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L L Simpson

Publications and source records attributed to L L Simpson.

17 recordsLinked to original sources
PubMed1992

Role of protein kinase C in short-term transmission at the mammalian neuromuscular junction.

Neuronal cells grown in culture were exposed to drugs that stimulate protein kinase C (phorbol myristate acetate), inhibit the catalytic site in protein kinase C (H7, staurosporine) or inhibit the regulatory site in protein kinase C (calphostin, sphingosine). In NG-108 and N1E-115 cells, phorbol myristate acetate produced substantial stimulation of protein kinase C activity (0.1 microM produced approximately 75% stimulation). In these same cells, H7 [100% inhibition concentration (IC100) approximately 1 mM] and staurosporine (IC100 approximately 0.2 microM) inhibited the catalytic site in the enzyme, and calphostin (IC80-IC90 approximately 2.0 microM) and sphingosine (IC80-IC90 approximately 1 microM) inhibited the regulatory site in the enzyme. Phorbol myristate acetate, as well as drugs that inhibit the catalytic and regulatory sites in protein kinase C, were tested for their effects on phrenic nerve-hemidiaphragm preparations. At concentrations that stimulated enzyme activity in neuronal cells in culture, phorbol myristate acetate did not augment normal transmission, nor did it restore transmission to preparations bathed in medium with low calcium (0.4-0.6 mM). At concentrations equivalent to the IC80 to IC100 values in neuronal cells in culture, H7, staurosporine, calphostin and sphingosine did not paralyze short-term transmission, nor did they depress transmission in tissues bathed in low calcium. Pretreatment of neuromuscular preparations with phorbol myristate acetate, H7, staurosporine, calphostin or sphingosine did not alter the amount of time necessary for botulinum neurotoxin type A, botulinum neurotoxin type B or tetanus toxin to paralyze transmission. The data indicate that protein kinase C is not required for short-term neuromuscular transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Botulinum C2 toxin and steroid production in adrenal Y-1 cells: the role of microfilaments in the toxin-induced increase in steroid release.

Exposure of adrenal Y-1 cells to C2 toxin results in an increase in steroid release that is accompanied by a rounding of the cell. The actions of C2 toxin mimic those of adrenocorticotropin and cholera toxin except that there is no increase in intracellular cyclic AMP content. In the present study we provide evidence that C2 toxin increases steroid output from Y-1 cells through an alteration in the microfilament network of the cell. C2 toxin significantly increased steroid output after 3 hr of exposure. This effect was accompanied by a significant increase in the transport of [3H]cholesterol to the mitochondrial fraction, independent of cholesterol uptake by the cell. The toxin was unable to increase steroid output from cells prerounded in suspension culture. The protease inhibitors benzamidine and phenylmethylsulfonyl fluoride did not attenuate the ability of C2 toxin to alter the morphology of Y-1 cells. A 3-hr exposure to C2 toxin resulted in the ADP-ribosylation of 50 to 60% of the total actin pool. Fluorescein isothiocyanate-labeled phalloidin visualization of the cytoskeleton of toxin-treated cells confirmed that the toxin caused a decrease in the stress fiber network. C2 toxin treatment of a protein kinase A mutant Y-1 cell (Kin 8) resulted in morphological changes and an increase in steroid output that was not different from that observed for wild type Y-1 cells. The data suggest that C2 toxin increases steroid output from adrenal Y-1 cells by a cyclic AMP-independent mechanism that involves the microfilament network of the cell.

Actin Cytoskeleton↗
PubMed1979

Combined use of molindone and guanethidine in patients with schizophrenia and hypertension.

Human sympathetic nerves have a high-affinity norepinephrine uptake system. This uptake system is inhibited competitively by chlorpromazine but not by molindone, which suggests that molindone will not interact adversely with guanethidine, an antihypertensive drug that enters sympathetic nerves via the high-affinity uptake system. Accordingly, patients with concomitant schizophrenia and hypertension were treated simultaneously with molindone and guanethidine; there was no evidence of an adverse drug interaction. The data indicate that molindone and guanethidine can be used in combination safely and effectively.

Autonomic Fibers, Postganglionic↗
PubMed1978

Tachyphylaxis to d-amphetamine: a reexamination of the phenomenon.

Single or multiple injections of d-amphetamine (10(-3)--10(0) mg/kg) were administered to rats, after which steady-state blood levels of drug were determined. After single injections of d-amphetamine, there was a linear relationship between amount of administered drug and steady-state blood level of drug. After multiple injections of d-amphetamine, steady-state blood levels of drug conformed to the equation D = Doe--kappaepsilont. An attempt was made to relate steady-state blood levels of drug to steady-state responses (e.g., increase in blood pressure or heart rate). At steady-state, amphetamine-induced pressor responses were too small to be analyzed, but tachycardic responses were easily analyzed. It was found that steady-state heart rate responses were dose related to steady-state blood levels of drug. This was true regardless of whether d-amphetamine was administered once or repeatedly. The data indicate that, when tested in rats at sub-toxic doses, d-amphetamine does not evoke tachyphylaxis in relation to heart rate responses which are measured under steady-state conditions.

Animals↗
PubMed1977

The effects of acute and chronic botulinum toxin treatment on receptor number, receptor distribution and tissue sensitivity in rat diaphragm.

Tritiated alpha-bungarotoxin was used to determine the number and distribution of acetylcholine receptors in innervated, denervated and botulinum toxin-treated muscles. Innervated hemidiaphragms bound approximately 2.3 x 10(11) molecules of alpha-bungarotoxin; binding sites were restricted to the end-plate region. Neither acute denervation nor acute poisoning with botulinum toxin altered the number or distribution of alpha-bungarotoxin binding sites. In chronically denervated hemidiaphragms, there was an increase in alpha-bungarotoxin binding sites (maximum about 5.7 x 10(12); these sites were distributed across the muscle surface. In chronically poisoned hemidiaphragms, there was also an increase in the number (maximum about 4.7 x 10(12)) and distribution of binding sites. Chronic denervation and chronic botulinum toxin treatment both produced supersensitivity to acetylcholine. At maximal sensitivity, the respective ED50 values were: denervated muscle, 1.1 x 10(-6) M; botulinum toxin-treated muscle, 5.0 x 10(-6) M. The combination of denervation plus botulinum toxin treatment did not have additive or synergistic effects on alpha-bungarotoxin binding (4.9 x 10(12) molecules/hemidiaphragm) or on tissue sensitivity to acetylcholine (ED50 = 2.1 x 10(-6) M). It is concluded that denervation and botulinum toxin have rather similar effects on the number and distribution of acetylcholine receptors in rat hemidiaphragm.

Acetylcholine↗
PubMed1976

The effect of behavioral stimulant doses of amphetamine on blood pressure.

Blood pressure responses to amphetamine have been studied both in humans and in rats. Blood pressure was monitored in patients who had experienced an adverse behavioral reaction to the drug. All of the patients had self-administereed amphetamine, and later sought medical attention for their adverse reaction. In a series of 14 patients, there was no evidence that amphetamine had evoked a sustained increase in blood pressure. In rats, experiments were conducted in two steps: (1) a determination of the doses of amphetamine that cause behavioral stimulation, and (2) an evaluation of the blood pressure effects of the same dose of amphetamine. In control animals, behavioral stimulant doses of amphetamine exerted only transient effects on blood pressure. In pithed animals, ie, animals devoid of all central mechanisms, amphetamine exerted a sustained effect on blood pressure. It is concluded that the potential ability of amphetamine to evoke sustained cardiovascular responses is damped by the central nervous system of intact animals.

Amphetamine↗
PubMed1976

A comparison of the abilities of chlorpromazine and molindone to interact adversely with guanethidine.

Chlorpromazine and molindone were tested for their abilities to impair conditioned avoidance behavior of rats. Chlorpromazine was effective within the dose range of 0.3 to 7.0 mg/kg (ID50approximately 2.0 mg/kg); molindone was effective within the range of 0.3 to 5.0 mg/kg (ID50 approximately 0.6 mg/kg). Behaviorally relevant doses of chlorpromazine and molindone were then tested for their effects on blood pressure and on adrenergic mechanisms. When given intravenously to anesthetized, hypertensive animals, both drugs (1.0 mg/kg) produced significant but transient vasodepression. When given intraperitoneally to anesthetized or to conscious hypertensive rats, the drugs did not produce significant effects on blood pressure. Both drugs (1.0 mg/kg) blocked responses to an alpha agonist (methoxamine), but chlorpromazine was significantly more potent than molindone. In addition, chlorpromazine produced a dose-dependent (1.0-10.0 mg/kg) inhibition of 3H-l-norepinephrine uptake into heart, but molindone at the same doses produced no inhibition of uptake. In related experiments, it was found that guanethidine (50 mg/kg) was an effective agent for lowering blood pressure of hypertensive rats. When chlorpromazine (3-10 mg/kg) was administered concomitantly with guanethidine, the blood pressure lowering properties of guanethidine were diminished or abolished. When molindone (1-10 mg/kg) was administered concomitantly with guanethidine, there was no loss of blood pressure control. It is concluded that molindone is an important drug, because it is an antipsychotic agent that does not interact adversely with guanethidine.

Animals↗
PubMed1976

The role of acetylcholine receptors and acetylcholinesterase activity in the development of denervation supersensitivity.

Strips of muscle from innervated and denervated rat hemidiaphragm were tested for sensitivity to acetylcholine and to carbachol. For both agonists, denervation (6-8 days) produced notable supersensitivity. However, the increase in sensitivity to acetylcholine (ca. 600-fold) was much greater than that to carbachol (ca. 51-fold). Denervation also produced an increase in [3H]alpha-bungarotoxin binding (ca. 20-fold), presumably indicative of an increase in the number of acetylcholine receptors. In addition to causing increases in tissue sensitivity and receptor number, denervation caused a marked loss of acetylcholinesterase activity (ca. 70%) and a modest loss of butyrylcholinesterase activity (ca. 20%). When innervated muscle was pretreated with eserine (5 X 10(-5) M), there was a loss of acetylcholinesterase activity (ca. 86%) and butyrylcholinesterase activity (ca. 36%). Simultaneously, there was an increase in tissue sensitivity to acetylcholine (ca. 26-fold). When denervated muscle was pretreated with eserine, there was no loss of enzyme activity beyond that caused by denervation. Furthermore, eserine pretreatment did not increase denervated muscle sensitivity to acetylcholine. The data suggest that both an increase in acetylcholine receptors and a decrease in acetylcholinesterase activity contribute to the phenomenon of denervation supersensitivity.

Acetylcholine↗
PubMed1975

Blood pressure and heart rate responses evoked by d- and l-amphetamine in the pithed rat preparation.

Isomers of amphetamine were tested for their ability to evoke changes in the spontaneous motor behavior of rats. d-Amphetamine was effective within the dose range of 0.2 to 2.0 mg/kg; l-amphetamine was effective within the range of 1.0 to 10.0 mg/kg. Both d- and l-amphetamine were also compared for their pressor and tachycardic activity in pithed rats. The doses of amphetamine tested (0.1-10.0 mg/kg) were identical to those which produced changes in behavior. d-Amphetamine was approximately 5-fold more potent than l-amphetamine in evoking pressor responses and approximately 3-fold more potent in evoking tachycardic responses. The two isomers differed little in their ability to block norepinephrine uptake into heart. The ID50 values were; d-amphetamine 0.7 mg/kg; l-amphetamine, 1.2 mg/kg. Cocaine, which also blocked norepinephrine uptake into heart (ID50 = 3.0 mg/kg), lacked significant pressor or tachycardic activity in pithed, adrenalectomized animals. The inability of cocaine to evoke responses was related to the marked reduction in norepinephrine turnover and release in pithed animals. It was concluded that differences in potency between d- and l-amphetamine cannot be explained on the basis of blockade of norepinephrine uptake. The difference may relate to evoked release of amine.

Adrenal Glands↗
PubMed1975

An analysis of the sympathomimetic activity of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (TIQ).

The pithed rat preparation has been used to study the sympathomimetic activity of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (TIQ). In this preparation, an increase in blood pressure is indicative of alpha stimulation, and an increase in heart rate is indicative of beta stimulation. Using this preparation, we have found that TIQ is approximately 3 orders of magnitude less potent than norepinephrine in evoking changes in blood pressure and heart rate. The activity of TIQ has also been studied in pithed animals which had been previously sympathectomized with 6-hydroxydopamine. Sympathectomy produced a marked reduction in cardiac norepinephrine, and it nearly abolished vascular responses to injected tyramine. Following sympathectomy, pithed animals were supersensitive to norepinephrine and subsensitive to TIQ. Similar results were obtained on pithed animals that had been pretreated with cocaine. It is concluded that TIQ is a weak sympathomimetic agent possessing both directly and indirectly acting properties. The data are discussed in terms of a proposal that TIQ may be a false adrenergic transmitter.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

The action of botulinal toxin.

Two areas of research on botulinal toxin are reviewed: (1) isolation and characterization of the toxin molecule and (2) the mechanism by which the toxin acts to paralyze transmission by cholingerrgic nerves. The various molecules of botulinal toxin (types A, B, D, E and F) have molecular weights of approximately 150,000. The toxins are composed of two subunits with molecular weights of approximately 100,000 and approximately 50,000, respectively. The subunits are linked by one or more disulfide bonds. The large-molecular-weight substance (approximately 150,000) is fully neurotoxic; neither subunit possesses neurotoxicity. Toxin-induced paralysis of cholingergic nerves involves three steps: (1) an initial binding step that involves an external receptor; (2) a translocation step during which the toxin molecule, or some portion of it, moves through the nerve membrane; and (3) a paralytic step during which the release of acetylcholine is blocked.

Animals↗