Effect of acute dapoxetine administration on the pudendal motoneuron reflex in anesthetized rats: comparison with paroxetine.

Purpose: Pudendal motoneuron reflex discharges elicited by bilateral electrical stimulation of the dorsal nerves of the penis were used as an experimental model of the expulsion reflex of ejaculation to investigate the effect of acute intravenous delivery of dapoxetine, a short acting selective serotonin reuptake inhibitor, in anesthetized rats. Dapoxetine was compared with paroxetine, the selective serotonin reuptake inhibitor of reference.

Materials And Methods: Stimulating electrodes were placed bilaterally on the dorsal nerves of the penis and a recording electrode was placed on the motor branch of the pudendal nerve to monitor pudendal motoneuron reflex discharges in urethane anesthetized rats.

Supraspinal site of action for the inhibition of ejaculatory reflex by dapoxetine.

Objectives: The aim of the study was to determine whether dapoxetine, a short-acting selective serotonin reuptake inhibitor, acts at the spinal or supraspinal level to inhibit the ejaculatory reflex.

Methods: The pudendal motoneuron reflex discharges (PMRDs) model was used as an experimental paradigm of the ejaculatory expulsion reflex in anaesthetised male rats. A spinal site of action was evaluated by testing the effect of intrathecal delivery of dapoxetine on PMRDs elicited by electric stimulation of the dorsal nerves of the penis (DNP).

ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid], a novel nonpeptide delta receptor agonist, reduces myocardial infarct size without central effects.

A novel delta-receptor selective compound, ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2, 5-dimethylpiperazin-1-ylmethyl)benzoic acid], was evaluated for activity on infarct size in a rat model of acute myocardial infarction. ARD-353 was characterized as having delta receptor selectivity using radioligand binding and had no apparent selectivity between delta receptor subtypes as determined by [(3)H] cyclic [D-Pen(2),D-Pen(5)]enkephalin (delta(1)) and [(3)H]Deltorphin II (delta(2)) competition binding. ARD-353 also showed selective delta receptor agonist activity in mouse-isolated vas deferens.

DPI-221 [4-((alpha-s)-alpha-((2s,5r)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide]: a novel nonpeptide delta receptor agonist producing increased micturition interval in normal rats.

There is a wealth of information from animal models and clinical opioid-analgesic use that indicates a significant role for opioid receptors in the modulation of bladder activity. The novel benzhydrylpiperazine compound DPI-221 [4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide] was characterized as having delta receptor selectivity using radioligand binding (K(i) = 2.0 +/- 0.

DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity.

Compound (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25 degrees C using membranes from rat brain or guinea pig cerebellum, the Ki values measured for DPI-3290 at delta-, mu-, and kappa-opioid receptors were 0.18 +/- 0.

DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. II. A mixed opioid agonist with potent antinociceptive activity and limited effects on respiratory function.

Allyl-2,5-dimethyl-1-piperazines have been of interest as analgesic agents for the management of moderate-to-severe pain. In this study, we compared the antinociceptive properties and respiratory depressant activity of one such agent, (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), with those of established narcotic analgesics, morphine and fentanyl. Intravenous administration of DPI-3290 in conscious laboratory rats increased antinociception in a dose-dependent manner with a corresponding ED(50) value of 0.

Preclinical neurochemical and electrophysiological profile of 1192U90, a potential antipsychotic.

11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity.

Ryanodine action at calcium release channels. 2. relation to substituents of the cyclohexane ring.

Ryanodine (1) and dehydroryanodine (2) are equipotent probes for the ryanodine receptor (ryr) of calcium release channels and differ only in 9eq-methyl for 1 and 9,21-methylene for 2. Ryanoids 1 and 2 are used here to prepare novel modifications of the cyclohexane substituents to determine their effects on ryr activity and selectivity. 10-Oxo-1 when reacted with carbonyl and other reagents gave 13 C-10 derivatives including the epi-amine and epi-4-azidobenzoyl hydrazide as a candidate affinity probe.

Ryanodine action at calcium release channels. 1. importance of hydroxyl substituents.

Ryanodine (1) and dehydroryanodine (2) have a polar face formed by cis-hydroxyls at C-2, C-4, C-6, and C-12. The importance of the hydroxyls to the action of 1 and 2 at the ryanodine receptor (ryr) of calcium release channels is examined at [3H]-1 binding sites in brain and skeletal muscle and in heart membranes relative to cardiac contractility, a pharmacologic response which appears to be mediated by the ryr. Five types of changes are considered: blocking the 4- and 6-hydroxyls as cyclic borates and boronates; blocking the 10- and 12-hydroxyls as cyclic phosphates, phosphonates, and phosphoramidates; methylation at nitrogen or hydroxyls at C-4 and C-10; dehydration of the C-2 hydroxyl; additional data for a 4,12-oxygen-bridged series.

Amrinone combined with dobutamine improves hemodynamics and oxygen delivery without down-regulation of cardiac beta-adrenergic receptor density in porcine endotoxemia.

Effects of amrinone (AMR), a phosphodiesterase inhibitor, alone and in combination with dobutamine (DOB), on hemodynamics and O2 delivery were studied during porcine endotoxemia. Pentobarbital-anesthetized pigs were randomly administered either Escherichia coli lipopolysaccharide (endotoxin) or equivolumetric .9% NaCl (control) as a continuous infusion for 4 h.

Decreased proportion of type I myofibers in skeletal muscle of dogs with chronic heart failure.

Background: Whether biochemical and histological abnormalities of skeletal muscle (SM) develop in patients with chronic heart failure (HF) remains controversial. In the present study, dogs with chronic HF were used to examine potential alterations of SM fiber type, fiber size, number of capillaries per fiber (C/F), beta-adrenergic receptor density (Bmax), and fiber ultrastructural integrity.

Methods And Results: HF was produced in 17 dogs by sequential intracoronary microembolizations.

Myocardial beta adrenoceptor and voltage sensitive calcium channel changes in a canine model of chronic heart failure.

Effects of chronic heart failure upon receptor binding and cardiac function were studied in mongrel dogs. Heart failure was induced by three to seven, graded, sequential, intracoronary microembolizations performed 1 to 3 weeks apart. Depressed systolic and diastolic left ventricular function, reduced cardiac output, increased systemic vascular resistance, increased plasma norepinephrine concentration, left ventricular hypertrophy, and dilation were associated with the development of heart failure in this model.

Cardiac inotropic responses to calcium and forskolin are not altered by prolonged isoproterenol infusion.

Effects of prolonged isoproterenol infusion upon the density of cardiac calcium channels, calcium-mediated contractile responses, and the ability of forskolin to enhance tension development and cyclic AMP accumulation were studied in ventricular muscle preparations from Sprague-Dawley rats. Isoproterenol infusion (400 micrograms/kg per h s.c.

Effect of thyroid status on beta-adrenoceptors and calcium channels in rat cardiac and vascular tissue.

To determine the influence of thyroid hormone on beta-adrenoceptors and Ca2+ channels, rats were treated with thyroxine (75 micrograms/100 g sc daily for 5 days) or propylthiouracil (0.05% in drinking water for 30 days). beta-Adrenoceptor density in ventricular tissue, measured by [125I]iodocyanopindolol binding, was significantly increased and decreased respectively, following thyroxine or propylthiouracil treatment to 124.

Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoceptor and muscarinic receptor levels.

Chronic administration of atropine (40-100 mg/kg, 23 days) produced a 29-33% increase in muscarinic receptors, measured by [3H]quinuclidinyl benzilate binding, in rat brain. Diisopropyl phosphorofluoridate (0.9 mg/kg, 14 days) produced a 35% decrease in muscarinic receptors.

Effects of prolonged phenylephrine infusion on cardiac adrenoceptors and calcium channels.

Effects of prolonged in vivo infusion of phenylephrine upon receptor binding and cardiac contractility were studied in Sprague-Dawley rats. A 1-hr i.v.

In vitro and in vivo characterization of 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-isothiocyano)phenyl-1,4- dihydropy ridine as a Ca2+ channel antagonist.

The actions of 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-isothiocyano)phenyl-1,4- dihydropyridine (o-NCS-DHP), a nifedipine analog bearing a reactive group, have been characterized in vitro by pharmacological and radioligand binding techniques in a number of smooth muscles and in vivo by blood pressure and radioligand binding. o-NCS-DHP exhibits persistent, but slowly reversible, antagonism in guinea pig ileal longitudinal smooth muscle, guinea pig bladder, taenia coli, rat portal vein, and rat tail artery to receptor responses (muscarinic and alpha-adrenoceptor) and K+ depolarization initiated responses. Duration of response was significantly longer than that of equivalent concentrations of nifedipine.

Interaction of phenoxybenzamine with muscarinic receptors and calcium channels.

Phenoxybenzamine (POB, 10(-6) - 10(-4) M) inhibited the responses of guinea pig ileal longitudinal smooth muscle to both muscarinic agonists and K+-depolarization but was more effective against the agonist-induced responses. POB inhibited binding of both the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) and the Ca2+ channel antagonist [3H]nitrendipine and was, paralleling its effects on mechanical responses, more effective against [3H]QNB binding. POB reduced specific [3H]QNB binding by a reduction in Bmax with no change in KD, but inhibited [3H]nitrendipine binding by reducing KD with no effect on Bmax.

Specific and non-specific desensitization of guinea-pig ileal smooth muscle.

The effects of cis-2-methyl-4-dimethylaminomethyl-1-3-dioxolane methiodide (CD), a muscarinic agonist, histamine, substance P and K+-stimulation on the mechanical responses, Ca2+-dependence and desensitization in guinea-pig ileal longitudinal smooth muscle have been studied. The mechanical responses to all four stimulants are highly dependent upon extracellular Ca2+(Ca2+EXT) and are blocked by the Ca2+ channel antagonist nicardipine. The tonic (slow) components of response are more dependent on Ca2+EXT and are more sensitive to nicardipine (IC50 values 5.

Characterization of binding of the Ca++ channel antagonist, [3H]nitrendipine, to guinea-pig ileal smooth muscle.

A chemically heterogeneous group of compounds, the Ca++ channel antagonists, which includes verapamil, diltiazem and nifedipine inhibits excitation-contraction coupling in smooth and cardiac muscle by blocking Ca+ entry at a specific class of Ca++ channels. The binding of the nifedipine analog, [3H]nitrendipine, to a microsomal fraction from guinea-pig longitudinal smooth muscle has been characterized. Specific binding was saturable, linear with protein concentration and reversible.