The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure.

OBJECTIVES: We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure. BACKGROUND: The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented. METHODS: Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF)< or =40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks. RESULTS: There was an improvement in functional status, as reported by the patient (p<0.001) and physician (p<0.001) at 12 weeks. Dose-dependent improvements in LVEF (p<0.001) and LV end-systolic wall stress (sigma) (p<0.05) were seen, together with a reduction in systolic blood pressure (p<0.05). There was evidence of a natriuretic effect (p<0.001), and total blood volume decreased (p<0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p<0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p<0.001) and epinephrine (p<0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated. CONCLUSIONS: The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.

A method of left ventricular ejection fraction estimation from cineangiocardiograms employing a special-purpose calculator.

A special-purpose calculator is described which computes the left ventricular ejection fraction and end-diastolic volume (and thus stroke and end-systolic volumes) from single-plane cineangiocardiograms. A pair of manual callipers is used to convert the length information of angiographic projections into digital form for processing by the calculator. Volumes are estimated by means of a first order numerical integration method assuming circular cross-section. The angiograms of 42 patients were analysed using both the calculator and a conventional method. The results of the 2 methods correlated very closely (r = 0.99) with a slope within 1% of unity. The calculator is suggested as a practical and cheaper alternative to computer-based systems.

Atrial natriuretic factor in hypertension: bioactivity at normal plasma levels.

To ascertain whether small shifts in plasma atrial natriuretic factor (ANF) exerted biological effects in hypertension, we studied the renal, hemodynamic, and hormonal effects of ANF [human ANF-(99-126)] infused at a dose (0.75 pmol/kg/min for 3 hours) that would induce changes in plasma ANF confined to the normal, resting range, in a group of six young men with uncomplicated, mild essential hypertension. During ANF infusions, the patients excreted 11.8 +/- 2.0 mmol (mean +/- SEM) sodium more than during the time-matched placebo phase natriuresis (p less than 0.001, mean increase of 53% above placebo values). Urinary excretion of cyclic guanosine monophosphate rose to more than double (212%, p less than 0.001) placebo values. Plasma renin activity (0.4 +/- 0.05 vs. 0.9 +/- 0.12 nmol/l/hr, p less than 0.0001) and aldosterone concentrations (102 +/- 4 vs. 184 +/- 47 pmol/l, p less than 0.05) were clearly suppressed during administration of ANF. Plasma norepinephrine also fell significantly below placebo values (268 +/- 17 vs. 439 +/- 35 pg/ml, p less than 0.05). Urine volume, the excretion of electrolytes other than sodium, hematocrit, effective renal plasma flow, glomerular filtration rate, and filtration fraction were unaffected by ANF. Similarly, plasma concentrations of epinephrine, arginine vasopressin, adrenocorticotropic hormone, and cortisol were unchanged. Blood pressure and heart rate were unchanged. Minor perturbations in plasma ANF concentrations exert clear biological effects in patients with mild essential hypertension. These data suggest that such minor shifts in plasma ANF are of physiological relevance in mild hypertension and probably contribute to volume homeostasis in this condition.

Brain natriuretic peptide administered to man: actions and metabolism.

To investigate the effects and metabolism of brain natriuretic peptide (BNP) in man, eight normal subjects received 3-h infusions of synthetic porcine BNP (2 pmol/kg.min) in a placebo-controlled study. The MCR and plasma half-life of BNP were 2.69 L/min and 3.1 min, respectively. BNP clearly suppressed PRA to less than 50% of placebo values (P less than 0.001). Plasma aldosterone concentrations were also significantly reduced by 30% (P less than 0.05). Urinary sodium excretion tended to rise (P = 0.054), and urinary cGMP excretion was clearly enhanced (P less than 0.01). Systemic and renal hemodynamics, hematocrit, plasma protein concentrations, plasma ACTH, arginine vasopressin, PRL, and catecholamines were unchanged. Porcine BNP has a similar range of effects and is similarly metabolized in man as human ANP. Further elucidation of the possible role of BNP as a circulating hormone in man awaits measurement of tissue and plasma concentrations of human BNP in health and disease and provision of fuller dose-response data for human as well as porcine BNP.

Atrial natriuretic peptide in humans. Production and clearance by various tissues.

Although it is assumed that the human heart secretes atrial peptides, direct proof is not available. We therefore measured immunoreactive atrial natriuretic peptide levels in coronary sinus blood and simultaneously in femoral arterial and venous blood from patients before and during stepwise incremental atrial pacing of up to 200 beats per minute. Since the fate of circulating atrial peptides is unknown, we also measured immunoreactive atrial natriuretic peptide concentrations in arterial and venous blood across the liver, kidney, lower limb, and lung in patients undergoing cardiological investigation. Peptide levels in coronary sinus blood were higher than in samples from the femoral artery or vein. As the heart rate was accelerated by atrial pacing, peptide concentrations increased in coronary sinus blood and to a lesser extent in peripheral samples. Whereas the levels in venous blood draining the liver, kidney, and lower limb were approximately 50% of those in arterial blood, concentrations were similar in samples drawn simultaneously from the pulmonary artery and the aorta. These results show that the human heart produces immunoreactive atrial natriuretic peptide and that secretion increases with atrial tachycardia. The liver, kidney, and lower limb remove the peptide from arterial blood, but there is little change in its concentration during circulation of blood through the lungs.

Mechanisms in human renovascular hypertension.

To clarify the pathophysiology of renovascular hypertension, we monitored intraarterial pressure continuously and measured hourly hormone levels for 24 hours under carefully controlled conditions in two hypertensive patients with unilateral renal artery occlusion. Comparison of the results with those obtained when the patients were normotensive 3 months after uninephrectomy indicated that, while the renin-angiotensin system played a central role in maintaining the hypertension, the sympathetic nervous system also contributed and, in addition, modulated short-term arterial pressure fluctuations. In the untreated state, the sympathetic regulation of renin secretion was heightened, and angiotensin II/aldosterone dose-responsiveness was augmented. It is suggested that these adaptive changes might serve to offset the tendency to severe sodium depletion and thence exacerbation of the hypertension.

Angiotensin II is more potent than potassium in regulating aldosterone in cardiac failure: evidence during captopril therapy.

Potassium and angiotensin II are major regulators of aldosterone secretion. To assess which of these stimuli is the more potent, we measured aldosterone, potassium, and angiotensin II responses to the oral converting enzyme inhibitor captopril in five patients with resistant congestive heart failure during digoxin and furosemide maintenance therapy. In spite of a positive cumulative potassium balance and a clear-cut rise in plasma potassium, aldosterone levels in plasma and urine declined in parallel with levels of angiotensin II. When captopril treatment was later withdrawn in three patients, angiotensin II and aldosterone levels increased in parallel, while plasma potassium remained steady. The results show that under these study conditions, angiotensin II is more potent than potassium in regulating aldosterone in patients with heart failure.

EC 24.11 inhibition in man alters clearance of atrial natriuretic peptide.

Metabolic clearance and the biological effects of exogenous human atrial natriuretic factor (ANF) were assessed in two groups each of eight normal volunteers receiving 2-h iv infusions of ANF (2.5 pmol/kg.min) on the fifth day of dosing with the orally active inhibitor of endopeptidase 24.11, candoxatril (25 mg every 12 h in group 1 and 100 mg every 12 h in group 2), and placebo in balanced randomized, double blind, placebo-controlled, cross-over experiments. Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively. Calculated MCRs for ANF were significantly reduced by both doses of candoxatril [group 1, 2.5 +/- 0.4 vs. 4.3 +/- 0.6 L/min (P less than 0.01); group 2, 2.3 +/- 0.4 vs. 5.6 +/- 0.8 L/min (P less than 0.001)]. ANF significantly enhanced urinary sodium excretion above preinfusion values in both study phases in both groups. Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1. Inulin clearance was minimally enhanced, and para-aminohippuran clearance was slightly decreased by candoxatril in both groups. Neither effect alone was statistically significant, but derived renal filtration fractions were significantly enhanced in both groups [group 1, 15.5 +/- 0.5% vs. 13.9 +/- 0.6% (P less than 0.01); group 2, 19.3 +/- 1.9% vs. 18.0 +/- 2.7% (P less than 0.01)]. Basal and stimulated cGMP concentrations in both plasma and urine were significantly enhanced by candoxatril in the two groups (P less than 0.001 and P less than 0.01, respectively, for combined data). Urinary ANF immunoreactivity was significantly enhanced by candoxatril in both groups (P less than 0.05 and P less than 0.01 in groups 1 and 2, respectively), with a more pronounced effect evident at the higher dose (P less than 0.01). These results show that chronic pretreatment with an endopeptidase inhibitor in normal man causes a dose-related reduction in the metabolic clearance of exogenous ANF, amplifies cGMP, and increases renal filtration and the natriuretic responses to infused ANF.

Inhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects.

The effects of an orally active inhibitor (UK 79300) of the neutral metalloendopeptidase EC 3.4.24.11 were investigated in six healthy male volunteers maintained on a constant diet (150 mmol sodium/day and 80 mmol potassium/day). Subjects were studied in a random order, single-blind study on two occasions, each 48 hours in length, when they were given UK 79300 (25 or 50 mg p.o.) or placebo at 12-hour intervals (each agent for 24 hours). The endopeptidase inhibitor enhanced plasma concentrations of atrial natriuretic factor in association with suppression of both plasma renin activity and aldosterone concentrations. Twenty-four-hour urinary excretion of sodium was doubled by UK 79300, and the urinary excretion rates of phosphorus, atrial natriuretic factor immunoreactivity, and cyclic guanosine monophosphate were also significantly enhanced, whereas urinary aldosterone excretion was halved. The profile of biological effects closely paralleled those previously reported with low dose infusions of atrial natriuretic factor in humans and animals. Therapeutic trials of such inhibitors are now indicated for hypertension or heart failure together with further studies to clarify the underlying mechanisms of action.

Endopeptidase 24.11 inhibition by SCH 42495 in essential hypertension.

The detailed integrated renal, hormonal, and hemodynamic effects of acute (first dose) and established (4 days) inhibition of endopeptidase 24.11 by SCH 42495 (200 mg, every 12 hours) were documented in eight patients with essential hypertension in a double-blind, balanced random-order, crossover study. SCH 42495 suppressed plasma endopeptidase activity (> 90%, P < .001) for the duration of the dosing period. Initially, plasma atrial natriuretic factor levels increased markedly (+123%, P < .01) and remained elevated, although to a lesser extent (+34%, P < .01), with established enzyme inhibition. Cyclic guanosine monophosphate in both plasma and urine remained elevated throughout the treatment period. Significant augmentation of sodium excretion in excess of placebo values (96 +/- 27 mmol sodium, P < .001) was established in the initial 24 hours of dosing but later became attenuated, with a mild antinatriuresis (P < .01) in the latter 3 days of treatment. Blood pressure, heart rate, the renin-angiotensin-aldosterone system, and plasma norepinephrine levels were all initially (first dose) unchanged. With established enzyme inhibition (day 4), however, blood pressure was significantly lower (mean 24-hour values, 9.3 +/- 3/-3.8 +/- 1 mm Hg, P < .05 for both systolic and diastolic pressures) than matched placebo values, whereas heart rate was higher (2.7 +/- 1 beats per minute, P < .01). Mean 24-hour values of plasma renin activity (+33%, P < .05), aldosterone (+36%, P < .05), and norepinephrine (+40%, P < .001) were all clearly increased above placebo values with established enzyme inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic hormone has biological effects in man at physiological plasma concentrations.

Whether atrial natriuretic hormone (ANH) has biological effects at physiological plasma levels in man is not known. Accordingly, we investigated the effects of a 3-h low dose infusion of human ANF (0.75 pmol/kg.min; i.e. 0.0023 micrograms/kg.min) in six normal men, whose sodium intake was normal while sitting, in a single blind, random order, placebo-controlled study. The ANF infusions induced changes in plasma ANH concentrations entirely within the range for normal subjects. The small increases in plasma ANH values were associated with a significant rise in urinary excretion of sodium, magnesium, calcium, and cGMP. PRA and plasma aldosterone concentrations uniformly decreased to 50% and 64% of placebo values, respectively. Systolic and mean arterial pressures fell significantly from preinfusion values during the ANH infusions. These findings constitute strong evidence that ANH is a hormone of physiological significance in the regulation of body fluid volumes in normal man.

The effects of pathophysiological increments in brain natriuretic peptide in left ventricular systolic dysfunction.

Plasma levels of brain natriuretic peptide (BNP) are raised in patients with left ventricular impairment and may play a role in the adaptation to left ventricular impairment. Manipulation of BNP levels may have therapeutic potential. The effects of BNP have not been well studied in patients with left ventricular impairment. We studied the effects of low-dose BNP infusion, reproducing the increment in plasma BNP seen with progression from mild to severe heart failure in patients with impaired left ventricular systolic function. BNP was infused in a placebo-controlled, single-blind, crossover design at a rate of 3.3 pmol x kg(-1) x min(-1) over 4 hours to 8 patients with a history of congestive heart failure and persistent impairment of left ventricular systolic function (left ventricular ejection fraction <35%). Endocrine, renal, and hemodynamic effects were measured. Compared with time-matched placebo-control, BNP infusion decreased mean systemic arterial pressure (peak decrease, 17.1 mm Hg; P=.04), mean pulmonary artery pressure (peak decrease, 6.1 mm Hg; P=.007), mean pulmonary capillary wedge pressure (peak decrease, 5.5 mm Hg; P=.04), and systemic vascular resistance (peak decrease, 1400 dyne s(-1) cm(-5); P=.015), but cardiac output and heart rate were unchanged. Urinary volume and urinary excretion of sodium and potassium were not altered. BNP infusion increased plasma cGMP (2.3-fold change, P=.002). Plasma atrial natriuretic peptide levels were increased for the first hour of BNP infusion (peak increase, 11.5 pmol/L; P=.005). Plasma aldosterone levels were unchanged during but increased over time-matched control levels after the end of the BNP infusion (peak increase, 90 pmol/L; P=.02). Plasma renin activity and cortisol and catecholamine levels were unchanged. Low-dose infusion of BNP causes favorable hemodynamic changes and relative neurohormonal suppression but has attenuated renal effects in patients with impaired left ventricular systolic function.

Endogenous angiotensin-aldosterone-pressure relationships during sodium restriction.

The effects of moderate restriction of dietary sodium and potassium supplementation on plasma levels of renin, angiotensin II, aldosterone, and cortisol and on arterial pressure were studied in 12 patients with mild essential hypertension. To define hormone-blood pressure relationships, venous hormone levels were measured hourly and intra-arterial pressure continuously for 24 hours after 4 to 6 weeks of sodium restriction, 4 to 6 weeks of potassium supplementation, and a similar period of control diet. Our results show that compared with the control diet, moderate sodium restriction was associated with increased levels of aldosterone but no overall change in renin, angiotensin II, or cortisol levels. Further, slopes of regression lines relating log renin and log angiotensin II to aldosterone were increased, as were log cortisol/aldosterone regression lines. On the contrary, regression lines of log renin and log angiotensin II versus arterial pressure were unaltered by sodium restriction. Hormone and blood pressure relationships were not changed by the potassium supplemented diet. Although confirmatory data are needed, our findings suggest that moderate sodium restriction enhances aldosterone responsiveness to endogenous angiotensin II and adrenocorticotropic hormone without diminishing the pressor activity of endogenous angiotensin II. These results may explain in part the disappointingly small hypotensive effect of modest sodium restriction in mild essential hypertension.

Effects of alpha-human atrial natriuretic peptide in essential hypertension.

Because there is little published information on the effects of atrial peptides in hypertensive humans, 100 micrograms of alpha-human atrial natriuretic peptide was injected intravenously into six patients with essential hypertension in a double-blind, placebo-controlled study under standardized conditions of body posture and dietary sodium and potassium intake. The peptide increased urine sodium excretion sixfold in the first 30 minutes. Smaller increments occurred in urine volume and in calcium, magnesium, and phosphorus excretion; the rise in urine potassium concentration was not statistically significant. Most of these indices returned to time-matched placebo values within 1 hour, but urine sodium excretion remained high for 2 1/2 hours. Arterial pressure fell within 2 minutes of alpha-human atrial natriuretic peptide injection, then returned to matching placebo levels by 10 minutes. Conversely, heart rate increased rapidly and remained elevated for 3 hours. The peptide induced a prompt, brief rise in plasma norepinephrine concentration and a more sustained fall in epinephrine and aldosterone levels, but it did not affect plasma renin activity or cortisol concentration. Compared with normotensive volunteers studied previously under the same conditions, the hypertensive subjects had a greater response in urine volume and sodium, calcium, and magnesium excretion but a less sustained fall in arterial pressure.

Arterial pressure and hormone relationships in phaeochromocytoma.

To investigate the regulation of arterial pressure and vasoactive hormones in phaeochromocytoma, we measured intra-arterial pressure and hourly venous hormones (renin, angiotensin II, aldosterone, catecholamines and cortisol) for 24 h in two patients before and three months after removal of a catecholamine-secreting tumour. Before surgery, plasma catecholamines, renin and angiotensin II levels showed a weak inverse correlation with arterial pressure, whereas after surgery norepinephrine-blood pressure correlations were close and positive. Heart rate and arterial pressure fluctuations were reciprocal during short-term recordings but were parallel after removal of the tumour. Renin, angiotensin II and aldosterone levels, initially elevated, fell into the normal range after surgery. Circulating norepinephrine correlated in a positive fashion with renin before and after operation. Slopes of log renin (or angiotensin II)/aldosterone, and log cortisol/ aldosterone regression lines were steeper in the initial study compared to the second. We conclude that arterial pressure fluctuations measured hourly are not determined by concurrent levels of catecholamines or angiotensin II in phaeochromocytoma, although we surmise that minute-by-minute changes in blood pressure are catecholamine-related. Renin release is, at least in part, controlled by circulating catecholamines. Aldosterone responsiveness to angiotensin II and to ACTH is enhanced in phaeochromocytoma.

Prolonged inhibition of endopeptidase 24.11 in normal man: renal, endocrine and haemodynamic effects.

The renal, hormonal and haemodynamic effects of chronic (4 days) dosing with an inhibitor of endopeptidase EC 3.4.24.11 (UK 79300) were assessed in two groups, each of eight normal volunteers, receiving 25 mg every 12 h (group 1) or 100 mg every 12 h (group 2) of UK 79300 in double-blind, balanced-randomized, placebo-controlled, crossover studies. Group 2 (but not group 1) exhibited a significant transient natriuresis (P less than 0.01) and a consequent sustained negative cumulative sodium balance (70 +/- 21 mmol) which was established within 48 h and remained for the duration of dosing with UK 79300. Urine and plasma cyclic guanosine monophosphate (cGMP) levels rose significantly above placebo values (P less than 0.01 and P less than 0.001, respectively) in both groups and the effect was sustained throughout the dosing period. Plasma atrial natriuretic factor (ANF) was slightly enhanced by UK 79300 in group 1 (P less than 0.05) but not significantly increased in group 2. Despite a significant increase in heart rate in both groups (P less than 0.001) and of natriuresis in group 2, there was minimal evidence of renin-aldosterone activation in either group. Trends towards lower systolic pressures, observed in both groups, did not attain statistical significance. These findings suggest chronic treatment with UK 79300 induces an increase in tissue ANF levels, with sustained enhancement of plasma and urine concentrations of ANF second messenger (cGMP) and increased heart rate.

Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II.

AIM: To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension. METHODS: Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies. RESULTS: Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-four-hour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic GMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides. CONCLUSIONS: Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems.

Hormone, calcium and blood pressure relationships in primary hyperparathyroidism.

The cause of hypertension in primary hyperparathyroidism and its response to corrective surgery remains a matter of controversy. We therefore studied blood pressure, vasoactive hormones and plasma calcium responses to parathyroidectomy in six hypertensive and two normotensive patients with primary hyperparathyroidism. Twenty-four-hour intra-arterial pressure recordings, together with hourly blood sampling for plasma renin activity (PRA), aldosterone, cortisol, catecholamines and calcium levels, were undertaken in each patient before surgery and were repeated under identical conditions 3-6 months after parathyroidectomy. Mean plasma calcium was 3.03 +/- 0.1 before, and 2.35 +/- 0.02 mmol/l after, parathyroidectomy. Changes in arterial pressure were small and variable in individual patients. Group mean arterial pressures before and after surgery were identical. Plasma cortisol and PRA were significantly higher in the hypercalcaemic state (P less than 0.01 and P less than 0.05, respectively) but there was no significant difference in plasma aldosterone or catecholamine levels. No correlations between changes in plasma calcium or parathyroid hormone levels and concomitant changes in plasma concentration of other hormones were observed. Our findings show that correction of primary hyperparathyroidism has no systematic effect on arterial pressure in a heterogeneous group, including some patients with probable background essential hypertension, when evaluated 3-6 months after surgery. Compared with values after corrective surgery, mean levels of PRA and cortisol-but not aldosterone or catecholamines--are elevated in patients with primary hyperparathyroidism. These findings are consistent with an inhibitory effect of raised ionic calcium concentration on the response of the adrenal glomerulosa to angiotensin and adrenocorticotrophic hormone.

Therapeutic controversies with use of beta-adrenoceptor blockade in heart failure.

In response to early reports indicating a beneficial adrenoceptor effect of beta blockade, 2 small trials were conducted to investigate the hemodynamic effects of acute and chronic beta-adrenoceptor blockade in patients with congestive cardiomyopathy. Acute beta-blocker therapy with intravenous acebutolol, 25 mg, resulted in a significant decline in cardiac performance, whereas chronic therapy with acebutolol, 200 mg twice daily, resulted in no beneficial effects on exercise tolerance, as reported by the original Swedish investigators. Further, beta-adrenoceptor blockade has been associated with a number of clinical problems: beta blockers tend to interfere with the compensatory mechanisms that support circulation during early or mild heart failure and therefore have little value as routine therapy at that stage of the disorder. Although excessive beta-adrenoceptor blockade may worsen ventricular function by decreasing myocardial contractility, beta blockers appear to have a useful role in patients with moderate heart failure accompanied by tachycardia. Carefully titrated doses of beta blockers in conjunction with afterload-reducing agents may also provide a benefit in patients with rapid heart rates and grossly elevated levels of circulating catecholamines.

Hemodynamic effects of nitroprusside on valvular aortic stenosis.

The effects of acute reduction of left ventricular (LV) loading in valvular aortic stenosis (AS) were examined. Thirty-five consecutive patients with AS (peak-to-peak aortic valve gradient 66 +/- 26 mm Hg, aortic valve area 0.65 +/- 0.22 cm2) were given intravenous sodium nitroprusside (1 to 3 micrograms/kg/min) to reduce systolic aortic pressures by greater than 10 mm Hg (mean aortic pressure 99 +/- 15 to 80 +/- 15 mm Hg; p less than 0.001). Overall, nitroprusside infusion resulted in little change in cardiac index (2.72 +/- 0.61 to 2.67 +/- 0.58 liters/min/m2; p = not significant). Individual patients had a range of responses. Fourteen patients (group 1) had an increase in cardiac index (2.42 +/- 0.59 to 2.74 +/- 0.67 liters/min/m2; p less than 0.001), whereas 21 (group 2) had a decrease or no change (2.93 +/- 0.56 to 2.61 +/- 0.52 liters/min/m2; p less than 0.001). Comparison of these subgroups showed that a cardiac index increase with nitroprusside was significantly predicted by a higher LV end-diastolic pressure (26 +/- 12 vs 15 +/- 6 mm Hg), lower LV ejection fraction (44 +/- 18 vs 62 +/- 12%). smaller aortic valve area (0.52 +/- 0.12 vs 0.74 +/- 0.22 cm2) and lower cardiac index (2.42 +/- 0.59 vs 2.93 +/- 0.56 liters/min/m2) (all values groups 1 and 2, respectively). It is concluded that there is a disparate response to acute vasodilatation in AS. Potentially beneficial effects are seen in a subgroup of patients, especially those with increased filling pressures and impaired LV function.(ABSTRACT TRUNCATED AT 250 WORDS)