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Biomedical subjects

B O'Connor

Publications and source records attributed to B O'Connor.

At least 91 records · Page 5Linked to original sources
PubMed1991

Inhibition of low Km cGMP phosphodiesterases and Ca+(+)-regulated protein kinases and relationship to vasorelaxation by cicletanine.

In the present studies we sought to determine if cicletanine, which is an antihypertensive agent of unknown mechanism, could alter cGMP metabolism via inhibition of cGMP phosphodiesterases (PDE) in vascular smooth muscle. Cicletanine was determined to be a mixed (competitive, noncompetitive) inhibitor of both calmodulin-regulated and cGMP-specific PDEs from monkey aortic smooth muscle with Ki values of 450 to 700 microM. Cicletanine also potentiated vasorelaxation by the guanylate cyclase activators sodium nitroprusside and atrial natriuretic peptide in isolated rat aortas. Potentiation was not dependent upon the contractile agonists nor was it indomethacin-sensitive. Neither potentiation nor inhibition of cGMP PDEs was stereoselective. Methylene blue attenuated a component of cicletanine-induced vasorelaxation, but did not completely obviate relaxation. Both cicletanine and the cGMP-PDE inhibitor zaprinast potentiated sodium nitroprusside-mediated cGMP formation and relaxation, although the increase in cGMP content was markedly greater with zaprinast compared to cicletanine. In further studies, cicletanine did not potentiate cGMP activation of cGMP-dependent protein kinase, but did inhibit calmodulin-activated myosin light chain kinase and protein kinase C at relatively high concentrations (approximately 1 mM). In summary, these data demonstrate that cicletanine inhibits vascular cGMP PDEs, potentiates vasorelaxation, and to a limited extent, cGMP formation by guanylate cyclase activators in vascular smooth muscle. However, these relationships for cicletanine are dissimilar from the reference cGMP PDE inhibitor, zaprinast. Thus, other mechanisms may also contribute to the vasorelaxant action of cicletanine.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1991

Anterior (cranial) cruciate ligament transection in the dog: a bona fide model of osteoarthritis, not merely of cartilage injury and repair.

To help elucidate the longterm outcome in the unstable knees of dogs that have undergone anterior cruciate ligament (ACL) transection, conventional radiography, gait analysis and magnetic resonance imaging (MRI) were performed serially on 3 dogs over a 45-month period after ACL transection. Gait analysis showed that vertical forces generated by the cruciate deficient leg were smaller than those produced by the contralateral leg, but the decrease in loading was not progressive and clinical findings did not suggest that the dogs developed pain in the unstable limb. Despite progressive osteophytosis and subchondral sclerosis, as seen on plain radiographs, MRI demonstrated that articular cartilage in the unstable knee was thicker than that in the contralateral knee 36 months after ACL transection. Nine months later, however, striking focal loss of articular cartilage was seen in the unstable knee of each dog. Our study, which provides the first longterm observations of the changes in the unstable knee after ACL transection, shows that they represent progressive osteoarthritis and emphasizes that a prolonged phase of cartilage hypertrophy may precede the stage of cartilage breakdown.

Animals↗
PubMed1990

Further characterization of the substrate specificity of a TRH hydrolysing pyroglutamate aminopeptidase from guinea-pig brain.

In this study the substrate specificity of a pyroglutamate aminopeptidase from synaptosomal membranes of guinea-pig brain was investigated. The enzyme was found to be specific for tripeptides, tripeptide-amides and tetrapeptides which possess the N-terminal sequence Glp-His and as such is specific for Thyrotropin Releasing Hormone or only very closely related peptides. The enzyme was found not to hydrolyse a number of analogues of Thyrotropin Releasing Hormone which have been shown to have therapeutical value in certain neuronal disorders.

Aminopeptidases↗
PubMed1990

Effect of minocycline on subgingival plaque bacteria.

The effects of minocycline on subgingival plaque samples from patients with chronic periodontitis were investigated in vitro. Minocycline concentrations as low as 1.0 microgram/ml inhibited 95.7% of the cultivable bacteria in the samples but 256 micrograms/ml was necessary to inhibit all of the cultivable bacteria in the samples. Although up to 99.9% of bacteria in the plaque samples were killed by a 6 h exposure to 8.0 micrograms/ml of minocycline, large numbers of viable bacteria remained. These results imply that adequate reductions in the numbers of viable subgingival plaque bacteria are unlikely to occur after exposure to minocycline at concentrations attainable in gingival crevicular fluid after systemic administration.

Adult↗
PubMed1990

Degradation of thyrotropin-releasing hormone and luteinising hormone-releasing hormone by enzymes of brain tissue.

In this article, the enzymes of brain and associated tissues that can degrade thyrotropin-releasing hormone (TRH) and luteinising hormone-releasing hormone (LH-RH) are reviewed. As both TRH and LH-RH are considered to act as neurotransmitters or neuromodulators in the CNS, attention is paid to the subcellular location of the enzymes described and how their topographies and substrate specificities fit them to playing roles as inactivating agents for TRH and LH-RH or as regulators of intracellular concentrations of TRH and LH-RH. Consideration is also given to enzymes involved in biotransformation of TRH to secondary metabolites that exhibit biological activity and to enzymes involved in the metabolism of secondary metabolites.

Amino Acid Sequence↗
PubMed1989

Legionella: an infrequent cause of adult community acquired pneumonia in Dublin.

The commonest infectious agents identified in community acquired pneumonia (CAP) amongst 50 patients admitted to a Dublin hospital were Streptococcus pneumoniae and Haemophilis influenzae. Legionella pneumophila pneumonia occurred in only one patient who acquired infection abroad. A serological screen of blood bank donors and renal transplant recipients failed to detect antibody to Legionella pneumophila supporting the clinical findings of a low prevalence of infection in this community. It is concluded that initial antibiotic therapy for patients with CAP need not routinely include cover for Legionella.

Adult↗
PubMed1989

A large outbreak of Salmonella enteritidis phage type 4 associated with eggs from overseas.

In February 1989 the largest reported outbreak to date in the United Kingdom of Salmonella enteritidis phage type 4 (PT4) infection occurred following a wedding reception at a hotel. One hundred and seventy-three people met the case definition of illness of whom 118 had the organism isolated from their stools. A further 17 were found to be S. enteritidis PT4 positive, but were asymptomatic. Lightly-cooked, egg-based sauces were the epidemiologically proven vehicles of infection. Investigations showed this outbreak to be the first to implicate imported European eggs as the source of infection. An unusual feature of this outbreak was a reported incubation period of less than 3 h for some of the confirmed cases of salmonellosis.

Animals↗
PubMed1988

Inhibition of the low Km cyclic AMP phosphodiesterase and activation of the cyclic AMP system in vascular smooth muscle by milrinone.

The purposes of the present study were to quantitate the effects of the cardiotonic/vasodilator milrinone on phosphodiesterase (PDE) isozymes isolated from vascular (aortic) smooth muscle from several species, and to quantitate changes in cellular cyclic AMP (cAMP) content, activation of cAMP protein kinase (cAPK) and vasorelaxation by milrinone in isolated guinea pig aortic smooth muscle. With PDE isozymes isolated from rat (Wistar-Kyoto or spontaneously hypertensive rats), guinea pig, monkey or canine aortic smooth muscle, milrinone is a potent (IC50 = 0.16-0.90 microM) and selective (100 times peak III relative to peak I) peak III inhibitor. The potency of milrinone and other vascular peak III PDE inhibitors parallels their potency as vasorelaxants in isolated guinea pig aortic rings (r = 0.86; P less than .01). Vasorelaxation of phenylephrine-contracted (3 microM) guinea pig aortic rings is accompanied by significant increases in cAMP content or cAPK activation with concentrations of milrinone greater than or equal to 10 microM. Temporally, significant increases in cAMP content accompany significant vasorelaxation; however, activation of cAPK is not significantly increased until at least 1 to 2 min after addition of milrinone. Similar concentration and temporal relationships are seen with the cAMP-related vasorelaxants papaverine and forskolin. As with milrinone, a temporal dissociation between increases in cAMP content and increases in cAPK activity ratio is evident.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Primary and secondary microneuroanastomotic repair of the mental nerve in the rat.

The rate of sensory recovery and axonal regeneration after primary and secondary graft and direct microneuroanastomotic repair of the mental nerve was examined in the rat. The mental nerve was subject to experimental transection and immediately approximated with epineurial sutures, with or without a 3 mm autogenous nerve graft, left unapproximated, or left intact. 8 weeks later, the unapproximated stumps were rejoined with suture, with or without a nerve graft. Repair was evaluated using horseradish peroxidase as a tracer and electrically-evoked head withdrawal as a measure of gross sensation. The association in rates of recovery for the anastomosis groups were statistically significant. There was no significant association between negative and positive controls or anastomosis groups. Gross sensory return was established within 28 days of repair and axonal continuity was confirmed by the uptake of HRP in trigeminal ganglion cells. The present study strongly suggests that direct approximation and small autogenous interpositional nerve grafts have the same rate of recovery of gross sensation following primary and secondary repair of mental nerve transections in the rat.

Anastomosis, Surgical↗
PubMed1987

Active site studies on a narrow-specificity thyroliberin-hydrolysing pyroglutamate aminopeptidase purified from synaptosomal membrane of guinea-pig brain.

The effect of protein-modifying reagents on the activity of a purified preparation of a thyroliberin-hydrolysing pyroglutamate aminopeptidase, solubilised from synaptosomal membranes of guinea-pig brain by treatment with papain, was investigated. The results indicated that tyrosine, histidine, arginine, and possibly lysine residues were necessary for expression of catalytic activity and that these tyrosine, histidine, and arginine residues were probably located at the active site of the enzyme. Cysteine, serine, glutamate, and aspartate residues were not involved in the expression of catalytic activity.

Aminopeptidases↗
PubMed1987

Acute renal failure following Yersinia pseudotuberculosis septicaemia.

Although Yersinia pseudotuberculosis has not been previously reported to cause acute renal failure, it accounted for two cases reported here out of eighty referrals with acute renal failure to our renal unit over the last year. This may suggest that the incidence of Yersinia pseudotuberculosis may be greater than that previously reported, and it should be suspected in patients presenting with bloody diarrhoea in association with renal failure. The septicaemic form of the disease is life threatening and requires intensive supportive therapy.

Acute Kidney Injury↗
PubMed1987

Potassium-sparing effect of trilostane in hydrochlorothiazide-treated rats and dogs.

Trilostane, which inhibits three beta-hydroxysteroid dehydrogenase and aldosterone synthesis in rats and monkeys, significantly attenuated the oral potassium-wasting effect of hydrochlorothiazide (HCTZ) in rats and dogs when coadministered with the diuretic. The steroid reduced the kaliuretic and enhanced the natriuretic (and hyperreninemic) activity of HCTZ in rats, thereby promoting the urinary sodium/potassium ratio. Trilostane completely prevented HCTZ-induced hypokalemia in dogs and tended to reduce the degree of secondary aldosteronism. The combination also promoted hematocrit of dogs by 8% and decreased serum Na+ concentration by 7 meq/liter. When administered alone, trilostane increased canine serum potassium levels slightly and promoted rat urinary Na+/K+ ratio. Results confirm previous reports of antikaliuretic activity of trilostane in diuretic-treated rats. Further, the data indicate that frank hypokalemia induced in dogs by hydrochlorothiazide can be prevented by adjunctive trilostane therapy without eliciting hyperkalemia.

Aldosterone↗
PubMed1986

Post-proline dipeptidyl-aminopeptidase from synaptosomal membranes of guinea-pig brain. A possible role for this activity in the hydrolysis of His-ProNH2, arising from the action of synaptosomal membrane pyroglutamate aminopeptidase on thyroliberin.

In this paper we report that while 55% of the total post-proline dipeptidyl-aminopeptidase activity in guinea-pig brain is associated with the soluble fraction of the cells, the remaining activity is widely distributed throughout the particulate fractions. A significant portion of this particulate activity is, however, associated with a synaptosomal membrane fraction. The specific activity of this enzyme rose as the synaptosomal membrane fraction was prepared from a synaptosomal fraction and had previously risen at the synaptosomal fraction was prepared from a postmitochondrial pellet. The synaptosomal membrane post-proline dipeptidyl-aminopeptidase was released from the membrane by treatment with Triton X-100 and partially purified by chromatography on Sephadex G-200. By contrast with the soluble enzyme the partially purified solubilised synaptosomal membrane post-proline dipeptidyl-aminopeptidase was not inhibited by 1.0 mM p-chloromercuribenzoate, 1.0 mM N-ethylmaleimide or 0.5 mM puromycin but was inhibited by 0.5 mM bacitracin. The partially purified solubilised enzyme was capable of releasing His-Pro from His-Pro-Val, His-Pro-Leu, His-Pro-Phe and His-Pro-Tyr and of releasing Gly-Pro from Gly-Pro-Ala but could not release Arg-Pro from Arg-Pro-Pro or from Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (bradykinin). It was also unable to release Pro-Pro from Pro-Pro-Gly or Glp-Pro from Glp-Pro-Ser-Lys-Asp-Ala-Phe-Ile-Gly-Leu-MetNH2 (eledoisin). Using [Pro-3H]thyroliberin we show that the membrane-bound enzyme converts His-ProNH2, produced by the action of the synaptosomal membrane pyroglutamate aminopeptidase, to His-Pro thus competing with the spontaneous cyclisation of His-ProNH2 to His-Pro diketopiperazine. Purified preparations of synaptosomal membrane pyroglutamate aminopeptidase were used to generate His-ProNH2, which could then be converted to His-Pro by the presence of the partially purified synaptosomal membrane post-proline dipeptidyl-aminopeptidase. This preparation was free of contaminating post-proline cleaving endopeptidase, carboxypeptidase P, aminopeptidase P, prolyl carboxypeptidase or proline dipeptidase.

Animals↗
PubMed1985

Purification of and kinetic studies on a narrow specificity synaptosomal membrane pyroglutamate aminopeptidase from guinea-pig brain.

A pyroglutamate aminopeptidase activity, distinct from that of cytoplasm, was released from a synaptosomal membrane preparation of guinea-pig brain by papain treatment. This activity was further purified 3560-fold relative to the homogenate with a yield of 17% by a procedure involving gel filtration chromatography, calcium phosphate cellulose chromatography and hydrophobic interaction chromatography on phenyl-Sepharose CL-4B. The purified synaptosomal pyroglutamate aminopeptidase hydrolysed only thyroliberin, acid-thyroliberin, the luliberin N-terminal tripeptide (Glp-His-Trp) and, only slightly, Glp-His-Gly. No hydrolysis was observed with dipeptides containing N-terminal pyroglutamic acid (Glp) or with pyroglutamyl peptides containing more than three amino acids. A Km value of 40 microM was recorded when thyroliberin was used as substrate; however, luliberin was found to inhibit the hydrolysis of thyroliberin competitively with a Ki value of 20 microM.

Aminopeptidases↗