Two Cases of Melanosis Ilei Developed after Long-standing Charcoal Ingestion / 대한소화기내시경학회지

Melanosis ilei is an extremely rare condition in which black pigment, consisted of aluminum, magnesium, or silicon, accumulate in the terminal ileal mucosa. Medical treatment with charcoal enhances the neutralization of the toxic material and elimination of many drugs. In addition, it has been used as a traditional remedy in some oriental countries to relieve chronic diarrhea, abdominal pain, or acute enterocolitis, which is made up carbon, oxygen, aluminum, magnesium, silicon, calcium, and palladium. Two patients taking the charcoal for a long time underwent a colonoscopy to evaluate chronic diarrhea or abdominal pain. The colonoscopy revealed a normal colonic mucosa and multiple geographic black-pigmented mucosal changes at the terminal ileum. Therefore, it was assumed that melanosis ilei can develop in patients with long-standing charcoal ingestion. To the best of our knowledge, this is the first case of melanosis ilei associated with the ingestion of charcoal.

Comparative Analysis of Food Habits and Bone Density Risk Factors between Normal and Risk Women Living in the Seoul Area / 대한지역사회영양학회지

This study was carried out to compare bone density risk factors affecting women's BMD, and to examine the relationship age, lifestyle and dietary habits for bone health by physical measurement and questionnaires. The subjects of this study were 194 women living in the Seoul area. When the subjects were divided into normal and risk groups, BMD, height, weight, BMI, total body water, soft lean mass, fat free mass, protein, mineral, body-fat of normal group were much higher than those of the risk group. The breakfast eating rate of the normal group was much higher than that of the risk group, walking time was significantly longer and exercise was more (p < 0.05). The normal group had more frequent intakes of tunas, squid, radishes, the green parts of radish, cucumbers, carrots and Iucchinis, tomatoes, and grapes than the risk group (p < 0.01 or p < 0.05). In conclusion, breakfast eating, exercise, intakes of some foods such as anchovies, radishes, carrots, zucchinis and tomatoes were significantly important factor to prevent bone density risk.

Analysis of Factors Affecting Bone Mineral Density with Different Age among Adult Women in Seoul Area / 대한지역사회영양학회지

Weight control diets induce reducing women' bone mineral density (BMD) that has a close relationship to risk in osteoporosis. This study was carried out to identify bone density risk factors affecting women's BMD, and to examine the relationship age, lifestyle and dietary habits for bone health by physical measurement and questionnaies. The subjects of this study were 194 women living on the Seoul area. When the subjects were divided into 4 age groups, BMI was the highest in the 50 years group (24.8) and the lowest in the 20 years group (21.63). Average T-score, which is BMD of forearm bone and calcaneus was the highest in the 40 years (.0.07) and the lowest in the 20 years (.0.59). The rate of eating breakfast was shown significantly higher in the 50 years group than that in the younger group. The frequencies of eating out, fried food intakes, and alcohol drinks were shown significantly different by age (p < 0.01). In conclusion, the risk rate of BMD was high in the 20syears and 50 years groups. It may due to the 20s' weight-control diet. Breakfast eating, exercise, intakes of anchovies, radishes, carrots, zucchinis and tomatoes were significantly important factors to prevent bone density risk.

The Effect of Epicatechin on the High Glucose-induced TSP-1 Expression and MMP-2 Activity in Rat Vascular Smooth Muscle Cells / 대한내분비학회지

BACKGROUND: The incidence of atherosclerosis is well correlated with the progression of type 2 diabetes mellitus. High plasma glucose in uncontrolled diabetic patients evokes many vascular complications such as atherosclerosis. Specifically, high glucose was reported to induce thrombospondin-1 (TSP-1), which activates matrix metalloproteinase-2 (MMP-2) and leads to the invasion of vascular smooth muscle cells (VSMCs) into the intima. Catechins with antioxidant effects are known to inhibit MMP-2 activity. Therefore, this study was aimed at revealing the effect of epicatechin, one of catechins, on high glucose-induced TSP-1 and the invasiveness of VSMCs. METHODS: VSMCs were primarily isolated from Sprague-Dawley rat aorta. The VSMCs were incubated with different doses (30, 100 and 300 micrometer) of epicatechin under high glucose concentration (30 mM). The TSP-1 protein and mRNA expressions were analyzed by performing Western blotting and Northern blot analyses, respectively. RT-PCR was performed to observe the MMP-2 mRNA expression. Gelatin zymography was performed for the measurement of MMP-2 activity. Invasion assays were performed to evaluate the invasiveness of VSMCs. RESULTS: Epicatechin inhibited the high glucose-induced TSP-1 expression and the MMP-2 activity in a dose-dependent manner. Also, epicatechin inhibited the high glucose-induced invasiveness of VSMCs across the matrix barrier in a dose-dependent fashion. CONCLUSION: Collectively, epicatechin may prevent the high glucose-induced proliferation and invasion of VSMCs by inhibiting the TSP-1 expression and the MMP-2 activity. Therefore, epicatechin appears to play a protective role in the development of atherosclerosis.

The Effect of Epicatechin on the High Glucose-induced TSP-1 Expression and MMP-2 Activity in Rat Vascular Smooth Muscle Cells / 대한내분비학회지

BACKGROUND: The incidence of atherosclerosis is well correlated with the progression of type 2 diabetes mellitus. High plasma glucose in uncontrolled diabetic patients evokes many vascular complications such as atherosclerosis. Specifically, high glucose was reported to induce thrombospondin-1 (TSP-1), which activates matrix metalloproteinase-2 (MMP-2) and leads to the invasion of vascular smooth muscle cells (VSMCs) into the intima. Catechins with antioxidant effects are known to inhibit MMP-2 activity. Therefore, this study was aimed at revealing the effect of epicatechin, one of catechins, on high glucose-induced TSP-1 and the invasiveness of VSMCs. METHODS: VSMCs were primarily isolated from Sprague-Dawley rat aorta. The VSMCs were incubated with different doses (30, 100 and 300 micrometer) of epicatechin under high glucose concentration (30 mM). The TSP-1 protein and mRNA expressions were analyzed by performing Western blotting and Northern blot analyses, respectively. RT-PCR was performed to observe the MMP-2 mRNA expression. Gelatin zymography was performed for the measurement of MMP-2 activity. Invasion assays were performed to evaluate the invasiveness of VSMCs. RESULTS: Epicatechin inhibited the high glucose-induced TSP-1 expression and the MMP-2 activity in a dose-dependent manner. Also, epicatechin inhibited the high glucose-induced invasiveness of VSMCs across the matrix barrier in a dose-dependent fashion. CONCLUSION: Collectively, epicatechin may prevent the high glucose-induced proliferation and invasion of VSMCs by inhibiting the TSP-1 expression and the MMP-2 activity. Therefore, epicatechin appears to play a protective role in the development of atherosclerosis.

A Case of Gastric Adenocarcinoma Presenting as a Submucosal Tumor / 대한소화기내시경학회지

Neoplasms of the stomach can originate from both epithelial and subepithelial cells. These two types of tumors have different morphological characteristics according to their origin including the mucosal surface texture and contour of the mass in endoscopic examination. However, on rare occasions, neoplasms of an epithelial origin manifest the features of a submucosal tumor on a gross examination, and require additional and more invasive approaches, such as a strip biopsy, computed tomography, and endosonography, to define their nature. We encountered a case of a gastric adenocarcinoma in a 44 year-old woman, which was initially considered to be submucosal tumor by the endoscopic examination and was finally diagnosed after resecting the tumor.

Role of Protein kinase C in Desensitization of Somatostatin-induced Calcium Signalling in NG108-15 Cells / 대한내분비학회지

BACKGROUND: Activation of G-protein coupled-somatostatin receptors induces the release of calcium from inositol 1, 4, 5-trisphosphate-sensitive intracelluar stores. G-protein-coupled receptor signaling decreases with prolonged exposure to an agonist. SEBJECTS and METHODS: Fura-2-based digital Ca2+ imaging was used to study the effects of prolonged exposure to an agonist on the somatostatin-induced intracellular Ca2+ concentration([Ca2+]i) increases in NG108-15 cells, which were differentiated with CO2-independent medium and 10micrometer forskolin. RESULTS: Exposure to somatostatin(1micrometer) for 30 min completely desensitized the NG108-15 cells to a second somatostatin-induced response. The cells recovered gradually over 20 min following washout of the somatostatin. The desensitization was not due to depletion of the intracellular Ca2+ stores, and pretreatment for 30 min with bradykinin(100nM), which activates phospholipase C, or DADLE(D-Ala2-D-Leu5 enkephalin, 1microM), which activates phospholipase C, failed to cross-desensitize the somatostatin-evoked [Ca2+]i increases. Treatment with 8-cpt-cAMP(0.1mM) for 30min did not influence the somatostatin-induced[Ca2+]i increases. Phorbol 12, 13-dibutyrate(PdBu, 1microM) blocked the response completely. Down-regulation of PKC due to 24 h exposure of PdBu (1microM) inhibited the somatostatin-induced desensitization. CONCLUSION: Prolonged exposure of somatostatin to NG108-15 cells desensitized the somatostatin-induced release of Ca2+ from the intracelluar store, with protein kinase C also involved in the desensitization.

The Medical Science Research and Development Supported by the Korea Science and Engineering Foundation

This study examined ways of promoting research in the medical sciences by evaluating trends in research funding, and the present status of research funding by the Korea Science and Engineering Foundation (KOSEF). This study analyzed statistics from KOSEF from 1978 to 2003 to examine support for research. In medical science field, group-based programs receive more funding than do individual-based programs. The proportion of research funds allocated to the medical sciences has increased markedly each year. Researchers in the medical sciences have submitted more articles to Science Citation Index (SCI) journals than to non-SCI journals, relative to other fields. Researchers supported by the Mission-Oriented Basic Grants program have published the majority of these papers, followed by those supported by the Programs for Leading Scientists, Regional Scientists, Leading Women Scientists, Young Scientists, and Promising Women Scientists, in that order. Funding by KOSEF reflects many decades of government support for research and development, the development and maintenance of necessary infrastructure, and the education and training of medical scientists.

Efffects of Fluoxetine on ATP-induced Calcium Signaling in PC12 Cells

Fluoxetine, a widely used anti-depressant compound, has several additional effects, including blockade of voltage-gated ion channels. We examined whether fluoxetine affects ATP-induced calcium signaling in PC12 cells by using fura-2-based digital calcium imaging and assay for [3H]-inositol phosphates (IPs). Treatment with ATP (100microM) for 2 min induced [Ca2+]i increases. The ATP-induced [Ca2+]i increases were significantly decreased by removal of extracellular Ca2+ and treatment with the inhibitor of endoplasmic reticulum Ca2+ ATPase thapsigargin (1microM). Treatment with fluoxetine for 5 min blocked the ATP-induced [Ca2+]i increase concentration-dependently. Treatment with fluoxetine (30microM) for 5 min blocked the ATP-induced [Ca2+]i increase following removal of extracellular Ca2+ and depletion of intracellular Ca2+ stores. While treatment with the L-type Ca2+ channel antagonist nimodipine for 10 min inhibited the ATP-induced [Ca2+]i increases significantly, treatment with fluoxetine alone blocked the ATP-induced responses. Treatment with fluoxetine also inhibited the 50 mM K+-induced [Ca2+]i increases completely. However, treatment with fluoxetine did not inhibit the ATP-induced [3H]-IPs formation. Collectively, we conclude that fluoxetine inhibits ATP-induced [Ca2+]i increases in PC12 cells by inhibiting both an influx of extracellular Ca2+ and a release of Ca2+ from intracellular stores without affecting IPs formation.

Effect of Fluoxetine on the Induction of Long-term Potentiation in Rat Frontal Cortex

Serotonin (5-hydroxytroptamine, 5-HT) has been shown to affect the induction of long-term potentiation (LTP) in the cortex such as the hippocampus, the visual cortex and the prefrontal cortex. Fluoxetine, as a selective serotonin reuptake inhibitor, is used in the management of a wide variety of psychological diseases. To study the effect of fluoxetine on the induction of LTP, we recorded the field potential in layer II/III of the frontal cortex from 3-wk-old. LTP was induced in horizontal input by theta burst stimulation (TBS). TBS with two-folds intensity of the test stimulation induced LTP, which was blocked by application of D-AP5 (50microM), an NMDA receptor antagonist. Whereas bath application of 5-HT (10microM) inhibited the induction of LTP, treatment with the 5-HT depleting agent, para-chloroamphetamine (PCA, 10microM), for 2hr did not affect the induction of LTP. Bath application of fluoxetine (1, 3, and 10microM) suppressed the induction of LTP in concentration-dependent manner, however, fluoxetine did not inhibit the induction of LTP in 5-HT-depleted slices. These results indicate that fluoxetine may inhibit the induction of LTP by modulating serotonergic mechanism in the rat frontal cortex.

Comparison of Postoperative Nausea and Vomiting between Gynecologic Surgery and Cesarean-Section during Intravenous Patient-Controlled Analgesia with Fentanyl / 대한마취과학회지

BACKGROUND: The purpose of this study was to compare the incidence of postoperative nausea and vomiting (PONV) in patients undergoing major gynecologic surgery with those undergoing Cesarean-section during intravenous patient-controlled analgesia (PCA). METHODS: Seventy two patients received general anesthesia with enflurane. Group 1 patients underwent major gynecologic surgery, and group 2 patients were parturients who underwent Cesarean-section. Postoperatively, fentanyl was continuously infused i.v. using Accufuser PLUS (basal, 2 ml/h; bolus, 0.5 ml; lockout interval, 15 min) containing fentanyl 25microgram/kg in saline. PONV was evaluated at 6, 12, 24 and 36 h after starting continuous infusion and compared in the two groups. RESULTS: The incidence of PONV was significantly lower in group 2 (14%) than in group 1 (67%) (P < 5). CONCLUSIONS: Our results show that the incidence of PONV was lower for Cesarean-section than for gynecologic surgery.

Comparative Analysis of Phospholipase D2 Localization in the Pancreatic Islet of Rat and Guinea Pig

To examine the localization pattern of phospholipase D2 (PLD2) in the pancreatic islet (the islet of Langerhans) depending on species, we conducted a morphological experiment in the rat and guinea pig. Since individual islets display a typical topography with a central core of B cell mass and a peripheral boundary of A, D, and PP cells, double immunofluorescent staining with a panel of antibodies was performed to identify PLD2-immunoreactive cells in the islets PLD2 immunoreactivity was mainly present in A and PP cells of the rat pancreatic islets. And yet, in the guinea pig, PLD2 immunoreactivity was exclusively localized in A cells, and not in PP cells. These findings suggest a possibility that PLD2 is mainly located in A cells of rodent pancreatic islets, and that the existence of PLD2 in PP cells is not universal in all species. Based on these results, it is suggested that PLD2 may play a significant role in the function of A and/or PP cells via a PLD-mediated signaling pathway.

Altered Cholecystokinin-induced Calcium Signal in Streptozotocin-induced Diabetic Rat Pancreatic Acini / 대한소화기학회지

BACKGROUND/AIMS: Pancreatic acini of streptozotocin (STZ)-induced diabetic rats release amylase less than normal acini on cholecystokinin (CCK) stimulation. Pancreatic enzyme secretion has been closely related to the intracellular calcium concentration ([Ca2+]i) of the acinar cell. In the present study, sequential changes of the intracellular calcium signal which probably underlie the altered enzyme secretion in response to CCK-8 were investigated using pancreatic acini from diabetic rats. METHODS: Diabetic rats were prepared by single intravenous injection of STZ (70 mg/kg). Stimulating experiments with CCK-8 were performed 7 days later. Pancreatic acini were isolated by collagenase digestion. Amylase release and [Ca2+]i were measured by colorimethod and calcium imaging, respectively. The geometry of intracellular calcium signal was analyzed. RESULTS: Normal acini exhibited concentration-dependent [Ca2+]i increase and regular oscillatory calcium signal on CCK-8 stimulation. Amylase release was also concentration-dependent. However, diabetic acini showed significantly less [Ca2+]i increase, prolonged time to peak [Ca2+]i, decreased calcium spikes number, and decreased amylase release compared with normal acini. The decreased [Ca2+]i in diabetic acini was restored significantly by insulin treatment. CONCLUSIONS: Relatively decreased amylase release in diabetic pancreatic acini in response to CCK, appears to be associated with altered calcium signal due to insulin deficiency.

Inhibition by Norfluoxetine, the Major Metabolite of Fluoxetine, of Voltage-Gated K+ Channels in Primary Cultured Rat Hippocampal Neurons / 대한마취과학회지

BACKGROUND: Fluoxetine (Prozac), a selective serotonin reuptake inhibitor, has been shown to be effective in the treatment of depression. We investigated the effects of norfluoxetine, the major active metabolite of fluoxetine, on voltage-gated K+ currents in primary cultured hippocampal neurons, and determined the potency and modes of actions of norfluoxetine. METHODS: Voltage-gated K+ currents were studied in primary cultured rat hippocampal neurons using the whole-cell configuration of the patch-clamp technique. Electrophysiological recordings were done in hippocampal neurons between 5-10 days in culture. Transient A-type K+ currents (KA) and delayed-rectifier K+ (KDR) currents were isolated from whole-cell K+ currents using a pulse protocol. RESULTS: Norfluoxetine accelerated the decay rate of whole-cell K+ currents, and thus decreased the current amplitude at the end of a pulse in a concentration-dependent manner. Norfluoxetine inhibited KA and KDR currents in a concentration-dependent manner with IC50's of 0.93 and 0.70micro M, respectively. Norfluoxetine also reduced the areas of KA currents and the steady-state KDR current over the range of test potentials, and the reduction was voltage-dependent (greater increase at more positive potentials). From the onset of the fractional block of KA currents by norfluoxetine during the initial 40 ms of a clamp step, we calculated k1 = 53.26/micro M.s for the association rate constant, and k2 = 70.24/s for the dissociation rate constant. The resulting apparent KD was 1.32micro M, which is similar to the IC50 value obtained from the concentration-response curve. CONCLUSIONS: Our results indicate that norfluoxetine, the major metabolite of fluoxetine, at therapeutic levels, produces a concentration- and voltage-dependent inhibition of KA and KDR currents in primary cultured hippocampal neurons. These effects could perturb the neuronal excitability in the hippocampus, and may contribute to the therapeutic antidepressant action of fluoxetine.

Electrophysiological and Morphological Classification of Inhibitory Interneurons in Layer II/III of the Rat Visual Cortex

Interneuron diversity is one of the key factors to hinder understanding the mechanism of cortical neural network functions even with their important roles. We characterized inhibitory interneurons in layer II/III of the rat primary visual cortex, using patch-clamp recording and confocal reconstruction, and classified inhibitory interneurons into fast spiking (FS), late spiking (LS), burst spiking (BS), and regular spiking non-pyramidal (RSNP) neurons according to their electrophysiological characteristics. Global parameters to identify inhibitory interneurons were resting membrane potential (> -70 mV) and action potential (AP) width ( 200 M omega) and the shorter P-T time (< 20 msec) than those of regular spiking pyramidal neurons. Confocal reconstruction of recorded cells revealed characteristic morphology of each subtype of inhibitory interneurons. Thus, our results provide at least four subtypes of inhibitory interneurons in layer II/III of the rat primary visual cortex and a classification scheme of inhibitory interneurons.

Altered Secretory Pattern of Pancreatic Enzymes and Gastrointestinal Hormones in Streptozotocin-induced Diabetic Rats

This study was performed to investigate the pancreatic exocrine dysfunction in streptozotocin- induced diabetic rats. Changes in pancreatic enzymes secretion and in pancreatic enzymes content were observed. The output and the tissue content of amylase were significantly reduced in diabetic rats, while the output and the content of lipase were increased. Plasma secretin and cholecystokinin (CCK) concentrations of diabetic rats were significantly increased compared to those of normal rats. The altered pancreatic exocrine function was abolished by the exogenous insulin administration. The exogenous insulin also restored the increased plasma secretin and CCK concentrations. From the above results, it is suggested that, in streptozotocin-induced diabetic rats, anticoordinated changes in pancreatic enzymes secretion as well as pancreatic enzymes content are attributable to insulin deficiency and that the insulin deficiency is responsible for the increased plasma concentrations of both secretin and CCK. However, it is not clear whether the elevated plasma secretin and CCK concentrations played a direct role in changes of pancreatic exocrine function.

The Morphologic Changes of Parvalbumin- Immunoreactive Interneurons of the Dentate Gyrus in Kainate-Treated Mouse Hippocampal Slice Culture Epilepsy Model

PURPOSE: Loss of hippocampal interneurons in dentate gyrus has been reported in patients with severe temporal lobe epilepsy and in animals treated with kainic acid(KA). Interneurons contain Ca2+- binding protein parvalbumin(PV). The effects of kainic acid on parvalbumin-immunoreactive (PV-IR) interneurons in dentate gyrus were investigated in organotypic hippocampal slice cultures. METHODS: Cultured hippocampal slices from postnatal day nine C57/BL6 mice were exposed to 10 muM KA, and were observed at 0, 8, 24, 48, 72 hours after a one hour KA exposure. Neuronal injury was determined by morphologic changes of PV-IR interneuron in dentate gyrus. RESULTS: Transient(1 hour) exposure of hippocampal explant cultures to KA produced marked varicosities in dendrites of PV-IR interneuron in dentate gyrus and the shaft of interbeaded dendrite is often much thinner than those in control. The presence of varicosities in dendrites was reversible with KA washout. The dendrites of KA treated explants were no longer beaded at 8, 24, 48 and 72 hours after KA exposure. The number of cells in PV-IR interneurons in dentate gyrus was decreased at 0, 8 hours after exposure. But there was no significant difference in 24, 48 and 72 hours recovery group compared with control group. CONCLUSIONS: The results suggested that loss of PV-IR interneurons in dentate gyrus is transient, and is not accompanied by PV-IR interneuronal cell death.

Oxygen-Dependent and -Independent Regulation of HIF-1alpha

Hypoxia-inducible factor-1 (HIF-1) is composed of HIF-1alpha and HIF-1beta, and is a master regulator of oxygen homeostasis, playing critical roles in physiological and pathological processes. Normally, the formation and transcriptional activity of HIF-1 depend on the amount of HIF-1alpha, and the expression of HIF-1alpha is tightly controlled by the cellular oxygen tension. Recent progress in the study of its regulation mechanism provided clues as to how HIF-1alpha is regulated by oxygen. It appears that HIF-1alpha is not regulated only by the oxygen tension, but also by various other stimuli, such as transition metals, nitric oxide, reactive oxygen species, growth factors, and mechanical stresses. In this review, we summarize the oxygen-dependent and -independent regulation of HIF-1alpha, and the respective physiological and pathological meanings.

Acute Dystonia by Droperidol during Intravenous Patient-Controlled Analgesia in Young Patients

Patient-controlled analgesia (PCA) is an important means for postoperative analgesia with parenteral opioid. However, postoperative nausea and vomiting (PONV) remains a major problem with a PCA system. Droperidol is used in PCA to prevent PONV. Extrapyramidal reactions by droperidol are, however, occasionally induced. We describe two cases of severe extrapyramidal hypertonic syndrome with an intravenous administration of droperidol in PCA in young patients, following orthopedic surgery.

Differential modulation of exogenous and endogenous adenosine-induced coronary vasodilation by dipyridamole

Some recent investigations revealed that vasodilatory action of adenosine is mainly not mediated by surface A2 receptor and suggested the existence of an intracellular action site. In the present study, we tried to differentiate intracellular from extracellular site of adenosine action in the regulation of coronary flow. In perfused rabbit hearts, concentration-response curve of coronary flow to exogenous adenosine was constructed in the presence or absence of dipyridamole, an inhibitor of transmembrane purine transport. Inhibition of cellular adenosine uptake by dipyridamole suppressed the increase of flow rate while enhancing the decrease in heart rate induced by exogenous adenosine. In another series of experiments, perfused rabbit hearts were subjected to energy deprivation in order to increase the production of endogenous adenosine. Energy deprivation along with dipyridamole administration resulted in higher coronary flow rate. Lower perfusate adenosine concentration was observed along with higher tissue adenosine content in this group. These results implied that coronary flow rate is determined not by interstitial adenosine concentration but by intracellular activity of adenosine. To confirm the effects of dypiridamole in vivo, direct measurement of interstitial adenosine concentration by mycrodialysis along with the assay of intracellular adenosine content was performed after intranenous dipyridamole administration. After dipyridamole infusion, intracellular adenosine content was markedly increased while interstitial adenosine concentration was not altered. In another series of experiments, the right shift of concentration-response curve of adenosine-induced vasodilation by 8-phenyltheophilline, a representative adenosine receptor antagonist, was mostly abolished by prior administration of prazosin, indicating that the influence of 8-PT on the adenosine action is not attributed to the inhibition of A2 receptor but related to the suppression of alpha-adrenoceptor activation. From these results, we concluded that adenosine acts intracellularly to regulate the coronary blood flow.