M. G. Nicholls

Immunoreactive amino‐terminal pro‐brain natriuretic peptide (NT‐PROBNP): a new marker of cardiac impairment

Human brain natriuretic peptide‐32 (BNP) (i.e. proBNP(77–108)), the mature form of BNP and secreted predominantly by the cardiac ventricle, is formed from a high molecular weight precursor, proBNP(1–108). We have recently identified the aminoterminal form proBNP(1–76) (NT‐proBNP) in human plasma but its source, metabolism and production in circulatory disorders are unknown. We have investigated the relationship between immunoreactive (IR) NT‐proBNP and BNP‐32 in normal and hypertensive subjects and in patients with cardiac impairment, as well as the regional plasma concentrations in patients undergoing routine cardiac catheterization.

RENAL, HAEMODYNAMIC, AND HORMONAL EFFECTS OF HUMAN ALPHA ATRIAL NATRIURETIC PEPTIDE IN HEALTHY VOLUNTEERS

The effects of atrial natriuretic peptide (ANP) were investigated in six healthy male volunteers taking a constant diet (120 mmol sodium and 60 mmol potassium daily). They were given an intravenous bolus of 100 micrograms human alpha-ANP on one day or placebo on another day 1-3 weeks apart in a double-blind randomised study. After ANP, urinary sodium excretion increased four-fold, and urine volume, calcium, magnesium, and phosphorus excretion doubled within 30 min of the injection. ANP induced an immediate fall in arterial pressure, followed by a longer vasodepressor phase which exceeded the duration of the effect on electrolyte excretion. There were no significant changes in plasma renin activity, aldosterone, antidiuretic hormone, or noradrenaline when compared with placebo.

Diurnal Patterns of Blood Pressure, Heart Rate and Vasoactive Hormones in Normal Man

In order to determine arterial pressure and vasoactive hormone relationships in normotensive man, we measured intra-arterial pressure continuously along with hourly venous hormone levels (renin, angiotensin II, aldosterone and catecholamines) for 24 hours in 5 healthy volunteers under standardized conditions. Mean 24-hour levels of intra-arterial pressure 106/63 +/- 5.4/4.9 mmHg were much lower than in patients with mild essential hypertension studied earlier. A common diurnal pattern was seen for plasma renin, angiotensin II, and catecholamines, with higher levels in the day time and lower levels at night. Aldosterone levels however, paralleled those of cortisol at night. Plasma norepinephrine levels showed close, positive correlations with arterial pressure in all volunteers. We conclude that the level of blood pressure as measured continuously over 24 hours is lower than might be expected from regular clinic recordings; that aldosterone regulation is contributed to by ACTH in the nocturnal hours; and that fluctuations in arterial pressure and sympathetic activity over 24 hours are closely coupled.

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.

The Role of the Circulation in Processing pro-Brain Natriuretic Peptide (proBNP) to Amino-Terminal BNP and BNP-32

Human proBNP (purified from cardiac tissue) was incubated at 37 degrees C in whole blood, serum and plasma and the products analyzed by size exclusion high pressure liquid chromatography and radioimmunoassay (RIA). In addition to RIAs for BNP-32 and NT-proBNP(1-13), a newly developed RIA for proBNP(62-76) was also used to identify the peptides. Incubation with serum resulted in the formation of a 9 kDa and a 3 kDa peptide, consistent with the N-terminal and the C-terminal peptides of the propeptide. Minimal processing of proBNP was seen in blood or plasma, suggesting that the circulation does not play a major role in the activation of proBNP. Analysis of degradation products of human proBNP using site directed specific antisera indicates that removal of N-terminal amino acids from proBNP occurs in serum. These findings support the view that the high molecular weight BNP-32 previously identified in human plasma comprises amino-terminal deleted forms, and is unlikely to be intact proBNP(1-108).

HAEMODYNAMIC, HORMONAL, AND ELECTROLYTE RESPONSES TO CAPTOPRIL IN RESISTANT HEART FAILURE

In five patients with resistant heart failure treated with the oral converting-enzyme inhibitor, captopril, standardised and intensive haemodynamic, hormone, and electrolyte monitoring showed significantly raised cardiac output and reduced arterial, pulmonary-wedge, and pulmonary-artery pressures which correlated closely with concomitant alterations in the activity of the renin-angiotensin system. These changes occurred in the absence of a natriuresis or diuresis. Clinical improvement was dramatic and paralleled the objective haemodynamic changes. Hyponatraemia and a rise in plasma-potassium were noted. Captopril is a major advance in the treatment of resistant heart failure, and its beneficial haemodynamic effects relate primarily to a blockade of the renin-angiotensin system, the activity of which is increased by conventional drug therapy.

Differing Metabolism and Bioactivity of Atrial and Brain Natriuretic Peptides in Essential Hypertension

Plasma concentrations of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in severe hypertension, acute myocardial infarction, and heart failure. In the current study of individuals with essential hypertension, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of these two peptides given alone or in combination in equimolar doses calculated to induce increments in plasma peptides to concentrations (30 to 60 pmol/L) observed in these disease states. The metabolic clearance rate of ANP (4.56 +/- 0.62 L/min) was greater than that for BNP (3.4 +/- 0.23 L/min, P <.001). Infusions of each cardiac hormone impaired the clearance of coinfused peptide. All peptide infusions enhanced natriuresis (17% to 70% above preinfusion levels versus placebo, 6%; P <.001), lowered blood pressure (10 to 18 mm Hg fall in mean arterial pressure below placebo levels; P <.001), increased hematocrit, suppressed the renin-angiotensin-aldosterone system, and enhanced plasma norepinephrine concentrations. The natriuretic and blood pressure-lowering effects of BNP were twofold to threefold those of ANP. In contrast, ANP-induced increments in plasma and urinary second messenger (cGMP) levels were greater than those for BNP. Both peptides suppressed the renin-angiotensin-aldosterone system (approximately one-third fall in renin activity and plasma aldosterone) and enhanced plasma norepinephrine concentrations (+30%) to a similar degree. Increments in plasma ANP and BNP that occur simultaneously in cardiovascular disease states appear capable of causing hemodynamic, endocrine, and renal effects that would tend to ameliorate conditions such as hypertension or heart failure.

Degradation of Human Adrenomedullin(1-52) by Plasma Membrane Enzymes and Identification of Metabolites

Very little is known about degradation or metabolism of adrenomedullin. To this end, we incubated adrenomedullin with ovine adrenal, kidney and lung plasma membrane preparations and showed the major degradation products were ADM(2-52) and ADM(8-52). Smaller amounts of ADM(26-52), (27-52), (28-52) and (33-52) were also produced. Degradation was inhibited by EDTA and 1,10 phenanthroline but not by phosphoramidon, leupeptin and pepstatin. The above data are consistent with initial hydrolysis adjacent to hydrophobic residues by a metalloprotease, generating ADM(8-52), (26-52) and (33-52), followed by an aminopeptidase action to produce ADM(2-52), (27-52) and (28-52). Improved understanding of the metabolism of ADM may have therapeutic implications, for example in the treatment of heart failure.

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)

Plasma Brain Natriuretic Peptide and Endopeptidase 24.11 Inhibition in Hypertension

In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angiotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (P < .05, both groups) but suppressed plasma brain natriuretic peptide (P < .01, both groups) in association with significant falls in arterial pressure (P < .05, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20 +/- 5 vs 13 +/- 3 pmol/L, P < .05), whereas brain natriuretic peptide was unchanged (7 +/- 0.3 vs 7 +/- 0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 +/- 11 vs 17 +/- 4 pmol/L, P < .05, and 7.5 +/- 0.6 vs 5.5 +/- 0.4 pmol/L, P < .05, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure.(ABSTRACT TRUNCATED AT 250 WORDS)