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J A Angus

Publications and source records attributed to J A Angus.

At least 127 records · Page 7Linked to original sources
PubMed1984

Role of auto-inhibitory feed-back in cardiac sympathetic transmission assessed by simultaneous measurements of changes in 3H-efflux and atrial rate in guinea-pig atrium.

Guinea-pig right atria were labelled with [3H]-noradrenaline or [3H]-dopamine before superfusion in a flow-cell. Choice of label did not significantly alter either the relationship between 3H-efflux and number of electrical field pulses or the inhomogeneity of labelling. The relationship between 3H-efflux and frequency of 4 field pulses (0.125-2 Hz) was hyperbolic and similar to the tachycardia-frequency relationship measured simultaneously. No evidence was found for a U shaped 3H-efflux-frequency relationship (Story, McCulloch, Rand & Standford-Starr, 1981). Phentolamine (1 microM) did not alter the 3H-efflux or atrial rate responses to 4 field pulses at stimulus levels that gave 50-60% of the maximum rate response. In the presence of neuronal uptake inhibition (desipramine, DMI 0.1 microM), rate and 3H-efflux responses to 4 field pulses were enhanced at all frequencies and were further increased by phentolamine. In the absence of DMI, prolonged trains of field pulses (8 and 12 pulses) at low frequency (0.25 Hz) were not sufficient to activate auto-inhibitory feed-back. At 2 Hz phentolamine enhanced both 3H-efflux and rate responses at 12 field pulses. We conclude that in guinea-pig right atrium auto-inhibitory feed-back plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. This is because neuronal uptake normally prevents synaptic concentrations of noradrenaline from activating prejunctional alpha 2-adrenoceptors. Stimulation sufficient to induce a near-maximal response or the presence of neuronal uptake inhibition are necessary to evoke autoinhibitory feed-back.

Animals↗
PubMed1984

Role of autoinhibitory feedback in cardiac sympathetic transmission.

The relationship between two indices of transmitter release measured simultaneously and the frequency of 4 field pulses (0.125-2 Hz) were obtained from superfused guinea pig right atria after labelling with 3H-noradrenaline. The relationships between 3H-efflux or rate responses and frequency were hyperbolic. Autoinhibitory feedback did not play a role since phentolamine (1 microM) did not alter the 3H-efflux or rate responses to 4 field pulses that gave 50-60% of the maximum rate response. In the presence of neuronal uptake block (desipramine (0.1 microM) phentolamine enhanced 3H-efflux and rate responses to 4 field pulses at all frequencies. In the absence of desipramine prolonged trains of field pulses (8-12 pulses) at low frequency (0.25 Hz) were not sufficient to activate autoinhibitory feedback. At 2 Hz phentolamine enhanced both responses at 12 field pulses. We conclude that in the right atrium autoinhibitory feedback plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. The presence of neuronal uptake inhibition or high stimulus strengths are necessary to evoke autoinhibitory feedback.

Animals↗
PubMed1983

Haemodynamic response to ketanserin in rabbits with Page hypertension: comparison with prazosin.

The role of alpha 1-adrenoceptors in the hypotensive response to ketanserin was studied in conscious normotensive (sham-operated) and Page hypertensive (two-kidney, two wrapped) rabbits. Ketanserin (0.01, 0.1 and 1 mg/kg i.v.) was administered at 30 min intervals on four experimental days: no pretreatment; after prazosin 1 mg/kg and infusion; after pharmacological 'total' autonomic effector block (TAB) and with repeated three point methoxamine dose-response lines. Only the highest dose (1 mg/kg) of ketanserin lowered blood pressure and dilated the iliac vascular bed (Doppler flowmeter) in both wrap and sham-operated rabbits. Prazosin pretreatment and TAB prevented these effects. Ketanserin (1 mg/kg) also caused significant alpha 1-adrenoceptor antagonism as measured by a 2.5-fold shift in the methoxamine dose-response lines. In separate experiments prazosin (0.01-0.1 mg/kg i.v. bolus) caused similar falls in blood pressure and alpha 1-adrenoceptor block as ketanserin 0.3 and 1 mg/kg. The only difference observed between prazosin and ketanserin was the substantial reflex tachycardia to prazosin that was absent after ketanserin. These results suggest that in normotensive rabbits and in rabbits with Page hypertension the hypotensive response to ketanserin can be explained by alpha 1-adrenoceptor antagonism.

Animals↗
PubMed1983

Comparison of vascular hemodynamics in experimental models of microvascular anastomoses.

Blood flow was measured in the canine saphenous artery using electromagnetic flowmetry. Significant increase in blood flow was noted after occlusion of the distal femoral artery. However, after raising a saphenous island flap there was no significant change in the blood flow before and after distal femoral artery occlusion. The flap peripheral resistance and blood flow were compared after end-to-end and end-to-side anastomosis and no statistical difference was noted.

Animals↗
PubMed1983

Disadvantages of cocaine as a neuronal uptake blocking agent: comparison with desipramine in guinea-pig right atrium.

Cocaine and desipramine (DMI) are widely used as neuronal uptake blocking agents in studies of cardiac sympathetic transmission in isolated tissue preparations. It is generally assumed that these pharmacological tools do not alter transmitter release or postjunctional effector response. To test this assumption, we have compared the effects of cocaine and DMI on rate responses to sympathetic nerve stimulation and exogenous noradrenaline in guinea-pig isolated right atria. Right atria were equilibrated with the irreversible alpha-adrenoreceptor antagonist benextramine to prevent any effect of presynaptic alpha-adrenoreceptors. Cumulative (-) noradrenaline concentration-response curves were shifted to the left by DMI (0.01-1 microM) without significant change in the resting or maximum rates. Cocaine (1-100 microM) also caused sensitisation to noradrenaline but caused a biphasic change in resting atrial rate. In addition there was a small but significant depression of the maximum rate at cocaine 10 and 100 microM. Sympathetic nerve stimulation was achieved by applying trains of 1, 2 and 4 electrical field pulses delivered during one atrial refractory period. DMI caused a concentration dependent potentiation of responses to field stimulation. Cocaine (1 microM) caused significant enhancement of peak responses to field stimulation but no further enhancement and indeed depressed peak responses were observed at cocaine 10 and 100 microM respectively. The time for atrial period to return halfway to baseline after field stimulation (t 1/2) was enhanced by cocaine in a concentration dependent manner as was observed with DMI. We conclude that cocaine (but not DMI) decreases the maximum response to exogenous noradrenaline (postjunctional depression). The reduction of the peak response to sympathetic nerve stimulation in the presence of cocaine to below control responses suggests that cocaine also depresses the release of transmitter. These additional depressant properties of cocaine, which occur in a concentration range of neuronal uptake block, are important disadvantages and should discourage its use in experiments on sympathetic transmission.

Animals↗
PubMed1983

Vasodilatation by acetylcholine is endothelium-dependent: a study by sonomicrometry in canine femoral artery in vivo.

External diameter of the femoral artery was measured by sonomicrometry in the anaesthetized dog. Intra-arterial acetylcholine lowered arterial pressure and thereby passively lowered diameter. When blood flow and distal resistance were controlled by roller pump and Starling resistor respectively, acetylcholine (0.1-10 microM) and substance P (0.1-1 nM) both caused up to 10% increase in diameter. Removal of endothelium by mechanically rubbing the artery lumen abolished the dilator response to acetylcholine and substance P but did not affect the response to nitroprusside. Constrictor responses to noradrenaline were unaltered by endothelium removal. Topical application of acetylcholine and substance P onto the adventitial surface of the artery also caused an increase in diameter but both agents were 50-100 times less potent by this route compared with intra-arterial infusion. These dilator responses were abolished by endothelium removal. In these circumstances acetylcholine caused constriction. We conclude that acetylcholine and substance P require an intact endothelium to elicit vasodilatation in vivo, at least for the large femoral artery. The results from the topical application experiments suggest that local neural release of vasoactive substances such as acetylcholine and substance P depend on an intact endothelium to cause vasodilatation.

Acetylcholine↗
PubMed1983

Characterization of the clonidine receptor site.

At the cardiac sympathetic nerve terminal the alpha 2-adrenoceptor is presynaptic and appears to be located at an extrasynaptic site. This is suggested by (1) absence of evidence of autoinhibitory feedback at physiologic stimulus levels up to about 50 percent of the maximum chronotropic response in the isolated guinea pig right atrium, and (2) absence of significant competition between clonidine and synaptically released noradrenaline (NA) for the presynaptic site. In the central nervous system (CNS) cardiovascular alpha 2-receptors are probably located at a postsynaptic site in bulbospinal regions of the brain, since they produce effects identical to those of synaptic release of NA. Experiments with the clonidine analog alinidine (ST 567) suggest that there are differences in central receptor type subserving clonidine-mediated baroreflex heart rate and blood pressure changes.

Animals↗
PubMed1982

Effects of alinidine (ST 567) on baroreceptor-heart rate reflexes and its interactions with clonidine on the baroreflex and on the sympathetic terminals of the isolated atrium.

Alinidine (ST 567), an N-allyl derivative of clonidine, slowed the heart rate of conscious rabbits by 41 +/- 2.3 (S.E.D.) b/min and reduced mean arterial pressure (MAP) by 6.4 +/- 1.4 mmHg (P less than 0.001). The cardiac slowing was considered to be a direct effect in agreement with previous findings by others, since it was present in rabbits without functioning autonomic nerves, but the fall in blood pressure did not occur in these animals. Alinidine produced no significant changes in the reflex tachycardia response evoked by infusing nitroprusside, or in the pressure-related parameters of the MAP-heart period (HP) curve of the baroreceptor-heart rate reflex (i.e. HP range, gain, or median blood pressure BP50). Intravenous (i.v.) clonidine produced characteristic rises in baroreflex HP range and gain, which were due to vagal facilitation, and also produced falls in BP50 and resting MAP. I.v. alinidine suppressed the clonidine-induced vagal facilitation, but had no effect on the blood pressure changes. Intracisternal alinidine could be given in only relatively low dose, but reduced the clonidine-induced rise in vagal component of HP range. The main site of antagonism between i.v. alinidine and clonidine was probably in the CNS. We studied the nature of the antagonism at the sympathetic nerve terminal of the isolated left guinea pig atrium. Clonidine depressed the inotropic response to field stimulation of the sympathetic nerves and this was competitively antagonised by phentolamine greater than yohimbine greater than alinidine at potencies of about 1200:80:1. Alinidine was considered to be a weak but specific alpha 2-antagonist; it has no alpha 1-antagonist properties since it was without effect on the contractile response to noradrenaline of the guinea pig aorta. The alpha 2-antagonist property explains the suppression by alinidine of the clonidine-induced facilitation of the vagal component of the baroreceptor-heart rate reflex.

Animals↗
PubMed1982

Actions of serotonin antagonists on dog coronary artery.

Serotonin released from platelets may initiate coronary vasospasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine, dihydroergotamine, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks agonist activity and has alpha-adrenoceptor blocking activity.

Adrenergic alpha-Antagonists↗
PubMed1982

Chronotropic effects of angiotensin I, angiotensin II, bradykinin and vasopressin in guinea pig atria.

Chronotropic responses to angiotensin I and angiotensin II, vasopressin and bradykinin were measured in guinea pig isolated right atria. Angiotensin II (100-30,000 pg/ml) was slightly more potent than angiotensin I and caused a maximum tachycardia of 30-40 b/min; only 20% of the maximum response to (--)-noradrenaline. Propranolol (1 micro M) or reserpine pretreatment (1 mg/kg i.p., 24 h) did not alter the response to angiotensin II or bradykinin. Converting enzyme inhibition by captopril (10 micrograms/ml) did not affect resting rate nor the response to angiotensin II but shifted the location of the angiotensin I curve by 40 fold to the right. Bradykinin (5-500 ng/ml) caused small increases in rate while vasopressin 1-100 ng/ml was completely without effect. These results suggest that angiotensin II has a small positive chronotropic effect that is not dependent on tissue noradrenaline release or beta-adrenoceptors and that tissue converting enzyme is active in right atria. Relatively high concentrations of angiotensin and bradykinin were required to directly stimulate the sino-atrial node compared with plasma levels measured during physiological stimuli. Therefore these effects on atria are probably of little physiological significance for peptide concentrations in plasma but may be important in relation to local tissue generation of angiotensin II.

Angiotensin I↗
PubMed1982

Comparison of angiotensin converting enzyme inhibitors captopril and MK421-diacid in guinea pig atria.

Angiotensin I (AI) and angiotensin II (AII) caused concentration-dependent increases in atrial rate in guinea pig isolated right atria. Converting enzyme inhibitors captopril and MK421-diacid did not alter the responses to AII but displaced the curves to AI to the right. The atrial response to generated AII from AI was used as a bioassay to estimate the dissociation constants of converting enzyme inhibitors (Kb) and test for kinetics of simple competition. MK421-diacid was 12-40 times more potent than captopril. However, estimations of Kb for captopril and MK421-diacid were unsatisfactory because at high concentrations of inhibitors the curves to AI were not displaced according to simple competition. We conclude that AI in high concentration can stimulate AII receptors accounting for the stationary displacement of curves to AI in the presence of converting enzyme inhibitors. MK421-diacid also potentiates responses to bradykinin in this assay.

Angiotensin I↗
PubMed1982

The interaction of choline esters, vagal stimulation and H2-receptor blockade on acid secretion in vitro.

Choline esters, bethanechol and carbachol, and electrical field stimulation increased acid secretion in the mouse, isolated, lumen-perfused, stomach. Electrical field stimulation was apparently mediated by vagal nerve ending because treatment with either tetrodotoxin or atropine abolished the response. Using a 2 + 2 assay design, experiments with bethanechol showed that the H2-receptor antagonists metiamide and cimetidine (1 mM) were devoid of antimuscarinic activity. However, the effects of carbachol, which unlike bethanechol stimulates both muscarinic and nicotinic receptors, were significantly antagonised by metiamide (1 mM) at a concentration which was not anticholinergic. We conclude that there are cholinergic receptors separate from histamine H2-receptors on parietal cells. The effects of vagal stimulation in this preparation however, are apparently mediated by histamine release. These results support the "two-cell hypothesis' where vagal nerve endings synapse with the parietal cell.

Animals↗
PubMed1982

Apparent frequency-dependent effect of clonidine on cardiac sympathetic transmission: the role of neuronal uptake.

Decreases in spontaneous atrial period (tachycardia) were measured in atropinized guinea-pig isolated right atria in response to intramural sympathetic nerve stimulation. Electrical field pulses were applied only during the atrial refractory period to avoid arrhythmias. Responses to one to six field pulses delivered in a single refractory period were substantially reduced by clonidine (1-1000 nM), providing no evidence that the blocking action of this drug is frequency-dependent. Stimulus-response lines to one, two or four field pulses delivered as one field pulse per refractory period (1/1) were displaced to the right by clonidine (0.1 microM) such that 8, 16 and 32 field pulses were required to obtain responses equivalent to control. Stimulus-response lines to lower frequencies of field stimulation (one field pulse every 4 or 8 refractory periods) were lower in slope and displaced further by clonidine, whereas lines from stimuli at higher frequencies (2/1 and 4/1) were steeper and less displaced by clonidine. These findings confirmed an "apparent" frequency-dependent blocking action of clonidine. However, substantial blockade of neuronal uptake by desipramine (0.1 microM) raised the slope and decreased the shift of the stimulus-response lines to the lower frequencies of field stimulation compared with 2/1 or 4/1. Clonidine (0.1 microM) had no effect on the responses to exogenous norepinephrine. We suggest that clonidine reduces the amount of norepinephrine released per field pulse independently of the frequency of stimulation. The decrease in tissue response may appear to be frequency-dependent under some circumstances due to the effects of uptake and removal processes.

Animals↗
PubMed1982

Verapamil: a selective antagonist of constrictor substances in dog coronary artery: implications for variant angina.

1. Canine circumflex coronary artery ring segments were contracted in vitro by ergometrine, serotonin, phenylephrine, noradrenaline (with propranolol) and a thromboxane A2 analogue, U46619. 2. Ergometrine was classified as a serotonin agonist since concentration-response curves were competitively inhibited by methysergide but not by alpha-adrenoceptor antagonists. 3. Glyceryl trinitrate (IC50 18.6 nmol/l) relaxed the coronary rings precontracted with serotonin, phenylephrine or U46619. In contrast (+/-)-verapamil (0.1-10 mumol/l) was more effective against serotonin than phenylephrine or noradrenaline and was almost inactive against U46619. 4. In a blood perfused left anterior descending coronary artery preparation external diameter was measured by sonomicrometry. Serotonin, U46619 and ergometrine infusions (i.a.) decreased diameter by up to 18% without causing spasm (zero lumen diameter). Lowering the perfusion pressure from 90 to 60 mmHg increased the fall in diameter during serotonin infusions. 5. The negative inotropic potency of verapamil against noradrenaline induced beta-adrenergic stimulation in guinea-pig left atria was compared with the vasodilator potency of verapamil in noradrenaline constricted dog coronary artery rings. Verapamil was eighteen times more potent in cardiac muscle than in coronary smooth muscle. 6. This apparent tissue selectivity of verapamil was confirmed in anaesthetized dogs where plasma concentrations of verapamil 50-150 ng/ml (in the therapeutic range) lowered blood pressure and heart rate and increased P-R interval without greatly reducing the constrictor response to serotonin in the coronary artery. 7. These studies suggest that inhibition of constrictor responses in large coronary vessels may not be an important site of action of verapamil in patients with variant angina.

Angina Pectoris, Variant↗
PubMed1981

Refractory period fluid stimulation of right atria: a method for studying presynaptic receptors in cardiac autonomic transmission.

A method is described for measuring the atrial period or beat interval from the surface electrogram in isolated spontaneously contracting guinea pig right atria. Stimulation of parasympathetic and sympathetic nerve endings can be readily obtained by applying electrical field pulses across the atria during the atrial refractory period to prevent arrhythmia. In the presence of atropine, the atria respond to a single field pulse with a slight tachycardia that can be taken as a measure of the released transmitter norepinephrine. Because the effector response is mediated by a beta-adrenoreceptor, this preparation is particularly suited for the study of the pharmacology of presynaptic alpha-adrenoreceptors. The fall in period (tachycardia) to one-, two-, or four-field pulses delivered one per consecutive refractory period is linear, and the responses are reproducible for many hours. This biological system offers advantages in sensitivity and stability over methods employing radiolabeled norepinephrine in the study of presynaptic receptors in cardiac autonomic transmission.

Animals↗