Captopril in congestive cardiac failure.
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Angiotensin II↗
Biomedical subjects
D J Webb
Publications and source records attributed to D J Webb.
Plasma immunoreactive endothelin in uraemia.
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Blood Circulation↗
Augmentation of sympathetic venoconstriction by angiotensin II in human dorsal hand veins.
The constriction produced by a single deep breath was measured simultaneously in two adjacent hand veins in normal subjects. One vein was infused with saline or angiotensin II; the other acted as a control. A dose of angiotensin II (1 pmol/min) that did produce venous constriction directly significantly augmented the constriction caused by deep breath in eight subjects (P less than .01). In a further six subjects the same dose had no effect on venoconstriction caused by infused noradrenaline. We conclude that angiotensin II causes venoconstriction indirectly by augmenting sympathetically mediated responses, possibly by a presynaptic mechanism.
Adult↗
The potassium channel opening drug cromakalim produces arterioselective vasodilation in the upper limbs of healthy volunteers.
1. The effect of the K+ channel opening drug cromakalim on forearm blood flow during direct infusion into the brachial artery, and on the size of noradrenaline preconstricted hand veins during infusion directly into the vein, was studied in eight healthy volunteers. 2. Cromakalim (0.01-10.0 micrograms min-1) produced a dose-dependent increase in blood flow in the infused forearm, from 5.4 +/- 2.5 to 15.1 +/- 7.3 ml 100 ml-1 forearm min-1 at 10 micrograms min-1 (P less than 0.001). The half-time of offset of its action was 30 min. There was no change in blood flow in the non-infused forearm. 3. There was no increase in the size of noradrenaline pre-constricted dorsal veins during local infusion of cromakalim (0.001-1.0 microgram min-1). Glyceryl trinitrate (0.4 microgram min-1) however, completely reversed the constriction to noradrenaline (P less than 0.001). 4. The clear arterioselectivity of cromakalim, as with other members of this new class of drug, accords with the dependency of venoconstriction on receptor-operated, rather than potential-operated mechanisms which are of importance in resistance vessels. With this haemodynamic profile cromakalim may prove of value in the treatment of arterial hypertension.
Adult↗
Local inhibition of converting enzyme and vascular responses to angiotensin and bradykinin in the human forearm.
1. The function of angiotensin converting enzyme was investigated in twenty-four healthy men. Forearm blood flow was measured under basal conditions and during administration of enalaprilat (a converting enzyme inhibitor) and/or peptide substrates of converting enzyme into the left brachial artery. Blood flow was compared in the two arms. 2. Enalaprilat had no effect on basal blood flow. The concentration of enalaprilat in venous blood from the control arm was low, and plasma renin activity was not increased, indicating that systemic inhibition of converting enzyme did not occur. 3. Effects of angiotensin and of bradykinin, administered intra-arterially, were limited to the infused arm. Enalaprilat (13 nmol min-1) inhibited converting enzyme in the infused arm, in which it caused approximately a 100-fold reduction in sensitivity to angiotensin I, while having no effect on the vasoconstriction caused by angiotensin II. Enalaprilat increased vasodilatation caused by bradykinin. 4. Aspirin, an inhibitor of cyclo-oxygenase, did not inhibit vasodilatation caused by bradykinin whether infused alone or with enalaprilat, indicating that these responses are not mediated by prostaglandins. 5. We conclude that under basal conditions neither conversion of angiotensin I to angiotensin II nor degradation of bradykinin determines resistance vessel tone in the human forearm. Converting enzyme may affect vascular tone in situations in which intravascular concentrations of peptides are increased over those present under basal conditions.
Adult↗
Endothelin is a potent long-lasting vasoconstrictor in men.
Endothelin, a 21-amino acid peptide synthesized by cultured porcine aortic endothelial cells, has recently been identified and shown to produce a potent and prolonged constriction of mammalian blood vessels in vitro. We have studied the effect of local infusion of this peptide on resistance and capacitance vessels of normal volunteers. Infusion of endothelin (5 pmol/min) reduced forearm blood flow by 39 +/- 7% from control observations. The maximum response was seen after approximately 55 min of infusion. After stopping the infusion, return of flow to basal values took approximately 120 min. This contrasts with the short onset and duration of action observed when angiotensin II was infused. During coinfusion studies, reversal by nicardipine (0.3-10 micrograms/min) occurred at similar concentrations in both endothelin-induced and angiotensin-induced flow reduction. This observation suggests that nicardipine nonspecifically antagonizes the flow-reducing effects of endothelin. A pattern of slow onset of constriction was found on local infusion of endothelin (5 pmol/min) into dorsal hand veins. During coinfusion of nicardipine (1.5 microgram/min), no reversal of endothelin-induced (5 pmol/min) constriction of dorsal hand veins occurred. The pharmacological profile of this peptide in the peripheral circulation of humans suggests that it may be involved in long-term regulation of vascular tone.
Adult↗
The effect of local angiotensin converting enzyme inhibition on the action of atrial natriuretic peptide in the human forearm.
It has been suggested that angiotensin converting enzyme (ACE) may play a role in the metabolism of atrial natriuretic peptide (ANP), and that ANP may interfere with angiotensin-induced vasoconstriction. This has been investigated within the forearm vascular bed during local ANP infusion and ACE inhibition. Six normotensive volunteers were studied, each on two occasions. On both occasions, after saline infusion, volunteers were given initially a 20 min infusion of ANP at 0.1 microgram/min via the brachial artery. This was followed, after 20 min, by a second infusion of ANP at the same dose, co-infused with enalaprilat (5 micrograms/min) on one occasion, and placebo (saline) on the other (in random order). Forearm blood flow was measured using venous occlusion plethysmography with mercury-in-silastic strain gauges. Blood flow in the cannulated arm increased significantly during the first ANP infusion; by 52 +/- 15% before placebo (P less than 0.05), and by 41 +/- 8% before enalaprilat (P less than 0.005). This increase was similar with the second ANP infusion during co-infusion of either placebo (40 +/- 10%) or enalaprilat (45 +/- 11%). Enalaprilat did not affect the half-life of vasodilatation produced by ANP (t1/2 = 5 min). These studies in healthy subjects demonstrate no effect of local ACE inhibition on resting blood flow, or on the vasodilatation produced by ANP in the human forearm, and provide no evidence of a role of ACE in the metabolism of ANP in this vascular bed.
Adult↗
Severe hypotension with bradycardia during renin inhibition with H142 in sodium deplete man.
A healthy sodium depleted subject received, on separate occasions, intravenous infusions of the renin inhibitor H142 at doses of 1.0, 2.5 and 5.0 mg/kg/h. The two lower doses of H142 produced dose-dependent reduction of both systolic and diastolic pressure associated with an increase in heart rate. The highest dose of H142 produced profound hypotension and bradycardia, both during drug infusion in the supine position, and again later, on return to standing, after H142 was stopped. An increase in plasma adrenaline, but not noradrenaline, was associated with this dose of H142. The subject differed from others studied in a randomised controlled trial of H142 at doses of 1.0 and 2.5 mg/kg/h in having the highest basal circulating plasma angiotensin II concentrations during sodium depletion, and in developing a clear reduction in systolic as well as diastolic pressure. The profound hypotensive response at the highest dose of H142 may represent an idiosyncratic response to the drug. Alternatively, and perhaps more likely, it may be a result of a reduction of angiotensin II concentrations in plasma or other tissues, with loss of arteriolar constriction, loss of facilitation of sympathetic activity, withdrawal of vagal inhibition, dilatation of capacitance vessels, or a combination of these events. Subsequent activation of the Bezold-Jarisch reflex is a possibility. The late fall in blood pressure, after H142 was stopped, and when circulating plasma angiotensin II concentrations had returned to normal, suggests that this response may have involved an effect of the inhibitor on renin in a site other than blood.
Adult↗
Angiotensin II augments sympathetically induced venoconstriction in man.
1. The constriction produced by a single deep breath was measured simultaneously in two adjacent hand veins in normal volunteers. One vein was infused with angiotensin II (ANG II) while the other acted as a control. 2. At a dose lower than that required to produce direct venous constriction (1 pmol/min), ANG II significantly augmented the constriction caused by a deep breath in eight subjects (P less than 0.01). The same dose had no effect on the venoconstriction caused by infused noradrenaline (NA) in a further six subjects. 3. It is concluded that ANG II at low doses may cause venoconstriction indirectly by augmenting sympathetically induced venous tone via a presynaptic mechanism. This observation may help to explain the apparent venodilating property of angiotensin-converting enzyme inhibitors in clinical situations where the renin-angiotensin system is stimulated.
Adult↗
Sympathetically mediated vasoconstriction is augmented by angiotensin II in man.
In order to determine whether angiotensin II may influence sympathetically mediated arteriolar constriction in man, we have examined the effect of angiotensin II, infused directly into the left brachial artery of normal subjects, on the reduction in forearm blood flow produced by a lower-body negative pressure (LBNP) of 15 mmHg. Angiotensin II (320 fmol/min) caused no reduction in blood flow when given alone but significantly augmented the reduction in blood flow in response to LBNP. The same dose of angiotensin II did not affect a similar reduction in forearm blood flow produced by infused noradrenaline (12.5-50 ng/min). We conclude that angiotensin II augments sympathetically mediated constriction of resistance vessels in man at concentrations with no direct effect on vessel tone. The lack of an effect of angiotensin II on constriction in response to infused noradrenaline suggests the involvement of a presynaptic mechanism.
Angiotensin II↗
Vascular responses to local atrial natriuretic peptide infusion in man.
1. The effect on skin and muscle blood flow of arterial infusion of atrial natriuretic peptide (ANP) directly into the forearm circulation, and on venous tone of direct infusion into a dorsal hand vein, was studied in normal subjects. 2. ANP produced a dose-dependent increase in both skin and muscle blood flow, but at equivalent doses, produced no dilatation of noradrenaline-preconstricted dorsal hand veins. These findings indicate that ANP acting locally, is an arterioselective dilator in the upper limb circulation in normal man. 3. Measurements of ANP in venous plasma during arterial infusion suggest marked clearance of ANP across the forearm vascular bed. Such peripheral clearance may, at least in part, account for the short plasma half-life of this peptide. 4. The lowest dose of ANP infused was calculated to produce plasma levels similar to those found in patients with heart failure. The findings with this dose suggest that, in heart failure, circulating levels of ANP may be within a range capable of influencing peripheral vascular resistance directly.
Adult↗
Regulation of regional vascular tone: the role of angiotensin conversion in human forearm resistance vessels.
Inhibition of the action of endothelially-located angiotensin converting enzyme (ACE) in blood vessels of the human forearm was studied using enalaprilat, the active metabolite of the prodrug enalapril. In a dose of 5 micrograms/min enalaprilat inhibits arteriolar vasoconstriction in response to angiotensin I (Ang I) and enhances vasodilation in response to bradykinin. At this dose enalaprilat had no effect on resting forearm blood flow, or on the reduction in forearm blood flow in response to application of lower body negative pressure, in subjects with normal sodium intake. Following sodium depletion, however, enalaprilat produced an increase in resting forearm blood flow compared with the response in the same subjects under normal-sodium conditions. It appears that local ACE within forearm resistance vessels of healthy volunteers is unlikely to play an important role in regulation of local vascular tone in the sodium-replete state. However, in sodium-depleted subjects, and perhaps also in other circumstances where circulating concentrations of Ang I are elevated, local ACE may significantly affect vascular tone.
Adult↗
The fixation of malar fractures with the transnasal Kirschner wire.
Our experience with a rapid and reliable method for the repair of selected unstable malar fractures using external pin fixation is reported. Following reduction through a Gillies temporal incision, a Kirschner wire is introduced on the contralateral side, advanced through the nasal vault and septum and the reduced malar bone is engaged. This method of immobilization can be used in isolated malar fractures or in conjunction with the repair of other facial injuries. In 38 patients where this procedure was utilized, there was low morbidity as well as excellent cosmetic and functional results. The advantages of this technique as well as a comparison with other available methods of malar fixation are discussed.
Adult↗
Cough associated with captopril and enalapril.
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Captopril↗
Influence of ramipril diacid on the peripheral vascular effects of angiotensin I.
Studies were performed to examine the effect on forearm blood flow of local brachial artery infusions of angiotensin I, angiotensin II and of the converting enzyme inhibitor ramipril diacid (the active metabolite of ramipril). Acute infusions of both angiotensins produced dose-dependent decreases in blood flow (measured by venous occlusion plethysmography). To produce equivalent effects the dose of angiotensin I was 2 to 4 times that of angiotensin II. After ramipril diacid the response to angiotensin II was unchanged, while the dose of angiotensin I required to produce an equipotent response was increased 20-fold. Ramipril diacid given alone produced a small, nonsignificant increase in forearm flow, although the response was significantly related to basal plasma renin. The study confirms the presence of converting enzyme activity within human resistance vessels, and suggests that inhibition of converting enzyme, at sites other than the pulmonary vascular bed, might contribute to the hypotensive action of converting enzyme inhibitors.
Adult↗
Weak bases inhibit cleavage and embryogenesis in amphibians and echinoderms.
The action of weak bases was studied on the early embryonic development of a number of species. Gastrulation was disrupted in the frog, Xenopus laevis, the newt, Pleurodeles watlii, the sea urchins, Paracentrotus lividus and Sphaerechinus granularis and the starfish, Asterias rubens. This required only submillimolar amounts of either NH+4 (pH 9.0) or procaine (pH 8.2). At higher concentrations even early cell division was inhibited in all the species with furrow regression particularly noticeable in Xenopus eggs. A similar action of the weak bases on early development, the lack of any action at lower extracellular pH, and the counteracting action of NH+4 on acidity-induced disruption of sea urchin development, all implicate an elevation of intracellular pH. However, a more direct intracellular action of the weak bases cannot be ruled out.
Ammonia↗
Dietary sodium deprivation raises blood pressure in the rat but does not produce irreversible hyperaldosteronism.
It is reported that dietary deprivation of sodium in young rats produces changes of sodium balance and aldosterone excretion which persist when normal sodium intake is restored. To test this further, sodium intake was reduced 10-fold in rats. In the first experiment sodium intake was reduced for 5 weeks in rats aged 3 weeks. Systolic blood pressure, heart rate and plasma renin concentration increased and growth rate was reduced. Sodium intake was then increased for 10 weeks. Blood pressure, heart rate and plasma renin concentration fell and growth rate increased but body weight did not regain control values. As compared with controls, plasma concentrations of aldosterone and corticosterone did not increase after the 10-week period. Thus, sodium depletion did not produce an irreversible change in aldosterone but it did raise arterial pressure. Further experiments confirmed the pressor effect in young and adult rats. Blood pressure was measured in the tail in these experiments but the increase in pressure was not a technical artifact as measurements made in the tail correlated well with measurements made simultaneously by intra-arterial catheter. Catheters were inserted under general anaesthetic for this comparison of pressure and rats previously deprived of sodium showed a significantly higher mortality rate due to the anaesthesia and surgery involved. Thus, a 10-fold reduction of dietary sodium raises blood pressure in young and adult rats and it may increase mortality from a minor surgical procedure. It does not produce irreversible changes in aldosterone.
Aldosterone↗
Clinical and biochemical effects of the renin inhibitor H142 in humans.
The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose, or with H142 at 1.0 or 2.5 mg/kg/h, for 30 min while supine and thereafter with dextrose for 1.5 h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after H142 infusion was stopped. In contrast, total renin concentration as measured by radioimmunoassay rose while ANG I and II fell, subsiding after H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited: plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.
Adult↗