Howard M. McAlpine's research while affiliated with Ninewells Hospital and other places

N. PRASAD, C. C. LANG, H. M. MCALPINE, A-M. J. CHOY, T. M. MACDONALD AND A. D. STRUTHERS Department of Clinical Pharmacology and Cardiology, Ninewells Hospital and Medical School, Dundee, UK. Introduction Brain natriuretic peptide (BNP) is a relatively recent addition to the family of natriuretic peptides (1). Although originally isolated from the porcine brain, BNP, like atria1 natriuretic peptide (ANP), is a cardiac hormone which is synthesized and secreted into the circulation by the heart (1,2). Increased cardiac secretion of BNP has been reported in patients with predominant left-sided heart failure (2,3). No information is available for patients with haemodynamic alterations limited to the pulmonary circulation for BNP, although plasma ANP concen- trations have been shown to be elevated in pul- monary hypertension (4,5). We report measurement of plasma BNP concentrations in two patients with pulmonary hypertension undergoing right heart car- diac catheterizations. The patients were maintained on oxygen during the study as hypoxaemia can cause ANP release (6). We also report the effect of nifedipine, a calcium antagonist and potent vaso- dilator, on plasma BNP levels in one of these patients. Case 1 A 57-year-old female was referred to our hospital with a 3-yr history of progressive fatigue and increas- ing dyspnoea with recent onset of ankle swelling. Her medical history was unremarkable. Physical exami- nation revealed peripheral cyanosis, a right ventricu- lar heave and a loud pulmonary component to the second heart sound. Investigations included a normal

This study examined the effects of lisinopril on diastolic function in 12 normotensive patients (mean age 72 years) with symptomatic congestive heart failure, intact left ventricular systolic function and abnormal diastolic function secondary to ischaemic heart disease in a placebo-controlled double blind crossover study, with each treatment dosed orally for 5 continuous weeks. Compared to placebo, lisinopril significantly decreased blood pressure, increased plasma renin activity without altering heart rate or plasma norepinephrine. There was no statistically significant improvement with lisinopril in radionuclide derived peak filling rate and time to peak filling rate, in Doppler echocardiographic measurements of the ratio of peak flow velocity in early diastole to the peak flow velocity of atrial contraction (E:A ratio) and in visual analogue scales of symptoms. Thus, although angiotension converting enzyme inhibitors may have an established role in the treatment of heart failure secondary to left ventricular systolic dysfunction, its use in patients with isolated diastolic dysfunction remains unclear.

A case is described in which bis (1, 1 dioxoperhydro-1, 2, 4-thiadiazinyl-4-) methane (Taurolin) has saferly been administered on a long term basis to prevent recurrent sepsis in a patient receiving parenteral nutrition. A 26-year-old male with Crohn's disease receiving parenteral nutrition suffered repeated episodes of sepsis and developed an infected intra-atrial thrombus despite repeated courses of antimicrobial chemotherapy and surgical intervention. Continued parenteral nutrition was essential du5e to intestinal failure. Taurolin was administered in the parenteral feed, as a 0.3% solution, to prevent recrudescent and recurrent infection. This concentration was shown, in vitro, to be bactericidal to a variety of pathogenic organisms. No recurrence of sepsis, nor any evidence of side effects was observed throughout the 12 month period of Taurolin administration. After 12 months the taurolin was discontinued and within 2 weeks the patient was re-admitted with recurrent septicaemia. Following re-introduction of Taurolin the infection was controlled and the patient remains well. In our experience the addition of taurolin to the nutritive feeds of a patient at risk of sepsis is a safe and effective method of preventing recurrent sepsis.

Brain natriuretic peptide (BNP) is a cardiac ventricular hormone that may be a sensitive and specific marker of changes in ventricular function. In a prospective, randomised open trial with 16 patients followed for 6 months after first Q wave anterior myocardial infarction we set out to determine: whether BNP concentrations are raised acutely, the effect on circulating BNP of angiotensin-converting enzyme (ACE) inhibition, how BNP and atrial natriuretic peptide (ANP) concentrations compared as correlates of left-ventricular ejection fraction, and whether plasma BNP concentrations could distinguish patients with low (< 40%) and relatively preserved (> 40%) ejection fractions. Plasma concentrations of BNP measured on days 2, 7, 8, 42, and 180 postinfarction were significantly raised in patients compared with normal controls and to a proportionately greater degree than ANP concentrations. Treatment with placebo (n = 8) or oral captopril (n = 8) from day 8 resulted in significantly lower BNP concentrations at days 42 (p = 0.05) and 180 (p < 0.05) in the captopril-treated group. Compared with ANP, BNP concentrations were much more strongly correlated with radionuclide-measured left-ventricular ejection fraction at days 2, 42, and 180. All 8 patients with baseline (day 2) ejection fractions of 40% or above had plasma BNP concentrations less than 10 pmol/L, whereas the 8 patients with ejection fractions less than 40% had BNP concentrations greater than 10 pmol/L. Our findings suggest that measurements of circulating BNP may identify those patients with significant left-ventricular dysfunction who have been highlighted by the Survival and Ventricular Enlargement study as likely to benefit from long-term ACE inhibition after myocardial infarction.

The purpose of this investigation was to study whether favorable renal effects might contribute to the influence of captopril in offsetting ventricular dilatation after infarction. Effective renal plasma flow and glomerular filtration rate were estimated by isotope injection methods in 20 patients on days 2, 7, 8, 42 and 180 after a first transmural anterior myocardial infarction. After measurements on day 7, patients were randomized to receive either captopril 25 mg 3 times daily (n = 10) or placebo (n = 10) for the remainder of the study. At baseline (day 7) there were no differences between the 2 treatment groups in radionuclide left ventricular ejection fraction, effective renal plasma flow, glomerular filtration rate or neurohormones. Left ventricular ejection fractions (40 +/- 4% [mean +/- 2 SD] at baseline) were higher in the captopril- than the placebo-treated patients on days 42 (p < 0.05) and 180 (p < 0.01) after infarction. Effective renal plasma flow became significantly higher at all time points after randomization in the captopril-treated group than in the placebo group (p < 0.001). A similar but lesser trend was observed for glomerular filtration rate. Plasma atrial natriuretic factor and aldosterone were significantly higher in the placebo group (p < 0.05). Renal hemodynamic indexes were directly correlated with and neurohumoral indexes inversely correlated with ejection fractions. In a second group of 12 patients with higher baseline ejection fractions (48 +/- 4%) after an inferior infarction, none of these beneficial effects of captopril were demonstrable. It is proposed that in the setting of left ventricular dysfunction after infarction, a prompt and sustained improvement in renal hemodynamics, by reducing inappropriate fluid retention and thus ventricular preload, may be one contributory mechanism by which captopril prevents progression of left ventricular dilatation.

Brain natriuretic peptide (BNP) is a new natriuretic peptide with marked similarity to atrial natriuretic peptide (ANP) in both its amino acid sequence and its biological actions.1 Although originally isolated from the porcine brain, subsequent studies in pigs, rats and humans have shown that BNP is also a cardiac hormone synthesized and secreted from the heart into the circulation.2 The stimulus for BNP release in humans is unclear, although plasma levels of human BNP-like immunoreactivity have been reported to be increased in classical conditions of volume overload, such as congestive heart failure.2 Therefore, it is likely that the release of BNP may be related to an increase in either cardiac pressure or distension. With regard to ANP, there is compelling evidence that atrial distension is the primary stimulus for its release based on observations in patients with cardiac tamponade.3 Relief of tamponade by aspiration results in a reduction in atrial pressure, but an increase in both atrial distension and plasma ANP concentration. Therefore, we compared the plasma concentrations of human BNP-like immunoreactivity and ANP during therapeutic pericardiocentesis in patients with cardiac tamponade.

The efficacy and tolerability of sustained release verapamil (Securon SR) was investigated in twenty-four patients with chronic stable angina. Patients entered four randomised, double-blind treatment periods, each lasting one week of verapamil-SR 240 mg once daily, 360 mg once daily, 240 mg twice daily, and matching placebo. Four patients were withdrawn, but in one instance this was attributable to side effects from verapamil. Among the remaining twenty patients, mean frequency of angina fell from 4.25 episodes during the last five days of placebo to 2.35, 2.6 and 1.3 episodes during respective active treatments (all P less than 0.001). Compared with placebo the median percentage increase in time to 1 mV ST depression during treadmill exercise (12 hours post dose) was significant only with the regimen of verapamil-SR 240 mg given twice daily at +11% (P = 0.04). Total duration of exercise was also significantly longer and maximum ST depression significantly less only with the twice daily treatment (704 + 186 sec vs 648 + 203 sec; P = 0.03, and 1.75 + 0.73 mm vs 2.15 +/- 0.62 mm; P = 0.02). Side effects, predominantly constipation, breathlessness, and swollen ankles, occurred most frequently with verapamil-SR 360 mg. Thus, sustained release verapamil is well tolerated and effective in the treatment of angina. A regimen of 240 mg given twice daily emerges as superior to once daily treatments for 24-hour prophylaxis of angina.