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Biomedical subjects

S N Yang

Publications and source records attributed to S N Yang.

At least 19 recordsLinked to original sources
PubMed2004

Early stage cervical cancer with negative pelvic lymph nodes: pattern of failure and complication following radical hysterectomy and adjuvant radiotherapy.

PURPOSE OF INVESTIGATION: The objective was to optimize the adjuvant treatment for patients with lymph node negative cervical cancer by analyzing patterns of failure and complications following radical hysterectomy and adjuvant radiotherapy. METHODS: From September 1992 to December 1998, 67 patients with lymph node negative uterine cervical cancer (FIGO stage distribution: 50 Ib. 17 IIa), who had undergone radical hysterectomy and postoperative adjuvant radiotherapy with a minimum of three years of follow-up were evaluated. All patients received 50-58 Gy of external radiation to the lower pelvis followed by two sessions of intravaginal brachytherapy with a prescribed dose of 7.5 Gy to the vaginal mucosa. For 21 patients with lymphovascular invasion, the initial irradiation field included the whole pelvis for 44 Gy. The data were analyzed for actuarial survival (AS), pelvic relapse-free survival (PRFS), distant metastasis-free survival (DMFS), and treatment-related complications. Multivariate analysis was performed to assess the prognostic factors. RESULTS: The respective five-year AS, PRFS, and DMFS for the 67 patients were 79%, 93% and 87%. Multivariate analysis identified two prognostic factors for AS: bulky tumor vs non-bulky tumor (p = 0.003), positive resection margin (p = 0.03). The independent prognostic factors for DMFS was bulky tumor (p = 0.003), while lymphatic permeation showed marginal impact to DMFS (p = 0.08). The incidence of RTOG grade 1-4 rectal and non-rectal gastrointestinal complication rates were 20.9% and 19.4%, respectively. The independent prognostic factor for gastrointestinal complication was age over 60 years (p = 0.047, relative risk 4.1, 95% CI 1.2 approximately 11.7). The incidence of non-rectal gastrointestinal injury for the patients receiving whole pelvic radiation and lower pelvic radiation was 28.5% and 15.2%, respectively (p = 0.25). CONCLUSION: For patients with lymph node negative cervical cancer following radical hysterectomy, adjuvant lower pelvic radiation appears to be effective for pelvic control. It is also imperative to intensify the strategies of adjuvant therapy for some subgroups of patients.

Adenocarcinoma↗
PubMed2002

Comparing whole body (18)F-2-deoxyglucose positron emission tomography and technetium-99m methylene diphosphonate bone scan to detect bone metastases in patients with breast cancer.

PURPOSE: At present, bone metastases are usually assessed using conventional technetium-99m methylene diphosphonate whole-body bone scan, which has a high sensitivity but a poor specificity. However, positron emission tomography with (18)F-2-deoxyglucose (FDG-PET) can offer superior spatial resolution and improved specificity. We attempted to evaluate the usefulness of FDG-PET for detecting bone metastases in breast cancer and to compare FDG-PET results with bone scan findings. PATIENTS: The study group comprised 48 patients with biopsy-proven breast cancer and suspected of having bone metastases who underwent bone scan and FDG-PET to detect the bone metastases. The final diagnosis of bone metastases was established by operative, histopathological findings or during a clinical follow-up longer than 1 year by additional radiographs or following FDG-PET/bone scan findings showing progressive widespread bone lesions. RESULTS: A total of 127 bone lesions including 105 metastatic and 22 benign bone lesions found by either FDG-PET or bone scan were evaluated. Using FDG-PET, 100 metastatic and 20 benign bone lesions were accurately diagnosed, and using bone scan 98 metastatic and 2 benign bone lesions were accurately diagnosed. The diagnostic sensitivity and accuracy of FDG-PET were 95.2% and 94.5%, and of bone scan were 93.3% and 78.7%, respectively. CONCLUSIONS: Our findings suggest that FDG-PET shows a similar sensitivity and a better accuracy than bone scan for detecting bone metastases in patients with breast cancer.

Adult↗
PubMed2001

Blockade of alpha1-adrenoceptors and cardiac depressant effect by a newly synthetic antihypertensive drug, DL-017 of quinazoline derivative.

The electromechanical effects of 3-[[4-(2-methoxy phenyl)piperazin-1-yl]methyl]-5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (DL-017), a newly synthesized quinazoline-derived antihypertensive agent, on mammalian cardiac tissues were evaluated. In driven canine Purkinje fibers, DL-017 decreased twitch tension, the maximal rate of upstroke of the action potential (Vmax), and intracellular Na+ activity (a(i)Na) in a concentration-dependent manner. The action potential duration was decreased in canine Purkinje fibers but increased in guinea pig papillary muscles. In guinea pig ventricular papillary muscles, phenylephrine in the presence of 1 microM propranolol increased the twitch tension in a concentration-dependent manner. At 10 microM, phenylephrine significantly decreased a(i)Na and shortened the action potential duration. DL-017 at 0.01 microM inhibited these phenylephrine-induced effects and shifted the concentration-dependent curve to the right. In sinoatrial nodes, DL-017 inhibited pacemaker activity, involving decreases in the slope of diastolic depolarization and Vmax and an increase in a delay of repolarization. These results suggest that, in addition to blockade of alpha1-adrenoceptors and Na+ channels, DL-017 reduces cardiac excitability and contractility in association with inhibition of slow inward Ca2+ and outward K+ channels. Since two order higher concentrations are required, the contribution of DL-017 to cardiac depressant from blockade of ionic channels seems to be less important when this compound is clinically used as an antihypertensive drug.

Action Potentials↗
PubMed2001

Cyclin-dependent kinase 5 promotes insulin exocytosis.

Cyclin-dependent kinase 5 (Cdk5) is widely expressed although kinase activity has been described preferentially in neuronal systems. Cdk5 has an impact on actin polymerization during neuronal migration and neurite outgrowth and deregulation of the kinase has been implicated in the promotion of neurodegeneration. Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function. In addition, Cdk5 phosphorylates munc-18 and synapsin I, two essential components of the exocytotic machinery. We have shown by reverse transcriptase-polymerase chain reaction, immunocytochemistry, and Western blotting that Cdk5 is present in the insulin-secreting pancreatic beta-cell. Subcellular fractionation of isolated beta-cells revealed a glucose-induced translocation of membrane-bound Cdk5 protein to lower density fractions. Inhibition of Cdk5 with roscovitine reduced insulin secretion with approximately 35% compared with control after glucose stimulation and with approximately 65% after depolarization with glucose and KCl. Capacitance measurements performed on single beta-cells that expressed a dominant-negative Cdk5 mutant showed impaired exocytosis. The effect on exocytosis by Cdk5 appeared to be independent of changes in free cytoplasmic Ca(2+) concentration. Taken together these results show that Cdk5 is present in beta-cells and acts as a positive regulator of insulin exocytosis.

Actins↗
PubMed2001

Synergistic apoptosis induced by bacterial endotoxin lipopolysaccharide and high glucose in rat microglia.

The present study investigates whether bacterial lipopolysaccharide (LPS) in the presence of increased levels of glucose induced synergistic cytotoxicity in primary cultured microglia. Significant cytotoxicity was only observed while the concentrations of LPS were increased to 10 microg/ml. D-glucose concentration-dependently (25-125 mM) generated cytotoxicity. Synergistic apoptosis of microglia was seen by LPS in the presence of increased levels of D-glucose. This synergistic cytotoxicity was attenuated by the use of superoxide dimutase and catalase, suggesting the involvement of oxidative free radicals. Collectively, the present results suggest that increased ambient levels of glucose rendered microglia vulnerable to LPS insults, and led to a synergistic apoptosis. The findings here may be important in certain patho-physiological implications in which hyperglycemia exacerbated the ambient functions contributed by microglia, and may provide new insight into a novel therapeutic intervention.

Animals↗
PubMed2001

Eye movements during reading: a theory of saccade initiation times.

As people read continuous text, on occasional single eye fixations the text was replaced by one of six alternate stimulus patterns. Frequency distributions of the durations of these fixations were used to test predictions from four types of theories of saccadic eye movement control. Contrary to current cognitive theories, cognitive influences appeared to delay saccades rather than trigger them. Two saccade disruption times were identified, suggesting the existence of three distributions of saccades, labeled early, normal and late. The Competition-inhibition theory, an enhanced version of Findlay and Walker's (1999) theory, is proposed to account for eye movement control during reading.

Adult↗
PubMed2001

Temperature-dependent separation of a delayed-onset long-lasting enhancement mediated by coactivation of NMDA and metabotropic glutamate receptors following a transient exposure of extracellular high Ca(2+).

Transient increases in the concentration of extracellular Ca(2+) play an essential role in various physiological and/or pathological implications. Here the effect of low temperatures on synaptic transmission modulated by a brief increase in extracellular high Ca(2+) was studied in CA1 area of hippocampal slices from hamsters. A high Ca(2+) pulse (4.5 mM) induced a long-lasting enhancement at 25, 20, or 17 degrees C, but not at 15 degrees C. While the temperature was lowered to 17 degrees C, the overall expression of synaptic responses following a high Ca(2+) pulse was separated into two sequential enhanced components: an initial component (approximately 30-40 min in duration), followed by a delayed-onset component that was sustained throughout the remainder of the experiment. Application of 100 microM D-2-amino-5-phosphonovalerate, a selective antagonist of N-methyl-D-asparate receptors, or (RS)-alpha-Methyl-4-carboxyphenylglycine, a selective antagonist of metabotropic glutamate (mGlu) receptors, during a high Ca(2+) pulse at 17 degrees C blocked the development of the delayed-onset enhanced component without affecting the initial enhanced component significantly. In contrast, the application of D-2-amino-5-phosphonovalerate or (RS)-alpha-Methyl-4-carboxyphenylglycine immediately after a high Ca(2+) pulse at 17 degrees C had no discernible effects on the development of both components. These results indicate that low temperatures (e.g. 17 degrees C) unmasked two enhanced components that cannot be seen as separate components in the overall potentiation, while long-lasting enhancement was generated at higher temperatures (e.g. 25 degrees C). The development of the delayed-onset enhanced component primarily depended on coactivation of N-methyl-D-asparate and mGlu receptors during a high Ca(2+) challenge at 17 degrees C. The findings here may provide new understanding of the use of low temperatures and promise significant insight into a novel therapeutic intervention in the CNS while the glutamatergic signaling pathway is abnormally activated by certain ambient insults, such as transient increases in the concentration of extracellular Ca(2+).

2-Amino-5-phosphonovalerate↗
PubMed2001

Intra-thoracic failure pattern and survival status following 3D conformal radiotherapy for non-small cell lung cancer: a preliminary report.

BACKGROUND: To study the intra-thoracic failure pattern, clinical target volume (CTV) and survival status following 3D conformal radiotherapy (3DCRT) boost for non-small cell lung cancer (NSCLC). METHODS: From May 1994 through June 1998, 33 patients (26 male, seven female) with NSCLC were treated with a complete course of radiotherapy (RT) in our institute. Group A included 10 patients receiving radical operation and adjuvant postoperative RT. The other 23 patients (groups B and C) received definitive radiotherapy as local treatment. Among them there were seven cases as group B (stage I-II) and 16 cases as group C (stage III). Fifteen (15/33) patients received chemotherapy. The radiotherapy strategy constituted conventional AP/PA radiotherapy (RT) 19.8-45 Gy (median 39.6 Gy) plus 3DCRT boost 6-34.2 Gy (median 20 Gy). The median total tumor dose was 59.6 Gy (ranging from 39.8 to 64.8 Gy). Patients were followed up regularly (6/33) or until their death (27/33). Nineteen patients received follow-up chest computed tomography (CT). The relationship between intra-thoracic failure found by chest CT and the initial RT and boost RT fields was analyzed. Local failure was defined as one of the following: clinical disease progression, CXR progression or relapse noted by CT. The overall survival (OS) and local failure free survival (LFF) were obtained using the Kaplan-Meier method. RESULTS: Sixteen intra-thoracic failures were noted in 15 follow-up chest CT examinations, which included nine in-field relapses, three partial in-field relapses and four out-field relapses. The 2-year OS and LFF for groups A, B and C were 78.8/59.2, 14.2/16.7 and 6.2/7.1% respectively. RTOG grade III/IV complications included one pneumothorax (RTOG grade III). CONCLUSION: Our retrospective study showed that selective omission of contralateral mediastinal lymph node station irradiation may be appropriate in RT for NSCLC. Chest wall and pleural relapses may not be a negligible cause of intra-thoracic failure after RT for NSCLC.

Adult↗
PubMed2001

Retrospective comparison of the AJCC 5th edition classification for nasopharyngeal carcinoma with the AJCC 4th edition: an experience in Taiwan.

OBJECTIVE: The aim of this study was to compare the new AJCC 5th edition classification system for nasopharyngeal carcinoma (NPC) with the AJCC 4th edition by re-evaluating the staging of patients treated in Taiwan. METHODS: From 1992 through 1996, 117 NPC patients without distant metastasis were treated using complete courses of radiotherapy. All patients had complete CT examinations of the nasopharynx and neck. Each patient was re-staged according to the 5th edition of the AJCC classification system. Their overall survival (OS), loco-regional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) were compared between the two staging systems, using the Kaplan-Meier method, log-rank test, Wilcoxon test and Cox proportional hazard model. RESULTS: After a median follow-up of 58.3 months, the 5-year OS for stage I, II, III and IV was 88, 86, 61 and 48%, respectively, according to the new staging. A more even distribution of patients was noted among the patients classified according to the AJCC 5th edition than the 4th edition. The distribution of stages I, II, III and IV was 13.7, 37.6, 15.4 and 33.3%, respectively, using the new staging system, whereas it was 0.8, 14.5, 20.5 and 64.2%, respectively, using the old staging system. More statistically significant differences among 5th edition stages and T classifications than the 4th edition were also noted. CONCLUSIONS: The 5th edition of the AJCC staging system appears to have a more even distribution of patients and more statistically significant differences in predicting prognosis than the 4th edition, mostly in stages and T classification.

Disease-Free Survival↗
PubMed2001

Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase.

Inositol hexakisphosphate (InsP6) is a most abundant inositol polyphosphate that changes simultaneously with inositol 1,4,5-trisphosphate in depolarized neurons. However, the role of InsP6 in neuronal signaling is unknown. Mass assay reveals that the basal levels of InsP6 in several brain regions tested are similar. InsP6 mass is significantly elevated in activated brain neurons and lowered by inhibition of neuronal activity. Furthermore, the hippocampus is most sensitive to electrical challenge with regard to percentage accumulation of InsP6. In hippocampal neurons, InsP6 stimulates adenylyl cyclase (AC) without influencing cAMP phosphodiesterases, resulting in activation of protein kinase A (PKA) and thereby selective enhancement of voltage-gated L-type Ca2+ channel activity. This enhancement was abolished by preincubation with PKA and AC inhibitors. These data suggest that InsP6 increases L-type Ca2+ channel activity by facilitating phosphorylation of PKA phosphorylation sites. Thus, in hippocampal neurons, InsP6 serves as an important signal in modulation of voltage-gated L-type Ca2+ channel activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Antihypertensive action and blockade of alpha1-adrenoceptors by DL-017, a quinazoline derivative.

3-[[4-(2-Methoxyphenyl)piperazin-1-yl]methyl]-5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (DL-017), a quinazoline derivative, exhibits alpha 1 -adrenoceptor antagonistic and type I antiarrhythmic effects on mammalian cardiac tissues. In the current study, the effects of DL-017 on the hemodynamic profile in anesthetized, spontaneously hypertensive rats were evaluated. Intravenous administration of DL-017 induced dose-dependent reductions of heart rate and blood pressure, which persisted over 2 h. DL-017 exerted a maximal antihypertensive effect at 0.1 mg/kg, which was similar to that of 0.1 mg/kg of prazosin. DL-017 was able to block the pressor response to phenylephrine but not to angiotensin II. Regional cerebral blood flow of the right parietal cortex decreased by 14 +/- 4% 10 min after bolus injection and then rapidly returned to control levels while the arterial pressure was still low. These results indicate that blockade of the alpha 1 -adrenoceptor by DL-017 contributes to reduction of arterial pressure. The antihypertensive effect without reflex tachycardia and loss of autoregulation of cerebral blood flow makes DL-017 suitable for chronic long-term treatment of hypertension.

Adrenergic alpha-Agonists↗
PubMed2001

Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.

Animals↗
PubMed2001

Effects of serum from patients with type 1 diabetes on primary cerebellar granule cells.

Type 1 diabetes is an autoimmune disease of unknown etiology. Our previous work has shown that a factor present in serum from type 1 diabetic patients causes increased Ca2+ channel activity and apoptotic DNA fragmentation in pancreatic beta-cells. Here we examined the effects of type 1 diabetic serum on primary cerebellar granule cells (CGCs). In CGCs, exposure to type 1 diabetic serum did not cause increased apoptosis or changes in Ca2+ channel activity. However, patient serum did cause modulation of Ca2+ signals in a cell type with triangular soma that exhibited low voltage-gated Ca2+ currents. This cell was present primarily in cultures exposed to type 1 diabetic serum. The presence of low voltage-gated Ca2+ currents and long neuronal dendrites indicated that this unique cell was of neuronal origin and not of glial origin.

Animals↗
PubMed2001

Femtomolar concentrations of dynorphins protect rat mesencephalic dopaminergic neurons against inflammatory damage.

The hallmark of Parkinson's disease is the death of nigral dopaminergic neurons, and inflammation in the brain has been increasingly associated with the pathogenesis of this neurological disorder. Dynorphins are among the major opioid peptides in the striato-nigral pathway and are important in regulating dopaminergic neuronal activities. However, it is not clear whether dynorphins play a role in the survival of nigral dopaminergic neurons. We have recently demonstrated that lipopolysaccharide (LPS) activates the brain immune cells microglia, in vitro and in vivo, to release neurotoxic factors to degenerate dopaminergic neurons. The purpose of this study was to explore the neuroprotective effect of dynorphins in the inflammation-mediated degeneration of dopaminergic neurons in rat midbrain neuron-glia cultures. LPS-induced neurotoxicity was significantly reduced by treatment with ultra low concentrations (10(-13)--10(-15) M) of the kappa-opioid receptor agonist dynorphin A (1--17) or the receptor binding ineffective [des-Tyr(1)]dynorphin A (2--17), but not by U50488, a synthetic kappa-receptor agonist. The glia-mediated neuroprotective effect of dynorphins was further supported by the finding that femtomolar concentrations of dynorphins did not prevent the killing of dopaminergic neurons by 6-hydroxydopamine. However, ultra low concentrations of dynorphins inhibited LPS-induced production of superoxide. These results suggest a glia-mediated and conventional opioid receptor-unrelated mechanism of action for the neuroprotective effect of ultra low concentrations of dynorphins. Understanding the underlying mechanisms of action should further define the roles of dynorphins in the regulation of dopaminergic neurons and help devise novel strategies to combat neurodegenerative diseases.

Animals↗
PubMed2000

Hyperpolarization contributes to vascular hyporeactivity in rats with lipopolysaccharide-induced endotoxic shock.

We have examined the role of membrane hyperpolarization in mediating vascular hyporeactivity induced by bacterial lipopolysaccharide (LPS) in endothelial-denuded strips of rat thoracic aorta ex vivo. The injection of rats with LPS caused a significant fall of blood pressure and a severe vascular hyporeactivity to norepinephrine. The membrane potential recording showed that endotoxemia caused a hyperpolarization when compared to the control. This hyperpolarization was fully restored by methylene blue (MB; 10 microM) and partially reversed by Nomega-nitro-L-arginine methyl ester (L-NAME; 0.3 mM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 microM), tetraethylammonium (TEA; 10 mM), charybdotoxin (CTX; 0.1 microM), or glibenclamide (GB; 10 microM), however, this hyperpolarization was not significantly affected by apamin (0.1 microM), 4-aminopyridine (4-AP; 1 mM), or Ba2+ (50 microM). In addition, the basal tension of the tissues obtained from endotoxemic rats was enhanced by the following order: MB > or = ODQ > TEA > or = L-NAME > or = CTX > GB; whereas apamin, 4-AP or Ba2+ had no significant effects on these tissues. In contrast, none of these inhibitors had significant effects on the membrane potential or the basal tension in control tissues. Our electrophysiological results further confirmed previous studies showing that in addition to nitric oxide, the large conductance Ca2+-activated K+-channels and ATP-sensitive K+-channels are, most likely, responsible for endotoxin-mediated hyporeactivity to vasoconstrictor agents in vascular smooth muscle.

Animals↗
PubMed2000

Munc-18 associates with syntaxin and serves as a negative regulator of exocytosis in the pancreatic beta -cell.

The Munc-18 protein (mammalian homologue of the unc-18 gene; also called nSec1 or rbSec1) has been identified as an essential component of the synaptic vesicle fusion protein complex. The cellular and subcellular localization and functional role of Munc-18 protein in pancreatic beta-cells was investigated. Subcellular fractionation of insulin-secreting HIT-T15 cells revealed a 67-kDa protein in both cytosol and membrane fractions. Immunohistochemistry showed punctate Munc-18 immunoreactivity in the cytoplasm of rat pancreatic islet cells. Direct double-labeling immunofluorescence histochemistry combined with confocal laser microscopy revealed the presence of Munc-18 immunoreactivity in insulin-, glucagon-, pancreatic polypeptide-, and somatostatin-containing cells. Syntaxin 1 immunoreactivity was detected in extracts of HIT-T15 cells, which were immunoprecipitated using Munc-18 antiserum, suggesting an intimate association of Munc-18 with syntaxin 1. Administration of Munc-18 peptide or Munc-18 antiserum to streptolysin O-permeabilized HIT-T15 cells resulted in significantly increased insulin release, but did not have any significant effect on voltage-gated Ca(2+) channel activity. The findings taken together show that the Munc-18 protein is present in insulin-secreting beta-cells and implicate Munc-18 as a negative regulator of the insulin secretory machinery via a mechanism that does not involve syntaxin-associated Ca(2+) channels.

Animals↗
PubMed2000

Sodium nitroprusside increases pacemaker rhythm of sinoatrial nodes via nitric oxide-cGMP pathway.

Effects of sodium nitroprusside (SNP), a nitric oxide donor, on the action potential in isolated guinea-pig sinoatrial nodes and ventricular papillary muscles were investigated. In the driven ventricular papillary muscle, SNP (10(-10)-10(-3) M) decreased the twitch tension in a concentration-dependent manner without significantly changing the configuration of action potential and the maximal velocity of depolarizing upstroke. In isolated sinoatrial nodes, SNP (10(-8)-10(-3) M) increased the pacemaker rhythm in a concentration-dependent manner. At 10(-5) M SNP, the pacemaker activity increased from 197.2+/-6.1 to 221.4+/-9.7 bpm. Changes of configuration of the action potential included a decrease of the duration of repolarization, i.e., from peak to the maximal diastolic potential (MDP), from 141.4+/-6.4 to 130.0+/-7.0 ms and an increase of the slope of the diastolic membrane potential from 101.6+/-5.3 to 116.5+/-7.3 mV/s (n=6, p<0.05). However, MDP and threshold potential were not significantly changed. Methylene blue (MB, 10(-5) M), a guanylate cyclase inhibitor, significantly decreased the pacemaker activity of the sinoatrial node by increasing the durations of repolarization and diastolic depolarization. After pretreatment with 10(-5) M MB, the effect of SNP was inhibited. The results indicate that nitric oxide, released from SNP, increases the pacemaker activity by enhancing the rates of repolarization and diastolic depolarization. These effects are possibly due to increases in delayed-rectifier K+ and diastolic slow inward currents, which are involved in a mechanism associated with the NO-cGMP pathway.

Action Potentials↗