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Biomedical subjects

C F Smith

Publications and source records attributed to C F Smith.

At least 73 records · Page 4Linked to original sources
PubMed1983

Comparison of the alpha-adrenoceptor profiles of clonidine and two oxygenated arylamino imidazolines.

The profiles of 2-(3,4-dimethoxyphenylamino)-imidazoline HCl (RX 77171) and 2-[6-(1,4-benzodioxanylamino)]imidazoline maleate (RX 801074) were compared with that of clonidine in isolated tissues and pithed rats. RX 77171 consistently displayed prejunctional alpha 2-adrenoceptor antagonist and postjunctional agonist properties. In contrast, RX 801074 had a complex profile which showed considerable variability between tissues. This variability is highlighted by comparing its effects at the prejunctional alpha 2-adrenoceptors of the isolated vas deferens and guinea-pig ileum; in the former RX 801074 was an agonist whereas only antagonist properties were apparent in the ileum.

Animals↗
PubMed1983

Opiate receptors in the rat vas deferens.

The nature of the opiate receptor population in the rat vas deferens (RVD) has been examined by evaluating the interaction of a range of antagonists with prototypic mu-, kappa- and sigma-opioid agonists in the tissue. Ke values for 5 antagonists against normorphine in the isolated mouse vas deferens showed excellent correlation with Ke values obtained against the mu-agonist RX783030 in the RVD. RX783030 could be effectively antagonised by naltrexone in the RVD but not by the sigma-antagonist ICI 154129 whereas D-Ala2,D-Leu5-enkephalin required both antagonists to yield parallel shifts of its dose response. The lack of agonist activity of morphine is a result of the low intrinsic activity of this agent in the RVD. The kappa-agonists ethylketocyclazocine, tifluadom and U50488 also showed antagonist properties in the RVD. These results can be rationalised by postulating that the RVD contains a mu-receptor population with a high intrinsic activity requirement together with some sigma-receptors. It is not necessary to propose the existence of a novel epsilon-receptor in order to rationalise the data reported.

Animals↗
PubMed1983

Photoaffinity probes for opiate receptors: synthesis and properties of a nitro-azido-derivative of 14-beta-aminomorphinone.

The potential photoaffinity ligand 14-beta-(o-nitro, p-azido)-cinnamoyl-amino-N-cyclopropylmethylnormorphinone (NAM) and its derivative NOM, lacking the p-azido function, were synthesised and their opiate receptor activity determined in isolated tissue preparations. The ligands showed slow receptor kinetics. NAM was a pure competitive antagonist of met5-enkephalin responses in MVD while its antagonism of normorphine responses in GPI appeared non-competitive and non-reversible. In radioligand binding assays NOM completely and irreversibly blocked specific binding of 3H-DHM. Partial blockade of 3H-DADL specific binding was reversible by washing. No binding of NOM to kappa sites was observed. The slow receptor kinetics of NAM preclude its use as a photoaffinity ligand but suggest that a chemically more stable derivative may have a role as a pseudocovalent blocker of mu-receptors.

Affinity Labels↗
PubMed1983

alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants.

The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.

Adrenergic alpha-Antagonists↗
PubMed1983

Comparison of heat production of chickens measured by energy balance and by gaseous exchange.

An open-circuit respiration calorimeter suitable for chickens or other small animals has been constructed. The system contains two animal chambers and is capable of determining heat production of two animals or groups of animals independently and simultaneously with gas collection apparatus for continuous sampling of chamber gases. The operation of the system was tested in two experiments by determining heat production of two groups of 10-week-old, full-fed cockerels over a 4-day period both by energy retention (body balance) and gaseous exchange. Heat production (kilocalories per bird per 24 hours) as determined by energy balance versus gaseous exchange was 359 versus 348 in one experiment and 395 versus 393 in the other. The agreement was sufficiently close to support the use of respiration calorimetry to measure heat production of chickens under experimental conditions in this laboratory without killing the experimental subjects. On the basis of metabolic body weight (in kilograms, W0.75) heat production measured in this manner was 161 and 173 kcal (day . W0.75) in experiments 1 and 2, respectively.

Animals↗
PubMed1983

Studies on RX 781094: a selective, potent and specific antagonist of alpha 2-adrenoceptors.

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX 781094 was also a competitive antagonist at the postjunctional alpha 1-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha 1-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of alpha 2/alpha 1-adrenoceptor selectivities for the antagonists studied was RX 781094 greater than RS 21361 greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4101 greater than prazosin. 5 RX 781094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. 7 In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX 781094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 21361 greater than WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha 1-adrenoceptors. 9 RX 781094 had little effect on the cardiovascular responses to 5-hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. 10 These results demonstrate that RX 781094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.

Acetylcholine↗
PubMed1983

Abnormalities of proteoglycans and glycoproteins synthesized by corneal organ cultures derived from patients with macular corneal dystrophy.

Macular corneal dystrophy has long been suspected of being a localized storage disease of glycosaminoglycans, but the nature of the storage product and the basic defect remain to be established. To learn more about this disease, the proteoglycans and glycoproteins synthesized by corneal organ cultures from five patients with macular corneal dystrophy and six individuals with surgically enucleated eyes and normal corneas were analyzed. This was done after incubating the corneas in Eagle's minimal essential medium supplemented by fetal or newborn bovine serum and 3H-glucosamine and 35S-sulfate for 24 hours and then extracting the tissues with 4 M guanidine hydrochloride. A consistent finding in organ cultures with macular corneal dystrophy was the diminished synthesis of keratan sulfate proteoglycan, and this was accompanied by the production of a glycoprotein of lower molecular weight with oligosaccharide side chains. A comparable amount of incorporated radioactivity was extracted with 4 M guanidine hydrochloride from corneas with macular dystrophy and corneas of controls. Despite this, corneas with macular dystrophy still contained abundant intra- and extracellular material with the histochemical attributes of nonextracted pathologic corneas, and this correlated with concentrations of nonextracted isotope as shown by autoradiography. Transmission electron microscopy of the guanidine hydrochloride-extracted corneas with macular dystrophy disclosed fibrillogranular material with a similar ultrastructure to the storage substance within nonextracted corneas to be located at sites of disrupted cells. Further work is needed to establish the basic defect in macular corneal dystrophy. Although it is possible that organ cultures of corneas with macular dystrophy synthesize the storage material, which characterizes the disorder, the abnormal product of the organ cultures of the dystrophic corneas may reflect an altered metabolic state of dystrophic corneal fibroblasts, caused by the excessive intracellular accumulation of the storage product that typifies macular corneal dystrophy.

Adolescent↗
PubMed1982

Common anionic receptor site hypothesis: its relevance to the antagonist action of naloxone.

Appropriate modification of 14 beta-methoxy- and 14 beta-ethoxycodeinone (prepared by alkylation of 14 beta-hydroxycodeinone) has generated four alkoxy analogues (3a-d) of naloxone and naltrexone. These agents were pure narcotic antagonists in contradiction to the predictions of the common anionic receptor site hypothesis, postulated to be of importance in the enhanced antagonism of naloxone. The molecular change from allyl to cyclopropylmethyl on the N atom increased selectivity of these antagonists for the mu receptor to the same extent as found for naloxone. Increase in the length of the C14 O-substituent had no effect on receptor selectivity, and either formation in most cases did not significantly alter oral/parenteral ratios of durations of action.

Animals↗
PubMed1982

Anthelmintic resistance survey in New Zealand.

The prevalence and level of thiabendazole resistance of sheep nematodes in the North Island of New Zealand was investigated by means of an in vitro egg-hatch technique; samples from sheep on 52 properties in six country areas were examined. Resistance of Haemonchus contortus and Trichostrongylus spp. was identified on the basis of egg hatch in 0.1 ppm thiabendazole. Evidence of resistance was obtained on 11(21.2%) of the properties. LD 50's and resistance ratios were calculated for the resistant nematode populations found.

Journal Article↗
PubMed1981

Analogues of beta-LPH61-64 possessing selective agonist activity at mu-opiate receptors.

Peptides based in the stabilised tetrapeptide HTyr-D-Ala-Gly-MePheOH have been synthesised and shown to have substantial opioid activity both in vitro and in vivo. The selectivity of these compounds of different receptor populations has been investigated using both isolated tissue assays and binding studies. Results suggest that the compounds are potent agonists at mu-receptors with little or no affinity for the delta-receptor population. One of the compounds, RX783006 (HTyr-D-Ala-Gly-MePhe-NH(CH2)2OH), has been tritiated to high specific radioactivity and may prove to be a useful probe in the elucidation of the function of the heterogenous opiate receptor population.

Animals↗
PubMed1981

Difference between the glycosaminoglycans synthetized by corneal and cutaneous fibroblasts in culture.

Although fibroblasts retain similar morphologic characteristics in various tissues, a body of evidence suggests that these cells possess disparate characteristics in different tissues. Keratan sulfate I, a specific product of the corneal fibroblast, is synthesized by the cornea in vivo and by organ cultures of the cornea in the absence of an associated corneal epithelium and endothelium. Confluent cultures of isolated corneal fibroblasts appear to lose this capacity, and the question of whether they produce any keratan sulfate in culture has remained uncertain, owing to the variable sensitivity and specificity of the different analytical methods employed. This study compares the 35S-sulfate- and 3H-glucosamine-labeled glycosaminoglycans produced by confluent cultures of human corneal and cutaneous fibroblasts with those synthesized by corneal organ cultures with different analytical techniques. Using the analytical method of sequential enzymatic degradation, confluent cultures of corneal fibroblasts, but not cutaneous fibroblasts, were found to synthesize and secrete into the nutrient medium a small quantity of sulfate glycosaminoglycans that was susceptible to keratan sulfate endo-beta-galactosidase (Pseudomonas)--an enzyme that degrades corneal keratan sulfate to oligosaccharides of variable size and sulfation. These difference between isolated corneal and cutaneous fibroblasts support the concept that fibroblasts, although ubiquitous, not only manifest metabolic differences but can retain some of these differences when isolated from other cells. Although cutaneous fibroblasts do not produce significant quantities of sulfated material with the attributes of keratan sulfate, they do incorporate 3H-glucosamine into macromolecules that are susceptible to keratan sulfate endo-beta-galactosidase. Most of the sulfated glycosaminoglycans produced by organ cultures of the cornea, which were susceptible to this enzyme, eluted from Dowex 1-X2(Cl-) with a salt concentration of less than 2 M. This observation, together with the findings of others, indicates that the traditional belief that corneal keratan sulfate elutes from Dowex 1-Cl predominantly in the 3 M NaCl fraction needs to be reevaluated.

Chondroitin Lyases↗
PubMed1980

Abnormal product of corneal explants from patients with macular corneal dystrophy.

The glycosaminoglycans synthesized by 5 corneal explants with macular corneal dystrophy were analyzed by sequential degradation using heparitinase (and/or butyl nitrite), chondroitin ABC lyase, chondroitin AC lyase, and keratan sulfate endo-beta-galactosidase. The tissue was first pulse-labeled by incubation in phosphate-buffered saline (pH 7.3) containing 100 muCi/ml 3H-glucosamine and approximately 1000 muCi/ml 35S-sulfate for 1 hour and chased with Eagle's minimum essential medium containing 10% fetal calf serum. Notable differences were detected between the products of these corneal explants with macular corneal dystrophy and controls that were prepared and analyzed in the same manner. As assayed by its susceptibility to keratan sulfate endo-beta-galactosidase degradation, corneal tissue with macular corneal dystrophy incorporated less 35S-sulfate, and usually less 3H-glucosamine, into keratan sulfate than normal corneas. The corneal explants with macular corneal dystrophy also synthesized prominent fractions which eluted from DEAE-Sephacel columns in 0.05 M tris(hydroxymethyl)aminomethane buffer (pH 7.2) with 0.15 M and/or 0.25 M lithium chloride after pronase digestion. Since normal corneas produced small quantities of material with a similar elution profile after preparation and analysis under identical conditions it is possible that the fractions are normal synthetic products of the cornea. The significance of these findings in the pathogenesis of macular corneal dystrophy remains to be determined.

Adolescent↗
PubMed1979

Acridine orange particles in cultured fibroblasts. A comparative study of macular corneal dystrophy, systemic mucopolysaccharidoses types I-H and II, and normal controls.

Vital staining with the fluorescent dye, acridine orange, was evaluated as a means of detecting abnormalities of lysosomes in cultivated fibroblasts of patients with macular corneal dystrophy and mucopolysaccharidoses types I-H (Hurler's syndrome) and type II (Hunter's syndrome). Multiple cultures were compared with normal fibroblasts using a "double-masked" design to exclude observer bias. Cells of patients with the mucopolysaccharidoses were easily and accurately separated from other fibroblasts. Contrary to a recent report, corneal fibroblasts of patients with macular corneal dystrophy were indistinguishable from control cells.

Acridine Orange↗
PubMed1977

Physical management of muscular low back pain in the athlete.

The Canadian medical staff at the 1976 Olympic Games found that muscular low back pain was a common problem among the athletes. The problem had usually developed during training as a result of neglect of certain anatomic areas, particularly the abdominal region. A five-point treatment and prevention program was used with good results. It included (a) relief of spasm and pain, (b) stretching, (c) exercise, (d) alteration of the training program and (e) education to prevent future problems or worsening of the present problem.

Back Pain↗
PubMed1977

Selectivity of blocking agents for pre-and postsynaptic alpha-adrenoceptors.

1. Low frequency (0.1 Hz) electrical stimulation of the rat isolated vas deferens produced regular contractions that were inhibited by low concentrations of clonidine. 2. The inhibition of the vas deferens produced by clonidine was presynaptic in origin and involved alpha-adrenoceptors. 3. Presynaptic alpha-adrenoceptor antagonist activity was assessed by studying the effects of increasing concentrations of the antagonists on cumulative clonidine dose-response curves on the stimulated vas deferens. 4. Postsynaptic alpha-adrenoceptor antagonist activity was assessed by comparison of control cumulative noradrenaline dose-response curves with those in the presence of increasing concentrations of antagonists in the rat anococcygeus muscle. 5. The results indicate that yohimbine and phentolamine are more potent in blocking presynaptic than postsynaptic alpha-adrenoceptors. Phenoxybenzamine and prazosin block postsynaptic alpha-adrenoceptors preferentially. 6. The findings support the view that presynaptic and postsynaptic alpha-adrenoceptors differ in their sensitivity to alpha-adrenoceptor antagonists.

Adrenergic alpha-Antagonists↗
PubMed1977

Macular corneal dystrophy. Studies of sulfated glycosaminoglycans in corneal explant and confluent stromal cell cultures.

The inherited disorder macular corneal dystrophy (MCD), a localized corneal mucopolysaccharidosis, is currently thought to result from an inability to catabolize corneal keratan sulfate (keratan sulfate 1). As studies on isolated cells have provided insight into metabolic abnormalities in other inherited disorders, we investigated cultured corneal fibroblasts from 4 patients with MCD from several standpoints. Lines of corneal fibroblasts with MCD could not be distinguished from controls with cytochemical methods known to stain the naturally occurring accumulations. In contrast to cultured fibroblasts from patients with mucopolysaccharidoses Type I-H (Hurler syndrome) and Type II (Hunter syndrome), corneal fibroblasts from patients with MCD did not accumulate abnormal quantities of (35)S-sulfate-labeled glycosaminoglycans, but like normal corneal and cutaneous fibroblasts reached a state of equilibrium within 2 days. Also, the rate at which sulfated glycosaminoglycans were removed from cultured corneal fibroblasts in MCD by secretion and degradation more closely resembled that of normal cells than those with the systemic mucopolysaccharidoses. The secretion of sulfated glycosaminoglycans into the nutrient medium by corneal fibroblasts from patients with MCD occurred at a linear rate comparable to that of other cells studied. The aforementioned data, nonetheless, remain consistent with the hypothesis that MCD is an inherited disorder of keratan sulfate I (corneal keratan sulfate) catabolism, as isolated corneal fibroblasts in contrast to corneal explants synthesize little or no keratan sulfate in culture. In view of the latter, we also compared the profile of (35)S-labeled glycosaminoglycans produced by a corneal explant from a patient with MCD with that normally synthesized by human corneal explants. The latter synthesized and secreted a population of (35)S-sulfate-labeled glycosaminoglycans with properties of keratan sulfate. Considerably less material with these attributes was identified with the same analytic techniques in the cornea with MCD or in its surrounding medium after the abnormal cornea had been incubated under identical conditions. In addition to manifesting an impaired synthesis of corneal keratan sulfate-like material, the cornea with MCD produced a greater percentage of chondroitin-6-sulfate than normal. These findings suggest that the synthesis of corneal keratan sulfate and other glycosaminoglycans may be altered in MCD.

Adult↗