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J A Angus

Publications and source records attributed to J A Angus.

At least 145 records · Page 8Linked to original sources
PubMed1981

Contribution of stenosis resistance to the rise in total peripheral resistance during experimental renal hypertension in conscious dogs.

1. Mild, moderate and severe renal artery stenosis was induced by uninephrectomized conscious dogs by inflating a renal artery cuff to lower distal pressure to 60, 40 or 20 mmHg respectively. The renal artery was narrowed progressively over the next 3 days by further inflation of the cuff to relower the distal renal artery pressure to the initial values. 2. Graded progressive stenosis produced graded progressive rises in blood pressure, plasma renin activity and total renal resistance to flow over the 3 day period, following by a return to control values 24 h after deflation. 3. The rise in total renal resistance to flow was almost entirely due to the stenosis, with only small changes occurring in renal vascular resistance. 4. In moderate and severe stenosis cardiac output did not alter significantly and thus increases in blood pressure were due to increases in total peripheral resistance. In these groups the resistance to blood flow of the stenosis accounted respectively for about 36 and 26% of the rises in total peripheral resistance. Vasoconstriction of the other non-renal vascular beds accounted for the remainder of the increase in total peripheral resistance. 5. In mild stenosis the changes in both cardiac output and total peripheral resistance was variable and not statistically significant. In this group the rise in stenosis resistance was compensated by vasodilatation of the non-renal vascular beds. 6. In all groups rises in plasma renin activity and blood pressure correlated with the haemodynamic severity of the stenosis. 7. Thus the resistance to blood flow of the moderate and severe renal artery stenoses accounted for one-quarter to one-third of the increases in total peripheral resistance. The remainder of the increase in total peripheral resistance was due to vasoconstriction of non-renal beds.

Animals↗
PubMed1981

Ergometrine contracts isolated canine coronary arteries by a serotonergic mechanism: no role for alpha adrenoceptors.

Studies were performed on isolated canine coronary artery segments to characterize the mechanism of the constrictor response of ergometrine (ergonovine), an agent used to induce coronary vasospasm in patients with variant angina. Changes in isometric tension were measured in coronary ring segments suspended in organ baths at 37 degrees C filled with a buffered salt solution. Single concentration-response curves were obtained in each tissue by cumulative addition of agonist. Maximum responses to 5-hydroxytryptamine (5-HT) were greater than for ergometrine or phenylephrine, but ergometrine had the lowest EC50. Alpha adrenoceptor block by prazosin (10 nM) or the irreversible antagonist benextramine tetrahydrochloride did not affect responses to 5-HT or ergometrine. Cyproheptadine and pizotifen (0.1-1 muM) depressed the ergometrine and 5-HT concentration-response curves with no change in the location of the EC50 values. Methysergide (0.01-1 muM) had concentration-dependent constrictor activity which was noncompetitively antagonized by cyproheptadine, but unaltered by benextramine tetrahydrochloride pretreatment. In addition, methysergide competitively antagonized the 5-HT and ergometrine concentration-response curves. Estimates of methysergide pKB values (-log dissociation constant) from computer analysis were 7.9 and 8.0 for the two agonists, respectively. It is concluded that methysergide is a partial 5-HT agonist, but cyproheptadine and pizotifen are noncompetitive 5-HT antagonists. Ergometrine is a potent 5-HT receptor agonist in canine coronary artery with negligable alpha adrenoceptor agonist activity.

Adrenergic alpha-Antagonists↗
PubMed1981

The histamine-like effects of tolazoline and clonidine:: evidence against direct activity at histamine receptors.

Both tolazoline and clonidine produce agonist effects sensitive to histamine H2-receptor antagonism in whole animals and a variety of isolated tissues. In guinea-pig right atria, tolazoline concentration-response curves were shifted to the right and progressively depressed by cimetidine. Clonidine produced a submaximal histamine-like tachycardia which was converted by cimetidine to a depression of sinus rate. Neither tolazoline nor clonidine stimulated histamine H2-receptors in rabbit right atria. Instead, these agents were very weak inhibitors of histamine with a pA2 for tolazoline of 3.3 and for clonidine of 3.7. No appreciable histamine H1-receptor activity was evident for either drug in experiments with guinea-pig ileum. The weak histamine H2-receptor affinity is inconsistent, from a quantitative point of view, with the hypothesis that the agonist activity results from direct stimulation of histamine receptors, but all data re compatible with previous evidence which suggests that these drugs release endogenous histamine.

Animals↗
PubMed1980

Estimation of pKB values for histamine H2-receptor antagonists using an in vitro acid secretion assay.

1 Histamine H2-receptor antagonism by burimamide, metiamide and cimetidine was analysed under apparent equilibrium conditions in the lumen-perfused isolated stomach preparation of the mouse. 2 The behaviour of these compounds was not incompatible with simple competitive antagonism but the estimated pKB values (-log KB) were all significantly lower, by about 1 log unit, than reference values reported for guinea-pig atrium or rat uterus. 3 There seems no need to propose that the parietal cell receptors are somehow different from the others; metiamide continually appears in the gastric juice so that a steady-state but not equilibrium can presumably be reached with respect to the bath concentration and this could keep the antagonist concentration artificially low in the region of the receptors.

Animals↗
PubMed1979

Analysis of anomalous pKb values for metiamide and atropine in the isolated stomach of the mouse.

1 In the isolated, lumen-perfused, stomach preparation of the mouse, metiamide was found by kinetic analysis to behave like a simple competitive antagonist of histamine-stimulated acid secretion. However, the pK(B) estimate of 5.08 was significantly lower than that found in guinea-pig atrium (6.0) or rat uterus (6.1) suggesting that H(2)-receptors might not be homogeneous.2 A similar analysis showed that atropine also behaved like a simple competitive antagonist of bethanechol-stimulated acid secretion and the estimated pK(B) (7.65) was significantly lower than the standard estimate of this parameter in guinea-pig ileum (9.0). Either the muscarinic cholinoceptors in mouse stomach were also anomalous or the preparation was introducing a systematic error. Lumen perfusion might distort this type of kinetic analysis by allowing steady-state conditions but not true equilibrium to develop at the receptor compartment due to loss of antagonist into the gastric secretion. Drug interactions at receptors in the muscle layers of the stomach would be expected to be much less sensitive to this error.3 When the atropine-bethanechol interaction was measured on the contraction of the isolated, lumen-perfused, stomach of the mouse the necessary conditions for simple competition were not met even though the sensitivity to atropine was obviously increased. The criteria for the expected simple competition were being obscured by events at low antagonist concentrations. Alterations in agonist or antagonist concentrations could be more or less eliminated so that physiological antagonism, perhaps by release of 5-hydroxytryptamine, was considered. This was supported, to some extent, by finding that, when stomachs from animals pretreated with reserpine were used, the kinetic analysis was normalized and gave a pK(B) of 8.99. Apparently, the muscarinic receptors in mouse stomach are homogeneous with those in other tissues.4 Therefore, we conclude that our results no more point to heterogeneity among histamine receptors than they point to differences in muscarinic cholinoceptors because this type of kinetic analysis can be readily distorted by special features of the measuring system.

Animals↗
PubMed1978

Guanethidine-induced vasodilatation in the rabbit, mediated by endogenous histamine.

1 The effects of guanethidine (0.5-4 mg/kg i.v.) on arterial pressure, hindlimb blood flow and hindlimb vascular resistance (HVR) were studied in unanesthetized rabbits subjected to "total" autonomic block. 2 Evidence that this response was mediated by histamine release was that (a) 3H-labelled histamine levels in the hindlimb venous blood rose substantially after guanethidine; (b) infusion of exogenous histamine caused an inhibition of the guanethidine-induced vasodilatation; and (c) competitive antagonism of the response was obtained with the H2-antagonist burimamide. 3 There was good correlation between the [3H]-histamine ;elease and the time course of the vasodilator response. Glyceryl trinitrate infusions that lowered HVR substantially, did not cause release of histamine. 4 Reserpine, desipramine and indomethacin pretreatment did not alter the vasodilator response to guanethidine. 5 The guanethidine vasodilator response was not influenced by the H1-antagonist mepyramine or by the other H2-antagonists, metiamide or cimetidine. The vascular receptors stimulated by endogenous histamine may be distinctive from those stimulated by exogenous histamine, or the action of guanethidine may involve greater production of histamine at an intracellular site that is more readily reached by burimamide than by the other H2-antagonists.

Animals↗
PubMed1978

Developments of computer-based estimation of pA2 values and associated analysis.

The standard statistical-computing package GLIM is used to analyze data from agonist-antagonist studies for the estimation of the dissociation constant of the antagonist. The method follows the general approach of D.R. Waud (Analysis of dose-response curves. In Methods in Pharmacology, vol. 3, Smooth Muscle, ed. by E.E. Daniel and M. Paton, Plenum Press, New York, 1975) in employing an iterative nonlinear least-squares curve-fitting procedure. However, it differs in two important respects: 1) it is interactive; and 2) it allows linear adjustments for covariates and experimental design variables. This paper develops develops an alternative useful formulation of departure from simple competitivity and also a graphical display called a "Clark plot" showing how the spacings of the dose-response lines fit the theory of simple competitive antagonism. This plot provides an alternative to the popular Schild plot for which, of necessity, the zero antagonist (control) dose-response line is heavily used both in the experimental design and in the analysis associated with it.

Computers↗
PubMed1977

Regional vascular resistance and heart rate responses mediated through H1- and H2-histamine receptors in the unanaesthetised rabbit.

The effects of histamine infusions (10-100 microgram/kg/min) on heart rate and hindlimb, carotid, mesenteric and renal vascular resistance were investigated in unanaesthetised rabbits after "total" autonomic effector block to abolish reflex effects. Histamine caused a rise in heart rate that was predominately due to stimulation of H2-receptors (blocked by metiamide). Hindlimb and carotid vascular resistance did not change significantly during histamine infusion. However, after blocking H2-receptors with metiamide histamine infusions produced dose-related vasoconstriction in these beds while after H1-receptor block with mepyramine histamine caused dose-related vasodilatation indicating that H1- and H2-RECEPTORS MEDIATED OPPOSITE VASCULAR EFFECTS WHICH WERE OF SIMILAR MAGNITUDE. By contrast, histamine infusion caused vasodilatation in both the mesenteric and renal vasculature before giving antagonists. This dilatation was mediated by both H1- and H2-RECEPTORS AS EITHER RECEPTOR ANTAGONIST ATTENUATED THE RESPONSE. These studies suggest that H1-receptors in the same species mediate vasoconstriction in som- beds and vasodilatation in others while H2-receptors mediate vasodilatation in all the beds studied and also account for most of the increase in heart rate.

Animals↗
PubMed1976

Assessment of autonomic and non-autonomic components of resting hindlimb vascular resistance and reactivity to pressor substances in renal hypertensive rabbits.

1. Hindlimb vascular resistance (HVR) was measured before and after pharmacological autonomic blockade in unanesthetized renal cellophan-wrap hypertensive or normotensive rabbits with previously implanted Doppler ultrasonic flowmeters. 2. When the blood pressure was restored to resting values after autonomic block, the elevated resting HVR in the hypertensive rabbits was entirely accounted for by an increased non-autonomic component (i.e. HVR after block). If the pressure was not restored after block the autonomic component (i.e. resting HVR minus non-autonomic HVR) was overestimated and the non-autonomic component was underestimated. 3. During maximum vasodilatation the minimum HVR was significantly higher in the hypertensive rabbits than in the normotensive group, probably due to structural differences of resistance vessels. 4. Reactivity of the hindlimb bed to noradrenaline, angiotensin II and vasopressin injections was approximately twice as great in the hypertensive rabbits as in the sham-operated group, probably as a consequence of the structural changes.

Animals↗
PubMed1976

Cardiac output changes during experimental renal hypertension in the rabbit.

1. The haemodynamic changes during the development of hypertension in rabbits have been studied for 1 week before and 4-5 weeks after sham-operation (thirteen rabbits) or bilateral renal cellophan wrapping (thirteen rabbits), Doppler flowmeters being used to measure cardiac output. 2. There was a significant but transient rise in cardiac output on post-operative day 4 in six of thirteen sham-operated rabbits and six of thirteen renal-wrap rabbits before development of hypertension. Both groups showed the same rise in mean cardiac output of 10%. The reise in cardiac output was more transient than in other species, and was not essential for subsequent development of hypertension.

Animals↗
PubMed1976

Cardiovascular action of verapamil in the dog with particular reference to myocardial contractility and atrioventricular conduction.

Verapamil (Isoptin) caused a dose-dependent peripheral vasodilation, increase in myocardial contractility, and tachycardia in the anaesthetized dog. Propranolol pretreatment blocked the cardiac stimulation following verapamil but the vasodilation was unaltered. Inflation of a thoracic aortic balloon prevented the fall in intravascular pressure and reduced the tachycardia and positive inotropic responses. These experiments suggest that clinical doses of verapamil cause peripheral vasodilation which leads to a sympathetic reflex induced increase in heart rate and myocardial contractility. Verapamil also had a direct myocardial depressant action which became evident at doses above the range used clinically. The drug increased the PR interval in conscious dogs for up to 60 minutes. This effect was partly mediated through cholinergic stimulation and partly through a direct depression on atrioventricular conduction.

Animals↗
PubMed1976

Changes in cardiac output and total peripheral resistance during development of renal hypertension in the rabbit: lack of confomity with the autoregulation theory.

Serial measurements of cardiac output (CO), mean arterial pressure (MAP), heart rate, and total peripheral resistance (TPR), were made on unanesthetized rabbits with previously implanted Doppler flowmeters. After 2 days of control measurements the rabbits were subjected alternatively to bilateral renal cellophane wrapping (wrap group) or to sham operation and additional measurements were made 1, 2, 4, 8, 16, 25, and 32 days after operation. During the 1st week after operation changes in CO were identical in the wrap and sham-operated groups, with an overall increase to a value of 110% of control on day 4 (P less than 0.05). Thereafter CO fell gradually, reaching 75% of control by day 32 in the wrap group, but only 95% of control in the sham-operated group. When CO was expressed per unit of body weight the latter differences were somewhat reduced, but still were significant. In wrap animals MAP and TPR rose progressively to 155% and 194% of control by day 32. In the sham-operated group the corresponding increases to 108% and 118% of control were significantly smaller. The MAP and TPR of the renal wrap rabbits exceeded the values in sham-operated rabbits, even over the 1st week after operation, by an average for MAP of 8.6 +/- 1.4% (P less than 0.001), and for TPR of 8.0 +/- 2.5% (P = 0.01). The results suggest that the changes in CO during the 1st week were a nonspecific consequence of the preceding wrap or sham operation. They bore no apparent relationship to the subsequent development of the hypertension which was "resistance-mediated" from the earliest stages. We conclude that the present findings for the rabbit differ from those reported for other species and do not conform to the changes predicted by the autoregulation theory of the pathogenesis of hypertension.

Animals↗