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K L Kirk

Publications and source records attributed to K L Kirk.

At least 145 records · Page 8Linked to original sources
PubMed1981

Cyclic AMP-generating systems: regional differences in activation by adrenergic receptors in rat brain.

Catecholamine, histamine, and adenosine-mediated accumulations of radioactive cyclic AMP were assessed in adenine-labeled slices from eight rat brain regions. 2-Fluoronorepinephrine, a selective beta-adrenergic agonist, elicited an an accumulation of cyclic AMP in cerebral cortex, cerebellum, hippocampus, striatum, superior colliculi, thalamus, hypothalamus, and medulla-pons. In cerebral cortex and most other brain regions, the beta-adrenergic-mediated response appeared to involve primarily beta 1-adrenergic receptors, while in cerebellum, there was a significant involvement of beta 2-adrenergic receptors. 6-Fluoronorepinephrine, a selective alpha-adrenergic agonist, elicited accumulations of cyclic AMP in all regions except cerebellum. Combinations of the two fluoro derivatives afforded in all brain regions an accumulation of cyclic AMP identical with that elicited by norepinephrine. In hypothalamus, the alpha- and beta-adrenergic responses were significantly greater than additive. In cerebral cortex, the alpha-adrenergic receptor-mediated response appeared to involve alpha 1-adrenergic receptors and to be nearly completely dependent on adenosine, while in other brain regions, the dependence of the alpha-adrenergic response on adenosine was less or absent. Combinations of 6-fluoronorepinephrine and histamine had greater than additive effects in cortex and hippocampus. The results indicate that the interactive control of cyclic AMP-generating systems by alpha-adrenergic, beta-adrenergic, adenosine, and histamine receptors differs significantly among rat brain regions.

Animals↗
PubMed1981

Utility of ten-second uptake periods for kinetic studies of serotonin uptake by intact platelets.

When washed human platelets accumulate serotonin (5HT), it is possible with the use of formaldehyde fixative to measure uptake over periods as short as 10 seconds. To evaluate the utility of these short times for kinetic studies of 5HT uptake, we have examined the accuracy with which the 10 second uptake rate reflects changes in the extracellular 5HT concentration. The amount of 5HT taken up over a 10 second period appears to be determined by the concentration of 5HT present in the extracellular medium during that time period, and the uptake rate can change rapidly following sudden changes in the extracellular 5HT concentration. However, the extent of inhibition of 5HT uptake in the presence of imipramine of extracellular 5HT concentrations greater than 10-5M is somewhat different depending on whether the 5HT is allowed to accumulate for a 10-second or a 5- or 10-minute uptake period. A 10-second uptake period thus appears to be useful for kinetic studies of initial 5HT uptake velocities under normal conditions, but under inhibitory conditions may give results differing from those obtained with minute-long periods.

Blood Platelets↗
PubMed1980

Active sodium transport by turtle colon via an electrogenic Na-K exchange pump.

Active sodium absorption by a variety of epithelia is abolished by ouabain, but the obligatory coupling between the movement of sodium and potassium expected from a basolateral (Na+ + K+) ATPase has not been convincingly demonstrated. According to the model of Koefoed-Johnsen and Ussing, the asymmetric cation selectivities of the apical and basolateral membranes prevent basolateral Na-K exchange from being expressed as opposing transmural ion flows. An additional consequence of this asymmetry is that the short-circuit current (Isc) cannot be identified with the current through the sodium-potassium pump. We used the polyene antibiotic, amphotericin-B, to reduce the resistance and the cation selectivity of the apical membrane of isolated turtle colon so that the basolateral membrane current could be dissected into two components: one through a barium-sensitive potassium channel and another which represents the current associated with ouabain-sensitive, electrogenic, Na-K exchange. Comparison of cation fluxes and short circuit current indicates that in these conditions active sodium absorption is entirely attributable to an electrogenic Na-K pump with a stoichiometry of approximately 3Na:2K.

Amphotericin B↗
PubMed1980

Nuclear magnetic resonance studies of blood platelets.

Blood platelets contain membrane-enclosed granules which have inside them high concentrations of 5-hydroxytryptamine (serotonin) along with adenine nucleotides and divalent metal ions. 19F n.m.r. of fluorinated serotonin incorporated into the granules of both human and pig intact platelets has shown that the motional state of the serotonin is restricted. Comparison with 31P n.m.r. experiments indicates that this restriction of motion is a consequence of high molecular weight aggregates formed by the adenine nucleotides and metal ions, and that it varies with the species from which the platelets are obtained. In the case of human platelet granules, at least, these high molecular weight aggregates are present in the absence as well as in the presence of serotonin. The biological significance of these data is briefly discussed.

Adenine Nucleotides↗
PubMed1980

Effects of 6-hydroxy-, 6-fluoro-, and 4,6-difluoromelatonin on the in vitro pituitary response to luteinizing hormone-releasing hormone.

The effects of 6-hydroxy-, 6-fluoro-, and 4,6-difluoromelatonin on the pituitary LH response to LHRH were studied in organ culture. Anterior pituitary glands obtained from 5-day-old female rats and maintained in culture in control medium for 24 h were incubated for an additional 6 h with the test substances. Medium LH content was determined by double antibody RIA. 6-Hydroxymelatonin, the primary metabolite of melatonin after iv administration, had no detectable effect on either basal or LHRH-stimulated release of LH when tested at concentrations up to 10(-6) M. This finding demonstrates that hydroxylation in position 6 will inactivate melatonin with regard to its pituitary effect. By contrast, 6-fluoro- and 4,6-difluoromelatonin at nanomolar concentrations both markedly suppressed the LH response to LHRH. Fluorine substitution for hydrogen in position 6, therefore, does not detectably interfere with activation of the pituitary melatonin receptor. Furthermore, in view of the increased strength of the carbon-fluorine bond compared to the carbon-hydrogen bond, the 6-fluoro analogs should be less susceptible than melatonin to inactivation by hydroxylation in position 6. These analogs, therefore, may be useful as long acting inhibitors of reproductive function in the intact animal.

Animals↗
PubMed1980

Effects of ring fluorination on the cardiovascular actions of dopamine and norepinephrine in the dog.

The 2-, 5- and 6-fluoro (F) analogs of dopamine (DA) and (+/-)-norepinephrine (NE) were compared with the respective parent molecules for alpha, beta-1 and beta-2 adrenergic and vascular DA activities in pentobarbital-anesthetized dogs. 2-F and 5-F DA were equipotent while 6-F DA was about 4-fold less active than DA in causing renal vasodilation in phenoxybenzamine pretreated dogs (vascular DA activity). The three analogs were indistinguishable from DA for vasoconstrictor activity in the femoral vascular bed (alpha adrenergic activity). 2-F and 6-F DA were equipotent to DA while 5-F was about 2-fold more active than DA in inotropic activity (beta-1 adrenergic activity). In contrast, F NE analogs showed marked differential activities. 2-F NE resembled isoproterenol in increasing cardiac contractility, lowering diastolic blood pressure and causing vasodilation in the femoral vascular bed. The 5-F analog was the most potent for (beta-1 adrenergic activity and produced biphasic effects on blood pressure and the femoral vascular bed. 6-F NE exerted no inotropic activity in dose 50- to 80-fold higher than the threshold dose of l-NE and caused vasoconstriction. Thus, fluorine substitution in either of the three positions in the benzene ring of DA induced only minor, if any, differences in receptor activation when compared with DA. On the other hand, fluorine substitution in the benzene ring of NE yielded compounds with marked differential receptor activity. These data indicate that the differences between the effects of F substitution on DA and NE analogs must be related to the only structural difference between the two catecholamines, the presence of a beta-hydroxyl group in NE.

Animals↗
PubMed1979

Effect of fluorine substitution on the agonist specificity of norepinephrine.

Substitution of fluorine for hydrogen in position 2, 5, or 6 of the aromatic ring of norepinephrine markedly alters the alpha- and beta-adrenergic agonist properties of norephinephrine. The 6-fluoro isomer is an beta-adrenergic agonist with virtually no beta agonist activity, while the 2-fluoro isomer is a beta-adrenergic agonist with little alpha activity. The 5-fluoro isomer is equipotent with norepinephrine as an alpha agonist and significantly more potent as a beta agonist. The possible physiochemical basis for these differences is discussed.

Animals↗
PubMed1979

Synthesis and biological properties of 2-, 5-, and 6-fluoronorepinephrines.

2-Fluoro-, 5-fluoro- and 6-fluorodimethoxybenzaldehydes were prepared by photochemical decomposition of the corresponding diazonium fluoroborates. The aldehydes were converted to the cyanohydrin trimethylsilyl ethers, which, in turn, were reduced to the dimethoxyphenethanolamines. Boron tribromide demethylation afforded the racemic ring-fluorinated norepinephrines. An alternate route, using the dibenzyloxyfluoroaldehyde, was also used to prepare 6-fluoronorepinephrine. The fluorine substituent markedly increases the phenolic acidities of these analogues. The biological properties conferred upon norepinephrine by the fluorine substituents in peripheral and central adrenergically responsive systems clearly demonstrate that 2-fluoronorepinephrine is a nearly a pure beta-adrenergic agonist, while 6-fluoronorepinephrine is an alpha-adrenergic agonist. 5-Fluoronorepinephrine retains both beta- and alpha-adrenergic agonist properties. Receptor-binding studies with specific radiolabeled ligands indicate that the specificity conferred by the site of fluorine substituents results from a change in the affinity of these analogues for the alpha- and beta-adrenergic receptors.

Animals↗
PubMed1979

Re-evaluation of the uptake of desoxyfructo-serotonin by human platelets, and of its effect on the uptake of serotonin.

Employing C14-glucose and C14-serotonin (5HT) as precursors, we have synthesized desoxyfructo-5HT [1-desoxy-1-(5-hydroxytryptamine)-D-fructose] labelled either in the sugar or 5HT moieties, and examined the uptake of the labelled substrate by washed human platelets. Desoxyfructo-5HT appears to interact with the 5HT uptake site, effectively inhibiting the uptake of H3-5HT. However, our data indicate that contrary to published reports, the entry of desoxyfructo-5HT into platelet vesicles or cytoplasm is negligible.

Biotransformation↗
PubMed1978

Fluorinated molecule as a tracer: difluoroserotonin in human platelets mapped by electron energy-loss spectroscopy.

The intracellular distribution of fluorine has been delineated in human platelets incubated with 4,6-difluoroserotonin, utilizing a scanning-transmission electron microscope equipped with an energy-loss spectrometer. Discrete intracellular structures corresponding in location to dense bodies contained high concentrations of fluorine. Electron energy-loss spectroscopy, which apparently can detect less than 10(-20) gram of fluorine in an area of 10 square nonometers, can thus localize fluorinated tracer molecules with biological activity.

Blood Platelets↗
PubMed1978

Effect of magnesium on sodium transport in toad urinary bladder.

Voltage-clamp techniques were employed to examine the effect of magnesium (Mg) on sodium transport in the isolated urinary bladder of the Dominican toad. Substitution of 1 mM Mg had no effect, but 3-mM Mg substitution resulted in a reversible increase in short-circuit current (27%) and potential difference (19%) and decrease in transepithelial resistance (14%); no greater effect was seen with 5- or 10-mM Mg substitution. The effect was produced by mucosal or mucosal and serosal Mg substitution; serosal Mg substitution was without effect. Analysis of electrical parameters disclosed that magnesium increased net sodium transport via an effect on the sodium pump.

Animals↗