PubMed Health⌕ Search

Biomedical subjects

M A Cook

Publications and source records attributed to M A Cook.

At least 55 records · Page 3Linked to original sources
PubMed1987

Possible heterogeneity of adenosine receptors present on myenteric nerve endings.

The presence of more than one adenosine receptor on enteric nerve endings was investigated using the electrically stimulated guinea pig ileum preparation and purified myenteric varicosities obtained from the same source. Competition experiments, using N6-cyclohexyladenosine and 5'-N-ethylcarboxamide adenosine as the labeled ligands allowed the binding characteristics of the adenosine receptor(s) on myenteric nerve endings to be examined. The results showed that both N6-cyclohexyladenosine and 5'-N-ethylcarboxamide adenosine were equieffective as displacers of labeled N6-cyclohexyladenosine binding. In contrast, the binding of labeled 5'-N-ethylcarboxamide adenosine revealed an inability of the A1 ligands N6-[R-1-methyl-2-phenethyl]adenosine and N6-cyclohexyladenosine to displace more than 50% of its specific binding. Competition curves generated using the potent and selective adenosine receptor antagonist 1,3-dipropyl-8-(4-sulfophenyl)xanthine revealed a clear difference between displacement profiles for N6-cyclohexyladenosine and 5'-N-ethylcarboxamide adenosine. These data are indicative of the presence of more than one binding site on enteric nerve endings. Schild analysis of the antagonism of the presynaptic inhibitory effects of the nucleosides on the ileum using theophylline yielded linear isoboles with unit slopes indicating competitive antagonism. Similar analysis using 1,3-dipropyl-8-(4-sulfophenyl)xanthine yielded comparable results for the A1 agonists whereas 5'-N-ethylcarboxamide adenosine gave rise to a curvilinear isobole, a finding consistent with possible receptor heterogeneity. These findings show that data derived from both binding and functional studies support the existence of more than one adenosine receptor on myenteric nerves although they do not permit the subclassification of these sites as A1 or A2 receptor subtypes.

Adenosine↗
PubMed1986

Affinity of various purine nucleosides for adenosine receptors on purified myenteric varicosities compared to their efficacy as presynaptic inhibitors of acetylcholine release.

Isolated myenteric varicosities (autonomic synaptosomes)prepared from the guinea-pig ileum were used as the substrate in competition experiments designed to study the properties of the adenosine receptor present on peripheral nerve endings. Competition experiments using [3H]-N6-[R-(-)-1-methyl-2-phenethyl] adenosine and [3H]-5'-N-ethylcarboxamidoadenosine as the labeled ligands permitted the affinities of several unlabeled adenosine analogs to be examined. In addition, the ability of theophylline, an antagonist at adenosine receptors, to compete for binding was determined. The relative affinities of the nucleosides were compared to their efficacies as inhibitors of acetylcholine release in the stimulated guinea-pig ileum preparation and an excellent correlation was obtained. The identity of the substrate used in the binding studies with the target in the bioassay system suggests that the isolated myenteric varicosity contains the adenosine receptor responsible for the observed biological activity. Similar affinities for theophylline as a competitor of the binding of both labeled ligands paralleled the establishment of similar PA2 values for the antagonist in the bioassay. These findings, together with the similarity of the biological efficacy of N6-[R-(-)-1-methyl-2-phenethyl]adenosine and 5'-N-ethylcarboxamidoadenosine, suggest that the adenosine receptor present on myenteric nerve endings is unitary but do not permit its designation as an A1 or A2 subtype.

Acetylcholine↗
PubMed1985

Antagonism by theophylline of the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine at the guinea pig ileum.

The inhibitory effect of the putative adenosine A2 receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) on acetylcholine release from the stimulated guinea pig ileum preparation and the nature of its antagonism by theophylline were investigated. NECA was shown to inhibit the response of the ileum preparation in a dose-dependent fashion, and an EC50 value of 1.62 X 10(-8) M was determined. This value was comparable with that determined for the A1 receptor agonist N6-R-phenylisopropyladenosine (R-PIA) (2.57 X 10(-8) M) using the same preparation. Competitive antagonism of the inhibitory effect of NECA by theophylline was quantitated and a pA2 value of 5.04 for the methylxanthine was obtained. This value was similar to those obtained previously for R-PIA and adenosine itself and suggests that these nucleosides may be interacting with the same receptor site on myenteric nerve endings. These findings do not permit the designation of the receptor as an A1 or A2 subtype according to current criteria.

Adenosine↗
PubMed1984

Oophorectomy and cortical bone remodeling in the beagle.

Cortical bone remodeling measurements were carried out on the ribs of 6 spayed and five control Beagle dams which had been subjected to a period of observation equal to more than one sigma of cortical bone remodeling activity. The results of the measurements of static and dynamic parameters indicate that the lack of ovarian hormones does not produce a major alteration in the rates of cortical bone remodeling, but does result in an increase in the number of resorption spaces per mm2 of cortical bone without altering the parameters of bone function. This latter fact supports the hypothesis that decreased levels of circulatory ovarian hormones may influence the duration of the resorption activity as well as possibly uncoupling the resorption/formation (R/F) mechanism of the bone remodeling unit.

Animals↗
PubMed1982

Effect of efferent denervation of the vagus nerve on nonadrenergic inhibitory responses obtained from the rat stomach in vitro.

The possibility that antidromic stimulation of afferent nerves is involved in the mediation of nonadrenergic inhibitory (NAI) responses obtained from isolated preparations was tested using the isolated rat stomach--vagus nerve preparation. Unilateral supranodose vagotomies 7-21 days prior to obtaining the preparations permitted efferent denervation to occur and the responses obtained in vitro from stimulation of the sectioned nerves were compared with those from the control nerves. Supranodose vagotomy abolished the responses obtained from the preparations while stimulation of the control nerves gave rise to normal biphasic responses consisting of both excitatory and NAI components. Histological examination of the nodose ganglia revealed the presence of normal sensory ganglion cells while abundant intact axons were observed in nerve trunks on the lesioned side. It is concluded that afferent nerves in the vagus are not involved in the mediation of NAI responses obtained from the rat stomach in vitro.

Animals↗
PubMed1982

The influence of glucosidic conformation and charge distribution on activity of adenine nucleosides as presynaptic inhibitors of acetylcholine release.

The electrically stimulated guinea-pig ileum preparation was used to establish the potency of adenosine and a series of nucleoside analogs as presynaptic inhibitors of acetylcholine output and a rank order was obtained. 2-Chloroadenosine was the most potent compound studied (pD2 = 7.74), whereas inosine yielded the lowest measurable efficacy (pD2 = 3.66). The 8-substituted nucleotides studied were either poorly active or inactive. The Iterative Extended Huckel Theory method was used to calculate the total conformational energy of each analog as well as the electronic properties at key positions in purine moiety. Spectra relating conformation energy to the dihedral angle of rotation of the purine base about the glycoside bond permitted the preferred glycosidic conformation of each analog to be determined. Comparison of this conformational data, which indicated few strong conformational differences, with the biological efficacy did not permit an association between potency and stability in the glycosidic high anti conformation to be drawn. however, the inactivity of the adenine nucleotides with bulky substituents at position 8 may suggest involvement of the entire anti-high anti range as essential conformations. A possible association between activity and charge density at the purine N1 atom, for a subset of the nucleosides investigated, was seen. It is suggested that the accessibility of nucleosides to the entire anti-high anti conformational region is a permissive condition in addition to which other molecular characteristics play a role in determining activity at the presynaptic locus.

Acetylcholine↗
PubMed1980

Lack of effect of botulinum toxin on nonadrenergic, noncholinergic inhibitory responses of the guinea pig fundus in vitro.

The nonadrenergic, noncholinergic inhibitory (NAI) response of guinea pig fundic strip to electrical field stimulation was examined in the presence of botulinum toxin and tetrodotoxin. Tetrodotoxin completely abolished the NAI response while botulinum toxin did not alter it. It is concluded that the mediator of NAI responses is unlikely to be released with acetylcholine from cholinergic nerves or that such release would have to occur by a mechanism resistant to botulinum toxin.

Animals↗
PubMed1979

Changes in platelet function and gastrointestinal bleeding following repeated administration of acetylsalicylic acid in the rat and the dog.

Two dogs were prepared with Pavlov pouches of the fundic area of the stomach using standard techniques. During treatment periods of 14 days, 200 mg acetylsalicylic acid (ASA) was introduced into the pouch twice daily by insufflation. One hour after each drug administration the pouch was washed with saline and the fluid assayed for blood. Bleeding from the pouch increased to a maximum on the 3rd or 4th day of the treatment period and subsequently declined such that by the 8th day blood loss was minimal and approximated that found during control periods. Platelet aggregation (in vitro) responses to adenosine diphosphate were significantly (p less than 0.01) inhibited on day 3 when aggregation curve heights were reduced by 66.2 +/- 13.11% (mean +/- SEM) from control values. On day 7 and during the ensuing 7-day period when ASA was given twice daily, the heights of aggregation responses were reduced by only 20-30% from controls. These responses were significantly (p less than 0.001) greater than those found on day 3. Similar changes in platelet reactivity were found in plasma from rats given ASA twice daily for 7 days. Aggregation responses to collagen were depressed by 95.5 +/- 4.49% on day 1 following two doses of ASA. As the treatment period continued, the aggregation responses increased in magnitude until the 7th day they were similar in height to those from control animals. The mechanism involved in this adaptation to ASA treatment seen with these platelets is not known.

Adenosine Diphosphate↗
PubMed1976

Effect of substance P on proximal tubular reabsorption in the rat.

Micropuncture and clearance techniques were used simultaneously to determine the effect of substance P on proximal tubular and overall renal function in anesthetized rats. This polypeptide, infused in saline at 50 pg/min into the abdominal aorta above the renal arteries, produced increases in urine flow, 2.7-3.7 mul/min.g kidney wt (P is less than 0.005); urinary sodium concentration, 32-61 meq/liter (P is less than 0.01); and sodium excretion, 89-223 neq/min (P is less than 0.005). Tubular fluid to plasma inulin concentration ratio measured in the last accessible proximal convolution fell from 2.21 to 1.80 (P is less than 0.001), and thus fractional reabsorption was reduced from 54 to 44% (P is less than 0.001). Absolute reabsorption by the proximal convoluted tubule was also reduced 15.5-12.5 nl/min (P is less than 0.025). In a control series of animals, saline alone infused at the same rate did not produce any statistically significant changes in the measured parameters over the same time period. The intrerenal mechanism responsible for the reduction in proximal reabsorption appears to be a tubular one since no consistent or significant changes were observed in kidney or single nephron glomerular filtration rate, renal plasma flow, or intrarenal hydrostatic pressures. No evidence was found to indicate redistribution of filtration rate, or plasma flow, or a reduction in filtration fraction.

Animals↗
PubMed1975

Uric acid excretion by the rat kidney.

The renal excretion of uric acid was studied in nondiuretic (ND) male Wistar rats and in the same animals subsequently made diuretic (D) by the infusion of hypertonic saline. Clearances of endogenous urate and of inulin, determined chemically, were compared with the simultaneous clearance of 14C infused as [6(-14)C]urate or [2(-14)C]urate. In rats infused with [6(-14)C]urate the isotope/inulin clearance ratios were 0.29 +/- 0.09 (ND) and 0.31 +/- 0.11 (D) ml/min; the simultaneous urate (chemical)/inulin ratios were 0.21 +/- 0.07 (ND) and 0.24 +/- 0.08 (D) ml/min. In rats infused with [2(-14)C]urate the isotope/inulin clearance ratios were 1.02 +/- 0.5 (ND) and 1.13 +/- 0.9 ml/min (D); the simultaneous urate (chemical)/inulin clearance ratios were much lower-0.19 +/- 0.09 (ND) and 0.32 +/- 0.19 (D) ml/min. Thin-layer chromatography of urine after [6(-14)C]urate inl uric acid. In contrast, a similar analysis of urinary radioactivity after [2(-14)C]urate infusion revealed that more than 70% of the 14C was excreted as allantoin and not as uric acid.

Allantoin↗