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Biomedical subjects

B J Clark

Publications and source records attributed to B J Clark.

At least 163 records · Page 9Linked to original sources
PubMed1985

Analysis of the cardiovascular effects of co-derocrine (Hydergine).

The antihypertensive effect of co-dergocrine (Hydergine) has previously been thought to be due to alpha-adrenoceptor blockade and/or an action exerted in the CNS. The present experiments do not support this view. The doses necessary to inhibit vasoconstrictor responses to phenylephrine and noradrenaline by 50% in anaesthetized cats and dogs are 10-50 times that which lowers blood pressure in these species by 30 mmHg. Despite the fact that co-dergocrine is a potent alpha-adrenoceptor antagonist in isolated tissues (pA2: 8.4-9.4), its activity in vivo is too weak to contribute significantly to its effect on blood pressure. Slow intravertebral artery infusion of 10 micrograms/kg co-dergocrine produces a smaller blood pressure fall in the dog than intravenous infusion of the same dose. The reverse is true for the centrally-acting alpha 2-adrenoceptor stimulant, guanfacine. In addition, efferent splanchnic nerve activity in the cat is not affected by doses up to 100 micrograms/kg i.v. The dose of co-dergocrine depressing nerve activity by 50% is approximately 900 micrograms/kg; the dose of clonidine producing comparable inhibition is 3.4 micrograms/kg i.v. Since falls in blood pressure and heart rate can be obtained with co-dergocrine at a dose of only 10 micrograms/kg i.v., a central action cannot be considered to play a role in the cardiovascular effects of the drug in response to acute administration. Heart rate increases evoked by stimulating the accelerans nerve of ganglion-blocked cats are inhibited dose-dependently by co-dergocrine from a dose of 1 microgram/kg i.v. The drug also depresses pressor responses to stimulation of the lumbar sympathetic outflow in pithed rats. Both effects are prevented by pretreatment with the dopamine receptor antagonist, sulpiride (300 micrograms/kg). Intravenous administration of 10 micrograms/kg co-dergocrine depresses pressor responses to a psychological stimulus or raising the forequarters in conscious dogs, and produces marked falls in blood pressure and heart rate in anaesthetized, baroreceptor-denervated dogs. These effects are also abolished by sulpiride. It is concluded that the cardiovascular responses to acute administration of low doses of co-dergocrine are due to stimulation of prejunctional dopamine receptors.

Adrenergic alpha-Antagonists↗
PubMed1984

Computer-aided strategies for archive retrieval and sensitivity enhancement in the identification of drugs by photodiode array detection in high-performance liquid chromatography.

An archive retrieval algorithm for high-performance liquid chromatography with UV detection (HPLC-UV) has been developed for the first time for the rapid identification of spectra acquired by rapid-scanning photodiode array detection in HPLC. The algorithm is based on a database of spectra (normalised with respect to area), inverse files of key spectral features, a selective search window, with parabolic weighting factors and least-squares comparison of test and retrieved spectra. The performance of the library search system is demonstrated with respect to a small library of solutes, including: cortisone acetate, ethynyl estradiol, ethisterone, progesterone; caffeine, theobromine, theophylline and 8-chlorotheophylline; morphine and diamorphine; and cycloserine. Since photodiode array detection operates in the domains of both wavelength and time, to generate a matrix of (A, lambda, t) data, the optimum conditions for sensitivity enhancement by ensemble averaging in these domains have been examined. At a given observation wavelength, increase in the detector bandwidth (or "diode bunching") yields a value of delta lambda which gives optimum sensitivity; this value is systematically related to the spectral bandwidth of the analyte. Sensitivity can also be optimised by varying the integration period in the time domain. Sensitivity can be further increased by combination of these instrumental optima, for which there is evidence of dependence on the particular instrument design. Response was found to be linear for detector bandwidths up to twice the optimum value. The comparative sensitivity of some commercially-available photodiode array detectors has been assessed relative to that of conventional detectors under strictly controlled conditions.

Chromatography, High Pressure Liquid↗
PubMed1984

Analysis and characterisation of aromatic amino acids, metabolites and peptides by rapid-scanning photodiode array detection in high-performance liquid chromatography.

The role of rapid-scanning UV detectors based on the linear photodiode array has been examined in studies on the chromatography of aromatic amino acids, some metabolites and peptides. Multichannel detectors can generate characteristic qualitative information presented as individual spectra, as three-dimensional spectrochromatograms or as contour maps in the (lambda, t) plane. The use of such contour plots for mapping amino acids and their metabolites, and for peptide mapping Tyr-Gly, Gly-Tyr, Phe-Gly, Tyr-Tyr and Phe-Val, is examined. The application of computer-aided methods for validating peak homogeneity by spectral suppression, second derivative in the time domain and by other methods is discussed with respect to Tyr and its metabolite dopamine, which are not resolved by the system described, and which have closely similar spectral characteristics. The use of colour graphics with the IBM Personal Computer is demonstrated for simplifying the presentation of contour maps of amino acids, metabolites and dipeptides.

Amino Acid Sequence↗
PubMed1983

Effects of pindolol on vascular smooth muscle.

Pindolol is a non-selective beta-adrenoceptor blocking agent with relatively marked intrinsic sympathomimetic activity. Stimulant effects in isolated, perfused mesenteric vessels (beta 2) equal those of isoprenaline. Effects on guinea-pig atria (beta 1) are negligible and those on guinea-pig trachea (beta 1 and beta 2) and cat atria (beta 1 and beta 2) are equivalent to 40-50% of the maximum effects of isoprenaline. It is concluded that the intrinsic sympathomimetic activity of pindolol is exerted principally on the beta 2-adrenoceptor. The beta-adrenoceptor blocking effect of pindolol is largely confined to the (-)enantiomer, whereas its stimulant effects are shared equally by the (+) and (-)enantiomers. Removal of the side chain hydroxyl group of pindolol does not diminish stimulant activity, but abolishes blocking activity. Pindolol-induced stimulation and blockade of beta-adrenoceptors may be brought about by different configurations of the molecule. Vasodilator effects observed in vitro and in vivo suggest that beta-adrenoceptor stimulation may make an important contribution to the antihypertensive effect of pindolol in man.

Animals↗
PubMed1983

Novel applications of multichannel spectroscopy in pharmaceutical analysis.

Multichannel detectors based on the linear photodiode array, the silicon vidicon tube and charge coupled (or injection) devices are reviewed with reference to their applications in analytical spectroscopy and high-performance liquid chromatography (HPLC). The use of computer-aided techniques, including second derivative spectroscopy and spectral deconvolution methods, for the multichannel spectroscopic analysis of pharmaceuticals is discussed, and applications are reviewed in clinical chemistry, enzyme analysis and studies on aromatic amino acids in proteins. In HPLC, the principles and applications of digital algorithms for validation of peak homogeneity are considered, with reference to spectral suppression, spectral deconvolution, absorbance ratio and the second derivative of the elution profile. The isometric projections of (A, lambda, t) data, and their cartographically equivalent contour plots, are discussed and the impact of multicolour graphics is assessed. The implications of two-dimensional multichannel detectors for detection of luminescence radiation are considered in the context of analytical spectroscopy, and detection in both HPLC and thin-layer chromatography. The potential contribution of charge coupled and charge injection devices as the next generation of multichannel detectors is considered.

Journal Article↗
PubMed1982

Beta-adrenoceptor-blocking agents: are pharmacologic differences relevant?

beta-Adrenoceptor-blocking agents constitute a heterogeneous group of compounds. Membrane- stabilizing (quinidine-like) effects can be demonstrated pharmacologically with most compounds, but only at relatively high concentrations. There is no evidence to suggest that this property is of clinical relevance. Some compounds have a certain selectivity for receptors of the beta 1-type, whereas others possess beta-adrenoceptor stimulant activity (partial agonism). The clinical importance of these latter properties remains controversial. The selectivity for beta 1-adrenoceptors, which can be demonstrated pharmacologically for atenolol, metoprolol, and practolol, appears quite broad. Nevertheless a clear advantage over nonselective compounds with respect to their effects on lung function and vascular resistance in patients has not been established. There are two possible explanations. The first is that the doses used therapeutically may lie outside the selective range; the second is that most tissues appear to possess and mixed population of beta 1- and beta 2-adrenoceptors. According to our present understanding, even absolute specificity for a given subtype cannot provide organ or tissue specificity. Partial agonists provide a constant stimulation of beta-adrenoceptors while at the same time preventing access of catecholamines to the receptor they occupy. With some compounds (e.g., pindolol), stimulant activity may be sufficient to counterbalance the myocardial depression normally resulting from blockade of basal sympathetic tone. Heart rate and cardiac output are thus maintained within normal limits and compensatory increases in vasomotor tone (seen with antagonists lacking intrinsic activity) do not occur. Pindolol has been shown to dilate blood vessels at very low doses and to produce significant relaxation of isolated tracheal smooth muscle at concentrations within the range of therapeutic plasma levels found in humans. These effects may underly the relatively low incidence of bronchopulmonary and vascular side effects reported for this compound.

Adrenergic beta-Antagonists↗
PubMed1982

Pindolol--the pharmacology of a partial agonist.

1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs.

Animals↗
PubMed1981

Dopamine receptors and the cardiovascular system.

The relatively high levels of dopamine compared with those of noradrenaline found in many tissues, together with the wide distribution of dopamine receptors in the periphery, suggest that the amine may have important physiological functions, and may act as a neurotransmitter in its own right. Compounds which selectively stimulate vascular and neuronal dopamine receptors, decrease vascular resistance in the mesenteric, renal and coronary vascular beds, inhibit sympathetic ganglionic transmission and decrease transmitter efflux from certain noradrenergic neurones may prove effective in the treatment of cardiovascular disease and serve, in addition, as useful pharmacological tools.

Animals↗
PubMed1980

Peripheral dopamine receptors.

Dopamine produces dilation predominantly in renal and mesenteric vascular beds. An action on a specific receptor has been confirmed in vitro using a perfused canine mesenteric vessel preparation. Reductions in resistance produced by dopamine are selectively inhibited by methylergometrine (pA2 = 8.3) and sulpiride (pA2 = 5.6). Evidence is accumulating which suggests that vascular dopamine receptors are innervated. Periaterial nerve stimulation in anesthetized dogs produces increases in blood flow in the superior mesenteric artery which are not influenced by atropine and propranolol but are inhibited by haloperidol. Dopamine receptors are also present at sympathetic ganglia and sympathetic nerve terminals. Inhibition of noradrenaline release resulting from stimulation of these receptors may make an important contribution to the depressor effects of dopamine receptor agonists in anesthetized animals and in man. Reductions in blood pressure induced by bromocriptine and other long-acting dopamine receptor stimulants are frequently associated with reductions in heart rate, but not always with a corresponding depression of myocardial contractile force. This phenomenon may be explained by a selective distribution of prejunctional receptors in sympathetic neurons innervating the sinus node.

Animals↗
PubMed1978

Cardiovascular actions of bromocriptine.

Bromocriptine lowers blood pressure in animals and in man. Results obtained in experiments performed in the dog and cat suggest three possible mechanisms of action: a) relaxation of vascular smooth muscle, principally in splanchnic and renal vessels, (b) inhibition of transmitter release from noradrenergic nerve endings, (c) central inhibition of sympathetic nerve activity. The effect of bromocriptine at each putative site of action can be explained in terms of dopamine receptor stimulation.

Animals↗
PubMed1975

Mean myoglobin oxygen tension during exercise at maximal oxygen uptake.

Changes in intracellular Po2 in myoglobin containing skeletal muscle during exercise were estimated in normal nonathlete subjects from measurements of shifts of CO between blood and muscle under conditions where the total body CO stores remained constant. Exercise was performed on a bicycle ergometer. In 1.5-2 and 6-7 min runs at Vo2 max with the subject breathing 21% O2, mean MbCO/HbCO increased 146 +/- 7 and 163 +/- 11% of resting values, respectively (P less than 0.05). With the subjects breathing 13-14% O2, in 1.5-2 and 6-7 min runs, Vo2 max fell an average of 4.3 +/- 5.1% and 12.0 +/- 5.2%, respectively, and mean MbCO/HbCO increased to 233 +/- 18% and 210 +/- 52% of resting value, respectively (P less than 0.05). These findings suggest that mean myoglobin Po2 fell during exercise at Vo2 max, with the subjects breathing 21% O2 and the decrease in mean myoglobin Po2 was greater with the subject breathing 13-14% O2. There was considerable variability in different subjects and in some, the data were not consistent with intracellular O2 availability limiting aerobic metabolism. The data support a postulate that there are several limiting factors for the aerobic capacity, including intracellular O2 availability.

Adult↗