Peter F. Semple

Putative mechanisms of cough after treatment with angiotensin converting enzyme inhibitors.

Background: A dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors, even if it is not particularly serious. Controlled studies have suggested that the incidence may eventually be as high as 20% and the problem seems to occur much more often in women. Mechanism of ACE inhibitor cough: The mechanism of the cough associated with ACE inhibitor treatment is unrelated to inhibition of the renin-angiotensin system because treatment with angiotensin receptor blockers and renin inhibitors has not caused similar problems. Other substrates of ACE have been implicated, and the side effect has been linked in particular to an accumulation of bradykinin or tachykinins in the airways with consequent stimulation of vagal afferents that subserve the cough reflex, particularly the non-myelinated or C fibres. Some of the effects of bradykinin in particular may be due to secondary activation of prostaglandins (PG), especially PGE2 and PGI2. Anecdotal evidence that cyclooxygenase inhibitors prevent the cough has not been sustained in well controlled clinical trials, but recent evidence suggests that inhaled cromoglycate may have a significant inhibitory effect. The mechanism of action of cromoglycate is not well understood but evidence of inhibition of local neural reflexes has been inferred, mostly from animal studies. The observation seems unlikely to have much practical benefit for it is difficult to envisage routine use of an inhaled agent to prevent a drug side effect. The question of whether ACE inhibitors are safe in patients with asthma is still open, and most rechallenge studies have shown little effect on lung function. Data from one large-scale surveillance study suggest that a few individuals may experience dyspnoea and wheezing but no causal relationship has been established. Conclusion: Delineation of the mechanism of the ACE inhibitor cough may lead to a better understanding of the mechanism of cough in inflammatory airways disease.

Renal artery stenosis managed by Palmaz stent insertion: technical and clinical outcome.

Objective To assess the technical and clinical outcome of Palmaz renal artery stent insertion in patients with renal artery stenosis. Design Twenty-nine patients with radiological evidence of renal artery stenosis and hypertension (16 patients, mean±SD diastolic blood pressure 100.5±8.16 mmHg) and/or renal impairment (17 patients, mean±SD serum creatinine 376±169 μmol/l) were referred for radiological intervention. Of these, 22 had ostial atheromatous lesions, six had atheromatous non-ostial lesions and one patient had fibromuscular dysplasia. Palmaz stent insertion was performed where either previous or concomitant percutaneous transluminal renal angioplasty (PTRA) had been unsuccessful. Technical success was defined primarily as <30% residual stenosis. A prospective radiological and clinical follow-up was performed and the results compared with the outcome following PTRA alone in a similar group of patients from our centre. Results Immediate technical success was achieved in all 29 patients. Follow-up angiography in 24 patients after a mean of 7 months showed restenosis in four patients. The hypertension was not ‘cured’ in any patient; a blood pressure fall was observed in seven patients (44%) and no change in the remaining nine subjects (56%). Renal function improved in four patients (24%), two of whom had angiotensin converting enzyme inhibitor-exacerbated renal impairment. This compares with an immediate technical success of 81% for PTRA alone, with cure in 50% and improvement in 32% of patients with hypertension and improvement in renal function in 64.7% of patients with renal impairment. Conclusions Palmaz renal artery stent insertion has a higher technical success rate than PTRA, but the clinical improvement is disappointing in our patient population.

Angiotensin II levels, hemodynamics, and sympathoadrenal function after low-dose captopril in heart failure

The angiotensin converting enzyme inhibitor captopril improves the altered hemodynamics in many patients with chronic heart failure, but the first dose may precipitate hypotension. Ten patients with chronic heart failure were studied, nine with high plasma concentrations of renin and one with a low concentration. Frequent measurements of plasma concentrations of angiotensin II, renin, and catecholamines were made over 60 minutes after a small dose (6.25 mg) of captopril and related to concurrently measured hemodynamic variables. Captopril caused a decrease in systemic and pulmonary artery pressure and an increase in cardiac index, and these changes coincided with reductions in the plasma concentrations of angiotensin II and increases in plasma concentrations of renin. The hemodynamic changes were accompanied by reductions in the plasma concentrations of norepinephrine but transient increases in plasma concentrations of epinephrine in patients in whom vasomotor syncope developed. The patient with a low plasma renin concentration showed little hemodynamic response to the drug. It is concluded that vasomotor syncope occurs quite frequently in patients with severe chronic heart failure after captopril in a small dose and is associated with a selective increase in epinephrine secretion from the adrenal medulla.

Effects of potassium on sodium balance, renin, noradrenaline and arterial pressure.

To determine the effects of potassium on blood pressure and factors affecting blood pressure, we conducted a randomized, placebo controlled trial of a potassium chloride-based substitute for table salt in 23 patients with mild to moderate essential hypertension. In addition, the effects of potassium chloride on sodium balance were studied in 10 normal subjects. Potassium loading with 100 mmol/day over five days in these normal subjects caused a cumulative negative sodium balance of 138 +/- 35 mmol, similar in degree to that achieved by severe dietary sodium restriction. However, two weeks of potassium treatment (100 mmol/day) in patients with essential hypertension did not lower blood pressure (BP) either in the supine or upright positions (potassium treatment: mean BP 108 +/- 3 lying and 113 +/- 3 mmHg standing; placebo treatment: mean BP 109 +/- 3 lying and 115 +/- 3 mmHg standing). Patients found it difficult to tolerate the potassium-based salt substitute in the dose given. We conclude that it is premature to recommend an increase in potassium chloride intake as treatment for raised blood pressure.

Relation of blood pressure with body and plasma electrolytes in Conn's syndrome.

Thirty-four patients with untreated Conns syndrome were studied in a metabolic ward. The final diagnosis in each case was based on the finding and removal of an adrenal cortical adenoma with histological features typical of the disorder. Compared with 34 age and sex-matched normal controls the untreated patients had increased plasma aldosterone concentration, increased blood pressure (183/112 mmHg), increased exchangeable sodium (116.7% of normal), hypokalaemia and increased plasma sodium concentration. Exchangeable potassium was lower than normal and plasma concentrations of active renin, total renin and angiotensin II were lower than normal mean values. Arterial pressure correlated significantly and positively with plasma and exchangeable sodium and there was a significant negative correlation with plasma potassium concentration. Partial regression analysis showed that the relation of exchangeable sodium with blood pressure did not depend on age or renal function but that the relation of blood pressure and plasma potassium could be attributed to the correlation of exchangeable sodium and blood pressure. Multiple regression analysis suggested that exchangeable and plasma sodium were the most important determinants of blood pressure in untreated patients. Spironolactone, amiloride and surgical removal of the adenoma corrected the electrolyte abnormality and usually lowered blood pressure. The fall in exchangeable sodium was related to the fall in blood pressure. The pattern of correlation found by multiple regression analysis in postoperative patients was similar to that in normal subjects. The findings are relevant to some of the mechanisms proposed for the hypertension of mineralocorticoid excess.

Regulation of platelet receptors for angiotensin II in man.

The effects of changes in dietary intake of sodium and potassium on 125I-angiotensin II binding to platelets were studied in normal subjects. We also defined binding to platelets from patients with essential hypertension and subjects with normal blood pressure. Restriction of sodium intake in normal subjects resulted in a decrease in the number of receptor sites from 6.2 +/- 0.3 sites/cell to 4.1 +/- 0.4 sites/cell (P less than 0.01) but there were no changes in affinity as measured by the Kd. Over a range of sodium intakes from 15 to 200 mmol/day there was a negative correlation between plasma concentration of angiotensin II and receptor site concentration (rs = 0.57, P less than 0.01). Changes in dietary potassium did not affect angiotensin II binding. Angiotensin II binding was also measured in 10 patients with essential hypertension (mean blood pressure [BP] 178/107 mmHg, plasma concentrations of renin [PRC] 12 +/- 2 microU/ml and angiotensin [pANG] II 14 +/- 2 pg/ml) and 10 subjects with normal blood pressure (mean BP 112/74 mmHg, PRC 13 +/- 2 microU/ml, pANG II 13 +/- 2 pg/ml). In the hypertensive patients, binding capacity and affinity (Kd = 5.0 +/- 0.6 X 10(-10) M, 5.7 +/- 0.8 sites/cell) were similar to those in the normotensive subjects (Kd = 4.9 +/- 0.8 X 10(-10) M, 5.4 +/- 0.5 sites/cell). Changes in sensitivity to angiotensin II in essential hypertension may not be determined at receptor level. Angiotensin II receptors in platelets respond to changes in sodium intake like receptors in arterial muscle.

Bromocriptine: lack of effect on the angiotensin II and aldosterone responses to sodium deprivation.

Five normal subjects took a low sodium diet for four days on two occasions, one with and one without added bromocriptine 2.5 mg three times a day by mouth. Daily measurements of urinary electrolytes and the concentrations of plasma renin (PRC), angiotensin II (AII), aldosterone, 18‐hydroxycorticosterone, cortisol, electrolytes and prolactin were made in both phases of the study. Deprivation of sodium without bromocriptine resulted in progressive and highly significant increases in the plasma concentration of aldosterone from 230 ± 50 to 418 ± 44 (SEM) pmol/l, 18‐hydroxycorticosterone from 627 ± 138 to 1420 ± 478 pmol/l, PRC from 108 ± 38 to 166 ± 14 μU/ml and AII from 16 ± 3 to 29 ± 4 pmol/l. Similar changes were found during bromocriptine administration despite suppression of prolactin secretion. Sodium deprivation together with bromocriptine resulted in increases in the plasma concentrations of aldosterone from 230 ± 47 to 416 ± 72 pmol/l, 18‐hydroxycorticosterone from 630 ± 99 to 1629 ± 552 pmol/l, PRC from 105 ± 12 μU/ml and AII from 14 ± 3 to 26 ± 5 pmol/l. Plasma cortisol did not change either in response to sodium deprivation or bromocriptine. Mean cumulative negative sodium balance was 101 ± 14 mmol on bromocriptine and 118 ± 14 mmol in the control period. We conclude that prolactin is not necessary for the steroidogenic response to sodium deprivation in man.

Potassium influx into erythrocytes in essential hypertension.

Sodium plus potassium (Na+K) cotransport in erythrocytes of patients with essential hypertension has mainly been studied elsewhere by measuring net outward frusemide-sensitive Na and K movements. We compared K influx (tracer 86 Rubidium) in control subjects and hypertensives who had never previously been treated for hypertension. The cotransport K influx rates in controls and hypertensives were 0.44 +/- 0.02 (mumol/ml cells/h; mean +/- s.e.; n = 20) and 0.67 +/- 0.06 (mumol/ml cells/h; mean +/- s.e.; n = 23) respectively. The active influxes were 1.03 +/- 0.03 and 2.06 +/- 0.13 (mumol/ml cells/h; mean +/- s.e.) respectively. The variance of both parameters was significantly greater in the hypertensive group but, taking this into account, the differences were significant (P less than 0.01).

Angiotensin Receptor Assay and Characterization

Publisher Summary This chapter reviews the methods used for characterization and quantification of the angiotensin receptor in different cells and tissues. Angiotensin II (AII) has effects on many tissues, mostly related to cardiovascular regulation and electrolyte homeostasis. Angiotensin peptides are readily radioiodinated at the tyrosine position using chloramine-T, lactoperoxidase, and solid-phase Iodogen methods. The latter method causes minimal oxidation damage to the peptide and is preferred. The chapter discusses the effects of ligand degradation and the use of peptidase inhibitors in receptor assays. The nonpeptide compounds act as pure competitive antagonists. High-affinity binding to a Golgi fraction from liver has been shown to represent receptors internalized from the cell surface. Receptor internalization has also been observed in cultured cells and in adrenal cortex in vivo, and intracellular receptors may be present in these and other tissues. In general, membrane fractions are used for receptor identification and characterization, and for quantification in altered physiological or pathological states. Internalized receptors appear to be rapidly recycled to the cell surface after release and subsequent degradation of the ligand, measuring the total cell receptor number, may, therefore, provide a valid measure of cell or tissue responsiveness to AII.