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Biomedical subjects

J A Angus

Publications and source records attributed to J A Angus.

At least 91 records · Page 5Linked to original sources
PubMed1990

Glibenclamide is a competitive antagonist of the thromboxane A2 receptor in dog coronary artery in vitro.

1. Glibenclamide, a sulphonylurea oral hypoglycaemic agent is a widely used antagonist of cromakalim-activated K+ channels in smooth muscle. 2. In isolated ring segments of the large circumflex coronary artery from the dog, glibenclamide (1-30 microM) caused a concentration-dependent reduction in both spontaneous isometric force and contractions induced by U46619, a thromboxane A2-mimetic. 3. Glibenclamide behaved as a competitive antagonist of U46619 with an estimated pKB (-log KB) value of 6.2 by Schild regression analysis (slope 1.07). 4. Glibenclamide (30 microM) was apparently selective since it had no effect on the concentration-contraction curves to endothelin-1, noradrenaline or KCl. 5. We suggest that this additional property of glibenclamide should be considered in any smooth muscle study where active force is raised by either the exogenous application or endogenous generation of thromboxane A2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Venous reactivity in canine renovascular hypertension.

The responsiveness of arterial smooth muscle to vasoactive stimuli is enhanced hypertension. It is however, unclear whether this increased reactivity is a generalised property of vascular smooth muscle, involving veins as well. We examined the responses of rings of cephalic vein in vitro taken from 11 dogs with chronic renovascular hypertension and 10 normal dogs. Mean blood pressure was 129 +/- 3 mmHg in the hypertensive dogs, 26% above control. Veins from hypertensive dogs had steeper passive circumference-tension relationships than veins from normal dogs, indicating reduced compliance. Sensitivity (defined as location of EC50) to potassium depolarisation was unchanged, but maximal contractile force (Fmax) developed was 35% greater in hypertension when compared with normotensive dogs. With noradrenaline and the selective alpha 1-adrenoceptor agonist methoxamine, there was no difference between normotensive and hypertensive dogs in either location of the EC50 or in the Fmax. With the selective alpha 2-adrenoceptor agonist UK 14304, there was a tenfold decrease in sensitivity in hypertension when compared with normotensive dogs, but no change in Fmax. There was, however a tenfold increase in sensitivity to serotonin in hypertension when compared to normotensive dogs, and a 22% increase in Fmax. Contractile responses to transmural sympathetic nerve stimulation were similar in the two groups. As desipramine caused equal increases in responses to neural stimulation, there was no demonstrable abnormality of neuronal uptake in hypertension. Morphometric examination showed no change in media thickness, media thickness/radius ratios or media cross sectional area in hypertension. Therefore, veins from dogs with chronic renovascular hypertension are stiffer but not hypertrophied, and exhibit some specific differences in contractile responses to vasoconstrictor agents when compared with veins from normotensive dogs.

Animals↗
PubMed1989

A functional study of the development of the cardiac sympathetic neuroeffector junction in the SHR.

We studied the function of the cardiac sympathetic nerve varicosity in isolated right atrial preparations of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 4, 9, 14, 20 and 50 weeks of age. Cumulative concentration-atrial period response (C-R) curves to isoprenaline showed similar maximum response and sensitivity (EC50) at all ages but there was an age-related fall in resting atrial rate. Similar results were found for methoxamine (alpha 1-adrenoceptor agonist) although the maximum response was significantly less than for isoprenaline. The time-dependent recovery (T 1/2) of the fall in atrial period in response to sympathetic nerve stimulation from electrical field pulses (1-32 at 1 Hz) was enhanced by neuronal uptake inhibition by desipramine (0.1-1 mumol/l), to a similar degree at all ages. Pre-junctional alpha 2-adrenoceptor stimulation by clonidine caused progressively more inhibition of the number of field pulses-fall in period relationship with age. SHR atria were similar to WKY rat atria at all ages except for a further impairment of the development of pre-junctional alpha 2-adrenoceptors. These studies indicate that the function of the cardiac sympathetic varicosity matures early (by 4 weeks) and overall there is very little impairment in SHR versus WKY rat atria.

Aging↗
PubMed1989

Endothelin is blood vessel selective: studies on a variety of human and dog vessels in vitro and on regional blood flow in the conscious rabbit.

1. Endothelin (Et), a vasoconstrictor peptide, was 5-10-fold more potent (lower EC50) on isolated ring segments of large veins than on large arteries removed from dog coronary, mesenteric, femoral, renal and internal mammary vasculature and from the human internal mammary pedicle. 2. In the dog large coronary artery, Et (10-30 nmol/L) caused transient relaxations partway through the generation of a concentration-contraction curve. These relaxations were endothelium dependent. 3. In conscious rabbits treated with mecamylamine, Et (0.025-0.4 nmol/kg) caused a marked rise in renal vascular resistance but hindquarter vasodilation. Under the same conditions angiotensin II constricted both beds. 4. These studies suggest that Et is vascular bed and large vein selective in activity. It did not appear to be selective for large or small coronary arteries in vitro.

Animals↗
PubMed1989

Phentolamine and structurally related compounds selectively antagonize the vascular actions of the K+ channel opener, cromromakalim.

1. The effects of cromakalim, a novel vasodilator agent believed to open K+ channels, were studied in a range of large and small arteries in vitro. In dog isolated coronary artery, precontracted with U46619 (a thromboxane A2-mimetic), cromakalim caused concentration-dependent relaxation which could be inhibited by phentolamine (10-100 microM). 2. The ability of phentolamine to antagonize cromakalim was selective since it did not affect responses to a number of other vasodilators including isoprenaline, nitroprusside or nicorandil. 3. The effect of phentolamine was not related to its alpha-adrenoceptor blocking actions since other alpha-adrenoceptor antagonists (prazosin 10 microM, rauwolscine 10 microM and phenoxybenzamine 1 microM) failed to influence the action of cromakalim. 4. A number of compounds structurally related to phentolamine were also able to block the vaso-relaxant response to cromakalim in the dog isolated coronary artery. The rank order of potency was alinidine = phentolamine = ST91 greater than tramazoline = naphazoline. Clonidine and tolazoline were inactive. The most potent compounds (alinidine and phentolamine) were effective only at concentrations above 1 microM. 5. Electrophysiological studies, in which resting membrane potential and tension were measured simultaneously, were carried out on rat isolated femoral artery. Phentolamine (30 microM) antagonized both the vasorelaxation and hyperpolarization caused by cromakalim. 6. These results suggest that phentolamine and some structurally related compounds, may inhibit K+ channel opening, an action which would account for their ability to antagonize the actions of cromakalim. Such compounds may prove useful in determining the role of K+ channels in regulating vascular smooth muscle tone in vivo and in vitro.

Animals↗
PubMed1989

5-carboxamidotryptamine elicits 5-HT2 and 5-HT3 receptor-mediated cardiovascular responses in the conscious rabbit: evidence for 5-HT release from platelets.

The selective "5-HT1-like" receptor agonist 5-carboxamidotryptamine (5-CT, 0.2-1.6 micrograms/kg bolus i.v.), serotonin (5-HT, 3-10 micrograms/kg), and phenylbiguanide (10-40 micrograms/kg) all elicited the "Bezold-Jarisch-like" bradycardia reflex in conscious rabbits. This reflex was antagonised by the 5-HT3 receptor antagonist, MDL 72222. After autonomic blockade (mecamylamine), 5-CT and 5-HT infusion (i.v.) caused renal artery spasm (Doppler flowmeter) that was antagonised by ketanserin, a 5-HT2-receptor antagonist. Both 5-CT and 5-HT caused 5-HT1-like receptor mediated increases in hindquarter conductance that were unaltered by ketanserin (0.5 mg/kg). The anomalous 5-HT3 and 5-HT2 receptor actions of 5-CT were completely prevented by 16 h pretreatment with reserpine (5 mg/kg) that lowered total serum serotonin to less than 3% of normal but did not reduce the cardiovascular actions of 5-HT. Fluoxetine (1 mg/kg i.v.), an inhibitor of 5-HT uptake into platelets, significantly attenuated the Bezold-Jarisch-like reflex evoked by 5-CT but not by 5-HT. These studies suggest that 5-CT is carried into platelets where it releases 5-HT. This illustrates how apparent receptor selectivity asserted in in vitro assays can be destroyed in vivo.

Animals↗
PubMed1989

Weak beta-adrenoceptor-mediated relaxation in the human internal mammary artery.

The function of beta-adrenoceptors in the human internal mammary artery was studied in vitro to predict the way in which the internal mammary artery graft would respond to beta-adrenergic agonists and antagonists given in the perioperative period. Ring segments of the distal internal mammary artery obtained from patients not receiving beta-blocker therapy were mounted in organ baths and isometric wall force was measured. For comparison, similar experiments were conducted on segments of canine coronary artery, a vessel known to have powerful beta-adrenoceptor function. All arteries were precontracted with potassium or the thromboxane mimetic agent, U46619, before isoproterenol cumulative concentration-relaxation curves were constructed. In the human internal mammary artery, the maximum relaxation induced by isoproterenol was only 14% of the potassium-induced contraction and 24% of the U46619-induced contraction. These responses were weak compared with 54% and 86% for beta-adrenoceptor relaxation measured in corresponding experiments in the canine coronary artery. In all experiments, propranolol antagonized the relaxation induced by isoproterenol. These studies suggested that the human internal mammary artery has only a small number of beta-adrenoceptors. We conclude that beta-adrenoceptors would contribute little to the reactivity of the human internal mammary artery graft to sympathomimetic drugs.

Animals↗
PubMed1989

Resistance control in hypertension.

In hypertension the small arteries undergo structural changes that increase vascular resistance, both in vivo and in vitro. The hallmark of a physiological vascular amplifier is that enhanced resistance responses must occur about the resting value. For this to happen, the average radius of the resistance vessels must be narrower than normal; increased wall thickness without narrowing does not result in this type of amplification. In primary hypertension in spontaneously hypertensive rats (SHR), the structural changes in the resistance vessels precede the elevation in blood pressure. This is consistent with the hypothesis that these changes cause hypertension. The role of the sympathetic nervous system in early vascular development is unclear, in view of the absence of regression of amplifier properties in the hindlimb vessels after extensive immunosympathectomy. However, short periods of enalapril treatment in young animals attenuate the development of hypertension and normalize hindlimb resistance properties, suggesting that the renin-angiotensin system may have a role in early vascular growth. Studies in tissue culture suggest that both systems could play a role in smooth muscle growth, in conjunction with growth factors such as platelet-derived growth factor (PDGF)-like peptides and endothelin. The early structural change that occurs in hypertension is probably a variant of normal development of the resistance vasculature, with greater secretion of 'normal' growth factors and/or enhanced responsiveness of the vascular smooth muscle.

Animals↗
PubMed1989

Reactivity of human isolated internal mammary artery to constrictor and dilator agents. Implications for treatment of internal mammary artery spasm.

Perioperative spasm of the internal mammary artery (IMA) may occur after coronary artery bypass surgery. To establish the most appropriate dilator agent, we tested the reactivity of ring segments of human IMA in organ baths to various constrictor and dilator agents. We found that the thromboxane mimetic U46619 was the most potent IMA constrictor agent, followed by norepinephrine, serotonin, phenylephrine, and potassium chloride (K+). In K+- or U46619-precontracted IMA, glyceryl trinitrate and papaverine caused full relaxation. In K+-precontracted arteries, nifedipine, verapamil, and diltiazem caused full relaxation, but nifedipine was 15-fold more potent than the other calcium antagonists. In contrast, pretreatment of vessels with glyceryl trinitrate failed to alter subsequent contraction to U46619 or K+ while nifedipine pretreatment abolished subsequent contraction to K+ and reduced sensitivity of the IMA to U46619. We conclude that perioperative IMA spasm could be treated with the rapid-onset, nonspecific, vasodilator glyceryl trinitrate, but for prophylaxis of IMA spasm, calcium antagonists or specific receptor antagonists should be tested in the clinical setting.

Dose-Response Relationship, Drug↗
PubMed1988

Reactivity of the canine isolated internal mammary artery, saphenous vein, and coronary artery to constrictor and dilator substances: relevance to coronary bypass graft surgery.

The internal mammary artery (IMA) and saphenous vein (SV) are used routinely in coronary artery (CA) bypass graft surgery. The IMA may develop spasm during surgery, and the SV often develops spasm during removal from the leg. We sought to determine the relative reactivity of the canine CA, IMA, and SV to potential vasoconstrictor substances and especially to determine which vasodilator agents were effective in these different blood vessels. All vessels were arranged as ring segments suspended at optimal stretch in organ baths. Glyceryl trinitrate (GTN) caused relaxation of the three vessels but was less sensitive, less potent (as determined by EC50 values), and had a reduced range of relaxation in the IMA. Papaverine was less sensitive in the IMA as compared with the CA and SV. Nifedipine, verapamil, and diltiazem were potent relaxing agents in all three vessels when precontracted by K+, but were less potent in vessels contracted by the thromboxane mimetic U46619 or phenylephrine, especially in the SV. These studies highlight the marked differences in the response of IMA and CA to constrictor and dilator agents and reinforce the notion that calcium antagonists of different chemical classes have widely differing activities in vascular tissue.

Animals↗
PubMed1988

Studies on the specificity of the inhibitory action of N,N-diisopropyl-N'-isoamyl-N'-diethylaminoethylurea (P-286) on adrenal catecholamine release in the anaesthetized rat.

1. The ability of P-286 (N,N-diisopropyl-N'-isoamyl-N'-diethylaminoethylurea) to reduce selectively the release of catecholamines from the adrenal medulla has been studied in urethane-anaesthetized rats. 2. Pressor responses to acetylcholine (Ach) and the nicotinic receptor-agonist 1,4-dimethylphenylpiperazine (DMPP) in rats treated with atropine, (+/-)-propranolol and guanethidine were used as the index of adrenal catecholamine release. 3. The injection of P-286 (1-10 mg/kg, i.v.) elicited a dose-dependent bradycardia which was associated with hypotension. P-286 reduced pressor responses to Ach and DMPP in a dose-dependent manner with an IC50 of 2.5 mg/kg and, following near complete blockade, pressor responses to DMPP returned to 50% of control after 90 min. 4. In non-atropinized rats, P-286 (30 mg/kg, i.v.) was without effect on the bradycardic responses elicited by stimulation of the right vagus nerve at frequencies of 5-40 Hz while pressor responses to DMPP in bilaterally adrenalectomized, non-guanethidine treated rats were reduced by approximately 50% after P-286 (10 mg/kg, i.v.). 5. The latter effect of P-286 on responses to DMPP in adrenalectomized rats cannot be attributed to ganglionic blockade since in rats with intact adrenals P-286 (10 mg/kg, i.v.) also reduced pressor responses to i.v. adrenaline and i.v. angiotensin II by approximately 50%. Thus the reduction in response to DMPP in adrenalectomized rats and to the non-nicotinic agonists may be a reflection of an action on the mechanism of contraction of vascular smooth muscle; that is, at a post-receptor event. 6. The results of the study show that P-286 selectively reduces adrenal catecholamine release at doses which do not affect autonomic ganglia. Its usefulness as a tool in cardiovascular research, however, may be limited by an action of vascular smooth muscle.

Acetylcholine↗
PubMed1988

Comparative assay of neuronal uptake and autoinhibitory feedback in guinea-pig and rat atria.

1. The roles of neuronal uptake and autoinhibitory feedback were studied in guinea-pig and rat isolated right atria. Tachycardia was used as a measure of noradrenaline concentration at the post-junctional beta-adrenoreceptors in response to electrical field stimulation, 1-16 pulses at 1 Hz, or to exogenous noradrenaline. 2. The EC50 values for noradrenaline concentration-response curves were similar (7.3, -log M) in the two species when neuronal uptake was inhibited by desipramine (DMI, 1 microM). In the absence of DMI, however, the EC50 values were different for the rat (7.0) and guinea-pig (6.3). 3. DMI (0.01-1 microM) caused a substantial increase in half-response time (t 1/2), an integrated measure of tachycardia, in the rat during field stimulation but only caused modest increases in the guinea-pig atria. Following pretreatment with the irreversible alpha 2-adrenoceptor antagonist benextramine, the t 1/2 values were substantially raised in guinea-pig atria with no further change to t 1/2 in the rat atria. 4. The existence of presynaptic inhibitory alpha 2-adrenoceptors in the rat was established using clonidine which caused parallel rightward shifts of field stimulation-tachycardia curves. 5. These results suggest that in the guinea-pig atria blockade of both autoinhibitory feedback and neuronal uptake cause a very large increase in tachycardia compared with blockade of either system alone. In rat atria the most important modulation is from neuronal uptake, which suggests that in this species autoinhibitory feedback is of little consequence.

Animals↗
PubMed1988

Amiloride analogues cause endothelium-dependent relaxation in the canine coronary artery in vitro: possible role of Na+/Ca2+ exchange.

1. A number of amiloride analogues were used to test the proposal that Na+/Ca2+ exchange may play a role in the secretion of endothelium-derived relaxing factor (EDRF). The analogues used were those substituted on either the 5-amino group or the terminal guanidino nitrogen atom. The former block both Na+/Ca2+ and Na+/H+ exchange whilst the latter block the Na+ channel and the Na+/Ca2+ exchange. 2. Both series of compounds caused relaxation in isolated rings of dog coronary artery (EC50 values, 1-10 microM) presumably due to release of EDRF since removal of endothelium greatly attenuated the response. 3. Amiloride (1-100 microM) had little effect on either endothelium-intact or denuded arteries. 4. The guanidino substituted analogues also appeared to block selectively the relaxation response to acetylcholine in the coronary artery, independently of their EDRF-releasing activity. 5. It is proposed that endothelial cells have an active Na+/Ca2+ exchange operating in the forward mode to extrude Ca2+. This mechanism may be important in the control of EDRF release.

Amiloride↗
PubMed1988

Role of alpha-adrenoceptors in constrictor responses of rat, guinea-pig and rabbit small arteries to neural activation.

1. We have investigated the adrenoceptors mediating the force and electrical responses of rat mesenteric small arteries (i.d. 100-300 microns). Some mechanical experiments were also performed using guinea-pig and rabbit mesenteric small arteries. 2. Vessels were mounted on an isometric myograph and stimulated either with short (3 s) trains of electric field stimuli (ca. 0.2 ms pulse width) at 25 Hz (nerve stimulation) or with 10 microM-exogenous noradrenaline. 3. Nerve stimulation caused a force response equal to ca. 40% of the response to exogenous noradrenaline and, in the rat vessels, excitatory junction potentials (EJPs), which normally summated to give a depolarization of ca. 10 mV (although action potentials were sometimes seen). 4. Almost complete and reversible inhibition of the force responses of all vessels to both exogenous noradrenaline and to nerve stimulation was obtained using prazosin (0.1 microM) or phentolamine (1 microM). 5. Irreversible blockade of alpha 2-receptors enhanced the force response of all vessels to nerve stimulation by ca. 50%, but did not affect the force response of rat and guinea-pig vessels to exogenous noradrenaline. In the rabbit vessels this force response was abolished by alpha 2-blockade. 6. Following alpha 2-blockade, in the rat vessels the alpha-antagonists prazosin (0.1 microM), phentolamine (0.1 microM), phenoxybenzamine (0.01 microM) and benextramine (10 microM) all totally abolished the force response to exogenous noradrenaline, and inhibited the response to nerve stimulation by at least 80%. Similar effects of phentolamine were seen in the guinea-pig and, for the response to nerve stimulation, in the rabbit vessels. 7. In the rat vessels, alpha-adrenoceptor antagonists did not affect the EJPs, but did inhibit the small depolarization which resulted from several seconds of nerve stimulation. The ATP analogue alpha, beta-methylene-ATP (3 microM) abolished the EJPs, but only slightly reduced the force responses. 8. The results suggest that the force response to nerve stimulation of the rat mesenteric small arteries is mediated primarily through alpha-adrenoceptors, but also to a small degree through non-alpha-adrenoceptors, possibly ATP receptors.

Action Potentials↗
PubMed1987

Relaxant effects of ATP and adenosine on canine large and small coronary arteries in vitro.

Rings from greyhound large (3-4 mm internal diameter) and small (less than 200 microns internal diameter) coronary arteries were mounted in water-jacketed tissue baths or a Mulvany myograph, respectively. Relaxations to ATP and adenosine were determined in arteries precontracted with the thromboxane A2 mimetic U46619 or with K+. ATP was a much more effective relaxant of large arteries than adenosine. ATP relaxed large coronaries by an endothelium-dependent mechanism whereas relaxations to adenosine were not endothelium-dependent. In contrast, adenosine appeared to be slightly more effective than ATP in relaxing small coronary arteries. Moreover, adenosine was more effective in relaxing K+-contracted small coronaries than K+-contracted large coronary arteries. These results suggest that ATP may be a more significant relaxant of large coronaries than adenosine but that adenosine may be a more significant relaxant than ATP in small coronary arteries.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗