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Biomedical subjects

L L Simpson

Publications and source records attributed to L L Simpson.

At least 91 records · Page 5Linked to original sources
PubMed1982

Disulfide bond reduction inhibits norepinephrine accumulation in postganglionic sympathetic nerve endings.

Accumulation of l-[3H]norepinephrine by sympathetic nerves in mouse atria was inhibited by disulfide bond reducing agents such as dithiothreitol (IC50 approximately 0.4 mM) and beta-mercaptoethanol (IC50 approximately 1.1 mM). Dithiothreitol-induced inhibition of l-[3H]norepinephrine accumulation was reversed by exposing tissues to oxygen or to oxidizing agents such as potassium ferricyanide (0.03 mM) or 5,5'dithiobis-(2-nitrobenzoic acid) (1.0 mM). The cycle of reduction-induced inhibition and oxidation-induced reactivation could be repeated within tissues by sequential exposure to dithiothreitol and potassium ferricyanide. Exposing rat atrial to concentrations of dithiothreitol (1.0 mM) that produced substantial inhibition of l-[3H]norepinephrine accumulation (approximately 50%) did not affect spontaneous atrial rate or l-isoproterenol-induced increases in rate. In addition to disulfide bond reducing agents, sulfhydryl blocking agents such as N-ethylmaleimide (IC50 approximately 0.3 mM) and p-chloromercuriphenylsulfonic acid (IC50 approximately 0.2 mM) inhibited l-[3H]norepinephrine accumulation by mouse atria. Inhibition induced by sulfhydryl blockers could not be reversed by oxygen or by oxidizing agents. Furthermore, tissues exposed to dithiothreitol and subsequently exposed to N-ethylmaleimide could not be reactivated by oxygen or by oxidizing agent. The data suggest that a protein with a disulfide bond is associated with l-[3H]norepinephrine accumulation and that reduction of the disulfide bond inhibits amine accumulation. Reduced disulfide bonds that have not been alkylated can be reoxidized, but reduced disulfide bonds that are alkylated are irreversibly inactivated.

Animals↗
PubMed1981

Charge-shift probes of membrane potential: a probable electrochromic mechanism for p-aminostyrylpyridinium probes on a hemispherical lipid bilayer.

The characteristics of the spectroscopic responses to membrane potential are examined for a series of dyes based on the 4-(p-aminostyryl)-1-pyridinium chromophore. An apparatus using an oxidized cholesterol hemispherical bilayer and phase-sensitive detection provides response spectra in either transmission or fluorescence excitation modes. All the probes with good binding properties display biphasic response spectra that are similar in both shape and magnitude. Detailed analysis of the response spectra allows all the previously discovered mechanisms for extrinsic potential sensitive molecular probes, which require a change in the probe's chemical environment, to be ruled out. The data are consistent with an electrochromic mechanism. Polarized fluorescence intensities from the membrane-bound probes indicate that the chromophore is optimally oriented for an electrochromic response.

Cholesterol↗
PubMed1980

Kinetic studies on the interaction between botulinum toxin type A and the cholinergic neuromuscular junction.

Botulinum toxin-induced paralysis of neuromuscular transmission involves at least three steps. There is an initial binding step that is nontoxic, a translocation step that is nontoxic and a subsequent lytic step that produces blockade of transmission. In the absence of nerve stimulation, the binding step has a half-time of similar to or approximately 12 min and a rate constant of similar to or approximately 0.058 . min-1. The binding step does not require calcium or nerve stimulation, and it has a low temperature dependence (Q10 similar to or approximately 1.6). In the absence of nerve stimulation, the translocation step has a half-time of similar to or approximately 4.9 min and a rate constant of similar to or approximately 0.141 . min-1. Translocation requires physiological concentrations of calcium. In the virtual absence of nerve stimulation (1 x 10(-2) Hz), the lytic step has a half-time of similar to or approximately 55 min and a rate constant of similar to or approximately 0.013 . min-1. The lytic step requires calcium, is facillitated by nerve stimulation and has a high temperature dependence by nerve stimulation and has a high temperature dependence (Q10 similar to or approximately 4.2). These data are used to propose a model for botulinum toxin interaction with the cholinergic nerve terminal.

Animals↗
PubMed1980

Blood pressure and heart rate response evoked by p-hydroxyamphetamine and by p-hydroxynorephedrine II. A quantitative assessment of the role of amphetamine metabolites in acute responses evoked by d-amphetamine.

At postganglionic sympathetic sites, p-hydroxyamphetamine is neither a receptor agonist nor a receptor antagonist; in addition the drug does not act presynaptically to antagonize or synergize d-amphetamine. p-Hydroxyamphetamine is an indirectly acting sympathomimetic amine with a potency approximately twice that of d-amphetamine. In the rat, a large fraction (approximately 0.5) of d-amphetamine is biotransformed to p-hydroxyamphetamine. However, the rate of biotransformation to p-hydroxyamphetamine (approximately 0.0099 . min-1) is slow compared to the rate of elimination of p-hydroxyamphetamine (0.049 . min-1). As a result, plasma levels of d-amphetamine exceed those of p-hydroxyamphetamine. The kinetic data suggest that: 1) p-hydroxyamphetamine plays little role in immediate responses to single injections of d-amphetamine; 2) p-hydroxyamphetamine is not involved in tachyphylactic responses to repeated injections of d-amphetamine; and 3) p-hydroxynorephedrine plays no role in immediate or tachyphylactic responses to d-amphetamine.

Amphetamines↗
PubMed1980

Kinetic studies on the entry of d-amphetamine into the central nervous system: I. Cerebrospinal fluid.

After intravenous administration to rats, d-amphetamine undergoes a rapid distributive phase (k approximately 0.99.min-1) during which the drug is lost from plasma. The rate of entry into the cerebrospinal fluid (CSF) is also rapid (k approximately 0.58.min-1), suggesting that the drug moves directly from plasma to CSF. Entry of drug into CSF is mainly by diffusion. Neither active transport associated with CSF formation nor active transport independent of CSF formation is quantitatively important. After intracerebroventricular injection, d-amphetamine disappears from CSF relatively slowly (k approximately 0.063.min-1). Egress of drug is mainly by diffusion (k approximately 0.044.min-1), although active transport associated with bulk absorption does play a measurable role (k approximately 0.019.min-1). At steady state, the concentration of free drug in plasma and in CSF is equivalent.

Animals↗
PubMed1980

Evidence that there are subcellular pools of norepinephrine and that there is flux of norepinephrine between these pools.

d-Amphetamine evokes blood pressure responses that are dose-dependent in magnitude and in shape. At a high dose, d-amphetamine evokes a response that decays biphasically. Response decay is not due to receptor desensitization or to decreasing plasma levels of drug. The first component of the biphasic decay (early, transient response) has an apparent peak of approximately 56 mm Hg and a rate constant for decay of approximately 0.043-min-1. The second component (late, relatively stable response) has an apparent peak of approximately 27 mm Hg and a rate constant for decay less than 0.0043-min-1. Chronic reserpine treatment diminishes the blood pressure response to a high dose of d-amphetamine, but it exerts a differential effect on the two components of the response. The ID50 for reducing the early, transient response is greater than 800 micrograms/kg; the ID50 for reducing the late, relatively stable response is approximately 100 micrograms/kg. Acute reserpine treatment enhances blood pressure responses to d-amphetamine, mainly by enhancing the early, transient response. In addition, acutely administered reserpine reverses the tachyphylactic effect of d-amphetamine. The data are used to construct a model for norepinephrine storage in postganglionic sympathetic nerves and to propose a model for d-amphetamine-induced tachyphylaxis.

Adrenalectomy↗
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↗