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Biomedical subjects

L Churchill

Publications and source records attributed to L Churchill.

At least 55 records · Page 3Linked to original sources
PubMed1991

Pharmacology of nasal provocation with bradykinin: studies of tachyphylaxis, cyclooxygenase inhibition, alpha-adrenergic stimulation, and receptor subtype.

We have evaluated mechanisms by which nasal provocation with bradykinin may induce symptoms of rhinitis. Repeated nasal challenges with 100 micrograms of bradykinin led to reproducible increases in symptoms and in vascular permeability. Premedication with aspirin did not alter bradykinin-induced responses. Topical application of the alpha-adrenergic agonist oxymetazoline significantly reduced bradykinin-induced subjective nasal congestion scores, but did not lead to a significant decrease in total symptoms or in vascular permeability. Finally, the B1 kinin receptor agonist des-Arg9-bradykinin (1 mg) was totally ineffective in inducing symptoms or increasing vascular permeability. Thus, nasal provocation with bradykinin leads to induction of symptoms and increased vascular permeability, presumably via stimulation of B2 kinin receptors, and is not dependent on prostanoid generation.

Aspirin↗
PubMed1990

Changes in gamma-aminobutyric acid, mu-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens.

Discrete quinolinic acid lesions in the nucleus accumbens altered [3H]muscimol binding to gamma-aminobutyric acid receptors, [125I]neurotensin binding to neurotensin receptors, [125I]Tyr-D-Ala-Gly-NMePHe-Gly-OH binding to mu-opioid receptors, and [3H]quinuclidinyl benzilate binding to muscarinic receptors. Within lesions of the lateral accumbens core, [3H]muscimol binding increased and [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH, [125I]neurotensin and [3H]quinuclidinyl benzilate binding decreased. Lesions of the medial nucleus accumbens resulted in decreased [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH and [3H]quinuclidinyl benzilate binding while no alterations were observed for [3H]muscimol or [125I]neurotensin binding. These data support anatomical distinctions between medial and lateral nucleus accumbens. Destruction of intrinsic neurons in the dorsomedial nucleus accumbens core increased [3H]muscimol binding in the dorsal rim of the ventral pallidum and the rostral globus pallidus without altering [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH binding. Destruction of neurons in the lateral nucleus accumbens core or medial shell did not alter [3H]muscimol binding in the ventral pallidum. The lack of upregulation in gamma-aminobutyric acid receptors suggests that the gamma-aminobutyric acid-containing projection from the dorsomedial core to the dorsal rim of the ventral pallidum differs from the projection from the lateral accumbens core and medial shell to the more ventral regions of the pallidum. Fluoro-gold retrograde tracer histochemistry confirmed the specific projection from the dorsomedial core to the dorsal ventral pallidum; and from the shell of the nucleus accumbens to more ventral regions of the ventral pallidum.

Animals↗
PubMed1990

The use of pregnancy test kits by college students.

The self-testing product market is experiencing tremendous growth. Technical breakthroughs are allowing tests to be conducted in the home that at one time were possible only in a clinical laboratory. One of the more rapidly expanding components of the self-testing market is home pregnancy test kits. We conducted a study to obtain information about the use of home pregnancy test kits by college students. Questionnaires were distributed to 1,000 women entering the student health service between October 1 and November 4, 1987. A total of 761 (76.1%) questionnaires were completed and returned. Results indicated that approximately 1 out of 6 respondents (17.2%) had used a pregnancy test kit at least once. Of those who had used a test kit, the majority did so because of the speed or confidentiality of obtaining results. The magnitude of test kit use by this sample suggests that college women should be encouraged to use self-testing products as a supplement to but not as a substitute for professional medical care.

Adolescent↗
PubMed1990

Soman- or kainic acid-induced convulsions decrease muscarinic receptors but not benzodiazepine receptors.

[3H]Quinuclidinyl benzilate (QNB) binding to muscarinic receptors decreased in the rat forebrain after convulsions induced by a single dose of either soman, a potent inhibitor of acetylcholinesterase, or kainic acid, an excitotoxin. A Rosenthal plot revealed that the receptors decreased in number rather than affinity. When the soman-induced convulsions were blocked, the decrease in muscarinic receptors at 3 days was less extensive than when convulsions occurred and at 10 days they approached control levels in most of the brain areas. The most prominent decrements in QNB binding were in the piriform cortex where the decline in QNB binding is probably related to the extensive convulsion-associated neuropathology. The decrements in QNB binding after convulsions suggest that the convulsive state leads to a down-regulation of muscarinic receptors in some brain areas. In contrast to the decrease in QNB binding after convulsions, [3H]flunitrazepam binding to benzodiazepine receptors did not change even in the piriform cortex where the loss in muscarinic receptors was most prominent. Thus, it appears that those neuronal processes that bear muscarinic receptors are more vulnerable to convulsion-induced change than those with benzodiazepine receptors.

Animals↗
PubMed1989

Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells.

The epithelial cell may contribute to the regulation of pulmonary function during inflammatory diseases of the airways by producing metabolites of arachidonic acid (AA). We have used human tracheal epithelial cells (HTE), grown in serum-free medium, to examine cyclooxygenase metabolism of endogenous AA by these cells. Gas chromatography-negative ion mass spectrometry demonstrated that, regardless of stimulus (buffer, bradykinin, or the calcium ionophore A23187), epithelial cells produce PGE2 and PGF2 alpha but no detectable levels of PGD2, thromboxane B2, 6-keto-PGF1 alpha, or 9 alpha, 11 beta-PGF2. Preincubation of cultures with medium containing 5% human serum led to striking increases in the production of PGE2 and PGF2 alpha, regardless of stimulus. Concomitant with these increases in prostanoids, serum exposure caused a 3.6-fold increase in total cellular arachidonate. Arachidonate levels increased in all phosphoglyceride classes, with the greatest increases in phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol. In serum-pretreated cells, PGE2 production was 1.46 +/- 0.12, 4.74 +/- 0.6, and 6.35 +/- 0.93 ng/10(6) cells (mean +/- SEM; n = 7) upon exposure to buffer, 10(-6) M bradykinin, and 1 micrograms/ml A23187, respectively, whereas PGF2 alpha levels were 1.53 +/- 0.22, 4.44 +/- 0.36, and 5.77 +/- 0.78 ng/10(6) cells, respectively. The response of HTE to bradykinin was dose-dependent (10(-8) to 10(-6) M) and was maximal within 5 min. We conclude that cyclooxygenase metabolism of endogenous arachidonate in HTE results in the specific production of PGE2 and PGF2 alpha. HTE in culture retain receptors for bradykinin and can be used to study lipid metabolism independent of other cell types.

Adult↗
PubMed1988

Angiotensin metabolism by cerebral microvascular aminopeptidase A.

Porcine cerebral microvessels were isolated by differential sieving and centrifugation and were characterized by microscopic examination and marker enzyme enrichment (gamma-glutamyltransferase; EC 2.3.2.2). Purified microvessels contained a membrane-bound enzyme immunologically indistinguishable from renal aminopeptidase A (AmA; EC 3.4.11.7). AmA hydrolyzed both alpha-glutamyl- and alpha-aspartyl-2-naphthylamide, and hydrolysis was competitively inhibited by angiotensin II. Micro-vessel AmA hydrolyzed the N-terminal Asp1-Arg2 bond of both angiotensin I and angiotensin II, whereas the angiotensin II antagonist saralasin [(Sar1, Ala8)angiotensin II] was resistant to N-terminal hydrolysis. Angiotensin metabolism was optimal at pH 8.5 and was inhibited by EDTA, o-phenanthroline and amastatin. Conversely, inhibitors of neutral endopeptidase (phosphoramidon), post-proline cleaving enzyme (Z-Pro-Prolinal), carboxypeptidase N [D-L-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MERGETPA)] and angiotensin I converting enzyme (captopril) had no effect. The Km values of angiotensin I, angiotensin II and (Asn1, Val5)angiotensin II for microvessel AmA were 40.1 +/- 8.2, 35.3 +/- 4.3 and 156 +/- 22 microM respectively. Cerebral microvascular aminopeptidase A may play a role in vivo in modulating angiotensin-mediated local cerebral blood flow, and in preventing circulating angiotensins from crossing the blood-brain barrier.

Aminopeptidases↗
PubMed1987

Metabolism of opioid peptides by cerebral microvascular aminopeptidase M.

Aminopeptidase M (EC 3.4.11.2), which can degrade low molecular weight opioid peptides, has been reported in both peripheral vasculature and in the CNS. Thus, we have studied the metabolism of opioid peptides by membrane-bound aminopeptidase M derived from cerebral microvessels of hog and rabbit. Both hog and rabbit microvessels were found to contain membrane-bound aminopeptidase M. At neutral pH, microvessels preferentially degraded low molecular weight opioid peptides by hydrolysis of the N-terminal Tyr1-Gly2 bond. Degradation was inhibited by amastatin (I50 = 0.2 microM) and bestatin (10 microM), but not by a number of other peptidase inhibitors including captopril and phosphoramidon. Rates of degradation were highest for the shorter peptides (Met5- and Leu5-enkephalin) whereas beta-endorphin was nearly completely resistant to N-terminal hydrolysis. Km values for the microvascular aminopeptidase also decreased significantly with increasing peptide length (Km = 91.3 +/- 4.9 and 28.9 +/- 3.5 microM for Met5-enkephalin and Met5-enkephalin-Arg6-Phe7, respectively). Peptides known to be present within or in close proximity to cerebral vessels (e.g., neurotensin and substance P) competitively inhibited enkephalin degradation (Ki = 20.4 +/- 2.5 and 7.9 +/- 1.6 microM, respectively). These data suggest that cerebral microvascular aminopeptidase M may play a role in vivo in modulating peptide-mediated local cerebral blood flow, and in preventing circulating enkephalins from crossing the blood-brain barrier.

Aminopeptidases↗
PubMed1987

Cholinergic systems influence local cerebral glucose use in specific anatomical areas: diisopropyl phosphorofluoridate versus soman.

The organophosphates, diisopropyl phosphorofluoridate and soman have a common mechanism of action (inhibition of acetylcholinesterase), but result in very different behavioral responses in the rat. Soman rapidly produced persistent tonic convulsions whereas diisopropyl phosphorofluoridate only infrequently produced transient convulsive-like activity. Soman increased local cerebral glucose use in most of the cortex, striato-pallido-nigral pathway, limbic system and in specific thalamic nuclei whereas diisopropyl phosphorofluoridate increased glucose use in a limited fashion, primarily in the dorsal striato-pallido-nigral pathway. When diazepam blocked soman-induced convulsions, the pattern of glucose use was strikingly similar to that caused by diisopropyl phosphorofluoridate. Soman or diisopropyl phosphorofluoridate depressed local cerebral glucose use in rats pretreated with the antidotal mixture of trimedoxime, atropine and benactyzine (muscarinic antagonists). Also, this antidotal mixture blocked the increased glucose use in the dorsal striato-pallido-nigral system produced by either acetylcholinesterase inhibitor, indicating that muscarinic receptors mediate the excitation of this pathway. Both diisopropyl phosphorofluoridate and soman activate the striato-pallido-nigral pathway but soman also causes spread of activity producing overt motor convulsions. Possible explanations for this difference in response to the organophosphates are differential responses in cholinergic actions within specific brain regions or some non-cholinergic action of soman.

Animals↗
PubMed1987

Conversion of B1 kinin receptor-mediated vascular relaxation to contraction.

We have previously reported that des-Arg9-bradykinin can relax the phenylephrine-precontracted rabbit mesenteric artery through B1 kinin receptor stimulation and the subsequent release of prostaglandins. In the present study, we have found that this relaxant response can be converted to a contractile response by the cyclooxygenase inhibitor indomethacin. Contraction was dose-dependent and was blocked by the B1 receptor antagonist [Leu8]des-Arg9-bradykinin, with a pA2 value obtained by Schild regression similar to that reported for relaxation in the absence of indomethacin. Des-Arg10-kallidin (ED50 = 5.0 +/- 0.9 X 10(-9) M) was 16 times more potent than des-Arg9-bradykinin (ED50 = 8.1 +/- 0.8 X 10(-8) M) in contracting the indomethacin-treated artery and was also blocked by [Leu8]des-Arg9-bradykinin. In contrast, only 13 out of 24 indomethacin-treated vessels contracted in response to bradykinin, which had only one tenth and one 160th the potency (ED50 = 9.9 +/- 1.8 X 10(-7) M) of des-Arg9-bradykinin and des-Arg10-kallidin, respectively. B1 kinin receptor-mediated contraction in the presence of indomethacin was unaffected by the dual cyclooxygenase-lipoxygenase inhibitor BW 755c. These results indicate that des-Arg-kinins can stimulate both relaxation and contraction of the phenylephrine-precontracted rabbit mesenteric artery through stimulation of B1 kinin receptors. The relaxation is dependent on the release of prostaglandins, while the contraction may represent a direct effect.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

An indoleamine system in photoreceptor cell terminals of the Long-Evans rat retina.

Uptake of 3H-serotonin is localized to the outer plexiform layer in Long-Evans rat retinas. Autoradiographic accumulation is seen only after in vitro incubation in the light, with retinas isolated from the underlying sclera. Potassium stimulates the release of 3H-serotonin. In this species, amacrine cells do not accumulate these compounds; thus the outer plexiform layer appears to be the only site of uptake and release of this indoleamine. The age-related loss of 3H-serotonin accumulation in the outer plexiform layer of retinal dystrophic rats coincides temporally with the spontaneous degeneration of photoreceptor cells that occurs in this species. Electron-microscopic autoradiography of 3H-serotonin accumulation further confirms that uptake is localized to rod and cone terminals in the outer plexiform layer. The specific accumulation of indoleamines into rod and cone terminals that is observed in the light but is absent in darkness suggests that indoles have an important physiological role in photoreceptors.

5,7-Dihydroxytryptamine↗
PubMed1986

Relaxation of isolated mesenteric arteries by des-Arg9-bradykinin stimulation of B1 receptors.

The present studies were conducted to determine whether des-Arg-kinins can produce relaxation of isolated vessels. Both des-Arg9-bradykinin and bradykinin produced dose-dependent relaxations of isolated rabbit superior mesenteric arteries. Des-Arg9-bradykinin (ED50 = 7.2 X 10(-9) M) was 8.5 times more potent than bradykinin (ED50 = 6.1 X 10(-8) M). Des-Arg9-bradykinin-mediated relaxation was inhibited by the specific B1 receptor antagonist [Leu8]des-Arg9-bradykinin which produced parallel shifts in the dose-response curve. Schild regression analysis of the data established a pA2 value (6.46) similar to that reported for B1 receptor-mediated contraction. Although the relaxant effect of bradykinin was also inhibited by the B1 antagonist, parallel shifts in the dose response curve were not produced. Relaxation of the mesenteric artery by both des-Arg9-bradykinin and bradykinin was inhibited by the cyclooxygenase inhibitor indomethacin. The results of these studies indicate that in addition to vasoconstriction, des-Arg9-bradykinin can produce vasorelaxation which may be mediated through stimulation of B1 kinin receptors and the subsequent release of prostaglandins.

Animals↗
PubMed1986

Kinin and enkephalin conversion by an endothelial, plasma membrane carboxypeptidase.

Utilizing both thin-layer chromatography and high pressure liquid chromatography, it was determined that a vascular plasma membrane preparation contains a carboxypeptidase capable of converting kinins (B2 agonists) to des(Arg)kinins (B1 agonists) by hydrolysis of C-terminal Arg. The plasma membrane carboxypeptidase also converted Leu5-enkephalin-Arg6 to Leu5-enkephalin. Carboxypeptidase activity was significantly higher in cultured endothelial (1.47 +/- 0.4 units/mg) than in cultured smooth muscle cells (0.16 +/- 0.4 units/mg). Both the vascular and endothelial activities had neutral pH optima and were activated 4- to 5-fold by 0.1 mM CoCl2. The carboxypeptidase N inhibitor MERGETPA (D-L-mercaptoethanol-3-guanidino-ethylthiopropanoic acid) inhibited the plasma membrane bound carboxypeptidase with an I50 of 0.3 microM. Conversion was also inhibited by o-phenanthroline and EDTA, whereas inhibitors of aminopeptidases (bestatin, puromycin), endopeptidases (phosphoramidon), "enkephalinase" (ZINCOV) or enkephalin convertase (PCMS) were without effect. The affinity of the endothelial plasma membrane carboxypeptidase for bradykinin (Km = 56.8 +/- 4.7 microM) was higher than that for Leu5-enkephalin-Arg6 (Km = 92.7 +/- 10.1 microM), whereas the maximal rates of conversion (calculated per mg of endothelial plasma membrane protein) were similar (17.1 and 21.3 nmoles/min/mg respectively). These results demonstrate that a carboxypeptidase is present on the cell surface of vascular endothelium which can convert kinins and enkephalins in the micro-environments of vascular cell surface receptors.

3-Mercaptopropionic Acid↗
PubMed1986

Action and metabolism of des(Arg)kinins in mesenteric arteries.

Kallidin and bradykinin can be hydrolyzed at their C-termini to produce des(Arg10)kallidin and des(Arg9)bradykinin respectively. These des(Arg)kinins, previously thought to be biologically inactive, are now known to have potent effects on B1 receptors. Although stimulation of B1 receptors has been reported to produce peripheral vasodepressor responses in certain experimental states, only constriction has been reported in isolated vessels (i.e., rabbit aorta, basilar artery, mesenteric vein). In the present study, we have investigated the biologic activity of des(Arg) kinins on a peripheral resistance vessel (rabbit mesenteric artery). We found that des(Arg)bradykinin relaxes mesenteric arteries, and that its potency relative to kallidin and bradykinin is consistent with the presence of B1 receptors. Further, intact mesenteric arteries, and a plasma membrane fraction purified from these arteries, contained a carboxypeptidase activity which was capable of producing des(Arg)kinins from both kallidin and bradykinin. Thus, these data demonstrate that the vasculature has the enzymatic capacity to form B1 kinins, and that stimulation of B1 receptors in resistance vessels can be associated with peripheral vasodilation.

Animals↗
PubMed1986

Effects of antidotes on soman-induced brain changes.

Rats were pretreated with either diazepam, atropine or benactyzine 10 min prior to soman injection. Local cerebral glucose use (LCGU) was determined during the seizure phase (15 min post soman) or pathology phase (72 h post soman). Diazepam and benactyzine pretreatment prevented convulsive activity, whereas atropine pretreatment only reduced the duration of convulsive activity after soman exposure. Each pretreatment agent had a unique impact on LCGU pattern during the seizure phase. During the pathology phase, the marked reduction in LCGU and the conspicuous brain damage associated with soman-induced seizures was minimized by all three pretreatments.

Animals↗
PubMed1985

Medical care for the poor: finite resources, infinite need.

Health care in this nation is becoming multitiered--with the poor in jeopardy of being excluded from even minimal care--because of the mistaken belief that money can buy unlimited health care for everyone. But our medical resources are finite, and choices must be made on how to distribute those resources. These choices should be based on a carefully reasoned concept of distributive justice; but even more important, they should be rooted in a Christian sense of community and in the conviction that service to others is more important than life itself. At least three basic models of justice can be identified. Market justice follows the general rule, To each according to his or her ability to pay. Merit justice holds that medical care should be apportioned relative to patients' efforts to stay healthy. Needs-based justice maintains that individuals' needs should be the sole criterion for allocating health care. Developing and testing such concepts of justice is necessary, but it is not enough. As those with economic and social power increasingly capture society's medical resources to keep their own deaths at bay through costly and extraordinary forms of treatment, Christians may well be impelled to take a stand in behalf of those who are being deprived of basic care. This stand may even include forgoing extraordinary treatment for themselves and accepting the appropriateness of their own deaths. Such a witness to the world, however, must be founded in faith and in Christian belief regarding the meaning of death.

Christianity↗
PubMed1985

Soman-induced brain lesions demonstrated by muscarinic receptor autoradiography.

Repeated exposure of rats to sublethal doses of soman resulted in moderate to severe symptoms of anticholinesterase intoxication and a pronounced weight loss within a small subgroup of these animals. A consistent pattern of cell loss and extensive neuronal necrosis appeared in specific brain areas within this subgroup. This neuropathology was not noted in rats unless they showed marked symptoms of poisoning including a precipitous weight loss. Neuropathology was most notable in the piriform cortex and thalamus. Quantitative receptor autoradiography indicated that these subjects had a significant decrease in muscarinic receptors in the piriform cortex and thalamus. The ratio of the muscarinic receptor densities in soman-treated rats with lesions to soman-treated rats without lesions was 57%, piriform cortex; 64%, ventrolateral thalamus; and 50%, mediodorsal thalamus. These decrements are distinguished from adaptive down-regulation because they are larger, there is no indication of recovery and there is a correspondence between histological lesions and the areas with decreases in muscarinic receptors. Thus, quantitative receptor autoradiography provides, in addition to kinetic information and topographical distribution, radiohistochemical evidence of neuronal damage.

Animals↗