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Biomedical subjects

S D Walker

Publications and source records attributed to S D Walker.

At least 19 recordsLinked to original sources
PubMed2001

Activation of endothelial cell IK(Ca) with 1-ethyl-2-benzimidazolinone evokes smooth muscle hyperpolarization in rat isolated mesenteric artery.

1. In rat small mesenteric arteries contracted with phenylephrine, 1-ethyl-2-benzimidazolinone (1-EBIO; 3-300 microM) evoked concentration-dependent relaxation that, above 100 microM, was associated with smooth muscle hyperpolarization. 2. 1-EBIO-evoked hyperpolarization (maximum 22.1+/-3.6 mV with 300 microM, n=4) was endothelium-dependent and inhibited by charybdotoxin (ChTX 100 nM; n=4) but not iberiotoxin (IbTX 100 nM; n=4). 3. In endothelium-intact arteries, smooth muscle relaxation to 1-EBIO was not altered by either of the potassium channel blockers ChTX (100 nM; n=7), or IbTX (100 nM; n=4), or raised extracellular K(+) (25 mM). Removal of the endothelium shifted the relaxation curve to the right but did not reduce the maximum relaxation. 4. In freshly isolated mesenteric endothelial cells, 1-EBIO (600 microM) evoked a ChTX-sensitive outward K-current. In contrast, 1-EBIO had no effect on smooth muscle cell conductance whereas NS 1619 (33 microM) stimulated an outward current while having no effect on the endothelial cells. 5. These data show that with concentrations greater than 100 microM, 1-EBIO selectively activates outward current in endothelial cells, which presumably underlies the smooth muscle hyperpolarization and a component of the relaxation. Sensitivity to block with charybdotoxin but not iberiotoxin indicates this current is due to activation of IK(Ca). However, 1-EBIO can also relax the smooth muscle by an undefined mechanism, independent of any change in membrane potential.

Animals↗
PubMed2000

An indirect influence of phenylephrine on the release of endothelium-derived vasodilators in rat small mesenteric artery.

1. The possibility that stimulation of smooth muscle alpha(1)-adrenoceptors modulates contraction via the endothelium was examined in rat small mesenteric arteries. 2. N(omega)-nitro-L-arginine methyl ester, (L-NAME, 100 microM to inhibit NO synthase) increased contraction to single concentrations of phenylephrine (1 - 3 microM) by approximately 2 fold (from a control level of 14.2+/-3.0 to 34. 1+/-4.2% of the maximum contraction of the artery, n=20). The action of L-NAME was abolished by disrupting the endothelium. 3. The subsequent addition of apamin (to inhibit small conductance Ca(2+)-activated K(+) channels, 50 nM) further augmented phenylephrine contractions, in an endothelium-dependent manner, to more than 3 fold above control (50.4+/-5.3% of the maximum contraction, n=11). 4.Charybdotoxin (non-selective inhibitor of large conductance Ca(2+)-activated K(+) channels, BK(Ca), 50 nM) plus L-NAME augmented the level of phenylephrine contraction to 4 - 5-fold above control (64.1+/-3.1%, n=5), but this effect was independent of the endothelium. The potentiation of contraction by charybdotoxin could be mimicked with the selective BK(Ca) inhibitor, iberiotoxin,. 5. Apamin together with L-NAME and charybdotoxin further significantly increased the phenylephrine contraction by 5 - 6-fold, to 79.9+/-3.5% of the maximum contraction of the artery (n=13). 6. Phenylephrine failed directly to increase the intracellular Ca(2+) concentration in endothelial cells freshly isolated from the small mesenteric artery. 7. Stimulation of smooth muscle alpha(1)-adrenoceptors in the mesenteric artery induces contraction that is markedly suppressed by the endothelium. The attenuation of contraction appears to reflect both the release of NO from the endothelium and the efflux of K(+) from both endothelial and smooth muscle cells. This suggests that the release of NO and endothelium-derived hyperpolarizing factor can be evoked indirectly by agents which act only on the smooth muscle cells.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1997

External alkalinization decreases intracellular Ca++ and spontaneous contractions in pregnant rat myometrium.

OBJECTIVES: As plasma pH rises during pregnancy, the effect of raising external pH on spontaneous contractions in pregnant rat myometrium was investigated to test the hypothesis that elevated external pH depresses contraction. STUDY DESIGN: Strips of longitudinal myometrium were loaded with SNARF (seminaphthorhodafluor) or Indo-1 for simultaneous intracellular pH or Ca++ and force measurements. Results were obtained from a minimum of five animals in each group, and significant differences were tested for by paired Student t tests. RESULTS: Raising the external pH significantly reduced spontaneous force and calcium transient in the pregnant uterus. Raising the external pH led to a slow rise in intracellular pH, but this could not account for the functional effect. K+ rubidium 86-labeled efflux rates were unaffected by external pH, suggesting no hyperpolarization. The Ca++ channel agonist Bay K8644 (5 mumol/L) restored contractions abolished by raised external pH. CONCLUSIONS: Raised external pH reduces spontaneous contractions in the pregnant rat uterus, probably by an external effect on Ca++ entry. This effect may contribute to uterine quiescence before term.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle.

The effects of niflumic acid on whole-cell membrane currents and mechanical activity were examined in the rat portal vein. In freshly dispersed portal vein cells clamped at -60 mV in caesium (Cs+)-containing solutions, niflumic acid (1-100 microM) inhibited calcium (Ca2+)-activated chloride currents (IC1(Ca)) induced by caffeine (10 mM) and by noradrenaline (10 microM). In a potassium (K+)-containing solution and at a holding potential of - 10 mV, niflumic acid (10-100 microM) induced an outward K+ current (IK(ATP)) which was sensitive to glibenclamide (10-30 microM). At concentrations < 30 microM and at a holding potential of -2 mV, niflumic acid had no effect on the magnitude of the caffeine- or noradrenaline-stimulated current (IBK(Ca)) carried by the large conductance, Ca(2+)-sensitive K+ channel (BKCa). However, at a concentration of 100 microM, niflumic acid significantly inhibited IBK(Ca)) evoked by caffeine (10 mM) but not by NS1619 (1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3 H) benzimidazolone; 20 microM). In Cs(+)-containing solutions, niflumic acid (10-100 microM) did not inhibit voltage-sensitive Ca2+ currents. In intact portal veins, niflumic acid (1-300 microM) inhibited spontaneous mechanical activity, an action which was partially antagonised by glibenclamide (1-10 microM), and contractions produced by noradrenaline (10 microM), an effect which was glibenclamide-insensitive. It is concluded that inhibition of ICl(Ca) and stimulation of IK(ATP) both contribute to the mechano-inhibitory actions of niflumic acid in the rat portal vein.

Adrenergic alpha-Agonists↗
PubMed1995

Protein kinase C chimeras: catalytic domains of alpha and beta II protein kinase C contain determinants for isotype-specific function.

Protein kinase C (PKC) is involved in the proliferation and differentiation of many cell types. In human erythroleukemia (K-562) cells, the PKC isoforms alpha and beta II play distinct functional roles. alpha PKC is involved in phorbol 12-myristate 13-acetate-induced cytostasis and megakaryocytic differentiation, whereas beta II PKC is required for proliferation. To identify regions within alpha and beta II PKC that allow participation in these divergent pathways, we constructed chimeras in which the regulatory and catalytic domains of alpha and beta II PKC were exchanged. These PKC chimeras can be stably expressed, exhibit enzymatic properties similar to native alpha and beta II PKC in vitro, and participate in alpha and beta II PKC isotype-specific pathways in K-562 cells. Expression of the beta/alpha PKC chimera induces cytostasis in the same manner as overexpression of wild-type alpha PKC. In contrast, the alpha/beta II PKC chimera, like wild-type beta II PKC, selectively translocates to the nucleus and leads to increased phosphorylation of the nuclear envelope polypeptide lamin B in response to bryostatin-1. Therefore, the catalytic domains of alpha and beta II PKC contain determinants important for alpha and beta II PKC isotype function. These results suggest that the catalytic domain represents a potential target for modulating PKC isotype activity in vivo.

Animals↗
PubMed1994

Treatment of bleb infection after glaucoma surgery.

OBJECTIVE: To assess the history, clinical course, and response to treatment of 14 patients with a bleb infection (blebitis) following glaucoma surgery. DESIGN: Retrospective study. SETTING: A university referral center in Atlanta, Ga. PATIENTS: Fourteen patients developed a bleb infection that ranged from 1 month to 22 years after glaucoma surgery. Infections were characterized by pain, a whitened bleb surrounded by intense conjunctival injection, marked anterior chamber reaction (hypopyon in six eyes), and a clear vitreous. Before infection, most blebs were described as thin. The results of Seidel's test were positive in six patients, and most patients had a low intraocular pressure without the use of any glaucoma medication. INTERVENTION: Treatment consisted of hospitalization, intravenous antibiotic therapy, and hourly topical fortified cefazolin sodium and gentamicin sulfate. RESULTS: The visual acuity in most patients improved to the level before the bleb infection, with only three eyes losing 2 or more lines of vision. CONCLUSIONS: Bleb infection without vitreous involvement (blebitis) may be a precursor of endophthalmitis. With aggressive treatment, bleb infection appears to have a much better prognosis for visual recovery than endophthalmitis.

Adolescent↗
PubMed1992

Fatal disseminated Conidiobolus coronatus infection in a renal transplant patient.

A case of fatal disseminated fungal infection due to Conidiobolus coronatus in a patient with a renal transplant is described. This organism, known to cause localized infections in otherwise healthy individuals in the tropics, is now recognized as a cause of fatal infection in immunosuppressed hosts. Histologically, localized infections are characterized by lack of vessel invasion and the presence of an eosinophilic sleeve around fungal elements, called the Splendore-Hoeppli phenomenon. The histologic findings in the present case were more typical of mucormycosis, and the correct diagnosis was established only after the organism was isolated and identified in culture.

Cytomegalovirus Infections↗
PubMed1987

Evaluation and assessment of high sensitivity thyrotropin methods as an index for thyroid function.

We report the evaluation of four new commercially available sensitive assay kits for determination of thyrotropin (TSH) and their clinical utility in normal subjects and patients with thyroidal and non-thyroidal illnesses. The sensitivity for the reliable detection of serum TSH by these methods ranged from 0.1-0.4 mU/L and their decreasing order was : NML greater than Serono greater than Abbott EIA greater than Hybritech. The coefficient of variation ranged from 2.0-5.8% for intra-assay and 2.3-8.6% for interassay at different concentration levels. Patients studied (n = 130) were assigned into four groups on the basis of the serum thyroxine value and their clinical findings. In total, there were 17 discrepancies (five with Hybritech, three with NML, five with Abbott EIA, and four with Serono) in making the correct diagnosis using these sensitive TSH methods as a single diagnostic test. These discrepancies were mainly in the same patients who were clinically euthyroid but had subnormal TSH values. There were no discrepancies in making the correct diagnosis for patients with hyperthyroidism or hypothyroidism using these sensitive TSH methods. Our observations indicate that the sensitive TSH methods are reliable in measuring subnormal levels and may be used to detect hyperthyroidism without affecting in any way their value in detecting hypothyroidism.

Adolescent↗
PubMed1985

Absence of rebound from diltiazem therapy in Prinzmetal's variant angina.

To determine the frequency of rebound anginal symptoms on abrupt withdrawal of calcium channel blocking agents, anginal symptoms were retrospectively examined in patients with Prinzmetal's variant angina abruptly withdrawn from diltiazem therapy as part of the design of a placebo-controlled multiple crossover trial. Rebound was defined as a return of anginal symptoms to levels exceeding those of the pretreatment baseline state. Values for daily frequency of angina were compared (after subtracting corresponding baseline values) between placebo periods following diltiazem periods and placebo periods following placebo periods. No intergroup differences existed between mean changes in daily frequency of angina from baseline value (-0.61 for placebo following diltiazem versus -1.10 for placebo following placebo) (p greater than 0.4). Furthermore, in 13 (28%) of 46 occurrences when placebo followed placebo, daily frequency of angina exceeded baseline value in the immediate 3 day period following placebo compared with 17 (21%) of 80 occurrences when placebo followed diltiazem. There was no increased rebound occurrence comparing high dose (240 mg/day) with low dose (120 mg/day) diltiazem therapy. No significant symptoms such as myocardial infarction or unstable angina occurred after withdrawal of diltiazem or placebo. The lack of difference in rebound after diltiazem or placebo withdrawal was consistent using paired and unpaired analyses. In conclusion, there appears to be no evidence that abrupt withdrawal of therapy with diltiazem results in rebound anginal symptoms.

Angina Pectoris, Variant↗
PubMed1982

Hypotony and aqueous humor dynamics in myotonic dystrophy.

A group of 26 subjects with myotonic dystrophy were studied with fluorophotometry to evaluate the relationship between aqueous humor dynamics and the hypotony found in this disorder. All 26 received topical fluorescein to determine the anterior chamber elimination coefficient; five received systemic fluorescein to evaluate the integrity of the blood-aqueous barrier. The group has a mean intraocular pressure of 7.1 mm Hg. The rate of clearance of fluorescein from the anterior chamber and the cornea-to-anterior chamber transfer coefficient for fluorescein were normal. An abnormally high level of fluorescence, three times normal, was observed in the anterior chambers of the myotonic subjects after oral administration of fluorescein. This finding could not be attributed to abnormal absorption and elimination of fluorescein or to abnormal plasma binding. This finding indicates that there is a defect in the blood-ocular barrier to fluorescein in myotonic subjects. Thus conclusions regarding aqueous humor flow cannot be made from the rate of clearance of topically applied fluorescein in myotonic subjects, since the clearance due to diffusion may represent a significantly large fraction of the total clearance.

Adolescent↗
PubMedDate not supplied

Clinical experience with diltiazem in Japan.

In a cooperative postmarketing study, 3,913 Japanese patients received diltiazem, an orally administered calcium channel blocking agent, for 30 to over 360 days. Drug safety was assessed by monthly evaluations of subjective symptoms, electrocardiographic recordings, adverse experiences, vital signs, and biochemical profiles. Original case report forms were processed and analyzed in the United States. None of the observed adverse experiences were serious or life threatening. They occurred in 1.8% of the patients and primarily involved the gastrointestinal system; anorexia and nausea were the most common adverse effects. The majority of the other adverse experiences were extensions of the drug's pharmacologic effects. Diltiazem appears to cause relatively minor clinical toxicity at a low frequency.

Aged↗
PubMedDate not supplied

Evidence for a differential cellular distribution of inward rectifier K channels in the rat isolated mesenteric artery.

The distribution of functionally active, inwardly rectifying K (K(IR)) channels was investigated in the rat small mesenteric artery using both freshly isolated smooth muscle and endothelial cells and small arterial segments. In Ca(2+)-free solution, endothelial cells displayed a K(IR) current with a maximum amplitude of 190 +/- 16 pA at -150 mV and sensitivity to block with 30 microM Ba(2+) (n = 7). In smooth muscle cells, outward K current was activated at around -47 +/- 3 mV, but there was no evidence of K(IR) current (n = 6). Furthermore, raising extracellular [K(+)] to either 60 or 140 mM, or applying the alpha(1)-adrenoceptor agonist phenylephrine (PE; 30 microM), failed to reveal an inwardly rectifying current in the smooth muscle cells, although PE did stimulate an iberiotoxin-sensitive outward K current (n = 4). Exogenous K(+) (10.8-16.8 mM) both relaxed and repolarized endothelium-denuded segments of the mesenteric artery contracted with PE. These effects were depressed by 100 microM ouabain but unaffected by either 30 microM BaCl(2) or 3 microM glibenclamide. These data suggest that functional, inwardly rectifying Ba(2+)-sensitive channels are restricted to the endothelial cell layer in the rat small mesenteric artery.

Animals↗