Effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on rat vascular smooth muscle in vitro--the role of the endothelium.

Hypotension is a frequent side effect of the antidepressant treatment. It is controversial whether this effect is attributable to interactions within the central nervous or the cardiovascular system. We examined often used antidepressants for their vasoactive properties in vitro in rat aortal rings with and without endothelium. The influence of pre-incubation with the antidepressants (0.5 µM) on adrenergic elicited smooth muscle contraction and the effects of cumulative concentrations (0.05 µM-500 µM) of the antidepressants on isometric tension were measured. In addition, conceivable modulation of the NO-cGMP, adrenergic and potassium channel pathways were examined. Amitriptyline and fluoxetine inhibited, whereas tranylcypromine enhanced adrenergic elicited responses of smooth muscle contraction. The antidepressants amitriptyline, fluoxetine and tranylcypromine showed, to a different extent, vasorelaxing properties in the preparations pre-contracted with phenylephrine 0.1 µM; the pEC50, (means and S.E.M.) in descending order of potency: amitriptyline 6.98 (0.13), fluoxetine 6.11 (0.05), tranylcypromine 5.33 (0.05) (n=8 each, preparations with endothelium); or after pre-contraction with KCl 20 mM: fluoxetine 6.00 (0.06), tranylcypromine 4.99 (0.30), amitriptyline, 4.89 (0.11), (n=7 each, preparations with endothelium). Venlafaxine did not relax the aortal rings and even lead to further contraction of the endothelium intact preparations. The observed effects were partially endothelium dependent via activation of the NO-cGMP pathway and some probably mediated through K+ channel activation. Amitriptyline, fluoxetine and tranylcypromine relax rat aorta in vitro. They partially delay vascular smooth muscle reactions to adrenergic agonists and can lead to sustained hypotension episodes despite administration of sympathomimetic drugs.

Skeletal muscle relaxants inhibit rat tracheal smooth muscle tone in vitro.

Neuromuscular blocking drugs (NMBD) can inhibit not only nicotinic but also muscarinic (M) receptors and thereby affect not only skeletal but also smooth muscle (SM) tone. A selective postjunctional muscarinic inhibition would relax, while prejunctional inhibition of muscarinic M2 receptor might hasten SM contraction thereby increasing the risk of bronchospasm. In rat tracheal rings in vitro we evaluated the effects of cumulative concentrations of some NMBD and M receptor blocking agents for their effects on tracheal smooth muscle (TSM) tone pre-contracted with carbachol (CARB; 5 x 10(-7)M or 10(-6)M), pilocarpine (PILO; 5 x 10(-6)M), or by electrical field stimulation. The NMBDs produced relaxation in the preparations precontracted with CARB or PILO. The order of potency after CARB (10(-6)M) was (EC(50)): 4-DAMP (9.8) >atropine (9.2) >methoctramine (6.4) >pancuronium (6.0) >mivacurium (5.8) >cisatracurium (5.6) >gallamine (5.2) >rocuronium (4.8) >succinylcholine (2.9); NMBDs also partially prevented contraction elicited by the electrical field stimulation. We demonstrated that the clinically used NMBD that were examined produced rat TSM relaxation, probably by predominantly blocking postjunctional muscarinic receptors.

Fractal and nonfractal analysis of cell images: comparison and application to neuronal dendritic arborization.

Neurons of the rat spinal cord were stained using the Golgi impregnation method. Successfully impregnated neurons from laminae II, III, and VI were subjected to fractal and nonfractal analyses. Fractal analysis was performed using length-related techniques. Since an application of fractal methods to the analysis of dendrite arbor structures requires caution, we adopted as appropriate a nonfractal method proposing a generalized power-law model with two main nonfractal parameters: (i) the anfractuosity, characterizing the degree of dendritic deviation from straight lines; and (ii) an estimate of the total length of arbor dendrites. The anfractuosity can distinguish between two sets of drawings where the fractal methods failed. We also redefine some basic concepts of fractal geometry, present the ruler-counting method, and propose a new definition of fractal dimension.

Excitotoxicity of lathyrus sativus neurotoxin in leech retzius neurons.

The effects of Lathyrus sativus neurotoxin were studied on the cell membrane potential and cellular cation composition in Retzius nerve cells of the leech Haemopis sanguisuga, with ion-selective microelectrodes using liquid ion-exchangers. Bath application of 10(-4) mol/l Lathyrus sativus neurotoxin for 3 min depolarized the cell membrane potential and decreased the input resistance of directly polarized membrane in Retzius neurons. At the same time the cellular Na+ activity increased and cellular K+ activity decreased with slow but complete recovery, while the intracellular Ca2+ concentration was not changed. Na+-free Ringer solutions inhibited the depolarizing effect of the neurotoxin on the cell membrane potential. Zero-Ca2+ Ringer solution or Ni2+-Ringer solution had no influence on the depolarizing effect of the neurotoxin on the cell membrane potential. It is obvious that the increase in membrane conductance and depolarization of the cell membrane potential are due to an influx of Na+ into the cell accompanied by an efflux of K+ from the cell.

Effects of acid Ca2+ Ringer on passive electrical properties and intracellular ion activities in leech Retzius neuron.

1. A significant drop in effective input resistance of the free membrane and an increase in effective coupling resistance in acid Ca2+ Ringer (complete replacement of Na+ with Ca2+, pH 4) compared to control medium has been obtained in leech Retzius neurons. 2. In neutral Ca2+ Ringer (pH 7.2), effective input resistance increased while effective coupling resistance did not change. In acid sodium, leech Ringer (pH 4) effective input resistance increased while coupling resistance decreased. 3. Ten millimolar manganese and 10 mmol tetraethylammonium did not block conductance changes obtained in acid Ca2+ Ringer. 4. Intracellular activity of Na+ decreased, cellular activity of Cl- increased and intracellular K+ activity was unchanged in both acid and neutral Ca2+ Ringer. 5. The main difference was intracellular acidification in acid Ca2+ Ringer while intracellular pH was unchanged in neutral Ca2+ Ringer. 6. We discuss the possibility that in acid Ca2+ Ringer, intracellular acidification in leech neurons may be responsible for accompanying conductive changes.

Vasoactive intestinal polypeptide excites mammalian dorsal horn neurons both in vivo and in vitro.

Vasoactive intestinal polypeptide (VIP) applied by iontophoresis and/or pressure microinjection causes a strong excitation of more than 75% of all tested spinal neurons in laminae I-VII of both the cat intact spinal cord and the rat spinal cord slice preparation. In the cat intact spinal cord the excitation is not limited to a single population of neurons but is observed in all categories of units recognized in spinal preparations of cats in this area on the basis of their excitability by different kinds of cutaneous afferent input. In the rat spinal cord slice preparation, VIP depolarized dorsal horn neurons and increased their excitability. The depolarization was associated with a decrease in neuronal input resistance. These results are consistent with the possibility that VIP may have a physiological role in synaptic function, either as a transmitter or as a modulator.

The actions of neuropeptides on dorsal horn neurons in the rat spinal cord slice preparation: an intracellular study.

Responses of dorsal horn neurons to bath application of substance P, somatostatin and enkephalin were studied by intracellular recording in the neonatal spinal cord slice preparation. Substance P depolarized dorsal horn neurons and increased their excitability. The depolarization was most commonly associated with an increase in neuronal input resistance. Somatostatin and enkephalin hyperpolarized dorsal horn neurons and caused reduction or abolition of spontaneous firing. While the hyperpolarization produced by enkephalin was always associated with a fall in neuronal input resistance, in the case of somatostatin the similar effect was less consistently observed.