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K Su

Publications and source records attributed to K Su.

48 records · Page 3Linked to original sources
PubMed1986

Opposing actions of cimetidine on naloxone-sensitive and naloxone-insensitive forms of footshock-induced analgesia.

The effects of the opiate antagonist naloxone (10 mg/kg) and the histamine H2-antagonist cimetidine (100 mg/kg; both administered i.p.) were studied on the analgesia elicited by 3 currents of continuous-scrambled AC footshock (FSIA). Repeated analgesic measurements were made in each animal by use of the radiant heat tail-flick test. As shown by others, naloxone effectively inhibited the FSIA produced by 3 min of 2.0 mA, but had no effect on the responses elicited by higher currents (2.5 and 3.5 mA) of the same duration. Cimetidine significantly reduced the naloxone-insensitive FSIA after 3.5 mA, had no effect on that produced by 2.5 mA and potentiated the naloxone-sensitive analgesia elicited by 2.0 mA. These findings add to existing data supporting a role for brain histamine as a mediator of naloxone-insensitive analgesia, and also suggest the possibility that histamine may mediate hyperalgesic responses.

Analgesia↗
PubMed1986

Cimetidine penetrates brain and inhibits non-opiate footshock-induced analgesia.

The inhibition of hindpaw (non-opiate) footshock-induced analgesia (HP-FSIA) by cimetidine, the histamine H2-receptor antagonist, was characterized in rats, and the drug's presence in brain was demonstrated. Cimetidine (100 mg/kg, IP) inhibited HP-FSIA when administered 30 min before testing, but was inactive when testing began sooner (15 min) or later (1-4 hr) than this time. Lower doses (20 mg/kg) were also ineffective when given 30 min before testing, whereas higher doses (200 mg/kg) effectively inhibited the response. Increasing the footshock current from 4 mA (which elicited cimetidine-sensitive analgesia) to higher currents (5 and 6 mA) yielded cimetidine-insensitive analgesia. Administration of isotopically labeled cimetidine (100 mg/kg, IP, 30 min) yielded whole brain cimetidine levels of 1.95 nmols/g, respectively, with a brain/blood ratio of 0.017. These findings confirm a limited penetration of brain by cimetidine, and show that large peripheral doses of cimetidine are required to block brain H2-receptors. The specific dose and time requirements for cimetidine to inhibit the HP-FSIA are probably attributable to the brain drug levels that can be achieved after peripheral administration.

Animals↗
PubMed1985

A role for histamine and histamine H2-receptors in non-opiate footshock-induced analgesia.

Scrambled DC current applied to the hind paws of rats caused an analgesic response that was inhibited by the histamine H2-receptor antagonists cimetidine, ranitidine and oxmetidine, but not by high doses of naloxone (the opiate antagonist), or other transmitter receptor antagonists. In contrast, AC current applied to all paws produced analgesia that was blocked by naloxone, but not cimetidine, showing the independence of these systems. These findings indicate a specific role for histamine and H2-receptors as mediators of endogenous non-opiate analgesia. In addition, a combination of cimetidine and naloxone did not abolish either form of footshock analgesia, implying the existence of a non-opiate, non-H2, endogenous pain-relieving system. These results also suggest that drugs capable of penetrating the brain and stimulating H2-receptors might have analgesic properties.

Animals↗
PubMed1983

Effects of captopril and propanolol on bradykinin-induced changes in vascular pressures, lymph total protein concentration, and weight in canine forelimbs.

Sixty-minute local intraarterial infusions of bradykinin (0.8, 5, or 10 micrograms base/min) produced transient forelimb vasodilation and dose-related increases in lymph flow, lymph total protein concentration, total protein transport, and weight in forelimbs perfused at a controlled flow rate. Mean aortic pressure was not affected by these infusion rates of bradykinin. Following pretreatment with captopril, the local intraarterial infusion of these same doses of bradykinin produced sustained systemic hypotension. The increase in protein efflux and edema formation produced by local infusions of bradykinin following pretreatment with captopril was markedly increased during the infusion of the low dose of bradykinin (0.8 micrograms base/min, ia), but was attenuated during the local infusion of the larger dose of bradykinin (5 micrograms base/min, ia). Following pretreatment with both captopril and propranolol, the increase in protein efflux and edema formation produced by this larger dose of bradykinin (5 micrograms base/min) was greater than that produced by infusions of this dose of bradykinin alone or after pretreatment with captopril. Moreover, the increase in protein efflux and edema formation was greater during the infusion of the higher dose of bradykinin than during the infusion of the low dose of this autacoid under these conditions. The 60-min infusion of a massive dose of bradykinin into the left ventricular chamber (280 micrograms base/min) produced sustained decreases in aortic and forelimb perfusion pressure, but little edema formation relative to that produced by local intraarterial infusions of this agent. In contrast, the 60-min intravenous infusion of only 5 micrograms base/min of bradykinin following pretreatment with both captopril and propranolol produced profound systemic hypotension and marked increases in protein efflux and edema formation in forelimbs perfused at a controlled flow rate comparable to that produced by the local intraarterial infusion of this dose of bradykinin alone. These data demonstrate that endogenous kininases and catecholamines may dramatically affect the increase in protein efflux and edema formation produced by either local or systemic infusions of bradykinin by modulating the magnitude of the increase in macromolecular permeability.

Animals↗
PubMedDate not supplied

MDA468 growth inhibition by EGF is associated with the induction of the cyclin-dependent kinase inhibitor p21WAF1.

Epidermal growth factor (EGF) usually stimulates the proliferation of a variety of normal and malignant cells. In contrast, MDA468, a human breast cancer cell line with a very high number of EGF receptors, is growth inhibited in response to concentrations of EGF that stimulate most other cells. The purpose of this study was to elucidate the cellular mechanisms involved in EGF-induced growth inhibition. EGF treatment stimulated the sustained expression of the cyclin-dependent kinase (CDK) inhibitor p21WAF1. The p21WAF1 induction in EGF-treated MDA468 cells is probably p53-independent since these cells contain no active p53. The promoter for p21WAF1 gene contains binding sites for signal transducer and activator of transcription (STAT) and EGF is known to activate members of this family of transcription factors. Using electrophoretic mobility shift assays (EMSA), we found that EGF activates STAT1 and STAT3 in the MDA468 cells. These activated STATs specifically recognized the three conserved STAT-responsive elements in the p21WAF1 gene promoter, suggesting that STATs may be responsible for the p21WAF1 induction by EGF in MDA468 cells. The sustained rise in p21WAF1 in response to EGF is proposed to be a means of growth inhibition in these cells.

Breast Neoplasms↗
PubMedDate not supplied

Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins.

Streptozotocin (STZ), an analog of N-acetylglucosamine (GlcNAc), is a specific toxin for the pancreatic beta cell. We found that treatment of rats with STZ results in an early beta-cell-specific increase in the level of intracellular protein modification by O-linked GlcNAc (O-GlcNAc). Using a model O-GlcNAc peptide based on the transcription factor Sp1, we show that treatment of cultured cells with STZ during peptide biosynthesis results in hyperglycosylation of the peptide as a result of the ability of STZ to specifically inhibit the activity of O-GlcNAc-selective N-acetyl-beta-D-glucosaminidase. Although this inhibitory activity of STZ probably can occur in all cells, we found, using in situ hybridization, that beta cells express very high levels of the mRNA encoding the enzyme responsible for cytoplasmic protein O-glycosylation, O-GlcNAc transferase (OGT). These findings suggest that the pancreatic beta cell is particularly sensitive to the toxicity of STZ because it expresses such high levels of OGT. When STZ blocks O-GlcNAc removal from intracellular proteins, the cell with the most rapid on-rate for O-GlcNAc, the beta cell, will experience the most rapid accumulation of this protein modification. Because we also show that the on-rate of O-GlcNAc is substrate driven in several cell types, we speculate that the beta cell, with its high level of OGT, may also respond to elevations of blood sugar with increased protein modification by O-GlcNAc. Thus, this proposed mechanism of STZ toxicity on the beta cell may result from an exaggeration of a heretofore unrecognized physiological response to glucose mediated through the high level of OGT in these cells.

Acetylglucosamine↗