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Biomedical subjects

William C Cole

Publications and source records attributed to William C Cole.

16 recordsLinked to original sources
PubMed2006

Na+ entry via TRPC6 causes Ca2+ entry via NCX reversal in ATP stimulated smooth muscle cells.

Reversal of the Na+/Ca2+ -exchanger (NCX) has been shown to mediate Ca2+ influx during activation of G-protein linked receptors. Functional coupling between the reverse-mode NCX and the canonical transient receptor potential channels (TRPCs) has been proposed to mediate Ca2+ influx in HEK-293 cells overexpressing TRPC3. In this communication we present evidence for similar functional coupling of NCX to endogenously expressed TRPC6 in rat aorta smooth muscle cells. Selective inhibition of reverse-mode NCX with KB-R7943 and of non-selective cation-channels with SKF-96365 abolished Ca2+ influx in response to agonist stimulation (ATP). Expression of a dominant negative TRPC6 mutant also reduced the Ca2+ influx in proportion to its transfection efficiency. Calyculin A, which is known to disrupt the junctions of the plasma membrane and sarco/endoplasmic reticulum, increased global Na+ elevations and reduced stimulated Ca2+ influx. Together our data provide evidence that localized Na+ elevations are generated by TRPC6 and drive reversal of NCX to mediate Ca2+ influx.

Adenosine Triphosphate↗
PubMed2006

Key role of Kv1 channels in vasoregulation.

Small arteries play an essential role in the regulation of blood pressure and organ-specific blood flow by contracting in response to increased intraluminal pressure, ie, the myogenic response. The molecular basis of the myogenic response remains to be defined. To achieve incremental changes in arterial diameter, as well as blood pressure or organ-specific blood flow, the depolarizing influence of intravascular pressure on vascular smooth muscle membrane potential that elicits myogenic contraction must be precisely controlled by an opposing hyperpolarizing influence. Here we use a dominant-negative molecular strategy and pressure myography to determine the role of voltage-dependent Kv1 potassium channels in vasoregulation, specifically, whether they act as a negative-feedback control mechanism of the myogenic response. Functional Kv1 channel expression was altered by transfection of endothelium-denuded rat middle cerebral arteries with cDNAs encoding c-myc epitope-tagged, dominant-negative mutant or wild-type rabbit Kv1.5 subunits. Expression of mutant Kv1.5 dramatically enhanced, whereas wild-type subunit expression markedly suppressed, the myogenic response over a wide range of intraluminal pressures. These effects on arterial diameter were associated with enhanced and reduced myogenic depolarization by mutant and wild-type Kv1.5 subunit expression, respectively. Expression of myc-tagged mutant and wild-type Kv1.5 subunit message and protein in transfected but not control arteries was confirmed, and isolated myocytes of transfected but not control arteries exhibited anti-c-myc immunofluorescence. No changes in message encoding other known, non-Kv1 elements of the myogenic response were apparent. These findings provide the first molecular evidence that Kv1-containing delayed rectifier K+ (K(DR)) channels are of fundamental importance for control of arterial diameter and, thereby, peripheral vascular resistance, blood pressure, and organ-specific blood flow.

Animals↗
PubMed2006

Heteromultimeric TRPC6-TRPC7 channels contribute to arginine vasopressin-induced cation current of A7r5 vascular smooth muscle cells.

The molecular identity of receptor-operated, nonselective cation channels (ROCs) of vascular smooth muscle (VSM) cells is not known for certain. Mammalian homologues of the Drosophila canonical transient receptor potential channels (TRPCs) are possible candidates. This study tested the hypothesis that heteromultimeric TRPC channels contribute to ROC current of A7r5 VSM cells activated by [Arg(8)]-vasopressin. A7r5 cells expressed transcripts encoding TRPC1, TRPC4beta, TRPC6, and TRPC7. TRPC4, TRPC6, and TRPC7 protein expression was confirmed by immunoblotting and association of TRPC6 with TRPC7, but not TRPC4beta, was detected by coimmunoprecipitation. The amplitude of arginine vasopressin (AVP)-induced ROC current was suppressed by dominant-negative mutant TRPC6 (TRPC6(DN)) but not TRPC5 (TRPC5(DN)) mutant subunit expression. These data indicate a role for TRPC6- and/or TRPC7-containing channels and rule a more complex subunit composition including TRPC1 and TRPC4. Increasing extracellular Ca(2+) concentration ([Ca(2+)](o)) from 0.05 to 1 mmol/L suppressed currents owing to native, TRPC7, and heteromultimeric TRPC6-TRPC7 channels, but not TRPC6 current, which was slightly enhanced. The relative changes in native and heteromultimeric TRPC6-TRPC7 current amplitudes for [Ca(2+)](o) between approximately 0.01 and 1 mmol/L were identical, but the changes in homomultimeric TRPC6 and TRPC7 currents were significantly less and greater, respectively, compared with the native channels. Taken together, the data provide biochemical and functional evidence supporting the view that heteromultimeric TRPC6-TRPC7 channels contribute to receptor-activated, nonselective cation channels of A7r5 VSM cells.

Arginine Vasopressin↗
PubMed2006

Essential role of nuclear medicine technology in tositumomab and 131I-tositumomab therapeutic regimen for non-Hodgkin's lymphoma.

Nuclear medicine technology has traditionally focused on diagnostic imaging, with therapeutics left mostly to other medical disciplines. However, after many years in development, radioimmunotherapy (RIT) has finally become a clinical reality in many nuclear medicine departments. The nuclear medicine technologist is a key player in the successful implementation of RIT. Delivery of a therapeutic regimen of tositumomab and (131)I-tositumomab provides a model for the technologist's roles and responsibilities in the developing field of RIT. This article examines the clinical rationale, logistic requirements, and imaging and dosimetry procedures required by this treatment regimen. Upon completion of this article, the reader should be able to describe the target patient population and identify the roles and responsibilities of various members of the treatment team. The reader will also gain an understanding of the treatment process, including drug administration, imaging, and therapeutic dose calculations.

Antibodies, Monoclonal↗
PubMed2004

Health risks of low dose ionizing radiation in humans: a review.

Radiobiologists have been struggling to estimate the health risks from low doses of radiation in humans for decades. Health risks involve not only neoplastic diseases but also somatic mutations that may contribute to other illnesses (including birth defects and ocular maladies) and heritable mutations that may increase the risk of diseases in future generations. Low dose radiation-induced cancer in humans depends on several variables, and most of these variables are not possible to correct for in any epidemiologic study. Some of the confounding factors include (i) interaction of radiation with other physical (UV light), chemical, and biological mutagens and carcinogens in a synergistic manner; (ii) variation in repair mechanisms that depend on dose; (iii) variation in sensitivity of bystander cells to subsequent radiation exposure that depends on whether they have been pre- or postirradiated; and (iv) variation in adaptive response that depends on radiation doses and protective substances (antioxidants). In our opinion, both the linear no-threshold-response and the threshold-response models might not be suitable in predicting cancer risk at low radiation doses in a quantitative sense. Low doses of ionizing radiation should not be considered insignificant for risks of somatic and heritable mutations and neoplastic and nonneoplastic diseases in humans.

Child↗
PubMed2003

ATP-sensitive K+ channels of vascular smooth muscle cells.

ATP-sensitive potassium channels (K(ATP)) of vascular smooth muscle cells represent potential therapeutic targets for control of abnormal vascular contractility. The biophysical properties, regulation and pharmacology of these channels have received intense scrutiny during the past twenty years, however, the molecular basis of vascular K(ATP) channels remains ill-defined. This review summarizes the recent advancements made in our understanding of the molecular composition of vascular K(ATP) channels with a focus on the evidence that hetero-octameric complexes of Kir6.1 and SUR2B subunits constitute the vascular K(ATP) subtype responsible for control of arterial diameter by vasoactive agonists.

Action Potentials↗
PubMed2003

Alpha-tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment: a review.

In 1982, it was established that alpha-tocopheryl succinate (alpha-TS) was the most effective form of vitamin E in comparison to alpha-tocopherol, alpha-tocopheryl acetate and alpha-tocopheryl nicotinate in inducing differentiation, inhibition of proliferation and apoptosis in cancer cells, depending upon its concentration. During the last two decades, several studies have confirmed this observation in rodent and human cancer cells in culture and in vivo (animal model). The most exciting aspect of this alpha-TS effect is that it does not affect the proliferation of most normal cells. In spite of several studies published on the anti-cancer properties of alpha-TS, the value of this form of vitamin E has not drawn significant attention from researchers and clinicians. Therefore, a critical review on the potential role of alpha-TS in the management of cancer is needed. In addition, such a review can also provide in-depth analysis of existing literature on this subject. alpha-TS treatment causes extensive alterations in gene expression; however, only some can be attributed to differentiation, inhibition of proliferation and apoptosis. alpha-TS also enhances the growth-inhibitory effect of ionizing radiation, hyperthermia, some chemotherapeutic agents and biological response modifiers on tumor cells, while protecting normal cells against some of their adverse effects. Thus, alpha-TS alone or in combination with dietary micronutrients can be useful as an adjunct to standard cancer therapy by increasing tumor response and possibly decreasing some of the toxicities to normal cells.

Animals↗
PubMed2002

Smooth muscle membrane potential modulates endothelium-dependent relaxation of rat basilar artery via myo-endothelial gap junctions.

The release of endothelium-derived relaxing factors, such as nitric oxide (NO), is dependent on an increase in intracellular calcium levels ([Ca(2+)](i)) within endothelial cells. Endothelial cell membrane potential plays a critical role in the regulation of [Ca(2+)](i) in that calcium influx from the extracellular space is dependent on membrane hyperpolarization. In this study, the effect of inhibition of vascular smooth muscle delayed rectifier K(+) (K(DR)) channels by 4-aminopyridine (4-AP) on endothelium-dependent relaxation of rat basilar artery to acetylcholine (ACh) was assessed. ACh-evoked endothelium-dependent relaxations were inhibited by N-(Omega)-nitro-L-arginine (L-NNA) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), confirming a role for NO and guanylyl cyclase. 4-AP (300 microM) also suppressed ACh-induced relaxation, with the maximal response reduced from approximately 92 to approximately 33 % (n = 11; P < 0.01). However, relaxations in response to exogenous NO, applied in the form of authentic NO, sodium nitroprusside or diethylamineNONOate (DEANONOate), were not affected by 4-AP treatment (n = 3-11). These data are not consistent with the view that 4-AP-sensitive K(DR) channels are mediators of vascular hyperpolarization and relaxation in response to endothelium-derived NO. Inhibition of ACh-evoked relaxation by 4-AP was reversed by pinacidil (0.5-1 microM; n = 5) or 18beta-glycyrrhetinic acid (18betaGA; 5 microM; n = 5), indicating that depolarization and electrical coupling of the smooth muscle to the endothelium were involved. 4-AP caused depolarization of both endothelial and vascular smooth muscle cells of isolated segments of basilar artery (mean change 11 +/- 1 and 9 +/- 2 mV, respectively; n = 15). Significantly, 18betaGA almost completely prevented the depolarization of endothelial cells (n = 6), but not smooth muscle cells (n = 6) by 4-AP. ACh-induced hyperpolarization of endothelium and smooth muscle cells was also reduced by 4-AP, but this inhibition was not observed in the combined presence of 4-AP and 18betaGA. These data indicate that 4-AP can induce an indirect inhibition of endothelium-dependent relaxation in the rat basilar artery by electrical coupling of smooth muscle membrane depolarization to the endothelium via myo-endothelial gap junctions.

4-Aminopyridine↗
PubMed2002

Mevastatin induces degeneration and decreases viability of cAMP-induced differentiated neuroblastoma cells in culture by inhibiting proteasome activity, and mevalonic acid lactone prevents these effects.

Statins with a closed-ring structure (mevastatin, lovastatin, and simvastatin) and with an open-ring structure (pravastatin and fluvastatin) are widely used in the human population to manage hypercholesterolemia. These statins may have neuroprotective or neurotoxic effects, but these effects remain controversial. We have utilized adenosine 3',5'-cyclic monophosphate-induced terminally differentiated murine neuroblastoma (NB) cells in culture as an experimental model to study the effect of statins. Results showed that mevastatin induced degenerative changes and reduced the viability of differentiated NB cells by inhibiting proteasome activity. Lactacystin, an established inhibitor of proteasome, also produced similar degenerative changes in these cells. In contrast, pravastatin neither affected the degeneration and viability of differentiated NB cells nor the proteasome activity. High-performance liquid chromatography (HPLC) analysis of the extract obtained from mevastatin-treated growth medium and differentiated cells revealed that about 50% of mevastatin is converted to an open-ring structure in the growth medium; however, differentiated cells did not convert any portion of mevastatin into an open-ring structure and accumulated only mevastatin with a closed-ring structure. Mevalonic acid lactone by itself did not affect the viability of differentiated NB cells or the proteasome activity, but it completely prevented mevastatin-induced degeneration and decreased viability by reducing the uptake of mevastatin and by blocking its action on proteasome activity. Mevalonic acid failed to prevent lactacystin-induced degeneration and inhibition of proteasome activity. Our results suggest that mevastatin could act as a neurotoxic agent or neuroprotective agent, depending upon the extent of its hydrolysis to an open-ring structure and the level of mevalonic acid.

Animals↗
PubMed2002

Protein kinase C modulation of recombinant ATP-sensitive K(+) channels composed of Kir6.1 and/or Kir6.2 expressed with SUR2B.

The molecular identity of smooth muscle ATP-sensitive K(+) channels (K(ATP)) is not established with certainty. Patch clamp methods were employed to determine if recombinant K(ATP) channels composed of Kir6.1 and SUR2B subunits expressed by human embryonic kidney (HEK293) cells share an identical modulation by protein kinase C (PKC) with the vascular K(NDP) subtype of K(ATP) channel. The open probability of Kir6.1/SUR2B channels was determined before and after sequential exposure to pinacidil (50 microM) and the combination of pinacidil and phorbol 12,13-dibutyrate (PdBu; 50 nM). Treatment with PdBu caused a decline in channel activity, but this was not seen with an inactive phorbol ester, 4 alpha-phorbol 12,13-didecanoate (PdDe; 50 nM). Angiotensin II (0.1 microM) induced a similar inhibition of Kir6.1/SUR2B channels in cells expressing angiotensin AT(1) receptors. The effects of PdBu and angiotensin II were blocked by the PKC inhibitor, chelerythrine (3 microM). Purified PKC inhibited Kir6.1/SUR2B activity (in 0.5 mM ATP/ 0.5 mM ADP), and the inhibition was blocked by a specific peptide inhibitor of PKC, PKC(19-31). In contrast, PdBu increased the activity of recombinant K(ATP) channels composed of Kir6.2 and SUR2B, or the combination of Kir6.1, Kir6.2 and SUR2B subunits. The results indicate that the modulation by PKC of Kir6.1/SUR2B, but not Kir6.2/SUR2B or Kir6.1-Kir6.2/SUR2B channel gating mimics that of native vascular K(NDP) channels. Physiological inhibition of vascular K(ATP) current by vasoconstrictors which utilize intracellular signalling cascades involving PKC is concluded to involve the modulation of K(NDP) channel complexes composed of four Kir6.1 and their associated SUR2B subunits.

ATP-Binding Cassette Transporters↗
PubMed2002

D-alpha-tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells.

OBJECTIVE: The purpose of this study was to measure and compare the effect of d-alpha-tocopheryl succinate (alpha-TS) in modifying radiation-induced chromosomal damage in human normal cells and cancer cells in culture. METHODS: Three human normal fibroblast cell lines (GM2149, AG1522 and HF19) and three human cancer cell lines, cervical cancer (HeLa) and ovarian carcinoma cells (OVGI and SKOV3) were treated with alpha-TS (37.6 microM) 20 hours before 100 cGy gamma-irradiation. After 30 minutes of irradiation, colcemid was added and cells were fixed. One hundred randomly selected metaphase cells were scored for the presence of chromatid gaps and breaks. To study the cellular accumulation of alpha-TS. cells were incubated in the presence of alpha-TS (18.8 and 37.6 microM) for 24 hours, and alpha-TS was extracted with hexane using a-tocopheryl acetate as an internal standard. The levels of alpha-TS were determined by HPLC. RESULTS: Results showed that alpha-TS induced chromosomal damage in both human cervical cancer cells and ovarian cancer cells, but not in human normal fibroblasts in culture. In addition, alpha-TS enhanced the level of radiation-induced chromosomal damage in cancer cells, but it protected normal cells against such damage. Both cancer cells and normal cells accumulated similar levels of alpha-TS, suggesting that increased sensitivity of cancer cells to alpha-TS is acquired during transformation. CONCLUSION: The use of alpha-TS during radiation therapy may improve the efficacy of radiation therapy by enhancing tumor response and decreasing some of the toxicities on normal cells.

Cell Line↗
PubMed2002

Risk factors for Alzheimer's disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment.

The etiology of Alzheimer's disease (AD) is not well understood. Etiologic factors, chronic inflammatory reactions, oxidative and nitrosylative stresses and high cholesterol levels are thought to be important for initiating and promoting neurodegenerative changes commonly found in AD brains. Even in familial AD, oxidative stress plays an important role in the early onset of the disease. Mitochondrial damage and proteasome inhibition represent early events in the pathogenesis of AD, whereas increased processing of amyloid precursor protein (APP) to beta-amyloid (Abeta) fragments (Abeta(40) and Abeta(42)) and formation of senile plaques and neurofibrillary tangles (NFTs) represent late events. We propose a hypothesis that in idiopathic AD, epigenetic components of neurons such as mitochondria, proteasomes and post-translation protein modifications (processing of amyloid precursor protein to beta-amyloid and hyperphosphorylation of tau), rather than nuclear genes, are the primary targets for the action of diverse groups of neurotoxins. Based on epidemiologic, laboratory and limited clinical studies, we propose that a combination of non steroidal anti-inflammatory drugs (NSAIDs) and appropriate levels and types of multiple micronutrients, including antioxidants, may be more effective than the individual agents in the prevention, and they, in combination with a cholinergic agent, may be more effective in the treatment of AD than the individual agents alone. In addition, agents, which can prevent formation of plaques or dissolve these plaques may further enhance the efficacy of our proposed treatment strategy.

Alzheimer Disease↗
PubMedDate not supplied

Myogenic regulation of arterial diameter: role of potassium channels with a focus on delayed rectifier potassium current.

The phenomenon of myogenic constriction of arterial resistance vessels in response to increased intraluminal pressure has been known for over 100 years, yet our understanding of the molecular mechanisms involved remains incomplete. The focus of this paper concerns the potassium (K+) channels that provide a negative feedback control of the myogenic depolarization of vascular smooth muscle cells that is provoked by elevations in intraluminal pressure, and specifically, the contribution of delayed rectifier (KDR) channels. Our knowledge of the important role played by KDR channels, as well as their molecular identity and acute modulation via changes in gating, has increased dramatically in recent years. Several lines of evidence point to a crucial contribution by heteromultimeric KV1 subunit-containing KDR channels in the control of arterial diameter and myogenic reactivity, but other members of the KV superfamily are also expressed by vascular myocytes, and less is known concerning their specific functions. The effect of pharmacological modulation of KDR channels is discussed, with particular reference to the actions of anorexinogens on KV1- and KV2-containing KDR channels. Finally, the need for a greater understanding of the mechanisms that control KDR channel gene expression is stressed in light of evidence indicating that there is a reduced expression of KDR channels in diseases associated with abnormal myogenic reactivity and vascular remodelling.

Animals↗