Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion.

We investigated atrial natriuretic factor (ANF) in humans, measuring plasma immunoreactive (ir) ANF (in femtomoles per milliliter), and renal, hormonal, and hemodynamic responses to ANF infusion, in normal subjects (NL) and congestive heart failure patients (CHF). Plasma irANF was 11 +/- 0.9 fmol/ml in NL and 71 +/- 9.9 in CHF (P less than 0.01); the latter with twofold right ventricular increment (P less than 0.05). In NL, ANF infusion of 0.10 microgram/kg per min (40 pmol/kg per min) induced increases (P less than 0.05) of absolute (from 160 +/- 23 to 725 +/- 198 mueq/min) and fractional (1-4%) sodium excretion, urine flow rate (from 10 +/- 1.6 to 20 +/- 2.6 ml/min), osmolar (from 3.2 +/- 0.6 to 6.8 +/- 1.2 ml/min) and free water (from 6.8 +/- 1.6 to 13.6 +/- 1.6 ml/min) clearances, and filtration fraction (from 20 +/- 1 to 26 +/- 2%). Plasma renin and aldosterone decreased 33% and 40%, respectively (P less than 0.01). Systolic blood pressure fell (from 112 +/- 3 to 104 +/- 5 mmHg, P less than 0.05) in seated NL; but in supine NL, the only hemodynamic response was decreased pulmonary wedge pressure (from 11 +/- 1 to 7 +/- 1 mmHg, P less than 0.05). In CHF, ANF induced changes in aldosterone and pulmonary wedge pressure, cardiac index, and systemic vascular resistance (all P less than 0.05); however, responses of renin and renal excretion were attenuated. ANF infusion increased hematocrit and serum protein concentration by 5-7% in NL (P less than 0.05) but not in CHF.

Sympathetic reinnervation of the sinus node and exercise hemodynamics after cardiac transplantation.

BACKGROUND: Sympathetic cardiac reinnervation occurs variably after cardiac transplantation (CT) in humans. We hypothesized that sinus node reinnervation would partially restore normal chronotropic response to exercise. METHODS AND RESULTS: Thirteen recent CT recipients, 28 late CT recipients (> or =1 year after CT), and 20 control subjects were studied. Sinus node sympathetic reinnervation was determined by heart rate (HR) change after tyramine injection into the artery that perfused the sinus node. HR changes of <5 and > or =15 bpm were defined, respectively, as denervation and marked reinnervation. During treadmill exercise, HR, blood pressure, and expired O(2) and CO(2) were measured. All early transplant recipients exhibited features typical of denervation (basal HR, 88+/-2 bpm; peak HR, 132+/-4 bpm, peaking 1.8+/-0.3 minutes after exercise cessation and slowly declining after exercise). A similar pattern was found in the 12 late transplant recipients with persistent sinus node denervation. However, in patients with marked reinnervation, exercise HR rose more (peak HR, 142+/-4 and 141+/-2 bpm), peaked earlier after cessation of exercise (0.7+/-0.4 and 0. 3+/-0.1 minute), and fell more rapidly. Exercise duration and maximal oxygen consumption were not related significantly to reinnervation status, but a trend existed for longer exercise time in markedly reinnervated patients. CONCLUSIONS: The present studies suggest that sympathetic reinnervation of the sinus node is accompanied by partial restoration of normal HR response to exercise. Both maximal oxygen consumption and exercise duration were markedly shorter in CT patients than in control subjects, and most of the difference was not related to innervation status.

Plasma endothelin concentrations in humans with end-stage heart failure and after heart transplantation.

OBJECTIVES AND BACKGROUND: Endothelin is an endothelium-derived vasoconstrictor peptide that increases systemic and renal vascular resistance at pathophysiologic concentrations. Recent studies have demonstrated its presence in the circulation and its elevation in animals with congestive heart failure, suggesting that endothelin may contribute to the vasoconstrictive state of heart failure. The current study was designed with two objectives: 1) to demonstrate the elevation of circulating endothelin in patients with heart failure, and 2) to determine the short- and long-term response of endothelin levels after heart transplantation. METHODS: Plasma endothelin concentrations were measured in two patient groups. Group 1 included 24 patients with end-stage heart failure who were studied during evaluation for potential heart transplantation. Group 2 included 12 patients from Group 1 who had had heart transplantation. Plasma endothelin concentrations were measured before and on days 1, 3 and 7 after heart transplantation. Eight of these patients also had levels measured 3 to 12 months later. RESULTS: Plasma endothelin concentrations were significantly elevated in patients with heart failure compared with those in an age-matched control group (11.7 +/- 1.1 vs. 6.8 +/- 0.3 pg/ml). In response to heart transplantation, plasma endothelin concentrations increased further and were sustained during a long-term follow-up. These later changes were associated with a significant increase in arterial pressure and serum creatinine. CONCLUSIONS: This study demonstrates that endothelin concentrations are increased in patients with heart failure and increase further after heart transplantation. It suggests a possible role for endothelin in the cardiovascular and renal adaptive responses to human heart transplantation.

Systemic and pulmonary hemodynamic responses to nicardipine during graded ergometric exercise in patients with moderate to severe essential hypertension.

In 10 patients with moderate to severe hypertension, the hemodynamic effects of ergometric exercise and nicardipine, a dihydropyridine calcium channel antagonist, were characterized under basal conditions and after 1 week of therapy. The responses of plasma renin activity and catecholamines were also assessed. Nicardipine induced significant reductions of systolic, diastolic and mean blood pressure under conditions of rest and peak exercise (p less than 0.001), mediated by reversal of vasoconstriction (p less than 0.001). Overall, cardiac index and stroke volume index responses were not significantly altered by nicardipine. Although rest pulmonary wedge pressure was unchanged (6 +/- 3 to 5 +/- 4 mm Hg), peak exercise pulmonary wedge pressure decreased from 24 +/- 22 to 7 +/- 5 mm Hg (p less than 0.001) with nicardipine therapy. This effect of nicardipine on pulmonary wedge pressure was present across all work loads studied, and was accompanied by reduction of peak exercise pulmonary artery pressure from 43 +/- 10 to 25 +/- 7 mm Hg (p less than 0.001). Oxygen consumption was unchanged, associated with reduction of arteriovenous oxygen difference (p less than 0.02). Both plasma renin activity (p less than 0.05) and norepinephrine (p less than 0.005) were significantly increased with nicardipine therapy. Thus, nicardipine produced significant blood pressure reduction by reversal of vasoconstriction in patients with essential hypertension. The preservation of cardiac output, with markedly reduced pulmonary wedge pressure, indicated that nicardipine improved ventricular performance in response to reversal of vasoconstriction.

Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure.

OBJECTIVES: This study was conducted to determine the relations among exercise capacity and pulmonary, peripheral vascular, cardiac and neurohormonal factors in patients with chronic heart failure. BACKGROUND: The mechanisms of exercise intolerance in heart failure have not been fully clarified. Previous studies have indicated that peripheral factors such as regional blood flow may be more closely associated with exercise capacity than cardiac function, whereas the role of pulmonary function has received less attention. METHODS: Fifty patients with stable heart failure underwent a comprehensive assessment that included a symptom-limited maximal cardiopulmonary exercise test, right heart catheterization, pulmonary function tests, neurohormonal levels, radionuclide ventriculography and forearm blood flow at rest and after 5 min of brachial artery occlusion. Univariate and stepwise linear regression analyses were used to relate peak exercise oxygen uptake to indexes of cardiac, peripheral vascular, pulmonary and neurohormonal factors both alone and in combination. RESULTS: The mean ejection fraction was 19% and peak oxygen uptake was 16.5 ml/min per kg in this group of patients. By univariate analysis, there were no significant correlations between peak oxygen uptake and rest cardiac output, pulmonary wedge pressure, ejection fraction and pulmonary or systemic vascular resistance. In contrast, even in the absence of arterial desaturation during exercise, the forced expiratory volume in 1 s (r = 0.55, p < 0.001), forced vital capacity (r = 0.46, p < 0.01) and diffusing capacity for carbon monoxide (r = 0.47, p < 0.01) were all significantly associated with peak oxygen uptake. Peak postocclusion forearm blood flow (r = 0.45, p < 0.01), the corresponding minimal forearm vascular resistance (r = -0.56; p < 0.01) and plasma norepinephrine level at rest (r = -0.45; p < 0.01) were also significantly correlated with peak oxygen uptake. By multivariate analysis, minimal forearm vascular resistance and forced expiratory volume in 1 s were shown to be independently related to peak oxygen uptake, with a combined R value of 0.71. Other two-variate models included forced expiratory volume and plasma norepinephrine (R = 0.67) and forced expiratory volume and diffusing capacity (R = 0.65). Because forced vital capacity was highly correlated with forced expiratory volume in 1 s, it could be combined with the same variables to yield similar R values. Addition of any third variable did not improve these correlations. CONCLUSIONS: In comparison with rest indexes of cardiac performance, measures of pulmonary function and peripheral vasodilator capacity were more closely associated with peak exercise oxygen uptake in patients with heart failure. Furthermore, the associations were independent of each other and together accounted for 50% of the variance in peak oxygen uptake. These data suggest that pulmonary and peripheral vascular adaptations may be important determinants of exercise intolerance in heart failure.

Milrinone in congestive heart failure: acute and chronic hemodynamic and clinical evaluation.

Acute and chronic hemodynamic and clinical responses to milrinone, a new oral inotrope-vasodilator agent, were evaluated prospectively in 37 patients with severe congestive heart failure. The majority of patients (n = 31) had not responded to prior vasodilator therapy, with a substantial number (n = 8) requiring intravenous inotropic support at the time of initial study. All patients showed acute hemodynamic improvement with oral milrinone, and an optimal maintenance dose was chosen for each patient during dose-ranging studies (average dose 48 mg/day). Milrinone was discontinued before follow-up hemodynamic study in 12 patients (because of worsening congestive heart failure in 6 patients, sudden death in 3 patients, arrhythmia in 1 patient and refusal by 2 patients). Hemodynamic effects of milrinone both acutely and after chronic therapy (average 37 days) were compared in the remaining 25 patients. Acutely, mean cardiac index increased from 1.9 +/- 0.5 to 2.5 +/- 0.5 liters/min per m2 (p less than 0.001), and mean pulmonary capillary wedge pressure decreased from 28 +/- 9 to 18 +/- 8 mm Hg (p less than 0.001). When oral milrinone was readministered after chronic therapy, mean cardiac index increased from 1.9 +/- 0.5 to 2.5 +/- 1.7 liters/min per m2 (p less than 0.001), and pulmonary capillary wedge pressure decreased from 27 +/- 8 to 20 +/- 8 mm Hg (p less than 0.001) at 1 hour. New York Heart Association functional class improved in 18 of the 25 patients treated over a long-term period (mean 5.5 +/- 2.3 months).(ABSTRACT TRUNCATED AT 250 WORDS)

Trends in patient selection for heart transplantation.

OBJECTIVES: The purpose of this study was to review specific outcomes of patient referrals and the utility of selection criteria for heart transplantation at a single transplant center and to assess important trends over a 5-year period. BACKGROUND: Although patient selection criteria are important for the clinical success of heart transplantation and the optimal utilization of the limited supply of donor organs, there are few data regarding actual outcomes and whether selection criteria are facilitating the identification of the most appropriate patients. METHODS: We retrospectively reviewed 511 consecutive referrals of adult patients with heart failure from January 1, 1987 to December 31, 1991. Patients were followed up to one of five end points: 1) acceptance onto the transplant waiting list, 2) rejection from the transplant waiting list, 3) death, 4) referral to another program, and 5) still pending evaluation. RESULTS: Of the 511 referred patients, 221 (43%) were accepted onto the waiting list, 222 (43%) were rejected, 39 (8%) died before the evaluation was completed, 15 (3%) were referred to another program and 14 (3%) are still pending evaluation. The rates for acceptance and rejection each year ranged between 30% and 51% and there were no consistent trends in the acceptance/rejection ratio from 1987 to 1991. Of the 221 patients accepted onto the waiting list, 115 (52%) underwent transplantation, 50 (22%) died, 12 (5%) were removed from the list because of clinical improvement, 9 (4%) were referred to another program and 35 (16%) are still on the waiting list. The continuing shortage of donor organs resulted in a marked increase in the size of the waiting list from 12.6 patients in 1987 to 36.5 in 1991, as well as a marked increase in the time on the waiting list before transplantation. Over 5 years, 50 patients were considered "too well" for transplantation (23% of all rejections). Of these 50 patients, 43 (86%) are alive and 7 were lost to follow-up during a mean period of 28.6 months (range 4 to 62). All 12 patients who were taken off the active transplant list because of improvement in symptoms, ejection fraction or peak exercise oxygen consumption are alive with a mean follow-up period of 27.7 months (range 11 to 61). CONCLUSIONS: These data confirm the fact that transplant referrals are a selected group of patients with a high mortality rate, as 8% died before the evaluation could be completed and 22% died while waiting for a suitable donor organ. Furthermore, patient selection criteria are able to identify a small subset of patients with a low mortality risk as patients who were rejected because they were too well or taken off the list for clinical improvement have a reasonably good prognosis.

Diuretic treatment for the sodium retention of congestive heart failure.

The use of diuretics for the treatment of sodium retention in congestive heart failure was evaluated. Particular focus was given to the altered renal response to diuretics in patients with heart failure and adverse responses to diuretic therapy. Highlighted information included historical aspects of the development of diuretics, mechanisms of sodium retention, the physiologic and clinical response to diuretics, and the altered pharmacokinetics and pharmacodynamics of diuretics in congestive heart failure. Despite more than 60 years of empiric diuretic use in heart failure, the actual database regarding the long-term efficacy, adverse effects, and altered mortality outcome in heart failure is relatively small. Existent pharmacokinetic and pharmacodynamic data are typically not collected within the context of heart failure efficacy trials. In addition to altered electrolyte transport and total-body electrolyte depletion, diuretics may be associated with adverse neurohormonal activation. Thus, guidelines for acute and long-term therapy with diuretics in heart failure remain somewhat empiric. Diuretics will remain a mainstay for the treatment of edema in congestive heart failure but must be accompanied by moderate sodium restriction. However, large clinical trials of diuretics would be necessary to demonstrate that improved clinical efficacy with edema reduction is not offset by adverse effects, which include electrolyte depletion, ventricular arrhythmias, and subsequent increased mortality.

Liver function abnormalities in chronic heart failure. Influence of systemic hemodynamics.

To characterize the incidence and severity of liver function abnormalities in patients with congestive heart failure, we analyzed systemic hemodynamics and biochemical profiles in 133 patients with stable chronic congestive heart failure, secondary to a dilated cardiomyopathy. The patients were divided into three groups, based on the severity of the reduction in cardiac index (CI). The mean values of all liver function tests in groups 1 (n = 43; CI greater than or equal to 2.0 L/min/m2) and 2 (n = 48; CI greater than 1.5 and less than 2.0 L/min/m2) were essentially normal, except for minimally elevated alkaline phosphatase levels and slightly decreased albumin levels in both groups, and slight increases in levels of gamma-glutamyl transpeptidase and total bilirubin in group 2. In contrast, group 3 patients (n = 42; CI less than or equal to 1.5 L/min/m2) had the most severe heart failure, as assessed by the lowest CI and highest cardiac filling pressures, and significantly higher levels of aspartate aminotransferase (65 +/- 82 U/L), alanine aminotransferase (77 +/- 102 U/L), lactate dehydrogenase (282 +/- 91 U/L), and total bilirubin (29 +/- 14 mumol/L [1.7 +/- 0.8 mg/dL]). The percentage of patients in group 3 with these abnormalities ranged between 27% and 80%. Although linear regression analysis showed that the elevations in right atrial and pulmonary wedge pressures, and the decreases in CI, were significantly correlated with liver function abnormalities, the correlation coefficients were small. Thus, liver function abnormalities remain common in patients with congestive heart failure but are generally small in magnitude and not associated with clinically apparent hepatic disease. It is likely that reduced forward flow and passive backward congestion are both contributing factors in the pathogenesis of these biochemical abnormalities, although nonhemodynamic factors may also be important.

Glucose, insulin, and glucagon levels during exercise in pancreas transplant recipients.

OBJECTIVE: To determine whether pancreas transplant recipients maintain normal blood glucose levels during physical exercise. RESEARCH DESIGN AND METHODS: We measured serum glucose, insulin, C-peptide, and plasma glucagon levels in six pancreas transplant recipients and six healthy control subjects matched for age, sex, body size, and level of conditioning during 1 h of bicycle exercise at a workload set to achieve 40% of each individual's previously determined peak oxygen consumption (VO2). RESULTS: Serum glucose values were not different between control subjects and transplant recipients before the start of exercise (5.0 +/- 0.1 and 4.9 +/-0.1 mmol/l, respectively). Serum glucose levels fell slightly but significantly in both recipients and control subjects during exercise. There were no significant differences in glucose levels between the two groups at any time point during exercise, although mean nadir glucose during exercise was slightly lower in transplant recipients compared with control subjects (4.4 +/- 0.1 vs. 4.8 +/- 0.1 mmol/l, P = 0.04). In control subjects, insulin and C-peptide levels fell significantly within 15-30 min of exercise and glucagon levels rose significantly after 60 min of exercise. In transplant recipients, there was a trend for insulin and C-peptide levels to fall and glucagon levels to rise during exercise, although these changes were delayed and were not statistically significant. CONCLUSIONS: No significant abnormalities in blood glucose were detected in pancreas transplant recipients during bicycle exercise at 40% of peak VO2 for 1 h. Compared with levels in control subjects, subtle alterations in insulin and glucagon levels may occur in transplant recipients during exercise. However, these alterations do not appear to result in either hyperglycemia or hypoglycemia during light exercise for up to 1 h.

Effect of angiotensin II on noradrenaline release in the human forearm.

OBJECTIVE: The aim was to test the hypothesis that in normal humans angiotensin II would stimulate local release of noradrenaline under basal conditions or during a sympathetic stimulus provided by lower body negative pressure (LBNP). METHODS: Nine healthy volunteers received intra-arterial infusions of angiotensin II, 5 ng.min-1, into the non-dominant forearm. Forearm blood flow (strain gauge plethysmography) and regional noradrenaline spillover (using the tracer methodology of Esler) were measured during angiotensin II alone, LBNP alone, and LBNP plus angiotensin II. RESULTS: Angiotensin II and LBNP decreased forearm blood flow comparably: from 3.1(SD 1.5) to 2.4 (0.9) ml.100 g-1.min-1 during angiotensin II, p < 0.05; and from 3.3(1.5) to 2.5(1.0) ml.100 g-1.min-1 during LBNP, p < 0.05 (p = NS, A-II v LBNP). Angiotensin II had no effect on forearm venous noradrenaline or regional noradrenaline spillover. LBNP increased venous noradrenaline outflow from the forearm, from 1.6(0.40) to 2.1(0.6) nmol.min-1 (p < 0.05), while regional noradrenaline spillover tended to increase, rising from 1.5(0.8) to 2.0(1.0) nmol.100 ml-1.min-1. Angiotensin II did not enhance forearm blood flow or noradrenaline responses to LBNP. CONCLUSIONS: In the human forearm, mildly vasoconstrictor infusions of angiotensin II do not increase local release of noradrenaline, either alone or during mild LBNP. At least under these conditions, angiotensin II would not appear to be a potent influence on local sympathetic activity.

Exercise hemodynamics and oxygen delivery in human hypertension. Response to verapamil.

To characterize the hemodynamic response to exercise and the effects of calcium channel antagonism in hypertensive subjects, invasive exercise hemodynamics were performed in the baseline state after intravenous infusion of verapamil and after 5 to 7 days of oral verapamil in 10 subjects with moderate to severe hypertension. We also assessed oxygen delivery and use and the response of the sympathetic nervous system by measuring plasma norepinephrine levels at rest and during exercise. Both routes of administration were associated with significant reductions of mean arterial pressure and systemic vascular resistance at rest and peak exercise (p less than 0.05). Changes in heart rate were not statistically significant. Following oral administration of verapamil, stroke volume increased significantly in both the resting and exercise states. Pulmonary wedge pressure did not increase; in fact, the Frank-Starling relationship of cardiac performance actually was improved. Oxygen delivery and use were unchanged with both routes of administration. There was no significant difference in rest and exercise plasma norepinephrine levels following verapamil therapy. Thus, verapamil resulted in a significant reduction of mean arterial pressure, mediated by a significant reduction of systemic vascular resistance, following both intravenous and short-term oral administration. This reduction occurred without expression of left ventricular dysfunction and was not at the expense of increased oxygen use or enhanced sympathetic nervous systemic activity.

Influence of baseline hemodynamic status and sympathetic activity on the response to nicardipine, a new dihydropyridine, in patients with hypertension or chronic congestive heart failure.

We evaluated the immediate hemodynamic response to nicardipine, administered as an intravenous bolus and 30-minute sustaining infusion, in 10 patients with systemic hypertension (HTN) and 10 patients with chronic congestive heart failure (CHF). Baseline systemic vascular resistance and the response to nicardipine for HTN (1968 +/- 657 to 905 +/- 256 dynes X sec X cm-5) and CHF (2002 +/- 988 to 1089 +/- 216 +/- 99 dynes X sec X cm-5) were virtually identical (P less than 0.01). In both groups there was a significant increase of cardiac index in response to afterload reduction: HTN, 2.70 +/- 0.46 to 4.47 +/- 1.01; CHF, 1.90 +/- 0.33 to 2.88 +/- 0.80 L/min/m2 (P less than 0.01), so that a negative inotropic effect was not evident. In HTN the increase in cardiac index was primarily the result of reflex increase of heart rate (67 +/- 16 to 95 +/- 25 bpm [P less than 0.05]), associated with norepinephrine increase from 402 +/- 243 to 744 +/- 364 pg/ml (P less than 0.001). In CHF the cardiac index increase was caused by a stroke volume index increase (23 +/- 4 to 33 +/- 9 ml/min; P less than 0.01), with no significant change in heart rate or norepinephrine. Thus nicardipine, by means of calcium channel antagonism, induced reversal of vasoconstriction. Differences in the cardiac response identify the importance of characterizing the pathophysiologic status of cardiac impairment to more accurately interpret pharmacologic interventions.

Reversal of a calcium-mediated vasoconstrictor component in patients with congestive heart failure.

The influx of calcium into vascular smooth muscle cells is a major determinant of vasoconstriction, yet this concept has not been explored in congestive heart failure (CHF). We therefore used an "isolated" forearm model to assess the direct effects of the inhibition of calcium influx into vascular smooth muscle in 11 patients who had CHF, with use of the soluble dihydropyridine, nicardipine. Nicardipine produced a dose-dependent increase of forearm blood flow and a reduction of resistance, without producing a systemic hemodynamic effect. Patients with the lowest baseline forearm blood flow levels had the greatest percentage increases in forearm blood flow (r = -0.729, p less than 0.01), and a favorable metabolic effect was documented by a reduction in oxygen extraction across the forearm. This study demonstrated the importance of vascular smooth muscle intracellular calcium as a determinant of vasoconstriction in patients who have CHF.

Local forearm vasodilation with intra-arterial administration of enalaprilat in humans.

To determine whether converting enzyme inhibitors could produce peripheral vasodilation through a local mechanism, we infused enalaprilat, 2 micrograms/min/dl forearm volume (FAV), into the brachial artery of normal subjects and measured changes in forearm blood flow (FBF) with strain-gauge plethysmography. Enalaprilat produced a peak increase in FBF of 2.82 +/- 0.54 ml/min/dl FAV (78% increase) at 1 minute (p less than 0.01 versus vehicle) and an increase of 1.11 +/- 0.28 ml/min/dl FAV at 4 minutes (p less than 0.05 versus vehicle). Blood pressure and plasma renin activity measured at the completion of infusion did not change. Intravenous enalaprilat infusion at the same dose in seven additional normal subjects did not increase FBF. Pretreatment of seven subjects with 75 mg oral indomethacin attenuated the peak response to enalaprilat (4.13 +/- 1.52 versus 0.58 +/- 0.32 ml/min/dl; p less than 0.05). We conclude that intra-arterial enalaprilat produces an increase in FBF in normal subjects. This peripheral vasodilation is caused by a local effect independent of circulating renin-angiotensin system inhibition. This response is attenuated by indomethacin, suggesting that prostaglandins contribute to the vasodilator response.

Effects of norepinephrine on endothelium-dependent vasodilation of forearm resistance vessels.

BACKGROUND: Endothelium-dependent dilatation of forearm resistance vessels is attenuated in patients with heart failure. Activation of the sympathetic nervous system could cause this abnormality by way of vasoconstriction and chemical inactivation of nitric oxide. METHODS AND RESULTS: The effects of concurrent intra-arterial norepinephrine infusions (25, 50 and 100 ng/min) on forearm blood flow responses to equipotent doses of an endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), and an endothelium-independent vasodilator, nitroprusside (1 and 5 micrograms/min), were studied in 12 normal subjects. Norepinephrine infusions increased the mean plasma norepinephrine from 255 pg/ml at baseline to 460, 629, and 1089 pg/ml, respectively. Basal forearm blood flow was reduced from 2.9 to 1.6 ml/min/100 ml of forearm volume at the highest dose (p < 0.01). The average response to the lowest dose of methacholine (4.5 ml/min/100 ml) was not significantly reduced by concurrent infusion of norepinephrine (4.4, 4.2, and 4.3 ml/min/100 ml, respectively), whereas the response to the higher dose of methacholine (8.9 ml/min/100 ml) tended to be lower (7.2, 6.7, and 7.4 ml/min/100 ml, respectively) but did not attain statistical significance. Methacholine induced vasodilation was not more sensitive to norepinephrine than nitroprusside responses. Lower body negative pressure (-20 mm Hg) also significantly reduced baseline forearm flow and increased plasma norepinephrine but did not effect either methacholine or nitroprusside induced vasodilation. CONCLUSION: Sympathetic stimulation induced by infusion of norepinephrine or lower body negative pressure is not a potent antagonist to endothelium-dependent vasodilation of the forearm vasculature. These data suggest that sympathetic activation does not completely explain the abnormal endothelium-dependent vasodilation seen in patients with heart failure.

Regional blood flow and neurohormonal responses to milrinone in congestive heart failure.

We measured systemic hemodynamics, regional blood flow, and neurohormonal parameters in 13 patients with severe chronic congestive heart failure before and after 1 month of therapy with oral milrinone, a bipyridine cardiotonic agent. After milrinone there were significant reductions in pulmonary wedge pressure (27 +/- 2 to 19 +/- 3 mm Hg; P less than 0.02) and systemic vascular resistance (1866 +/- 152 to 1393 +/- 93 dyne X sec/cm5; P less than 0.05) that were associated with increases in cardiac index (1.85 +/- 0.15 to 2.47 +/- 0.20 L/min/m2; P less than 0.02). There was a marked improvement in forearm blood flow (1.98 +/- 0.14 to 3.02 +/- 0.16 ml/min/dl; P less than 0.01) and a reduction in forearm vascular resistance (45 +/- 3 to 30 +/- 3 U; P less than 0.01). Overall there was no significant change in renal blow flow, renal vascular resistance, or glomerular filtration rate. However, there was a heterogeneous response of renal blood flow and glomerular filtration rate, such that both were directly correlated with the magnitude of increase of cardiac index (r = 0.587 [P less than 0.05] and r = 0.721 [P less than 0.01], respectively). After milrinone there were no significant overall or subgroup changes in urinary sodium excretion, blood volume, plasma renin activity, urinary aldosterone levels, plasma or platelet vasopressin levels, or plasma norepinephrine levels. Thus 1 month of therapy with milrinone improves systemic and forearm hemodynamics, but its effects on renal blood flow and function were heterogeneous. These heterogeneous effects on regional blood flow may depend on the relative vasodilator and inotropic effects of milrinone.

Abnormal desmopressin-induced forearm vasodilatation in patients with heart failure: dependence on nitric oxide synthase activity.

BACKGROUND: Peripheral vasodilatation in response to muscarinic agonists has been shown to be subnormal during heart failure. However, a more recent study suggested that the abnormal muscarinic-induced vasodilatation was not due to abnormal nitric oxide synthase activity. This study was designed to show that nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation and to determine whether vasodilatation mediated by nitric oxide synthase is abnormal during heart failure. METHODS: Desmopressin (10, 50, and 100 ng/min) was infused into the brachial artery of 10 healthy subjects and eight patients with heart failure, and forearm blood flow was measured by venous occlusion plethsymography. Desmopressin responses were then recorded during inhibition of nitric oxide synthase with L-monomethylarginine or after aspirin. RESULTS: In healthy subjects, desmopressin caused a significant (p < 0.001) dose-dependent increase in forearm blood flow of 0.9 +/- 0.6, 4.0 +/- 2.6, and 7.9 +/- 2.6 ml/min/dl, respectively. Desmopressin responses in heart failure of 0.8 +/- 0.6, 1.7 +/- 1.4, and 3.1 +/- 1.0 ml/min/dl were significantly less (p < 0.001) than normal. L-Monomethylarginine reduced desmopressin responses in normal subjects (p < 0.01), and this inhibitory effect was significantly (p < 0.01) greater than in patients with heart failure. Aspirin did not affect desmopressin-induced vasodilatation. CONCLUSION: Nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation. In response to desmopressin, patients with heart failure have subnormal vasodilatation mediated through nitric oxide synthase.

Adverse influence of baroreceptor dysfunction on upright exercise in congestive heart failure.

To test the hypothesis that baroreceptor autoregulation is an important determinant of exercise performance, the hemodynamic responses to the gravitational stress of head-up tilt and upright exercise were assessed in 41 patients with severe chronic congestive heart failure. Three patterns of autonomic dysfunction during head-up tilt were identified. Group A patients had near-normal circulatory reflexes whereas Group B patients experienced orthostatic hypotension and Group C patients lacked the afferent stimulus of venous pooling. Group A patients had a significantly longer exercise duration than both Groups B and C (607 +/- 104 versus 330 +/- 86 and 365 +/- 53 seconds, respectively, p less than 0.05) and a significantly higher double product at peak exercise (17,779 +/- 956 versus 12,235 +/- 869 and 13,760 +/- 998, respectively, p less than 0.05). Thus, baroreceptor abnormalities in the autoregulatory response to postural change are important determinants of the cardiovascular responses required during exercise and influence exercise performance. These abnormalities may help clarify the discrepancies between supine and upright exercise performance and may influence the long-term efficacy of vasodilator therapy in chronic congestive heart failure.

Evaluation of calcium-mediated vasoconstriction in chronic congestive heart failure.

Intercellular vascular smooth muscle calcium results in vasoconstriction and is therefore a potentially adverse mechanism of increased afterload in chronic congestive heart failure. Therefore, an evaluation was made of supine and tilt hemodynamic data, sympathetic reflexes, and the hormonal response to calcium channel antagonism after administration of nifedipine in nine patients with severe chronic congestive heart failure. After a 10 mg oral dose, the peak hemodynamic response occurred at 30 minutes and was characterized primarily by afterload reduction, improvement of systemic flow, and reduction of pulmonary hypertension. Despite reduction of supine blood pressure, there was no orthostatic hypotension during head-up tilt at the same time of peak response. Reflex responses to sympathetic stimulation (cold pressor test) were improved but still attenuated when compared with normal responses. Plasma renin activity increased significantly, but a dissociation of the aldosterone response was observed. Plasma catecholamine levels were not significantly altered. In summary, calcium antagonism resulted in significant afterload reduction and hemodynamic improvement in chronic congestive heart failure. This was associated with improved reflex responsiveness and, potentially, altered other vasoconstrictor hormones independently of the hemodynamic response. Calcium antagonism may provide a means to further understand vasoconstrictor mechanisms in heart failure and enhance therapy in appropriate patient subsets.