Effect Of DMPP Research Articles

Sympathetic regulation of cutaneous circulation in the rat

The purpose of the present study was to characterize, in vivo, the function and origin of peripheral α-adrenergic mechanisms in acral regions of the cutaneous microvasculature. Laser-Doppler flowmetry was used to continuously monitor changes in local cutaneous microvascular perfusion (CP) measured at the plantar surface of the terminal phalange in the rat. In ketamine-anesthetized rats, the intravenous administration of phentolamine (a nonselective α-adrenoceptor antagonist) elicited a dose-dependent (0.01–1.0 mg/kg, i.v.) increase in CP, a decrease in mean arterial pressure (MAP) and a marked reduction in cutaneous vascular resistance (CVR). These results demonstrate a high degree of endogenous α-adrenergic tone in the cutaneous microvasculature of the rat. In pithed rats, cutaneous vasoconstriction could be evoked by ganglionic stimulation with DMPP or by electrical stimulation of the peripheral cut end of the sciatic nerve trunk. DMPP and sciatic nerve responses were not altered by propranolol or atropine, but were inhibited by phentolamine. In addition, the effects of DMPP on CP were abolished by bilateral adrenal demedullation, but were unaltered by hindlimb denervation. These results suggest that the predominant vasoconstrictor tone in the cutaneous vasculature is mediated by a humoral action of circulating catecholamines at postjunctional α-adrenoceptors. The adrenal medulla appears to be the origin of this humoral tone. Postganglionic sympathetic nerves play an insignificant role in mediating cutaneous vasoconstriction elicited by ganglionic stimulation.

Cholinergic Stimulation of Inositol Phosphate Formation in Bovine Adrenal Chromaffin Cells: Distinct Nicotinic and Muscarinic Mechanisms

The ability of cholinergic agonists to activate phospholipase C in bovine adrenal chromaffin cells was examined by assaying the production of inositol phosphates in cells prelabeled with [3H]inositol. We found that both nicotinic and muscarinic agonists increased the accumulation of [3H]inositol phosphates (mainly inositol monophosphate) and that the effects mediated by the two types of receptors were independent of each other. The production of inositol phosphates by nicotinic stimulation required extracellular Ca2+ and was maximal at 0.2 mM Ca2+. Increasing extracellular Ca2+ from 0.22 to 2.2 mM increased the sensitivity of inositol phosphates formation to stimulation by submaximal concentrations of 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) but did not enhance the response to muscarine. Elevated K+ also stimulated Ca2+-dependent [3H]inositol phosphate production, presumably by a non-receptor-mediated mechanism. The Ca2+ channel antagonists D600 and nifedipine inhibited the effects of DMPP and elevated K+ to a greater extent than that of muscarine. Ca2+ (0.3-10 microM) directly stimulated the release of inositol phosphates from digitonin-permeabilized cells that had been prelabeled with [3H]inositol. Thus, cholinergic stimulation of bovine adrenal chromaffin cells results in the activation of phospholipase C by distinct muscarinic and nicotinic mechanisms. Nicotinic receptor stimulation and elevated K+ probably increased the accumulation of inositol phosphates through Ca2+ influx and a rise in cytosolic Ca2+. Because Ba2+ caused catecholamine secretion but did not enhance the formation of inositol phosphates, phospholipase C activation is not required for exocytosis. However, diglyceride and myo-inositol 1,4,5-trisphosphate produced during cholinergic stimulation of chromaffin cells may modulate secretion and other cellular processes by activating protein kinase C and/or releasing Ca2+ from intracellular stores.

Cholinergic modulation of the release of 5-hydroxytryptamine from the guinea pig ileum.

Isolated segments of the guinea pig ileum were vascularly perfused and the release of 5-HT and its metabolite 5-HIAA into the portal venous effluent determined by HPLC with electrochemical detection. Test substances were applied via the arterial perfusion medium. Oxotremorine inhibited concentration-dependently the release of 5-HT and 5-HIAA (by 47% at 1 mumol/l). Scopolamine (0.1 mumol/l) did not affect the release of 5-HT and 5-HIAA, but antagonized the effect of oxotremorine. In the presence of TTX (1 mumol/l), oxotremorine (1 mumol/l) increased the release of 5-HT by 150% and that of 5-HIAA by 220%. This increase was completely blocked by scopolamine. Hexamethonium (100 mumol/l) and TTX (1 mumol/l) reduced the release of 5-HT by 32 and 40%, respectively. DMPP (10 mumol/l) increased the release of 5-HT by 57%, and this effect was prevented by hexamethonium. Neither DMPP nor hexamethonium significantly affected the release of 5-HIAA. The enhancing effect of DMPP on 5-HT release was increased and prolonged in the presence of TTX or scopolamine. Nicotine (1, 10 or 30 mumol/l) alone did not cause a consistent increase in the release of 5-HT. However, in the presence of scopolamine nicotine increased the release of 5-HT by 57%. In conclusion, the release of intestinal 5-HT is facilitated via muscarine and nicotine receptors located on the enterochromaffin cells. Indirect evidence suggests that the release of 5-HT is additionally modulated by an as yet unknown inhibitory neurotransmitter released by muscarine receptor activation.

An atropine-like inhibitory effect of DMPP on rat isolated urinary bladder.

DMPP inhibits the nerve-mediated contractions of the rat isolated bladder, its effect being greater in preparations from newborn (2 day old) than adult animals. This effect of DMPP was unaffected by hexamethonium. In preparations from adult animals the effect of DMPP increased with frequency of stimulation and was fully prevented by the presence of atropine. In bladders from newborn rats low concentrations of furthrethonium (FHR) (10 nM) activated a series of rhythmic contractions which were unaffected by tetrodotoxin and abolished by DMPP through an hexamethonium-insensitive action. On the other hand DMPP did not affect rhythmic contractions produced by a low concentration of eledoisin (60 nM). In bladders from adult rats FHR (10 microM) and KCI (30 mM) produced contractures of comparable magnitude. DMPP inhibited, in concentration-related manner the FHR-induced tonic contraction but had little effect on that produced by KCI. These findings indicate that in the rat bladder, DMPP antagonizes selectivity cholinergically-mediated contractions through a mechanism which is unaffected by hexamethonium or tetrodotoxin. An "atropine-like' activity of DMPP should be considered.

Actions of a nicotinic agonist, DMPP, on intestinal ion transport [formula omitted][formula omitted

High-dose carbachol (10 −3 M) has previously been shown to cause NaCl absorption in short-circuited rabbit ileum. The mechanism of this effect may be norepinephrine release induced by carbachol activation of presynaptic nicotinic receptors on adrenergic neurons. Norepinephrine then interacts with postsynaptic α-adrenergic receptors on intestinal mucosal cells to stimulate neutral NaCl absorption and inhibit electrogenic bicarbonate secretion. The present paper examines the in vitro intestinal ion transport effects of DMPP an agent which is more specific than carbachol on nicotinic cholinergic receptors. DMPP (10 −5 M) caused a transient increase followed by prolonged depression of the short-circuit current, increased NaCl absorption and increased tissue conductance. This effect was antagonized by hexamethonium and phentolamine. It is concluded that nicotinic cholinergic agents stimulate norepinephrine release from adrenergic nerves and effect intestinal ion transport just as norepinephrine does.

Analysis of the cardiovascular responses to McN-A-343 and DMPP in pithed guinea-pigs

General characteristics and pharmacological properties of the presser response and tachycardia produced by intravenous administration of 4-( m-chlorophenylcarbamoyloxy-2-butynyltrimethylammonium (McN-A-343) in pithed guinea-pigs were compared with those of 1,1-dimethyl-4-phenylpiperazinium (DMPP). The pressor effect and positive chronotropic effect of McN-A-343 were abolished and reduced, respectively, by atropine; both effects were blocked by bretylium and small doses of nicotine, but not by large doses of nicotine. The cardiovascular response to DMPP was reduced by bretylium and hexamethonium; in addition it was sensitive to both small and large doses of nicotine. The cardiovascular effect of McN-A-343 was not appreciably affected by hexamethonium, while that of DMPP by atropine. It is concluded that the pressor response to McN-A-343 results mainly from the activation of muscarinic receptors in sympathetic ganglia, providing evidence that these receptors exist in guinea-pig ganglia as well. The tachycardia produced by McN-A-343 is mediated via the cardiac sympathetic ganglia and consists of one component sensitive to atropine and the other component resistant to atropine and hexamethonium. The cardiovascular effect of DMPP is due to the activation of nicotinic receptors both in the sympathetic ganglia and the adrenal medulla, and probably to a tyraminelike action of the drug.

Antagonism by propranolol of the ganglion stimulant action of 5-hydroxytryptamine

The effects of racemic propranolol and its constituent isomers were studied on ganglionic stimulation produced in situ by close arterial injection of 5-HT and DMPP to the superior cervical ganglion. Ganglion stimulation was recorded in terms of the resultant contraction of the nictitating membrane. d,l-Propranolol caused a biphasic antagonism of the ganglion stimulant effect of 5-HT. At low doses, 0.5–10 μg, the antagonism was surmountable by increasing the amount of 5-HT. The l-isomer (0.2–4 μg) but not d-propranolol also caused antagonism. At higher doses, 0.1–5 mg, both d,l- and d-propranolol caused a second type of blockade of 5-HT which was not surmountable and resembled that seen with procaine. The ganglion stimulatn effects of DMPP and acetylcholine were only antagonised by the higher doses of d- and d,l-propranolol. d,l-Propranolol did not reduce the direct stimulation by 5-HT on the muscle of the nictitating membrane.

射精の研究

The effects of autonomic drugs on seminal emission and ejaculation were investigated in mongrel dogs. Changes in the posterior urethral pressure (Posterior Urethrogram) and the volume of seminal emission during continuous hypogastric nerve stimulation were measured in different dogs. The seminal emission induced by hypogastric nerve stimulation caused continuous rise in the posterior urethral pressure. When the pressure reached the maximum level, a rhythmic alteration of the pressure which was considered to be a phenomenon identical to ejaculation occurred. The drugs were administered into the aorta close to the bifurcation.The following results were obtained: Tetrodotoxin (1-5μg) abolished both seminal emission and rhythmic alterations of the posterior urethral pressure. Phenylephrine (10-100μg) and methoxamine (10-30μg) markedly increased the seminal emission and induced the rhythmic alterations. Phentolamine (1-10mg) and phenoxybenzamine (1-10mg) abolished both seminal emission and the rhythmic alterations. Administration of isoproterenol (10-30μg) or propranolol (1-10mg) affected neither seminal emission nor the rhythmic alterations. Acetylcholine (1-10μg) or atropine (1-10μg) did not show any definite effect on both seminal emission and on the rhythmic alterations. No significant effect of DMPP (10-30μg) on seminal emission or on the rhythmic alterations was observed. No significant change in seminal emission was caused by hexamethonium (100-500μg). The rhythmic alterations were not affected by the agent in most dogs.From these results it is concluded that both semiqal emission and ejaculation are predominantly under the influence of the adrenergic nervous system, particularly through an α-adrenergic receptor mechanism.

The role of alpha-adrenergic receptor mechanism in ejaculation.

The effects of autonomic drugs on seminal emission and ejaculation were investigated in mongrel dogs. Changes in the posterior urethral pressure (posterior urethrogram) and the volume of seminal emission during continuous hypogastric nerve stimulation were measured in test animals. The seminal emission induced by hypogastric nerve stimulation caused continuous rise in the posterior urethral pressure. When the pressure reached the maximum level, rhythmic alterations of the pressure which was considered, to be a phenomenon associated with ejaculation occurred. The drugs were administered into the abdominal aorta just above its bifurcation. Tetrodotoxin (1-5 μg) abolished both seminal emission and rhythmic alterations of the posterior urethral pressure. Phenylephrine (10-100 μg) and methoxamine (10-30 μg) increased markedly the seminal emission and induced the rhythmic alterations. Phentolamine (1-10mg) and phenoxybenzamine (1-10mg) abolished both seminal emission and the rhythmic alterations. Administration of isoproterenol (10-30 μg) or propranolol (1-10mg) affected neither seminal emission nor rhythmic alterations. Acetyl-choline (1-10 μg) or atropine (1-10 μg) did not show any definite effect on both seminal emission and the rhythmic alterations. No significant effect of DMPP (10-30 μg) on seminal emission and rhythmic alterations were observed. No significant change in seminal emission was caused by hexamethonium (100-500 μg). The rhythmic alterations were not affected by this agent in many dogs. From these results it is concluded that both seminal emission and ejaculation are predominantly under the influence of adrenergic nervous system, particularly through an a-adrenergic receptor mechanism

The effects of DMPP on adrenergic nerves in perfused hearts

Correlation of changes in the norepinephrine content with histochemically observed changes in adrenergic nerves within the perfused guinea-pig heart was made after intermittent injections of 1,1-dimethyl-4-phenylpiperazinium (DMPP). Heart rates and amplitude of contractions were also recorded for 2 hr. DMPP was administered to untreated hearts and to hearts of animals pretreated with α-methyl-p-tyrosine (α-MPT), H 22/54 [(3,4-dihydroxyphenyl) β-propylacetamide], or reserpine. Multiple injections of DMPP (2 hr) did not change the NE content of the ventricle. DMPP caused a significant decrease in ventricular NE in hearts of animals pretreated with α-MPT, H 22/54, or reserpine. Visualization of adrenergic nerves of the ventricles after DMPP administration showed a reduction in intensity of fluorescence only in hearts of animals pretreated with H 22/54 or reserpine. The explanation for the lack of visual discrimination of changes in fluorescence of the α-MPT-pretreated hearts is unknown. No change in intensity of fluorescence was noted in the chromaffin cells of the atria in any of the groups of animals studied. These experiments support the concept that certain ganglion stimulants, such as DMPP, serve to release the sympathetic neurohumor from the terminal ground plexus of nerve fibers within the heart. It also appears that release of NE is accompanied by a very efficient resynthesis within the nerve terminals.

Use of nitrification inhibitor DMPP to improve nitrogen recovery in irrigated wheat on a calcareous soil

The 3,4-dimethyilpyirazole phosphate (DMPP), commercialized as Entec, is a nitrification inhibitor developed by BASF (Germany) that may help to minimize N losses and to obtain a higher profit from N fertilizers. A two-year field trial was established in 2001 in the Northeast of Spain to assess the effects of DMPP on N use efficiency (NUE) and to determine the economic returns. Seven treatments have been carried out comparing the effect of DMPP on pig slurry and on mineral fertilizers. The application of DMPP resulted in better efficiency indexes on mineral fertilizers. An apparent nitrogen recovery of 0.465 kg kg-1, on average, was obtained for the Entec treatment. A net benefit of € 809 ha-1, on average, was obtained for the Entec treatment compared with € 607 ha-1 for the control treatment. The results of this study suggest that the nitrification inhibitor could improve farmer profit in irrigated wheat on a calcareous soil.

Effect of 1,1-dimethyl-4-phenylpiperazinium iodide on peristaltic reflexes of isolated guinea pig ileum.

DMPP has been shown, like nicotine, to augment the peristaltic reflex of an isolated ileum to increasing pressure at low concentrations but inhibits it at high concentrations. This is apparently due to its stimulating and paralyzing action on the parasympathetic ganglion at low and high concentrations, respectively. The fact that the paralyzing effect of DMPP on the ganglia was not evident on repeated administrations in animals of submaximal doses may be explained by the rapid elimination of it from the site of action. Whereas physostigmine antagonized the blocking effect of d-tubocurarine, it does not influence that of DMPP on peristaltic reflexes of the ileum.

Cardiovascular action of 1, 1-dimethyl-4-phenylpiperazinium iodide (DMPP): A ganglion stimulating agent useful in the diagnosis of pheochromocytoma

1. 1. DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) stimulated sympathetic ganglia more powerfully than nicotine and tetramethylammonium iodide and had less ganglion paralyzing action than nicotine in dogs, cats, rabbits and man. It differed from nicotine also in that its vasopressor action was largely independent of carotid and aortic chemoreceptor function. Respiratory stimulation, however, depended in part upon stimulation of these chemoreceptors. 2. 2. The pressor effect of DMPP depended upon release of epinephrine and/or norepinephrine from the adrenal glands and liver and stimulation of sympathetic ganglia with resultant vasoconstriction and cardioacceleration. The drug had no prominent direct action on blood vessels, at least in the perfused denervated dog's leg. 3. 3. Stimulation of parasympathetic ganglia caused initial transient bradycardia and fall in blood pressure that tended to inhibit the pressor action of DMPP. This opposing action was especially prominent after spinal cord section at C 6 and was eliminated by atropine or section of the vagus nerves. 4. 4. Section of the spinal cord at C 6 or paravertebral sympathectomy augmented the pressor action of DMPP, since these procedures also augment the pressor action of epinephrine and nor-epinephrine. 5. 5. TEAC, nicotine and hexamethonium all inhibited the ganglion-stimulating action of DMPP. The adrenergic blocking agents, priscoline, regitine and RO 2-3248, inhibited the pressor action of DMPP to a degree directly dependent on the inhibition of pressor response to nor-epinephrine. 6. 6. Response to DMPP was not altered by production of chronic neurogenic hypertension in dogs by section of the carotid sinus and aortic depressor nerves. But during the acute hypertension immediately following section of the buffer nerves the late sustained pressor action of DMPP was often replaced by a pronounced depressor effect. The significance of this difference is unknown, other than it may be listed with other observations suggesting that the two forms of hypertension depend on different mechanisms. 7. 7. DMPP has proved useful in the diagnosis of pheochromocytoma because of its strong and specific action on ganglia and adrenal medullary tissue. It ensures a high secretory activity of the tumor, the effect of which is specifically inhibited by adrenergic blocking agents.