Genetic hypertension. A direct link to salt.
The basis of one type of inherited hypertension has been discovered-it is caused by mutations in the gene for the beta subunit of a renal sodium channel.
Amino Acid Sequence↗
Biomedical subjects
B Leckie
Publications and source records attributed to B Leckie.
Production of atrial natriuretic peptide and cell proliferation in ventricular myocytes given angiotensin II in culture.
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Angiotensin II↗
Inactive renin levels in recurrent nephroblastoma.
A prospective study of four children with nephroblastoma has demonstrated elevation of plasma inactive renin levels at the time of detection of recurrent disease. Three of the four children had been shown to have elevated inactive renin levels at their initial presentation with primary nephroblastoma. These levels returned to normal following operation and chemotherapy. The observation provides further evidence that plasma inactive renin may be a useful tumour marker for nephroblastoma.
Child↗
Importance of RAA system and the treatment of patients with ACE inhibition after myocardial infarction.
There is activation of the renin angiotensin system after both complicated and uncomplicated myocardial infarction. Angiotensin II increases myocardial oxygen consumption whilst reducing coronary flow and is also directly toxic to the myocardium. Angiotensin converting enzyme inhibitors produce beneficial haemodynamic and neuroendocrine changes in patients with acute left ventricular failure, and may have a role in selected patients with cardiogenic shock. There is evidence to suggest that they might prevent the development of late cardiac failure by limiting the extent of post infarction ventricular dilation. Further research is necessary to define their role in the treatment of acute myocardial infarction.
Angiotensin II↗
Hypertension. Stress on the renin gene.
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Animals↗
Atrial natriuretic peptide after acute myocardial infarction.
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Atrial Natriuretic Factor↗
Plasma renin levels in patients with thoracic neuroblastoma.
Plasma renin levels are elevated in neuroblastoma as in nephroblastoma patients. Unlike nephroblastoma, the active component appears to predominate. Patients with thoracic neuroblastoma produce high levels of renin by the tumour, which thus excludes an ischaemic aetiology as the source.
Humans↗
Effects of the renin inhibitor H77 on angiotensin II, arterial pressure and cardiac function in conscious dogs: comparison with captopril.
The renin inhibitor H77 and the angiotensin I converting enzyme (ACE) inhibitor captopril were compared in separate experiments with infusion of 5% dextrose as a control for the effects on plasma angiotensin II (Ang II) concentration, arterial pressure and cardiac function, measured by Swan-Ganz catheter, in conscious dogs. The effects of a high dose of H77 (10 mg/kg per h) were similar to those of high-dose captopril (6 mg/kg per h). Both reduced plasma Ang II concentration, systemic vascular resistance and arterial pressure; both increased the heart rate; both increased cardiac output but the change was significant only with captopril; neither affected stroke volume, pulmonary artery pressure or pulmonary vascular resistance; both reduced left and right atrial pressures. The similar pattern of effects for the two inhibitors suggests that the mechanism by which they act is the same--reduction in Ang II--and that the cardiovascular effects of H77 are not a specific action of the peptide that is unrelated to the reduction in plasma Ang II concentrations.
Angiotensin II↗
Effect of metoprolol on serial measurements of exchangeable sodium, blood pressure, renin and pulse rate in spontaneously hypertensive rats.
The cardioselective beta-blocker metoprolol was mixed with the diet (6 mg metoprolol/g food) and given to 9 spontaneously hypertensive rats (SHR) for four weeks, while 9 other SHR were given the plain diet only and served as controls. All rats were also given 0.5% drinking saline labeled with isotope 22Na (37 kBq/1) to drink. Measurements of total exchangeable sodium, blood pressure, pulse rate and weight were performed before and repeatedly during treatment. Plasma renin activity was measured at the end of the study. Before treatment exchangeable sodium, blood pressure, pulse rate and weight were no different between the groups. Metoprolol reduced the pulse rate and prevented the usual blood pressure increase in SHR. Both groups gained weight similarly. Exchangeable sodium increased similarly in both groups along with the weight increase. Plasma renin activity was not significantly different in the two groups. Thus, chronic metoprolol treatment of SHR reduced blood pressure and pulse rate in SHR but did not lower plasma renin or cause measurable sodium or fluid retention.
Animals↗
Twice-daily low-dose captopril in diuretic-treated hypertensives.
Twice-daily captopril (25 mg) and placebo were compared in ten hypertensive patients who were already receiving bendrofluazide. After six weeks therapy, captopril produced significant antihypertensive effects one to six hours after dosing but these did not persist at eleven to twelve hours. Plasma renin concentration was increased for twelve hours after captopril but inhibition of angiotensin II activity was lost by twelve hours. During the period when captopril reduced blood pressure significantly, effective renal plasma flow and hepatic blood flow were unchanged although renal vascular resistance was reduced. There was no evidence that captopril altered plasma sodium, potassium or magnesium concentrations following bendrofluazide. Thus, in thiazide-treated patients, captopril 25 mg produces significant blood pressure reduction for at least six hours after dosing, without impairing renal or hepatic blood flow. However, twice-daily low-dose captopril does not adequately control blood pressure throughout the dosage interval.
Adult↗
The contractile effects of porcine tetradecapeptide renin substrate in human resistance vessels: evidence of activation by vascular wall renin and serine proteases.
In order to test the hypothesis that the contraction induced in human resistance arterioles by porcine tetradecapeptide renin substrate (TDP) is mediated by enzymes specific to the renin-angiotensin cascade, human resistance vessels from skin and subcutaneous fat were mounted in a myograph and exposed to TDP in the presence and absence of the human renin inhibitor H261, the serine protease inhibitor aprotinin, a polyclonal anti-human renin antibody and captopril. TDP induced a dose-dependent contraction that could be abolished by saralasin. The sensitivity to TDP was significantly attenuated by H261, aprotinin and combinations of captopril with aprotinin and captopril plus aprotinin and H261, as indicated by a significant reduction in pD2 (-log10ED50 [mmol/l]) for TDP. However, captopril alone was ineffective. It was concluded that at physiological pH, porcine TDP induces contraction in human resistance vessels by the action of enzymes not specific to the renin-angiotensin cascade. Whilst a clear inhibitory effect of H261 was demonstrated, a significant comparable inhibition by captopril and a polyclonal renin antibody was not observed. This may reflect the difficulty with which these inhibitors gain access to their intracellularly located substrates.
Electric Stimulation↗
Neuroendocrine activation after acute myocardial infarction.
The extent of neuroendocrine activation, its time course, and relation to left ventricular dysfunction and arrhythmias were investigated in 78 consecutive patients with suspected acute myocardial infarction. High concentrations of arginine vasopressin were found within six hours of symptoms, even in the absence of myocardial infarction (n = 18). Plasma catecholamine concentrations also were highest on admission, whereas renin and angiotensin II concentrations rose progressively over the first three days, not only in those with heart failure but also in patients with no clinical complications. Heart failure, ventricular tachycardia, and deaths were associated with extensive myocardial infarction, low left ventricular ejection fraction, and persistently high concentrations of catecholamines, renin, and angiotensin II up to 10 days after admission, whereas in uncomplicated cases concentrations had already returned to normal.
Arginine Vasopressin↗
Haemodynamic effects of captopril in acute left ventricular failure complicating myocardial infarction.
Activation of the renin-angiotensin system in acute myocardial infarction may have important haemodynamic consequences. The effects of captopril were assessed in nine patients with acute left ventricular failure complicating myocardial infarction. Plasma angiotensin II was elevated at 16.8 (3.6) pmol/l (mean [SE]) including high levels in three of four patients in the absence of any previous therapy, including diuretics. Repeated low doses of captopril were administered to reduce pulmonary capillary wedge pressure less than 14 mm Hg or to a maximum total dose of 25 mg. Right atrial pressure fell from 12.4 (0.9) to 9.4 (0.7) mm Hg p less than 0.001, pulmonary arterial pressure from 32.7 (3) to 26.4 (2.2) p = 0.01, and pulmonary capillary wedge pressure from 25.7 (2.9) to 19.9 (2.2) p = 0.01. Despite a fall in systemic vascular resistance from 1,540 (110) to 1,330 (76) dyn/s/cm5, and mean arterial pressure from 84.8 (3.9) to 76.7 (2.7) p = 0.001, changes in cardiac output were small: 3.8 (0.3) to 4.2 (0.3) NS. Angiotensin II fell in all patients even after only 3.125 mg to a mean of 3.6 (1.0). These improvements occurred whether basal angiotensin II was elevated or normal, and in the presence or absence of diuretic therapy. At 24 hours, seven patients received captopril in the maximum titrated dose of the previous day. Haemodynamic changes at one hour were of similar magnitude to those during incremental dosing. These results suggest that reduction of angiotensin II exerts beneficial haemodynamic effects in heart failure complicating acute myocardial infarction.
Angiotensin II↗
Malignant hypertension due to a renin-secreting renal cell carcinoma--an ultrastructural and immunocytochemical study.
This is a case report of a 14-year-old girl who presented with malignant hypertension. She had high plasma levels of both active and inactive renin and investigation revealed a renal tumour. The tumour, a renal cell carcinoma, was removed by nephrectomy following which the blood pressure and the plasma renin levels fell to normal. An immunocytochemical study using an antibody to pure human renin showed no detectable renin in the kidney but the tumour contained a population of granular cells which showed strong positive staining for immunoreactive renin. We present the clinical, biochemical, histological, immunocytochemical and ultrastructural features of this case as evidence that this was a renin-secreting renal cell carcinoma.
Adolescent↗
Renin inhibitors: their use in understanding the role of angiotensin II as a pressor hormone.
Infusion of H.261, the inhibitor of human renin in the baboon, lowered blood angiotensin I, plasma angiotensin II, and arterial pressure suggesting that in the sodium-depleted state angiotensin II contributes to the maintenance of arterial pressure. In a second experiment dose-response infusions of angiotensin II were given in conscious sodium-depleted dogs before and during infusion of the renin inhibitor H.77. These suggested that the contribution of angiotensin II to the maintenance of arterial pressure in this state was made mainly by a circulating peptide. Preliminary results in normal humans show that infusion of H.142 intravenously lowered angiotensin I, angiotensin II, and arterial pressure.
Adult↗
Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects.
Amiloride (75 mg daily) and spironolactone (300 mg daily) were given to five normal subjects for 7 days in order to compare metabolic effects at maximal doses. Blood pressure, body weight, Na+ and K+ balance, and plasma concentrations of Na+, K+, active and total renin, angiotensin II, aldosterone, 11-deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OH DOC), corticosterone (B), 18-hydroxycorticosterone (18-OH B) and cortisol were measured before and on each day of treatment. Natriuresis and K+ retention were significantly greater with amiloride. Plasma K+ increased from 4.1 +/- 0.2 to 4.9 +/- 0.2 mmol/l (mean +/- s.d.) on amiloride and from 4.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l with spironolactone. Stimulation of renin, angiotensin II, aldosterone and 18-OH B occurred with both drugs but was greater with amiloride in each case. A transient decrease in systolic and diastolic blood pressure was observed after 2 days of spironolactone treatment but not with amiloride. The slope of the regression of aldosterone on angiotensin II during spironolactone treatment was less than that with amiloride, consistent with partial blockade of aldosterone synthesis by spironolactone. These data suggest that the maximum metabolic effects of amiloride exceed those of spironolactone.
Adult↗
Purification of human renin by affinity chromatography using a new peptide inhibitor of renin, H.77 (D-His-Pro-Phe-His-LeuR-Leu-Val-Tyr).
A new affinity column for renin was prepared by coupling the isosteric peptide inhibitor of renin, H.77 (D-His-Pro-Phe-His-LeuR-Leu-Val-Tyr, where R is a reduced isosteric bond, -CH2-NH-), to activated 6-aminohexanoic acid-Sepharose 4B. Chromatography of a crude extract of human kidney cortex on this material resulted in a 5500-fold purification of renin in 76% yield. The purified enzyme (specific activity 871 units/mg) was free of non-specific acid-proteinase activity and was stable at pH 6.8 and -20 degrees C over a period of several weeks.
Chromatography, Affinity↗
New inhibitors of human renin tested in vitro and in vivo in the anaesthetized baboon.
A new inhibitor of human renin (H. 189) is described. It is a decapeptide analogue of human renin substrate with the amino acid, statine, substituted for leucine in the scissile bond. Its inhibitory potency as shown by IC50 is 1.0 X 10(-8) M with human plasma renin and 1.5 X 10(-8) M with baboon plasma renin. It is less effective with dog and rat renin, but its inhibitory potency with human renin is similar to that of another inhibitor of ours (H. 142) having a reduced isostere in the scissile bond. H. 189 has some inhibitory effect on cathepsin D (IC50 6.5 X 10(-5) M) but H. 142 has no discernible effect. Pepstatin, on the other hand, was highly effective against cathepsin D (IC50 1.2 X 10(-8) M). H. 142 and H. 189 were infused intravenously at 10 mg/kg/h in four anaesthetized salt-deplete baboons (Papio hamadryas). The activity of renin in plasma decreased markedly as did the circulating concentration of its products, angiotensin I and angiotensin II.
Anesthesia, General↗