Advances in the treatment of high blood pressure.
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Antineoplastic Agents↗
Biomedical subjects
A E Doyle
Publications and source records attributed to A E Doyle.
The effects of varying doses of angiotensin on renal function and blood pressure in man and dogs.
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Angiotensin II↗
Evaluation of indapamide in the treatment of hypertension.
A randomized double-blind, crossover trial was carried out in twenty hypertensive patients to evaluate the hypotensive efficacy and safety of indapamide. Indapamide in doses of 2.5 mg per day in combination with other antihypertensive agents was as effective in reducing the blood pressure in hypertensive patients as one tablet of Moduretic (50 mg hydrochlorothiazide and 5 mg amiloride). Indapamide induced no changes in serum potassium or uric acid levels and there were no major side effects.
Adult↗
Verapamil in the treatment of hypertension.
A randomized, double-blind, crossover trial was carried out in 17 hypertensive patients to evaluate the hypotensive efficacy and safety of verapamil. Verapamil in doses of 120 mg thrice daily was compared with pindolol in doses of 7.5 mg twice daily. A thiazide diuretic was given with both drugs. Blood pressure fell about 14/11 mm Hg during treatment with either drug compared to the placebo period, and neither drug caused significant side effects. Verapamil did not affect plasma renin concentration.
Adult↗
Comparative trial of mexiletine and lignocaine in the treatment of early ventricular tachyarrhythmias after acute myocardial infarction.
The antiarrhythmic effects of intravenously administered lignocaine and mexiletine were compared over a period of 48 hr in a randomized trial on 24 patients who developed ventricular tachyarrhythmias within 48 hr of the onset of acute myocardial infarction. Mexiletine was given as an initial bolus of 200 mg, followed by an infusion of 1 mg/min reduced to 0.5 mg/min after 1 hr. Lignocaine was given as a bolus of 100 mg, followed by an infusion of 3 mg/min reduced to 2 mg/min after 1 hr. Plasma levels of mexiletine, lignocaine, and monoethylglycinexylidide were monitored. The frequency of "complex" ventricular tachyarrhythmias was significantly lower in the mexiletine-treated group. This group of patients also had significantly fewer ventricular extrasystoles than those receiving lignocaine, the difference being most marked during the second 24 hr of treatment. Too few episodes of ventricular fibrillation occurred for statistical comment. The greater efficacy of mexiletine was not associated with increased drug toxicity.
Adult↗
Comparison of the actions of the angiotensin-converting enzyme inhibitors enalapril and S-9490-3 in sodium-deplete and sodium-replete spontaneously hypertensive rats.
The hypotensive action of the angiotensin-converting enzyme (ACE) inhibitors enalapril and S-9490-3 was examined in conscious, chronically cannulated Na+-replete and Na+-deplete spontaneously hypertensive rats (SHR) of the Okamoto strain. Blood pressure, plasma ACE activity, plasma renin activity (PRA), and pressor responses to intravenous bolus injections of angiotensin I (AI) were measured over a 24-h period following a single oral dose of ACE inhibitor (0.3, 1.0, and 3.0 mg/kg) or vehicle. S-9490-3 caused a significantly greater hypotensive response and inhibition of plasma ACE and AI pressor responses than enalapril for each dose in both diet groups. Single oral doses of both drugs (3 mg/kg) caused slow, progressive falls in blood pressure which were maximal at 12 h. In contrast, inhibition of plasma ACE was maximal 1 h following the oral dose and returned to control levels over the 24-h period. The inhibition of the pressor response to intravenous AI paralleled, and was significantly correlated with, the inhibition of plasma ACE. There was no correlation between the maximal fall in blood pressure with PRA or with inhibition of plasma ACE activity in either diet group. The hypotensive response to both drugs at the 3-mg/kg dose was greater in Na+-deplete SHR than in Na+-replete animals. Both drugs caused large rises in PRA. The ACE inhibitor S-9490-3 is a significantly more potent hypotensive agent than enalapril in the SHR and a significantly more potent ACE inhibitor in vivo. The hypotensive response to both drugs was dissociated in onset and duration from the inhibition of plasma ACE and AI pressor responses.
Angiotensin I↗
The metabolic fate of levodopa in man and animals.
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Animals↗
The relationship of plasma levels of pindolol in hypertensive patients to effects on blood pressure, plasma renin and plasma noradrenaline levels.
1. Fifteen, previously untreated, hypertensive patients were given 20 mg of pindolol, orally. The systolic and diastolic blood pressures fell significantly in 1 h; the effect was maximal 4 h after pindolol, and persisted for at least 8 h. 2. After oral administration of 20 mg of pindolol, its concentration in the plasma reached a peak in 2-3 h. At the end of 8 h, pindolol was not detectable in the plasma. 3. There was a significant relationship between the peak concentration of pindolol in plasma and the maximal change in blood pressure in fifteen previously untreated hypertensive patients. In a separate study of nine-nine hypertensive outpatients taking 15-80 mg of pindolol daily, the blood pressure responses corresponded generally to the concentration of pindolol in plasma 2-3 h after the morning dose. 4. There were no significant changes in plasma renin activity, plasma renin concentration or plasma noradrenaline concentration in the previously untreated patients taking 20 mg of pindolol. There was no relationship between initial plasma renin or noradrenaline levels and blood pressure responses to pindolol. Nor was there any significant relationship between the changes in plasma renin or noradrenaline levels and the changes in blood pressure.
Blood Pressure↗
Sodium balance and plasma renin activity during the development of two-kidney Goldblatt hypertension in rats.
1. In two experiments severe hypertension (systolic blood pressure 180 mmHg) was induced in rats by constricting one renal artery with a silver clip (two-kidney, one clip hypertension; 2KIC). Blood pressure, plasma renin activity (PRA) and body weight were measured for 35 days after clipping. Plasma sodium concentration and carcass sodium content were measured at the conclusion of the experiment. To determine the relationship between sodium intake, PRA and the development of severe hypertension, half of the rats were given a normal diet and water to drink; the other half were given a low sodium diet and 0.9% saline to drink. 2. In both experiments, two patterns of responses were observed. Group (1) had reduced growth rate, and marked elevation of PRA. Some, but not all of these animals had histological evidence of malignant nephrosclerosis in the untouched kidney. In the other group (11), weight gain was normal and PRA was normal or only slightly elevated. 3. Group 1 animals drinking saline, had raised carcass sodium levels, whereas those drinking water had no increase in carcass sodium. 4. The results confirm that hypertension in the 2KIC model is not always associated with a raised PRA. 5. The coexistence of a raised PRA and increased total body sodium suggests that the PRA does not rise as a result of sodium depletion in this model.
Animals↗
Increased sodium permeability of erythrocytes in spontaneously hypertensive rats.
1. The Na permeability of red cells from spontaneously hypertensive rats (SHR) has been studied. In the Japanese Wister-Kyoto strain, a significant increase of 30% in 22Na influx for male SHR was found compared with normotensive male controls. In contrast the Na influx for genetically hypertensive and normotensive New Zealand rats did not differ. Normotensive Wister-Kyoto rats rendered hypertensive by unilateral renal artery clipping, did not show any difference in Na influx from control animals. 2. These results suggest that the Japanese strain of SHR has a genetically determined increase in erythrocyte Na permeability.
Animals↗
Increased conversion of arachidonic acid to vasodilator prostanoids in spontaneously hypertensive rats.
1. Vasodepressor responses to intravenous injection of prostacyclin, arachidonic acid, and nitroprusside were examined in anaesthetized, spontaneously hypertensive rats (SHR) of the Okamoto strain, and in their normotensive Wistar-Kyoto (WKY) controls. 2. Depressor responses to prostacyclin and nitroprusside did not differ significantly between the two strains. 3. The vasodepressor effects of arachidonic acid were greater and much more prolonged in SHR than in WKY. In rats treated with indomethacin (2 mg/kg) arachidonic acid induced only transient depressor responses which did not differ significantly between these strains. 4. It is concluded that SHR do not differ from WKY in their sensitivity to prostacyclin but they have enhanced ability to transform exogenous arachidonic acid into vasodilator prostanoids.
Animals↗
Metabolism of arachidonic acid in the aorta of spontaneously hypertensive rats.
1. The metabolism of [14C]-arachidonic acid has been studied in isolated aortae from age-matched spontaneously hypertensive (SH) rats and their normotensive Wistar Kyoto (WK) controls. 2. High pressure liquid chromatography of extracts of the incubation mixture from both SH and WK rats revealed the presence of 6-oxo-prostaglandin F1 alpha, the hydration product of prostacyclin, and a single, broad peak of unknown metabolites. No thromboxane B2, or prostaglandins E2 of F2 alpha could be detected in aortic incubations. 3. The SH rats produced significantly more 6-oxo-prostaglandin F1 alpha than the WK rats, but there was no difference between the strains in the proportion of label appearing in the unknown peak of the chromatograms. 4. These data confirm that vascular tissue of SH rats has enhanced ability to transform arachidonic acid into prostacyclin. Induction of these enzymes may be an adaptive response to elevated blood pressure, but the mechanism of this effect has yet to be elucidated.
Animals↗
A comparison of the activity of the angiotensin converting enzyme inhibitors SQ 14 225, SA 446, and MK 421.
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3-Mercaptopropionic Acid↗
Differences in arachidonic acid metabolism and effects of aspirin between one- and two-kidney Goldblatt hypertensive rats.
Vasodepressor responses to prostacyclin, nitroprusside and arachidonic acid were compared in two groups of anaesthetized, two-kidney, one-clip Goldblatt rats. The groups were composed of rats which had high blood pressure (greater than 150 mmHg systolic) or normal blood pressure (less than 140 mmHg systolic). The vasodepressor effects of prostacyclin and nitroprusside and arachidonic acid did not differ significantly between hypertensive and normotensive groups when measured as percentages of resting blood pressure. Thus, in contrast to one-kidney Goldblatt hypertensive rats, there is no evidence for increased vascular conversion of arachidonic acid to prostacyclin in the two-kidney hypertensive model. The effect of cyclo-oxygenase inhibition on development of hypertension in one- and two-kidney Goldblatt rats was also studied by treating them daily with aspirin (200 mg/kg orally) from 3 days before until 3 weeks after clipping the renal artery. Aspirin-treated two-kidney rats developed significantly higher blood pressures than vehicle-treated controls, but the blood pressures of aspirin-treated one-kidney rats increased less after clipping than those of vehicle-treated controls. It appears paradoxical that transformation of arachidonic acid to prostacyclin is increased, while aspirin has a blood pressure lowering effect in one-kidney Goldblatt rats. It is suggested that there might be a more fundamental disturbance in arachidonate metabolism in hypertension which might contribute to increased vascular reactivity.
Animals↗
Effect of captopril on brain converting enzyme in the spontaneously hypertensive rat.
The effect of oral captopril (30 mg/kg per day) on the blood pressure, plasma aldosterone concentration, urinary electrolytes and brain angiotensin-converting enzyme activity of spontaneously hypertensive rats of the Okamoto strain was examined. Over a seven day period, captopril caused a progressive fall in blood pressure with increased sodium excretion and urine volume and a significant fall in plasma aldosterone concentration. Following captopril, angiotensin converting enzyme activity increased significantly in the midbrain and medulla oblongata; the pituitary level of angiotensin converting enzyme activity was significantly decreased. The hypotensive action of captopril in the spontaneously hypertensive rat is associated with changes in body sodium, water and plasma aldosterone concentration. The alterations in brain angiotensin-converting enzyme activity following captopril treatment suggest that, with chronic administration, captopril can alter the activity of the brain renin-angiotensin system.
Animals↗
Effect of magnesium on passive fluxes of lithium in the human erythrocyte.
Extracellular Mg2+ is known to inhibit the passive Na+ and K+ fluxes in the human erythrocyte. In this study the effect of extracellular Mg2+ on Li+ efflux was measured in erythrocytes from 29 normotensive and essential hypertensive subjects. Magnesium produced a variable inhibition of between 0 and 47% in Li+ efflux in different subjects and this effect was unrelated to initial cell Li+, blood pressure or to an action on the co- or counter-transport pathways for this cation. A positive correlation was observed between the magnitude of the passive Li+ efflux and its inhibition (0 to 47%) by Mg2+ ions. Thus Mg2+ has an inhibitory effect on passive Li+ permeability which is unrelated to essential hypertension.
Adult↗
Total body sodium in immature spontaneously hypertensive and Wistar Kyoto rats.
Total body sodium of male and female spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats was estimated weekly during the first 8 weeks of life by measuring exchangeable sodium (ENa). Blood pressure and sodium intake was measured from weeks 4 to 8. SHR had significantly higher blood pressure and sodium intake than WKY from 4 to 8 weeks of age. ENa was higher in SHR than WKY throughout the first 8 weeks of life. Relative sodium retention was observed in SHR during weeks 5 to 8 despite a significant rise in SHR blood pressure and fall in sodium intake. These findings suggest a change in the renal pressure/natriuresis relationship at this age in the SHR.
Age Factors↗
Persistent effects on blood pressure and renal haemodynamics following chronic angiotensin converting enzyme inhibition with perindopril.
Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats aged 4 and 16 weeks were given an acute oral dose of either Perindopril (3 mg/kg) or vehicle. Direct blood pressure (BP), glomerular filtration rate (GFR) and renal blood flow (RBF) were measured, and renal vascular resistance (RVR) calculated. GFR and RBF were lower in vehicle-treated SHR than WKY at 4 weeks of age, but were not different at 16 weeks. Acute Perindopril increased GFR and RBF and reduced RVR in both strains at both 4 and 16 weeks. Total body sodium, sodium intake and blood pressure were measured in SHR and WKY from 1 to 28 weeks of age. Rats of both strains were treated daily between 4 and 16 weeks of age with either Perindopril (3 mg/kg per day) or vehicle. Chronic Perindopril treatment prevented the development of hypertension in the SHR. From 16 to 28 weeks of age, after stopping Perindopril, BP rose slowly in SHR, but remained lower than vehicle-treated SHR. No changes in total body sodium occurred during Perindopril treatment. GFR and RBF were measured in SHR and WKY chronically treated with either Perindopril or vehicle, 3 days or 12 weeks after stopping treatment. In WKY, GFR and RBF were not different between Perindopril-treated and untreated rats at either measurement. In SHR, GFR and RBF remained significantly higher in rats previously treated with Perindopril at both ages. These findings suggest that renal haemodynamic abnormalities may be important in the initiation of hypertension in the SHR. These renal circulatory abnormalities and the hypertension of the SHR depend, at least in part, on intact converting enzyme activity, yet appear to be independent of abnormalities of total body sodium. At a later age, hypertension seems to develop independently of renal vascular abnormalities.
Angiotensin-Converting Enzyme Inhibitors↗