Biomedical subjects

J A Angus

Publications and source records attributed to J A Angus.

At least 109 records · Page 6Linked to original sources

PubMed1987

Vasodilatation and the discovery of endothelium-derived relaxing factor.

Whether endothelium-derived relaxing factor (EDRF) is important in the physiology and pathology of vascular reactivity must await the discovery of the nature of the factor and an appropriate antagonist substance. Nevertheless the demonstration that EDRF is powerful, short-lived and can be released by a wide variety of stimuli adds a new dimension to our knowledge of the control of the circulation. The macroenvironment of the vessel wall is influenced by nerves, blood-borne factors and the architecture of the wall. The discovery of a role of the endothelial cell has for the first time forced pharmacologists to consider cell-cell interactions in the micro-environment of the blood-vessel wall. This is a potentially important target for new therapy.

Acetylcholine↗

PubMed1987

Diverse vascular responses to serotonin in the conscious rabbit: effects of serotonin antagonists on renal artery spasm.

Vascular conductance in the mesenteric, hindquarter, and renal beds of the conscious rabbit was derived from regional blood flow (pulsed Doppler flowmeter) and ear artery pressure. After autonomic ganglion blockade (mecamylamine), serotonin (5-HT, 5-hydroxytryptamine) infusion, 3-60 micrograms/kg/min i.v., dilated the mesenteric and hindquarter beds but caused renal blood flow to fall to zero. Angiography confirmed that serotonin had caused the conduit renal arteries to spasm. This response was unaltered by 1 mg/kg prazosin but was antagonised by 0.5 mg/kg ketanserin and 0.5 mg/kg methysergide. Only the latter drug shifted the dilator-response curves in the other two beds. Methiothepin, 1 mg/kg, flattened both the dilator and constrictor response curves, perhaps by binding to an allosteric site on the serotonin receptor. 5-Carboxamidotryptamine (5-CT) caused about half the renal arteries to spasm at less than 30 ng/kg/min and dilated the other beds. From the antagonist data, we suggest that 5-HT2 receptors mediate the contraction of the renal artery, but that "5-HT1-like" receptors mediate the dilatation in the renal, mesenteric, and hindquarter beds in the conscious rabbit. 5-CT is not helpful in defining the receptors in the renal artery. The rather special spasmogenic response to serotonin in the renal artery is worthy of further research to reveal what factors may lead to large artery spasm.

Animals↗

PubMed1987

The half-life of endothelium-derived relaxing factor released from bovine aortic endothelial cells in culture.

1. The half-life of endothelium-derived relaxing factor (EDRF) in Krebs solution was determined by bioassay in vitro. 2. A column of bovine aortic endothelial cells grown on microcarrier beads in suspension culture was perfused with Krebs solution. EDRF was released from these cells by sequential treatment with increasing concentrations of bradykinin (0.01-100 nM). EDRF was detected by the relaxation of an endothelium-denuded ring segment of dog coronary artery. 3. Complete bradykinin concentration-relaxation curves were determined in the absence or presence of coils of tubing that increased the transit time (delay) between the cell column and the assay tissue. An estimate of the falls in concentration, and hence of the half-life of EDRF, was obtained from the shift of the bradykinin concentration-relaxation curves. 4. Mass-action equations were used to model the relationship between the indirectly acting agonist bradykinin and the relaxation via EDRF. The modelling adequately predicted the consequences of different transit delay times (0-4 half-lives). 5. This new analysis of half-life of an active intermediate emphasizes the measurement of changes in concentration with increasing transit time rather than a fall in tissue response. 6. The half-life of EDRF in Krebs solution is 41 s.

Animals↗

PubMed1987

The cardiovascular amplifiers in human primary hypertension and their role in a strategy for detecting the underlying causes.

The present review considers evidence that in chronic hypertension, hypertrophy of the muscles of the resistance vessels and left ventricle (LV) accounts for their intrinsic properties as haemodynamic amplifiers. In spontaneously hypertensive rats (SHR) there is early hypertrophy of both vessels and LV, suggesting that they may initiate hypertension; slow development of alpha-adrenoceptors may contribute to the early preponderance of the LV amplifier. In human hypertension LV hypertrophy occurs in most patients, including a high proportion of mild hypertensives. In Goldblatt one-kidney hypertension the stenosis resistance, which is the initiating cause, accounts for 25% of the rise in blood pressure throughout, with 75% initially due to systemic constrictor action of angiotensin II and later due to the amplifier properties of the hypertrophied heart and vessels. The cardiovascular amplifiers must be important in all chronic hypertension, so that if hypertrophy can be reversed, detection of the initiating mechanism should be easier. Studies in patients indicate that drug therapy can reverse hypertrophy and that subsequent redevelopment of hypertension is markedly slowed. We postulate an intrinsic disturbance of muscle performance in all primary hypertension, which may be triggered through the sympathetic nervous system in some patients and through altered cation transport in others.

Animals↗

PubMed1987

Development of a large fibromuscular intimal thickening does not impair endothelium-dependent relaxation in the rabbit carotid artery.

The release of endothelium-derived relaxing factor (EDRF) was examined in the rabbit carotid artery 6 weeks after denudation with an inflated balloon catheter in vivo. A concentric, fibromuscular intimal thickening of variable width developed in all areas lined with either regenerated endothelium or modified luminal smooth muscle cells. In vitro studies showed that in vessels precontracted with serotonin, only the re-endothelialized areas could relax to the endothelium-dependent dilators methacholine, substance P and the Ca2+ ionophore A23187. Re-endothelialized areas with large concentric, fibromuscular intimal thickening (between 10 and 20 cells thick) relaxed with a similar sensitivity and maximum to methacholine compared with control areas. It is concluded that newly generated endothelial cells release EDRF whilst the specialized lining smooth muscle cells present 6 weeks after injury do not, and that the presence of a large fibromuscular intima does not prevent EDRF from reaching the media to cause relaxation.

Animals↗

PubMed1987

Vascular amplifier properties in renovascular hypertension in conscious rabbits. Hindquarter responses to constrictor and dilator stimuli.

The local responses of the resistance vessels of the hindquarters of conscious, renal hypertensive (cellophane wrap) and sham-operated normotensive rabbits were studied during infusions of constrictor (norepinephrine, methoxamine, angiotensin II) and dilator (acetylcholine, adenosine, serotonin) drugs. The rabbits had implanted Doppler ultrasonic flow probes on the lower aorta and an indwelling catheter for intra-arterial infusion of drugs. Autonomic blockade with mecamylamine and propranolol was used to determine local vascular effects of each drug uncomplicated by reflex changes. Logistic dose-vascular response curves were characterized by their range from resting to maximum response, their 50% effective dose (i.e., sensitivity or dose at middle of the response range), and the average slope about the 50% effective dose. At maximum dilatation the vascular resistance was about 70% greater in hypertensive rabbits than in normotensive rabbits. There were no significant differences in 50% effective dose values between curves for hypertensive and normotensive rabbits for constrictor or dilator drugs. However, with all drugs the hypertensive rabbits showed about twice the change in vascular resistance per unit dose compared with the normotensive rabbits. These results suggest that hypertrophy of the muscles of the precapillary vessels makes them a nonspecific amplifier of vascular resistance changes evoked by constrictor and dilator stimuli. They do not support previous claims of specific changes in "sensitivity" or claims that local amplifier action is unimportant in hypertension.

Animals↗

PubMed1987

Role of brain amine transmitters and some neuromodulators in blood pressure, heart rate, and baroreflex control.

We studied the acute effects of transmitter release induced by intracisternal (i.c.) 6-hydroxydopamine (6-OHDA) from mainly noradrenergic (NA) neurons and by 5,6-dihydroxytryptamine (5,6-DHT) from serotonergic (5HT) neurons. Each group of neurons affects blood pressure and heart rate in conscious rabbits through both suprapontine and bulbospinal pathways that alter both sympathetic and vagal function. Some of the pathways are complex with 5HT neurons and NA neurons in series with one another, while in others a given autonomic function is altered through parallel independent mechanisms. The central effects of alpha-methyldopa and clonidine on blood pressure and heart rate are mediated through both groups of neurons. We examined the role of the main bulbar NA neuron groups by producing bilateral electrolytic lesions of the A1, A2, A1 + A2, A5, and A6 + A7 regions, allowing time for degeneration and noting which component of the 6-OHDA transmitter release response had become affected by the lesion. These studies suggest that each is an integrative site with distinctive NA projections to the different autonomic motoneuron pools. We also examined how physiological changes in plasma levels of angiotensin II (AII) modulate the properties of the baroreceptor-heart rate reflex. The vagal component of the reflex is depressed and this is mediated through the action of AII on peripheral vagal ganglia, so that less acetyl choline is released per nerve impulse. This provides one model of the mechanisms by which central peptide transmitters may alter the action of other transmitters.

Angiotensin II↗

PubMed1986

No effect of atrial natriuretic factor on cardiac rate, force and transmitter release.

The effects of atrial natriuretic factor (ANF, 1-300 nmol/l) on cardiac rate, force and neurotransmitter release were examined in guinea-pig isolated heart preparations. Synthetic ANF had little effect on the contractile force of electrically driven papillary muscle regardless of the presence or absence of isoprenaline. The pulse period of spontaneously beating right atria was not affected by ANF. Neither the positive nor negative chronotropic effect of isoprenaline or bethanechol respectively were changed in the presence of ANF. ANF did not affect the release of neurotransmitter from the nerve endings in the isolated atrium. ANF was confirmed to relax isolated aortic rings precontracted with either noradrenaline (ANF,IC50 = 3 nmol/l,s.e.m. = 0.2, n = 5) or potassium (ANF,IC50 = 24 nmol/l, s.e.m. = 0.2, n = 5). These results demonstrate that ANF within doses effective for vasorelaxation has no appreciable effect on myocardial function or neutrotransmitter release in the heart.

Adrenergic Fibers↗

PubMed1986

Endothelium-dependent relaxation is unaltered by hypertension, cholesterol or intimal thickening.

The effect of cellophane wrap hypertension (WRAP) and hypercholesterolemia (1% cholesterol diet, CHOL) for 4 weeks was assessed on the endothelium-dependent vasodilator response to acetylcholine in conscious rabbits after pharmacological autonomic blockade. Dose-response curves for the hindlimb vascular resistance (ear artery pressure/lower aortic blood flow; Doppler flowmeter) and acetylcholine infusion (i.v.) doses were unaltered in sensitivity (ED50) for any of the treatment groups. The range and slope of the curves were significantly altered by WRAP, CHOL or WRAP plus CHOL for acetylcholine and adenosine infusions consistent with medial hypertrophy in resistance vessels and raised serum viscosity. The effect of intimal thickening on the response to endothelium derived relaxing factor (EDRF) was tested in dog carotid artery ring segments in vitro 4 weeks after endothelium removal. The relaxation responses to acetylcholine (EDRF-dependent) and adenosine or nitroglycerin were not significantly altered by the neo-intima. Therefore the response to EDRF released by acetylcholine in resistance vessels was unaltered by hypertension, hypercholesterolemia or both together. Neo-intimal thickening in response to initial endothelium loss does not appear to alter EDRF responses in the carotid artery.

Animals↗

PubMed1986

Hypertension alters slope and range but not sensitivity to vasoconstrictor and vasodilator agents in the rabbit hindquarter.

The vascular reactivity (slope and range) and location parameter (ED50) of dose-response curves in the hindquarter vascular bed in conscious rabbits previously subjected to renal cellophane wrapping or sham operation were examined. The animals were instrumented with pulsed Doppler flow transducers and chronic indwelling aortic catheters for intra-arterial drug infusion. The rabbits were ganglion-blocked with mecamylamine before constructing full dose-response curves to intra-arterial infusions of methoxamine, noradrenaline, angiotensin II, acetylcholine, adenosine and serotonin. Curves relating dose to conductance were fitted to the experiments involving constrictors and curves relating dose to vascular resistance fitted to those involving dilator drugs. With both classes of drugs the reactivity was significantly higher in the hypertensive animals than in sham-operated rabbits. There was no difference in sensitivity (ED50 value) between the hypertensive and control animals for any agonist tested. The increased reactivity, but not sensitivity, could be entirely accounted for by the vascular amplifier action of medial hypertrophy in hypertension.

Animals↗

PubMed1986

Alpha 2-adrenoceptors and endothelium-dependent relaxation in canine large arteries.

Ring preparations from the carotid, coronary, renal, mesenteric and femoral arteries of the dog were precontracted with the thromboxane mimetic U46619, after ensuring that the resting conditions were comparable from the Laplace relationship. In the presence of prazosin (1 microM) and propranolol (3 microM), noradrenaline (NA) relaxed the arteries in the order coronary greater than carotid greater than femoral greater than renal = mesenteric. When maximum relaxation to nitroglycerin (10 microM) was taken to be 100% the maximum relaxation to noradrenaline in each artery was: coronary 70%; carotid 34%; femoral 19%; renal 7% and mesenteric 2%. In endothelium-intact arteries UK14304 mimicked the relaxation responses to NA and idazoxan shifted the curves to both agonists to the right, consistent with an alpha 2-adrenoceptor classification. Substance P relaxed the arteries in the same order as for NA but showed higher efficacy i.e.: coronary 100%; carotid 80%; femoral 71% renal 49%; and mesenteric 41%. Removal of the endothelium abolished the relaxation to NA. We conclude that endothelium-dependent relaxation to NA and substance P varies greatly across 5 large arteries of the dog. This may indicate that endothelium-derived relaxing factor (EDRF) release is site-dependent or that the efficacy of EDRF on smooth muscle varies; being greatest in the coronary and weakest in the renal and mesenteric arteries.

Animals↗

PubMed1986

Effects of hypertension and hypercholesterolemia on vasodilatation in the rabbit.

Vasodilator substances act either directly on vascular smooth muscle (e.g., adenosine) or indirectly (e.g., acetylcholine) on endothelial cells that respond by releasing an unknown powerful, short-lived relaxing factor. To determine whether chronic hypertension or hypercholesterolemia or both would alter the release of the endothelium-derived relaxing factor, experiments were performed in hypertensive rabbits (5-week cellophane wrap perinephritis; mean blood pressure, 134.7 mm Hg) and normotensive rabbits (mean blood pressure, 80 mm Hg) with a Doppler flow transducer and perivascular balloon implanted on the lower abdominal aorta. Rabbits were fed either 1% cholesterol or control diet for 4 weeks before the experiment. On the day of the experiment, resting hindlimb vascular resistance was greatest in hypertensive rabbits fed 1% cholesterol diet, followed (in descending order) by hypertensive rabbits, normotensive rabbits fed 1% cholesterol diet, and normotensive rabbits. Pharmacological autonomic reflex blockade was induced, and steady state intravenous infusion curves to acetylcholine, serotonin, and adenosine were constructed. Sensitivity (location of effective dose, 50%) to the three vasodilator agents was altered less than twofold from the values in normotensive rabbits for any treatment group. The maximum vasodilator response to acetylcholine, but not to adenosine or serotonin, infusion was reduced significantly in the treated rabbits compared with that in normal rabbits. Reactive hyperemic responses to 5 to 80 seconds of ischemia were not significantly different among the treatment groups. These results indicate that hypertension with or without hypercholesterolemia does not greatly alter the responsiveness of the hindlimb resistance vasculature to these three vasodilator agents or to ischemia.

Acetylcholine↗

PubMed1986

The alpha adrenoceptors on endothelial cells.

Endothelial cells release a powerful factor (endothelium-derived relaxing factor [EDRF]) that relaxes smooth muscle cells in response to some vasodilating agents such as acetylcholine. Contraction curves to norepinephrine (NE) in greyhound, mongrel dog, and pig coronary artery rings were studied in vitro in the presence of propranolol. Removal of endothelium increased the sensitivity and maximum contraction in response to NE. In other experiments pig coronary rings were precontracted with a thromboxane mimetic U 46619 in the presence of propranolol. NE relaxed these arteries only if endothelium was present. Methoxamine was without effect but the relaxation response to NE was antagonized by phentolamine, idazoxan, and yohimbine, which suggests that there are alpha 2 adrenoceptors on endothelial cells that mediate the release of EDRF. Greyhound and mongrel dog large coronary arteries relaxed to NE only if prazosin was present, which suggests that alpha 1-adrenoceptor stimulation on the vascular smooth muscle can override the relaxation response to EDRF. Comparison of NE responses in carotid, mesenteric, renal, and femoral large arteries of the pig, greyhound, and mongrel dog indicate the nonuniformity of distribution of alpha 2 adrenoceptors on endothelium and alpha 1 and alpha 2 adrenoceptors on vascular smooth muscle. The integrity of the endothelium must now be considered in interpreting the vascular responses to alpha-adrenoceptor agonists.

Animals↗

PubMed1985

Release and properties of endothelium-derived relaxing factor (EDRF) from endothelial cells in culture.

Cultured bovine endothelial cells were seeded onto the intimal surface of endothelium-denuded rings of canine coronary artery. These rings did not previously relax to acetylcholine, substance P, bradykinin, and A23187. After seeding, the same rings relaxed to bradykinin and A23187, but not to acetycholine or substance P. Indomethacin pretreatment did not affect these responses. Cells from the same source were then grown to confluence on microcarrier beads, poured into small columns, and perfused with Krebs' solution. The perfusate from the columns was bioassayed on endothelium-denuded rings of coronary artery from either the dog or pig. Challenge of the column in the presence of indomethacin with either bradykinin or A23187 as well as acetylcholine or substance P caused release of a substance that relaxed both types of artery. Its activity half-life was 6.4 +/- 0.4 sec at 37 degrees C and it was hydrophilic and negatively charged. Prostacyclin (PGI2) as a candidate for EDRF was ruled out because 1) indomethacin failed to block its release and 2) the pig coronary artery, although insensitive to PGI2, relaxed to the endothelium-derived substance. These results show that, in response to a number of dilator drugs, cultured endothelial cells release a vascular relaxing substance (EDRF) that has characteristics similar to the EDRF of normal endothelium. The chemical nature of EDRF awaits clarification.

Animals↗

PubMed1985

Topical use of prostacyclin in microvascular surgery.

Prostacyclin was investigated for its ability to overcome surgically induced spasm of the femoral artery and to increase blood flow through the rabbit epigastric free flap. Topical prostacyclin (200 ng/ml) and lignocaine (20 mg/ml or 2%) each produced near-maximal vasodilatation of large conducting vessels. This resulted in a significant increase in blood flow after 5 minutes for each form of topical treatment, compared to a saline control. However the vasodilatation obtained from lignocaine tended to wear off over 30 minutes. Treatment with systemic indomethacin did not prevent surgical spasm nor the action of prostacyclin in relieving it. Topical 6-oxo-prostaglandin F1 alpha, the major breakdown metabolite of prostacyclin, was not responsible for the vasodilatory action of prostacyclin. Topical prostacyclin (200 ng/ml) also caused platelet disaggregation and some rebleeding from the anastomotic site, nevertheless there was no significant difference in flap survival between the use of topical prostacyclin and topical lignocaine.

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Pharmacologic modification of blood flow in the rabbit microvasculature with prostacyclin and related drugs.

The rabbit epigastric free flap was used to investigate the effect of prostacyclin and drugs modifying its synthesis in vivo on microvascular blood flow. Prostacyclin and its analogue carbacyclin caused an increase in flow with a maximal twofold increase at approximately 6.5 and 250 ng/ml, respectively, in the flap. Thromboxane synthetase inhibitors such as dazoxiben hydrochloride, UK-38,485, 7-IHA, and imidazole (up to 7 X 10(-4) M in the flap) as well as the prostaglandins 6-oxo-PGF1 alpha and PGE2 (up to 3.7 and 9.2 ng/ml, respectively, in the flap) all failed to modify the control flow rate in the cutaneous microcirculation. It is concluded that the vasodilatory properties of prostacyclin and carbacyclin, together with their known platelet antiaggregatory properties, warrant further study in problem areas of microsurgery such as flap ischemia. The use of thromboxane synthetase inhibitors had no demonstrable effect on the normal flap, and their effect on the ischemic flap remains to be investigated.

6-Ketoprostaglandin F1 alpha↗

PubMed1984

Reversible inhibition of neuronal uptake by benextramine, an irreversible presynaptic alpha-adrenoceptor antagonist.

Benextramine, a covalently binding alpha-adrenoceptor blocking agent, potentiated the action of noradrenaline but not isoprenaline in guinea pig isolated right atria. This potentiation was probably caused by inhibition of neuronal uptake. When the benextramine was washed from the tissues for 60 min, no potentiation of the action of noradrenaline was observed. This easily reversed inhibition of neuronal uptake by benextramine contrasts with the effects of desipramine and phenoxybenzamine because the potentiating effect of these drugs was unaffected by 60 min of washing. The presence of benextramine also caused a small tachycardia in both rabbit and guinea pig right atria which was probably due to the release of endogenous noradrenaline. Clonidine a presynaptic alpha 2-adrenoceptor agonist, inhibited the responses to electrical field stimulation. Pretreatment with benextramine greatly diminished the effect of clonidine. This alpha 2-adrenoceptor antagonism was not reversed by washing the benextramine from the tissue for 240 min. We conclude that benextramine is a readily reversible inhibitor of neuronal uptake and an irreversible antagonist of presynaptic alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed1984

Phentolamine--an unexpected agonist in the rabbit.

Phentolamine (0.1-10 microM) caused an anomalous rightward shift of the relationship between the number of electrical field pulses and tachycardia in the rabbit isolated right atrium. Phentolamine was apparently acting as a presynaptic agonist on sympathetic nerve endings to inhibit transmitter release. The effect was prevented by benextramine treatment and antagonized 10 fold by yohimbine (1 microM) but not by prazosin (0.1 microM). In ganglion-blocked (mecamylamine) conscious or anaesthetized rabbits, phentolamine (3-1000 micrograms kg-1) caused a dose-related rise in blood pressure that was antagonized by yohimbine (1 mg kg-1). These pressor and inhibitory cardiac sympathetic nerve effects of phentolamine are not found in similar preparations from the guinea-pig or rat. Therefore, these rabbit-specific agonist effects of phentolamine at sites similar to alpha 2-adrenoceptors make this drug unsuitable as an alpha-adrenoceptor antagonist in rabbits.

Adrenergic alpha-Agonists↗