induced by 2-deoxy-glucose (arterial norepinephrine level = 636 +/- 70 pg/mL). These data suggest that also the norepinephrine extraction process by the pancreas is not saturable.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation between radionuclide angiography and Doppler echocardiography during contractile changes with infusions of epinephrine

To define the quantitative relations between radionuclide and Doppler measures of systole during sympathetic activation with epinephrine, 10 young normal men were studied with simultaneous radionuclide angiography and M-mode and Doppler echocardiography during graded infusions of epinephrine (10, 25 and 50 ng/kg/min for 12 minutes each). During a nine-fold increase in circulating levels of epinephrine in arterialized plasma (94 +/- 59 to 879 +/- 310 pg/ml, P less than 0.001), the heart rate increased from 58 +/- 8 to 73 +/- 7 beats/min (P less than 0.01), whereas the mean arterial pressure fell from 82 +/- 3 to 75 +/- 6 mmHg (NS) and end-systolic wall stress decreased from 97 +/- 6 to 67 +/- 10 dynes/sec (P less than 0.01). The ejection fraction as estimated using radionuclide techniques increased from 68 +/- 6 to 83 +/- 6%, the peak ejection rate measured in this way increased from -3.36 +/- 0.3 to -5.10 +/- 0.5 end-diastolic volumes/sec, the ejection fraction as estimated with M-mode echocardiography increased from 66 +/- 5 to 83 +/- 5%, the echocardiographic ventricular dimension shortening increased from -1.78 +/- 0.2 to -2.7 +/- 0.4 sec-1, the peak aortic outflow velocity as measured with Doppler techniques increased from 98 +/- 13 to 147 +/- 25 cm/sec, and the aortic outflow acceleration velocity increased from 11 +/- 3 to 27 +/- 7 m/sec2 (all P less than 0.001). There was a significant correlation between the changes in radionuclide and M-mode estimations of ejection fractions (r = 0.82), between the radionuclide peak ejection rate and M-mode peak dimension shortening (r = 0.80) and between the radionuclide peak ejection rate and the Doppler peak aortic outflow velocity (r = 0.90) (all P less than 0.01). We conclude that corresponding radionuclide and Doppler echocardiographic measurements of systolic function are altered similarly during increased sympathetic activation with epinephrine.     

Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities

Plasma free epinephrine, norepinephrine, and dopamine concentrations were determined in 48, 63, and 45 patients, respectively, with overt congestive heart failure, and compared with those in 26 patients with stable angina but without heart failure. Systemic hemodynamic values were determined to assess the severity of heart failure. Arterial epinephrine levels were not different between patients with heart failure (73 +/- 92 pg/ml) and patients without heart failure (55 +/- 73 pg/ml). In patients with congestive heart failure, norepinephrine (665 +/- 510 pg/ml, mean +/- SD) and dopamine (407 +/- 405 pg/ml) levels were significantly higher than in patients with stable angina without heart failure (norepinephrine 184 +/- 136 pg/ml, p less than 0.001, and dopamine 197 +/- 259 pg/ml, p less than 0.02). However, in patients with congestive heart failure, the plasma norepinephrine levels did not correlate with cardiac index (r = 0.21, p = NS), pulmonary capillary wedge pressure (r = 0.11, p = NS), mean arterial pressure (r = 0.11, p = NS), or systemic vascular resistance (r = 0.18, p = NS). Similarly, there was no correlation between dopamine levels and the hemodynamic abnormalities in patients with congestive heart failure. These findings suggest that although endogenous norepinephrine and dopamine levels are frequently elevated in patients with heart failure, reflecting enhanced sympathetic activity, catecholamine levels do not reflect the severity of heart failure.     

Alpha-receptor restriction of coronary blood flow during atrial fibrillation

The effects of atrial fibrillation (AF) on coronary circulation before and after alpha-receptor blockade were studied in 14 anesthetized, open-chest dogs. AF was induced by electrical stimulation of the left atrial appendage; identical rhythmic heart rates were adjusted by left atrial pacing. During atrial pacing, coronary vascular resistance (CVR) was 0.97 +/- 0.10 mm Hg X min X 100 g/ml (resistance units [RU]), coronary blood flow (CBF) 125 +/- 14 ml/min X 100 g, and oxygen saturation 30 +/- 2%; plasma epinephrine was 193 +/- 42 pg/ml and norepinephrine 584 +/- 111 pg/ml. During AF, CVR was higher (1.16 +/- 0.11 RU, p less than 0.0005), whereas CBF (92 +/- 9 ml/min X 100 g, p less than 0.001) and coronary sinus oxygen saturation (24 +/- 2%, p less than 0.0025) were lower than during atrial pacing. When AF was induced, epinephrine increased to 333 +/- 98 pg/ml (p less than 0.05) and norepinephrine to 1,005 +/- 214 pg/ml (p less than 0.005). The large increase in plasma catecholamines suggested an activation of the sympathoadrenal system during AF. In addition, the alpha-receptor blocker phenoxybenzamine (10 mg/kg, intravenously) abolished the differences in CVR, CBF and oxygen saturation between AF and atrial pacing. The data suggest that the decrease in CBF and increase in CVR during experimentally induced AF are caused by coronary vasoconstriction, mediated by sympathetic activation of alpha receptors in the coronary vascular bed.     

Neuro-hormonal activation predicts ventilatory response to exercise and functional capacity in patients with heart failure

BACKGROUND: Heart failure (HF) is characterised by reduced tolerance to effort, associated with progressive fatigue and dyspnoea. Neuro-hormonal activation is a hallmark of HF and influences its clinical evolution. AIM: To evaluate the relationship between neuro-hormonal activation, exercise capacity and ventilatory efficiency. METHODS AND RESULTS: 154 HF patients (127 males, 62 +/- 1 years) underwent cardiopulmonary exercise testing and resting blood sampling for assay of plasma brain natriuretic peptide (BNP), NT-proBNP, norepinephrine, epinephrine, aldosterone and plasma renin activity (PRA). BNP and NT-proBNP levels correlated with peak oxygen consumption (VO2) (both R = -0.53, p < 0.001), VE/VCO2 slope (R = 0.56; p < 0.001 and R = 0.58; p < 0.001, respectively) and maximum workload (R = -0.49; p < 0.001 and R = -0.47; p < 0.001, respectively). Norepinephrine correlated slightly less with peak VO2 (R = -0.38, p < 0.001), VE/VCO2 (R = 0.45; p < 0.001) and maximum workload (R = -0.35; p < 0.001). There was a significant inverse correlation between left ventricular ejection fraction and BNP (R = -0.48, p < 0.001), NT-proBNP (R = -0.42; p < 0.001) and norepinephrine (R = -0.43; p < 0.001). Weaker correlations were found for PRA, exercise parameters and ejection fraction. ROC curves showed that BNP was able to identify patients with peak VO2 < 14 ml/min/kg (cut-off 98 pg/ml, AUC 0.775) and a VE/VCO2 > 35 (cut-off 183 pg/ml, AUC 0.797), as well as NT-proBNP (cut-off 537 pg/ml, AUC 0.799 and cut-off 1010 pg/ml, AUC 0.768, respectively) and norepinephrine (cut-off 454 pg/ml, AUC 0.716 and cut-off 575 pg/ml, AUC 0.783, respectively). CONCLUSION: Haemodynamic impairment (as indicated by BNP and NT-proBNP plasma values) and sympathetic activation predict exercise capacity and ventilatory efficiency in HF patients.     

Effect of a benzodiazepine (alprazolam) on plasma epinephrine and norepinephrine levels during exercise stress

To determine whether a benzodiazepine central nervous system depressant, alprazolam, inhibits sympathetic discharge during exercise stress, 11 healthy men, aged 21 to 35 years, performed symptom-limited treadmill tests before and on the third day of drug therapy (0.5 mg 3 times daily). Plasma epinephrine and norepinephrine levels were measured at rest and at 8 minutes, 11 minutes and maximal exercise. Owing to catheter malfunction during vigorous exercise, paired samples could be obtained from only 8 subjects at 8 minutes and from only 4 subjects at 11 minutes of exercise. During drug treatment, the plasma epinephrine level was lower at rest (30 +/- 4 vs 53 +/- 7 pg/ml, p less than 0.01), and at 8 minutes (60 +/- 13 vs 117 +/- 19 pg/ml, p less than 0.01), 11 minutes (120 +/- 39 vs 193 +/- 52 pg/ml, p less than 0.05), and maximal exercise (520 +/- 125 vs 970 +/- 324 pg/ml, p = 0.13). Plasma norepinephrine was unchanged at rest (452 +/- 57 vs 413 +/- 45 pg/ml) but lower at 8 minutes (730 +/- 75 vs 886 +/- 82 pg/ml, p less than 0.01), 11 minutes (1,077 +/- 197 vs 1,447 +/- 301 pg/ml, p less than 0.05) and at maximal exercise (3,453 +/- 487 vs 5,590 +/- 1,100 pg/ml, p = 0.09). Exercise duration (17 +/- 1 and 17 +/- 1 minutes) was unchanged on drug. Thus, alprazolam reduces the plasma catecholamine response to exercise stress, possibly by inhibiting centrally mediated sympathetic discharge. Blunting of sympathetic activation may be beneficial in cardiac disorders in which increased sympathetic tone is potentially deleterious.     

Dissociation of sympathetic responses to baroreceptor loading and unloading in compensated congestive heart failure secondary to ischemic or nonischemic dilated cardiomyopathy.

This study tested the hypothesis that abnormalities of baroreceptor-mediated suppression of sympathetic activity may persist in chronic congestive heart failure (CHF) despite pharmacologic treatment and clinical stability. Plasma norepinephrine and norepinephrine kinetics (using 3HNE infusions) were measured during head-up and head-down tilt in 8 patients with chronic CHF and 6 normal control subjects. In response to upright tilt, normal subjects increased plasma norepinephrine (270 +/- 45 to 413 +/- 60 pg/ml, p less than 0.001) and norepinephrine spillover (540 +/- 103 to 781 +/- 124 ng/min, p less than 0.001). Patients also increased plasma norepinephrine (436 +/- 105 to 600 +/- 112 pg/ml, p less than 0.05) and norepinephrine spillover (802 +/- 180 to 1,037 +/- 370 ng/min). During head-down tilt, plasma norepinephrine decreased in normal subjects (from 413 +/- 60 to 256 +/- 26 pg/ml, p less than 0.001). The decrease was due entirely to a decrease in norepinephrine spillover (781 +/- 124 to 466 +/- 40 ng/min, p less than 0.001). In contrast, there was no significant change in norepinephrine spillover (1,037 +/- 370 to 949 +/- 338 ng/min) during head-down tilt in patients with CHF. These data suggest that suppression of sympathetic activity during baroreceptor loading may be defective in CHF despite relative preservation or correction of the response to baroreceptor unloading.     

Role of vasopressin in cardiovascular and neurohormonal responses to intracerebroventricular hypertonic NaCl

To determine the significance of vasopressin in cardiovascular and neurohormonal responses caused by centrally administered hypertonic NaCl, we examined the effects of a vasopressin antagonist on blood pressure, heart rate, plasma levels of catecholamines, cortisol and renin activity in anesthetized dogs. Intracerebroventricular (ICV) injections of 0.2 ml of 1.5 M NaCl increased mean arterial blood pressure (+29.7 +/- 3.0 mmHg, mean +/- SE), heart rate (+27.9 +/- 7.0 beats/min), plasma concentrations of vasopressin (+48.9 +/- 8.2 pg/ml), norepinephrine (+40.0 +/- 6.2 pg/ml), epinephrine (+231.4 +/- 21.4 pg/ml) and cortisol (+5.3 +/- 1.1 micrograms/dl) and decreased plasma renin activity (-2.0 +/- 0.4 ng/ml/hr). An intravenous vasopressin antagonist, d(CH2)5Tyr(Me)AVP, at a dose of 10 micrograms/kg, attenuated the pressor response and augmented the heart rate response to ICV 1.5 M NaCl. The vasopressin antagonist also augmented the change in plasma norepinephrine and significantly attenuated the responses of cortisol and renin. Baseline levels of these variables were not altered by the vasopressin antagonist except for an increase in renin activity. Two injections of hypertonic NaCl without any pretreatment produced similar cardiovascular and hormonal responses. These results suggest that vasopressin contributes not only to an increase in blood pressure, but also to changes in the sympathetic nervous system, the hypothalamo-adrenocortical axis and the peripheral renin-angiotensin system in response to a central sodium stimulus.     

The acute response of plasma norepinephrine, renin activity, and arginine vasopressin to short-term nitroprusside and nitroprusside withdrawal in patients with congestive heart failure

Activation of the sympathetic nervous system, manifested by an increase in heart rate and circulating plasma norepinephrine, can occur in normal subjects when they are given vasodilators. The extent to which this activation occurs in patients with congestive heart failure (CHF) and whether this activation could account for the hemodynamic rebound sometimes observed following abrupt withdrawal of nitroprusside in such patients are unclear. We prospectively and retrospectively studied the effects of nitroprusside on plasma norepinephrine in 38 patients with CHF to determine if acute vasodilator therapy activates this vasoconstrictor system during or following such treatment. Thirty-six of these patients also had plasma renin activity (PRA) measured and plasma arginine vasopressin was measured in 12 patients. Baseline supine plasma norepinephrine (714 +/- 72 pg/ml, +/- SEM), PRA (15 +/- 2 ng/ml/hr), and arginine vasopressin (10 +/- 1 pg/ml) were increased at least twofold in the CHF patients. Nitroprusside (96 +/- 11 micrograms/min) was infused for 63 +/- 5 minutes after achieving an optimal hemodynamic response: cardiac index increased (2.01 +/- 0.08 to 2.67 +/- 0.1 L/min/m2, p less than 0.001), pulmonary artery wedge pressure decreased (25 +/- 1 to 16 +/- 1 mm Hg, p less than 0.001), mean arterial pressure decreased (83 +/- 1 to 72 +/- 1 mm Hg, p less than 0.001), and heart rate was unchanged. Plasma norepinephrine (632 +/- 43 pg/ml), PRA (18 +/- 3 ng/ml/hr), and arginine vasopressin (11 +/- 1 pg/ml) did not change significantly for the group during peak effect of the vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure

Patients with heart failure have increased vascular resistance and evidence for increased neurohumoral drive. High levels of circulating norepinephrine are found in patients with heart failure, but it is not known whether they reflect increased sympathetic neural activity or result from altered synthesis, release, or metabolism of norepinephrine. We used microneurography (peroneal nerve) to directly record sympathetic nerve activity to muscle (mSNA) and also measured plasma norepinephrine levels in patients with heart failure and in normal control subjects. Our goal was to determine whether sympathetic nerve activity is increased in patients with heart failure and whether plasma norepinephrine levels correlate with levels of mSNA in heart failure. Resting muscle sympathetic nerve activity in 16 patients with moderate to severe heart failure (54 +/- 5 bursts/min, mean +/- SE) was significantly higher (p less than .01) than the levels of activity in either nine age-matched normal control subjects (25 +/- 4 bursts/min) or 19 "young" normal control subjects (24 +/- 2 bursts/min). We found a significant correlation between plasma norepinephrine levels and mSNA (r = .73, p less than .05). Neither mSNA nor plasma norepinephrine levels correlated with total systemic vascular resistance, cardiac index, left ventricular ejection fraction, or heart rate. However, both mSNA and plasma norepinephrine levels showed significant positive correlations (p less than .05) with left ventricular filling pressures (r = .80, mSNA vs filling pressures; r = .82, norepinephrine levels vs filling pressures) and mean right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced cardiovascular responsiveness to exercise-induced sympathoadrenergic stimulation in patients with cirrhosis

Cardiovascular responsiveness to sympathoadrenergic activation obtained by muscle exercise in the supine position was evaluated in 22 patients with cirrhosis (11 alcoholic, 11 postnecrotic/cryptogenic; 14 with ascites) and 10 controls of comparable age. Plasma norepinephrine, heart rate, diastolic arterial pressure and cardiac function, as evaluated by systolic time intervals, were monitored. At rest, cirrhotics had higher norepinephrine (154 +/- 19 S.E.M. ng/l) and heart rate (79 +/- 2 beats per min) than controls (71 +/- 3 ng/l, p less than 0.01; 67 +/- 2 beats per min, p less than 0.001), whereas diastolic arterial pressure was similar. Among systolic time intervals, electromechanical systole, pre-ejection period, electromechanical delay and pre-ejection period to left ventricular ejection time ratios were prolonged (p less than 0.05 or less). Exercise led to significant increases in plasma norepinephrine, heart rate and diastolic arterial pressure in both controls and patients. In the latter, however, whereas the increase in norepinephrine was greater (p less than 0.001), those in heart rate and diastolic arterial pressure were less (p less than 0.005). As expected, most systolic time intervals shortened, but the decrease in pre-ejection period (p less than 0.05), isometric contraction time (p less than 0.02) and pre-ejection period to left ventricular ejection time ratio (p = 0.06) was less in patients than in controls. Direct correlations between exercise-induced changes in norepinephrine and both diastolic arterial pressure (r = 0.81; p less than 0.005) and heart rate (r = 0.85; p less than 0.002) were observed in controls, while inverse correlations (r = -0.67, p less than 0.001 and r = -0.44; p less than 0.05) were found in cirrhotics. These results suggest that cardiovascular reactivity to the sympathetic drive is impaired in cirrhotics. The impairment of cardiac contractility may be due to altered electromechanical coupling.     

New insights into pacemaker syndrome gained from hemodynamic, humoral and vascular responses during ventriculo-atrial pacing

Ventricular pacing is performed during programmed electrical stimulation and during normal functioning of single chamber (VVI or VVIR) pacemakers. In many patients, retrograde ventriculoatrial (V-A) conduction may occur and evoke hemodynamic and reflex neurohumoral responses, which are unique to this pacing mode. Accordingly, forearm blood flow, forearm vascular resistance, mean and phasic arterial pressure, cardiac output and plasma norepinephrine, epinephrine and dopamine were measured during atrial, ventricular and V-A pacing at a cycle length of 600 ms (100 beats/min) before and after regional alpha blockade with intraarterial phentolamine in 16 patients with a left ventricular ejection fraction greater than 35% and little or no symptoms of congestive heart failure. During V-A pacing, cardiac output decreased by 10%, whereas forearm vascular resistance increased from 52 +/- 7 to 70 +/- 9 U (p less than 0.001) and plasma norepinephrine increased from 183 +/- 27 to 232 +/- 27 pg/ml (p less than 0.01). Phentolamine nearly abolished the increase in forearm vascular resistance in response to V-A pacing (18 +/- 4.1 U before vs 5.8 +/- 1.5 U after, p less than 0.05). The change in forearm vascular resistance with V-A pacing correlated with systolic arterial pressure, but not with changes in mean arterial pressure, pulse pressure, cardiac output, mean or peak right atrial pressure, pulmonary artery or pulmonary capillary wedge pressure. These results suggest that forearm vascular resistance responses to V-A pacing are mediated mainly by alpha-adrenergic receptors, through the arterial baroreflexes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exercise on circulating atrial natriuretic peptide and left ventricular ejection fraction in healthy persons and patients with coronary artery disease

Radionuclide angiographic measurements of left ventricular ejection fraction were performed at rest and during exercise in 10 normal persons and 11 patients with coronary artery disease. Exercise was continued on a supine bicycle exercise table up to a symptom-limited maximum. Plasma levels of atrial natriuretic peptide (ANP) were also determined at rest and during exercise. Ejection fraction in the normal volunteers was 59 +/- 3% (mean +/- SEM) at rest and increased significantly (p less than 0.01) to 69 +/- 3% during exercise. Ejection fraction in the patients was 47 +/- 5% at rest and did not change significantly during exercise (51 +/- 7%). Plasma ANP in the normals rose significantly (p less than 0.01) from 62 +/- 16 pg/ml at rest to 454 +/- 94 pg/ml during exercise. Plasma ANP in the patients also rose significantly (p less than 0.01) from 231 +/- 102 pg/ml to 794 +/- 170 pg/ml. The response of plasma ANP to exercise was enhanced significantly (p less than 0.05) in the patients as compared with the normals in relation to ejection fraction by analysis of covariance. In both the normals and the patients, plasma ANP was inversely and significantly correlated with ejection fraction during exercise (r = -0.46, p less than 0.05, n = 21), however, not at rest. Because it has been reported that plasma ANP is correlated positively with pulmonary artery wedge pressure, the estimation of plasma ANP during an exercise stress test might be used for the evaluation of cardiac reserve in coronary artery disease.