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Biomedical subjects

J A Angus

Publications and source records attributed to J A Angus.

At least 163 records · Page 9Linked to original sources
PubMed1975

Estimation of non-autonomic and autonomic components of iliac bed vascular resistance in renal hypertensive rabbits.

Iliac bed vascular resistance (IVR) was measured before and after pharmacological block of the autonomic effectors in unanaesthetized renal hypertensive and normotensive rabbits with previously implanted Doppler flowmeters. This permitted partitioning the resting IVR into a non-autonomic component (ie, steady-state IVR after block) and an autonomic component (ie, resting IVR minus non-autonomic IVR). When IVR was measured at the same mean arterial pressure (MAP) before and after block in each animal, the increase in estimated non-autonomic IVR accounted entirely for the rise in resting IVR in renal hypertensive rabbits. However, if IVR measurements after block were made at a lower MAP than before block, the estimated non-autonomic and autonomic components were both significantly increased in renal hypertensive rabbits. It is concluded that in the latter experiment non-autonomic IVR in renal hypertension was underestimated, whilst the autonomic component was overestimated. The rise in non-autonomic IVR in renal hypertension was partly due to structural changes in the iliac bed, since IVR remained higher in hypertensive than in normotensive rabbits after abolishing smooth muscle tone with vasodilator drugs.

Animals↗
PubMed1971

Cardiovascular actions of substituted adenosine analogues.

1. The effects of adenosine on systemic blood pressure, coronary blood flow and cardiac contractility and rate were studied in anaesthetized open-thorax dogs.2. The potency and duration of action of substituted adenosine analogues were compared with that of adenosine.3. With the exception of 2-chloroadenosine, in which coronary dilator activity was enhanced, substitution in the 2-position of the adenosine molecule reduced activity.4. In all cases 2-substitution prolonged the duration of the coronary dilator activity of adenosine.5. N(6)-Methylation of adenosine and 2-chloroadenosine reduced their coronary dilator activities, but had no effect on the duration of the response.6. Comparison of the coronary dilator potencies and hypotensive activities of 2-ethylaminoadenosine and 2-methoxyadenosine indicates that these analogues have some specificity for the coronary bed.

Animals↗
PubMedDate not supplied

Synthesis and biological characterization of a series of analogues of omega-conotoxin GVIA.

The 27-residue polypeptide omega-conotoxin GVIA (omega-CgTx), from the venom of the cone shell Conus geographus, blocks N-type neuronal calcium channels. It contains three disulphide bridges. We report here the synthesis and biological characterization of a series of analogues in which one disulphide has been replaced by substitution of appropriate Cys residues with Ser, viz. [Ser1,16]-omega -CgTx, [Ser8,19]-omega-CgTx, [Ser15,26)-omega-CgTx, [Ser16]-omega-CgTx8-27 and [Ser15]-omega-CgTx1-19. All syntheses were conducted manually using either Boc or Fmoc methodology. Deprotected peptides were oxidized to their bridged forms using either aerial oxidation or aqueous dimethyl sulphoxide. Peptides were purified using RP-HPLC, and their purity and identity were checked by RP-HPLC, capillary electrophoresis and mass spectrometry. Inhibition of neuronal N-type calcium channels was assessed as the inhibition of the twitch responses of rat vas deferens stimulated with single electrical pulses at 20 second intervals. None of these analogues was biologically active, suggesting that the disulphides play an important role in maintaining biological activity.

Amino Acid Sequence↗
PubMedDate not supplied

Techniques to study the pharmacodynamics of isolated large and small blood vessels.

Techniques are described for the mounting of large artery and vein ring segments on wire hooks in an organ bath chamber. Each vessel is set to normalised conditions of passive force directly determined from its circumferential length-tension relationship. This rigorous set up follows the normalisation routine established by Mulvany and Halpern for small resistance arteries mounted under isometric conditions on a wire myograph. Techniques for electrical field stimulation, and simultaneous force and membrane potential (Em), are described. An example of electrical field stimulation is given for the unravelling of the role of ATP in sympathetic co-transmission in rat mesenteric small arteries. Other techniques described include isobaric, isotonic mounting of small vessels, their morphology and receptor characterisation. Examples include human buttock skin arteries, small coronary arteries (CAs), and vasa vasorum arteries taken at coronary bypass graft operations. The underlying philosophy is that every segment of blood vessel constituting the intact resistance bed has its own pharmacology. There is no 'ideal' preparation. Whether the vessel is studied under isometric, isotonic, or isobaric conditions, the experimentalist must be wary of the influence of the methodology on the pharmacodynamics. These influences may not be the same between normal and diseased vessels.

Acetylcholine↗
PubMedDate not supplied

Techniques to measure pharmacodynamics in the intact vasculature.

Techniques are described for the intravenous, close intraarterial, or perivascular delivery of drugs in conscious or anaesthetized animals. Examples of the determination of pharmacodynamic parameters such as regional blood flow, large artery diameter, resistance, conductance, and blood pressure are given for conscious rabbits and anaesthetized dog preparations. An important issue is how to determine the direct vascular action of an injected drug in the light of rapid and powerful autonomic reflex buffering effects especially in healthy conscious animals. The methods of measurement of drug action on the baroreceptor-heart rate reflex and postural adaptation (90 degrees tilt) reflex in the conscious rabbit are explained. Finally, the changes to large and small artery morphology are explored in the rabbit hindlimb following conduit femoral artery ligation to induce arteriogenesis and angiogenesis. This work aims to highlight approaches to exploring drug action in vivo, a much neglected skill in the repertoire of the modern cardiovascular pharmacologist.

Animals↗
PubMedDate not supplied

Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin.

Arteries relax to the vasodilators acetylcholine, substance P, ATP and bradykinin only if the endothelium is present. One hypothesis is that these substances stimulate the endothelial cells to release a vasodilator substance which in turn relaxes the underlying smooth muscle. We considered that other hormones which have direct actions on smooth muscle cells may also release the dilator substance. If the hormone contracts smooth muscle cells and also activates the release of the dilator from endothelial cells, the algebraic sum of these stimuli would determine the physiological response. Our preliminary experiments in pig and dog isolated coronary arteries showed that noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) were significantly more powerful vasoconstrictors in the absence of endothelium. We report here the unexpected finding that these constrictor amines release a vasodilator substance from endothelial cells that can act as a physiological antagonist of the well known smooth muscle contractile responses. We suggest that the potential involvement of the vasodilator signal should be considered in the responses to vasoconstrictors in both normal and diseased blood vessels.

Animals↗
PubMedDate not supplied

Relaxation of large coronary artery by verapamil, D600, and nifedipine is constrictor selective: comparison with glyceryl trinitrate.

We compared the vasodilator potencies of a number of Ca2+-entry blockers with glyceryl trinitrate (GTN) in isolated ring segments of dog coronary arteries contracted by a variety of substances. Rings were contracted to 80% of maximum by serotonin, phenylephrine (PE), noradrenaline (NA), K+ (KCl), or U46619 (stable thromboxane A2 analogue). Cumulative additions of a vasodilator then relaxed the ring towards basal tone. GTN had a similar IC50 value (0.1 - 0.3 microM) regardless of the substance used to contract the ring. In contrast, nifedipine and verapamil were weak relaxant drugs against arteries contracted by U46619. Nifedipine was most potent in rings contracted by K+, whereas verapamil was similarly effective towards K+ and serotonin, but threefold less potent against PE or NA. The (-)enantiomers of verapamil and D600 were more potent (seven-to 26-fold) than the (+)enantiomers in arteries contracted by K+ or serotonin, but not for PE or NA. A combination of (-)verapamil and GTN showed additive effects without a change in the IC50 for GTN. We conclude that, in contrast with GTN, the effectiveness of Ca2+-entry blockers in the treatment of coronary vasospasm may be dependent on the nature of the constrictor signal.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMedDate not supplied

The effect of heart rate on indices of myocardial contractility in the dog.

1. Changes in heart rate were evoked by atrial pacing in anaesthetized dogs with no pretreatment and in dogs given reserpine or guanethidine for 72 h. The effect of alterations in heart rate were related to two indices of myocardial contractility: the maximal rate of change of left ventricular pressure (dp/dt), and an index which was independent of initial fibre length (dp/dt)/IIT, where IIT is integrated isometric tension. 2. An increase in heart rate in control dogs was accompanied by a rise in both dp/dt and (dp/dt)/IIT confirming that the Bowditch staircase does exist in the intact ventricle. The regression line relating heart rate to (dp/dt)/IIT was significantly steeper than that relating heart rate to dp/dt because the reduction in left ventricular preload at high heart rate tends to attenuate the rise in dp/dt. 3. Reserpine, but not guanethidine pretreatment was accompanied by either a slight decrease or no change in (dp/dt)/IIT during pacing. 4. Acute elevation of (dp/dt)/IIT by either calcium or isoprenaline infusion in reserpine pretreated dogs did not restore the Bowditch effect. 5. Acute depression of (dp/dt)/IIT by propranolol and pentobarbitone was accompanied by a greater rise in (dp/dt)/IIT with pacing in control dogs and a rise rather than a fall in reserpine-pretreated dogs.

Animals↗
PubMedDate not supplied

Effects of histamine bolus injections and continuous infusions on the H1- and H2-receptors in the hindlimb vessels of the rabbit.

1. Hindlimb vascular resistance (HVR) was continuously measured after pharmacological block of the autonomic effectors in unanesthetized rabbits with previously implanted Doppler ultrasonic flowmeters. 2. Histamine bolus injections caused a dose-related short lived fall in HVR followed by a more sustained rise. The fall was due to H2-receptor stimulation (blocked by burimamide or metiamide) and the rise to H1-receptor stimulation (blocked by mepyramine). At the doses of histamine tested the magnitude of the H1-mediated vasoconstriction had a larger peak effect than the H2-mediated vasodilatation. 3. Histamine infusions up to 200 microgram kg-1 min-1 did not alter HVR significantly but both increases and decreases in HVR were observed after giving H2- or H1-antagonists, respectively. 4. From the double reciprocal plots of 1/peak HVR change and 1/dose of histamine the magnitude of the predicted H1- and H2-mediated peak HVR effects at large doses were the same. This suggested that the number of H1- and H2-receptors were similar in the hindlimb vascular bed, in agreement with the infusion data.

Animals↗