Interaction of the sympathetic nervous system and electrolytes in congestive heart failure

Congestive heart failure is characterized by both disturbances in electrolyte homeostasis and neuro-hormonal regulation. Total body potassium is reduced, and this reduction bears a modest relation to activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Patients with decompensated heart failure show increases in both plasma epinephrine and plasma norepinephrine, whereas patients with chronic stable heart failure usually have an increase only in plasma norepinephrine. High levels of circulating epinephrine may contribute to the development of hypokalemia by activating skeletal muscle and liver membrane beta 2-adrenergic receptors, which in turn stimulate intracellular cyclic adenosine monophosphate to activate the membrane-bound Na+K(+)-adenosine triphosphatase pump. The net result is that potassium flux across the cell membrane from the extracellular to the intracellular space increases, setting the stage for hypokalemia and possibly serious ventricular arrhythmias. Other mechanisms that may contribute to the development of hypokalemia in heart failure include the kaliuresis brought on by excessive levels of aldosterone. Moreover, it is likely that the activity of facilitated by concomitant activation of the renin-angiotensin system. Increased sympathetic nerve activity may then release additional renin from the kidney (by way of a beta 2-adrenergic mechanism). Therefore, both the sympathetic nervous system and the adrenal medulla may interact to cause hypokalemia in patients with heart failure. Because hypokalemia is known to predispose patients to ventricular arrhythmias, it may be prudent to aggressively maintain serum potassium levels in patients with heart failure in the range of 4 to 5 mEq/liter.     

Deactivation of the sympathetic nervous system in patients with chronic congestive heart failure

In this article, we review the basic biology, signal transduction pathways, and clinical pharmacology associated with cardiac β-adrenergic receptors (β-ARs) in the context of the use of β-blocking agents in patients with chronic congestive heart failure. Adrenergic receptors, particularly the β-AR subtypes (β₁-AR and β₂-AR), are known to play a critical role in the modulation of cardiac function, providing for both "adaptive" and "maladaptive" compensatory changes. In the context of exercise or self-preservation, the adrenergic nervous system, acting via β-ARs permits an appropriately rapid, highly-dynamic increase in cardiac function. Conversely, in individuals with chronic congestive heart failure, the sustained, heightened activation of adrenergic nervous system, as manifested by increases in circulating catecholamines, results in downregulation and desensitization of myocardial β-ARs, and potentially, significant myocardial damage. A number of recent clinical trials have demonstrated a marked mortality benefit from using β-blocking agents such as metoprolol and carvedilol in patients with heart failure. The pharmacologic properties of several of these drugs and some of the specifics of their usefulness and limitations are discussed herein.     

The relationship of the sympathetic nervous system and the renin-angiotensin system in congestive heart failure

Congestive heart failure is a complex clinical syndrome characterized by circulatory and metabolic abnormalities. It has been apparent for more than 25 years that the sympathetic nervous system and the renin-angiotensin-aldosterone system are markedly activated in the late stages of heart failure. These two systems interact to facilitate sympathetic drive and promote salt and water retention. Circumstantial evidence is now accumulating to indicate that excessive sympathetic drive and angiotensin II activity may contribute to the pathophysiology of heart failure. These observations suggest that a dual strategy of modulating sympathetic nervous system activity to the heart while blocking angiotensin II activity may provide a rational therapeutic approach to the treatment of heart failure. Xamoterol, a beta 1 partial agonist, may enhance myocardial contractile force in the steady state, while acting to inhibit excessive sympathetic drive during exercise or severe heart failure. The concomitant use of a converting-enzyme inhibitor would be expected to blunt the detrimental effects of excessive angiotensin II activity. Modulation of adrenergic drive coupled with inhibition of marked angiotensin II activity may be potentially more effective in the treatment of congestive heart failure than either strategy used alone.     

Angiotensin inhibitors and other vasodilators with special reference to congestive heart failure

Summary ACE inhibitors have emerged as important pharmacologic agents for treatment of hypertension and heart failure. Attenuation or inhibition of angiotensin mediated vasoconstriction appears to be the principal mechanism for the reduction of arterial pressure and systemic vascular resistance.     

Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term maintenance therapy with prazosin in congestive heart failure

We evaluated the effects of long-term maintenance therapy with oral prazosin (6-20 mg, mean 14 +/- 2 mg/d) in 14 patients with congestive heart failure. The patients were followed for 6 +/- 1 months. Eleven of the fourteen patients reported subjective improvement. Two patients required increased diuretics because of gain in body weight. Systolic blood pressure showed a slight but sustained decrease suggesting persistent vasodilator effect. Reductions in echocardiographic left ventricular end-diastolic (6.35 +/- 0.25-5.88 +/- 0.25 cm, p less than 0.05) and end-systolic (5.16 +/- 0.35-4.73 +/- 0.28 cm, p less than 0.05) diameters were observed at 2 months. However, the cardiothoracic ratio on chest x ray was unaltered. Maximum exercise tolerance time increased in eight patients (57%) during prazosin therapy. Improvement in exercise tolerance time was observed in patients with most marked clinical improvement, suggesting presence of cardiac reserve. Two patients died suddenly after reporting subjective improvement. This study shows sustained clinical improvement in most patients with heart failure treated with oral prazosin.     

Dissociation of the responses of the renin-angiotensin system and sympathetic nervous system to a vasodilator stimulus in congestive heart failure

The ability of neurohumoral reflex control mechanisms to respond to a vasodilator mediated alteration in hemodynamic status was studied. A sodium nitroprusside infusion was administered to 5 normal subjects and 47 patients with severe congestive heart failure resulting in significant decreases in mean arterial pressure and in systemic vascular resistance. As expected in normals the vasodilator stimulus caused a reflex activation in both the renin-angiotensin system and sympathetic nervous system as measured by increased plasma renin activity and plasma norepinephrine, respectively. In the patients with heart failure, plasma renin activity rose similarly in response to nitroprusside (+63% in heart failure, 100% in normals, P = NS) while plasma norepinephrine remained essentially unchanged (+11% in heart failure, 98% in normals, P less than 0.01). These data demonstrate that the neurohumoral dysfunction seen in patients with heart failure is not uniform. In patients with severe congestive heart failure the renin-angiotensin system apparently is activated by mechanisms other than sympathetic nervous stimulation. This intact reflex humoral response may still function in opposition to the beneficial hemodynamic effects produced by direct vasodilators such as nitroprusside.     

Sympathetic nervous system response to exercise in patients with congestive heart failure

The response of the sympathetic nervous system to exercise in patients with congestive heart failure was studied in 65 patients (NYHA functional class I 28, II 23, and III 14) and 22 normal subjects (N) by submaximal treadmill testing with the modified Bruce's or Sheffield's protocols. Plasma norepinephrine (NE) and epinephrine (E) levels were also measured at rest, at the end of each stage, and immediately after and 5 min after exercise. In accordance with the severity by NYHA functional class, the exercise duration became shorter and the discontinuation of exercise with symptoms occurred more frequently. Systolic blood pressure and double products (DP) at the peak exercise were significantly lower in patients with NYHA class III. NE and increments of NE increased during exercise [peak NE (pg/ml); N: 589, I: 646, II: 1253, and III: 997] and were higher at rest, during exercise and in recovery in patients with NYHA classes II and III than in the normal subjects and NYHA class I patients. E increased gradually during exercise [peak E (pg/ml); N: 60, I: 66, II: 63, and III: 66] and there were no significant differences among the four groups. A negative correlation (r = -0.53) between the peak NE and exercise duration was observed in normal subjects, while a positive correlation (r = 0.55) was observed in patients with NYHA class II. A positive correlation (r = 0.54) between DP at the peak exercise and the peak NE was observed in patients with NYHA class I, whereas a negative correlation (r = -0.46) was observed in patients with NYHA class III. The NE response in patients with NYHA classes II and III increased significantly, suggesting compensatory activation of the sympathetic nervous system for impaired cardiac function. In conclusion, the NE response to submaximal exercise testing differs in each NYHA functional class and it might be a useful indicator to evaluate cardiac function of patients with congestive heart failure.     

Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure.

AIMS: To investigate whether strong cardiac sympathetic activity contributes primarily to sudden death or to worsening heart failure, and to determine the relationship of the size of cardiac noradrenaline stores to the mode of death. METHODS AND RESULTS: The study population comprised 116 patients with congestive heart failure (ejection fraction 19+/-7%) and a mean follow-up of 18+/-19 months. Cardiac sympathetic nervous function was measured using coronary sinus blood sampling and noradrenaline isotope dilution methodology. Cardiac sympathetic activity was estimated from cardiac noradrenaline spillover, and noradrenaline stores from the overflow of the tritiated noradrenaline metabolite [(3)H]dihydroxyphenylglycol, which is produced by monoamine oxidase inside nerve endings. Small cardiac noradrenaline stores (below median) predicted death from worsening heart failure (hazard ratio=4.18, P<0.05), particularly if cardiac noradrenaline spillover was elevated (hazard ratio=2.36 per tertile, P<0.01), indicating progression of disease associated with defective sympathetic innervation. In contrast, large stores (hazard ratio=2.81, P<0.05), especially if coupled with increased noradrenaline spillover (hazard ratio=1.64 per tertile, P<0.05), were related to sudden death. CONCLUSION: High cardiac sympathetic activity is a risk factor for sudden death, particularly in the presence of intact cardiac sympathetic innervation. Conversely, progression of myocardial disease and heart failure is closely associated with depletion of sympathetic nerves in the heart, especially if rates of noradrenaline release paradoxically remain high.     

Contribution of the renin-angiotensin-aldosterone system to development of tolerance and fluid retention in chronic congestive heart failure during prazosin treatment

To determine the effects of the renin-angiotensin-aldosterone system on development of tolerance and fluid retention in patients with chronic congestive heart failure during long-term prazosin treatment, plasma renin concentration, aldosterone, norepinephrine and maximal exercise tolerance were measured during chronic therapy with digitalis and diuretics, to which prazosin, captopril or a combination of both drugs was added. Plasma renin concentration and aldosterone level decreased slightly during prazosin therapy and norepinephrine level increased significantly. When captopril was given, plasma renin concentration increased as expected, aldosterone level normalized and norepinephrine level decreased significantly. When prazosin was added to captopril therapy, norepinephrine level increased and plasma renin concentration and aldosterone level did not change. Exercise capacity did not increase during prazosin treatment, but was increased with captopril treatment. Prazosin treatment was associated with an increase in body weight even though the dose of furosemide was increased. Inhibition of the renin-angiotensin system did not prevent fluid retention induced by prazosin during combination therapy. These findings suggest that the renin-angiotensin-aldosterone system is not substantially involved in development of tolerance and fluid retention during prazosin therapy; stimulation of plasma norepinephrine may be of decisive importance.     

First dose hypotension with enalapril and prazosin in congestive heart failure

Since the introduction of angiotensin converting enzyme inhibitors into the adjunctive treatment of patients with congestive heart failure, cases of severe hypotension, especially on the first day of treatment, have occasionally been reported. To assess the safety of the angiotensin converting enzyme inhibitor enalapril a multicenter, open, randomized, prazosin-controlled trial was designed comparing the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 mg prazosin. Subjects were 1210 inpatients with New York Heart Association functional class (I)/II and III who were not adequately compensated with digitalis and/or diuretics. In the group receiving enalapril, 3 patients (0.5%) experienced severe hypotension on day 1 and 28 patients (4.7%) moderate hypotension. In those given prazosin, 15 patients (2.6%) experienced severe hypotension and 60 patients (10.3%) moderate hypotension. The difference is statistically significant (P less than or equal to 0.000012). All patients recovered. It was concluded that treatment of patients suffering from congestive heart failure New York Heart Association functional class (I)/II or III with enalapril is comparably well tolerated.     

Beneficial hemodynamic response to chronic prazosin therapy in congestive heart failure

Thirteen patients with advanced congestive heart failure (CHF) were treated with prazosin. Following the first dose, cardiac output (CO) (mean ± SD) rose from 3.2 ± 1.2 to 4.3 ± 1.1 L/min, pulmonary artery diastolic pressure (PAD) decreased from 23 ± 12 to 18 ± 11 mm Hg, mean arterial pressure (MAP) decreased from 85 ± 10 to 76 ± 10 mm Hg, and heart rate did not change (92 ± 15 vs 92 ± 14 bpm). At the end of a 48 to 72 hour titration to an optimal regimen, significant effects on CO (3.2 ± 1.1 vs 4.5 ± 1.3 L/min), PAD (24 ± 12 vs 18 ± 8 mm Hg), and MAP (84 ± 10 vs 76 ± 10 mm Hg) were still seen. The patients were restudied after 3 months of treatment. In contrast to reports of rapid development of tolerance to prazosin, we found continued beneficial effects on CO (3.0 ± 1.3 vs 3.8 ± 1.0 L/min) and PAD (23 ± 12 vs 18 ± 10 mm Hg), without significant change in MAP (81 ± 11 vs 78 ± 8 mm Hg). We found wide variability in the CO rise in response to prazosin, which was not accounted for by differences in plasma prazosin concentration. Systemic vascular resistance in the untreated state did correlate with the percentage change in CO. In addition, excessive lowering of the PAD appeared to blunt the CO response in some cases.     

The contributions of sympathetic tone and the renin-angiotensin system to severe chronic congestive heart failure: Response to specific inhibitors (prazosin and captopril)

The contribution of sympathetic tone and the renin-angiotensin system to the pathogenesis of chronic heart failure was evaluated. In 20 paired studies of the same 10 patients, the baseline hemodynamic and humoral correlates of congestive heart failure, and the response to alpha adrenergic blockade (prazosin) and angiotensin converting enzyme inhibition (captopril) were assessed. Despite the extent of failure, baseline plasma renin activity ranged from normal to very high. In contrast, baseline plasma catecholamlne levels were always elevated. Baseline plasma norepinephrine reflected the severity of heart failure, correlating inversely with baseline cardiac index before administration of both drugs. Comparable improvement in left ventricular function was noted after acute therapy. Baseline renin and norepinephrine did not predict the response to prazosin, but baseline renin did predict the response to captopril: pulmonary wedge pressure (r = ?0.776, p < 0.01), stroke index (r = 0.752, p < 0.02), systemic vascular resistance (r = ?0.673, p < 0.05).In summary, elevated levels of plasma norepinephrine were inversely correlated with baseline cardiac function, but norepinephrine levels did not change despite improved hemodynamics with specific prazosin therapy. The renin-angiotensin system exhibited a wide spectrum of activity and hemodynamic improvement with captopril was related to this activity. Absence of a correlation between plasma norepinephrine and plasma renin activity suggested that their contributions to vasoconstriction were not interdependent. Increased sympathetic tone was consistent in severe heart failure, whereas renin-angiotensin activity differed widely. The response to captopril can be used to identify a subset of patients with severe heart failure and adverse angiotensin-mediated vasoconstriction.     

Renal effects of low dose prazosin in patients with congestive heart failure

Activation of the sympathetic nervous system may contributeto the renal vasoconstriction and sodium retention seen in congestiveheart failure. Previous studies in congestive heart failurepatients employing large doses of prazosin that lowered systemicblood pressure have been generally disappointing. The renalhaemodynamic and segmental tubular effects of low non-depressordoses of prazosin (0.25 mg and 0.50 mg) were examined in eightfemale patients with mild to moderate congestive heart failure.Segmental tubular function was assessed by the lithium clearancemethod. Compared to placebo, prazosin caused a significant increasein urinary sodium excretion (from 56±7 to 92±7µmol. min^–1, P<0.01), paralleled by significantincreases in fractional excretion of sodium and lithium. Glomerularfiltration rate and effective renal plasma flow were not alteredby prazosin. Prazosin pre-treatment did not alter any of therenal responses to frusemide treatment (mean dose 85±14mg).This study demonstrates that low non-depressor doses of prazosinhave a clear natriuretic effect in congestive heart failurepatients, which is predominantly established by interferencewith tubular reabsorption.