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Biomedical subjects

R Bal

Publications and source records attributed to R Bal.

11 recordsLinked to original sources
PubMed2003

Experimental hyperkalaemia in rabbits: effects of salbutamol and norepinephrine treatments on blood biochemistry and electrocardiography.

The effects of salbutamol and norepinephrine on the electrocardiogram (ECG), serum potassium level and enzyme activities were studied in rabbits with hyperkalaemia; norepinephrine and salbutamol may be therapeutically useful. For induction of hyperkalaemia, 300 mM KCl solution was used and then isotonic saline solution containing 6 microg salbutamol and 3.9 microg norepinephrine per ml were administered. Norepinephrine and salbutamol decreased the serum potassium from 7.36 +/- 0.26 and 7.21 +/- 0.31 mmol/L to 5.62 +/- 0.27 and 4.35 +/- 0.33 mmol/L, respectively, and caused the ECG changes (flatness of P wave, widening of QRS complex and bradycardia) to return to the control conditions (time 0). Norepinephrine, but not salbutamol, decreased the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) to the control levels. These results suggest that monitoring of the enzyme activities might be useful as it yields indexes suitable for evaluating the therapeutic approach with norepinephrine in hyperkalaemia.

Adrenergic alpha-Agonists↗
PubMed2002

[Centenary of the Health Council of the Netherlands. VI. Coordination mechanisms and the authority of the Health Council of the Netherlands].

What do scientific advisory boards such as the Health Council of the Netherlands get their authority from? How does the Council ensure that its advice is incorporated into policy and into the practices at which the advice is directed? A frequently heard answer to this question is: by describing 'the state of knowledge' as optimally as possible. However, case studies on advisory work by the Health Council have shown that this explanation is too simplistic. It is more likely that the explanation lies in the use of 'co-ordination tools'--such as problem definition, the committee process and a specific use of language--that enable the Council to both separate and bridge science and policy. The authority of the Council is based on the hybrid nature of its work.

Advisory Committees↗
PubMed2001

Two kinds of transient outward currents, I(A) and I(Adepol), in F76 and D1 soma membranes of the subesophageal ganglia of Helix aspersa.

Transient outward currents were characterized with twin electrode voltage clamp techniques in isolated F76 and D1 neuronal membranes (soma only) of Helix aspersa subesophageal ganglia. In this study, in addition to the transient outward current (A-current, I(A)) described by Connor and Stevens (1971b), another fast outward current, referred to as I(Adepol) here, is described for the first time. This is similar to the current component characterized in Aplysia (Furukawa, Kandel & Pfaffinger, 1992). The separation of these two current components was based on activation and steady-state inactivation curves, holding potentials and sensitivity to 4-aminopyridine (4-AP). In contrast to I(A), I(Adepol) did not require hyperpolarizing conditioning pulses to remove inactivation; it was evoked from a holding potential of -40 mV, at which I(A) is completely inactivated. I(Adepol) shows noticeable activation at around -5 mV, whereas I(A) activates at around -50 mV. The time courses of I(Adepol) activation and inactivation were similar but slower than I(A). It was found that I(Adepol) was more sensitive than I(A) to 4-AP. 4-AP at a concentration of 1 mm blocked I(Adepol) completely, whereas 5-6 mm 4-AP was needed to block I(A) completely. This current is potentially very important because it may, like other A currents, regulate firing frequency but notably, it does not require a period of hyperpolarization to be active.

4-Aminopyridine↗
PubMed2001

Potassium currents in octopus cells of the mammalian cochlear nucleus.

Octopus cells in the posteroventral cochlear nucleus (PVCN) of mammals are biophysically specialized to detect coincident firing in the population of auditory nerve fibers that provide their synaptic input and to convey its occurrence with temporal precision. The precision in the timing of action potentials depends on the low input resistance (approximately 6 MOmega) of octopus cells at the resting potential that makes voltage changes rapid (tau approximately 200 micros). It is the activation of voltage-dependent conductances that endows octopus cells with low input resistances and prevents repetitive firing in response to depolarization. These conductances have been examined under whole cell voltage clamp. The present study reveals the properties of two conductances that mediate currents whose reversal at or near the equilibrium potential for K(+) over a wide range of extracellular K(+) concentrations identifies them as K(+) currents. One rapidly inactivating conductance, g(KL), had a threshold of activation at -70 mV, rose steeply as a function of depolarization with half-maximal activation at -45 +/- 6 mV (mean +/- SD), and was fully activated at 0 mV. The low-threshold K(+) current (I(KL)) was largely blocked by alpha-dendrotoxin (alpha-DTX) and partially blocked by DTX-K and tityustoxin, indicating that this current was mediated through potassium channels of the Kv1 (also known as shaker or KCNA) family. The maximum low-threshold K(+) conductance (g(KL)) was large, 514 +/- 135 nS. Blocking I(KL) with alpha-DTX revealed a second K(+) current with a higher threshold (I(KH)) that was largely blocked by 20 mM tetraethylammonium (TEA). The more slowly inactivating conductance, g(KH), had a threshold for activation at -40 mV, reached half-maximal activation at -16 +/- 5 mV, and was fully activated at +30 mV. The maximum high-threshold conductance, g(KH), was on average 116 +/- 27 nS. The present experiments show that it is not the biophysical and pharmacological properties but the magnitude of the K(+) conductances that make octopus cells unusual. At the resting potential, -62 mV, g(KL) contributes approximately 42 nS to the resting conductance and mediates a resting K(+) current of 1 nA. The resting outward K(+) current is balanced by an inward current through the hyperpolarization-activated conductance, g(h), that has been described previously.

Animals↗
PubMed2000

Detection of synchrony in the activity of auditory nerve fibers by octopus cells of the mammalian cochlear nucleus.

The anatomical and biophysical specializations of octopus cells allow them to detect the coincident firing of groups of auditory nerve fibers and to convey the precise timing of that coincidence to their targets. Octopus cells occupy a sharply defined region of the most caudal and dorsal part of the mammalian ventral cochlear nucleus. The dendrites of octopus cells cross the bundle of auditory nerve fibers just proximal to where the fibers leave the ventral and enter the dorsal cochlear nucleus, each octopus cell spanning about one-third of the tonotopic array. Octopus cells are excited by auditory nerve fibers through the activation of rapid, calcium-permeable, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors. Synaptic responses are shaped by the unusual biophysical characteristics of octopus cells. Octopus cells have very low input resistances (about 7 M Omega), and short time constants (about 200 microsec) as a consequence of the activation at rest of a hyperpolarization-activated mixed-cation conductance and a low-threshold, depolarization-activated potassium conductance. The low input resistance causes rapid synaptic currents to generate rapid and small synaptic potentials. Summation of small synaptic potentials from many fibers is required to bring an octopus cell to threshold. Not only does the low input resistance make individual excitatory postsynaptic potentials brief so that they must be generated within 1 msec to sum but also the voltage-sensitive conductances of octopus cells prevent firing if the activation of auditory nerve inputs is not sufficiently synchronous and depolarization is not sufficiently rapid. In vivo in cats, octopus cells can fire rapidly and respond with exceptionally well-timed action potentials to periodic, broadband sounds such as clicks. Thus both the anatomical specializations and the biophysical specializations make octopus cells detectors of the coincident firing of their auditory nerve fiber inputs.

Acoustic Stimulation↗
PubMed2000

Effect of calcium and calcium channel blockers on transient outward current of F76 and D1 neuronal soma membranes in the subesophageal ganglia of Helix aspersa.

Twin-electrode voltage-clamp techniques were used to study the effect of calcium and calcium channel blockers on the transient outward current in isolated F76 and D1 neurones of Helix aspersa subesophageal ganglia in vitro (soma only preparation with no cell processes). On lowering extracellular Ca(2+) concentration from 10 to 2 mm or removing extracellular calcium from the bathing medium, the threshold for this current shifted in a negative direction by 11. 5 and 20 mV, respectively. On the other hand, increasing the extracellular Ca(2+) concentration from 10 to 20 and to 40 mm shifted the steady-state inactivation curves in positive directions on the voltage axis by 7 and 15 mV, respectively. Upon application of calcium channel blockers, Co(2+), La(3+), Ni(2+) and Cd(2+), transient potassium current amplitude was reduced in a voltage-dependent manner, being more effective at voltages close to the threshold. The current was elicited even at a holding potential of -34 mV. The specific calcium channel blockers, amiloride and nifedipine did not shift the activation and steady-state inactivation curves and did not reduce the transient outward current amplitude. It was concluded that the transient outward current is not dependent on intracellular Ca(2+) but that it is modulated by Ca(2+) and di- and trivalent ions extracellularly. The effects of these ions are very unlikely to be due to a surface charge effect because the addition of La(3+) (200 microm) completely reverses the shift in a hyperpolarizing direction when the extracellular Ca(2+) concentration was reduced from 10 to 1 mm and additionally shifts the kinetics further still in a depolarizing direction. The responses seen here are consistent with a specific effect of di- and trivalent ions on the transient outward current channels leading to a modification of gating.

Amiloride↗
PubMed2000

Hyperpolarization-activated, mixed-cation current (I(h)) in octopus cells of the mammalian cochlear nucleus.

Octopus cells in the posteroventral cochlear nucleus of mammals detect the coincidence of synchronous firing in populations of auditory nerve fibers and convey the timing of that coincidence with great temporal precision. Earlier recordings in current clamp have shown that two conductances contribute to the low input resistance and therefore to the ability of octopus cells to encode timing precisely, a low-threshold K(+) conductance and a hyperpolarization-activated mixed-cation conductance, g(h). The present experiments describe the properties of g(h) in octopus cells as they are revealed under voltage clamp with whole-cell, patch recordings. The hyperpolarization-activated current, I(h), was blocked by extracellular Cs(+) (5 mM) and 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyridinium chloride (50-100 nM) but not by extracellular Ba(2+) (2 mM). The reversal potential for I(h) in octopus cells under normal physiological conditions was -38 mV. Increasing the extracellular potassium concentration from 3 to 12 mM shifted the reversal potential to -26 mV; lowering extracellular sodium concentration from 138 to 10 mM shifted the reversal potential to -77 mV. These pharmacological and ion substitution experiments show that I(h) in octopus cells is a mixed-cation current that resembles I(h) in other neurons and in heart muscle cells. Under control conditions when cells were perfused intracellularly with ATP and GTP, I(h) had an activation threshold between about -35 to -40 mV and became fully activated at -110 mV. The maximum conductance associated with hyperpolarizing voltage steps to -112 mV ranged from 87 to 212 nS [150 +/- 30 (SD) nS, n = 36]. The voltage dependence of g(h) obtained from peak tail currents is fit by a Boltzmann function with a half-activation potential of -65 +/- 3 mV and a slope factor of 7. 7 +/- 0.7. This relationship reveals that g(h) was activated 41% at the mean resting potential of octopus cells, -62 mV, and that at rest I(h) contributes a steady inward current of between 0.9 and 2.1 nA. The voltage dependence of g(h) was unaffected by the extracellular application of dibutyryl cAMP but was shifted in hyperpolarizing direction, independent of the presence or absence of dibutyryl cAMP, by the removal of intracellular ATP and GTP.

4-Aminopyridine↗
PubMed1996

2,4-Diarylpyrrolidine-3-carboxylic acids--potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722.

We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indian ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrroli din e-3- carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC(50)=0.36 nM for inhibition of ET-1 radioligand binding at the ET(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC(50)=0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA(2)=9.20. The compound has 70% oral bioavailability in rats.

Animals↗
PubMed1996

Azole endothelin antagonists. 2. Structure-activity studies.

Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N-Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.

Animals↗
PubMed1996

Drafting guidelines for occupational exposure to chemicals: the Dutch experience with the assessment of reproductive risks.

The Dutch procedure for standard setting for occupational exposure to chemicals, just like the European Union (EU) procedure, is characterized by an organizational separation between considerations of health on the one side, and of technology, economics, and policy on the other side. Health considerations form the basis for numerical guidelines. These guidelines are next combined with technical-economical considerations. Standards are then proposed, and are finally set by the Ministry of Social Affairs and Employment. An analysis of this procedure might be of relevance to the US, where other procedures are used and criticized. In this article we focus on the first stage of the standard-setting procedure. In this stage, the Dutch Expert Committee on Occupational Standards (DECOS) drafts a criteria document in which a health-based guideline is proposed. The drafting is based on a set of starting points for assessing toxicity. We raise the questions, "Does DECOS limit itself only to health considerations? And if not, what are the consequences of such a situation?" We discuss DECOS' starting points and analyze the relationships between those starting points, and then explore eight criteria documents where DECOS was considering reproductive risks as a possible critical effect. For various reasons, it will be concluded that the starting points leave much interpretative space, and that this space is widened further by the manner in which DECOS utilizes it. This is especially true in situations involving sex-specific risks and uncertainties in knowledge. Consequently, even at the first stage, where health considerations alone are intended to play a role, there is much room for other than health-related factors to influence decision making, although it is unavoidable that some interpretative space will remain. We argue that separating the various types of consideration should not be abandoned. Rather, through adjustments in the starting points and aspects of the procedure, clarity should be guaranteed about the way the interpretative space is being employed.

Decision Making↗