Short-lasting Hypotension Research Articles

The Effect and Safety of Prostaglandin Administration in Pediatric Liver Transplantation.

BackgroundProstaglandins are often administered after liver transplantation (LT) to diminish ischemia-reperfusion injury (IRI), to favor liver recovery and to prevent vascular thrombosis. Possible beneficial effects in adult liver recipients are controversial, but the single existing pediatric small case series shows no significant impact of prostaglandin administration after LT. The purpose of this study was to analyze the effect of the prostaglandin dinoprostone in pediatric liver recipients.MethodsA retrospective analysis of 41 children (<16 years) who underwent LT between March 2008 and December 2013 was performed. Dinoprostone was administered at a rate from 0.1 to a maximum of 0.6 μg/kg per hour immediately after LT and for a maximum of 5 days. Effect of dinoprostone on post-LT IRI and hepatic function up to 60 postoperative days and number of hypotensive episodes were analyzed.ResultsThe median cumulative dose of dinoprostone was 28 μg/kg (interquartile range, 23.2). Dinoprostone had no significant effect on post-LT liver function tests and factor V levels at any of the administered dosages. There was no significant association between the total quantity of vasopressor given and the number of hypotensive episodes observed in 8 patients. One patient showed a short-lasting hypotension, possibly related to the administration of dinoprostone.ConclusionsThis study did not show, at any dosage between 0.1 and 0.6 μg/kg per hour, any differences in beneficial or harmful effects of high- or low-dose dinoprostone administered immediately after pediatric LT on markers of IRI, hepatic function, or hypotension.

On the “swelling” of mitochondria under palmitic acid, calcium, and hypotension treatment

The high-amplitude swelling of mitochondria is critically considered. In contrast to numerous statements by some authors about a marked swelling of isolated liver mitochondria under the influence of palmitic acid, calcium ions, or hypotension, we have shown that mitochondria are generally not subject to highamplitude swelling. According to optical-microscopy data even during long-lasting incubation (in distilled water) where full hypotension takes place, the size of liver mitochondria (approximately 1 µm) can be enlarged by no more than by 40%. Under short-lasting hypotension or the addition of palmitic acid the mitochondrial diameter becomes greater by only 20% or remains virtually unchanged. The light scattering of the mitochondrial suspension measured using a photometer according to the decrease in optical density declines by 2.5 times. A decrease in the light scattering in hypotension or via the addition of palmitic acid or calcium (in an isotonic medium) occurs because of damage (even destruction) to the outer membrane, rather than due to the swelling of mitochondria, as was previously believed. The inner membrane is not significantly expanded. The destruction of the outer membrane reduces the probability of light scattering by each mitochondrion at the boundary layer of the water/membrane interface. Release of substances from the matrix resulting in a decrease of its refractive index may additionally contribute to the decrease in light scattering. Palmitic acid and calcium (at concentrations of 10 to 100 µM) cause permeabilization and disruption of the outer membrane gradually, over several minutes. Full hypotension activates this process very rapidly, viz., within a fraction of a second. Under low ionic-strength conditions, the addition of calcium leads to neutralization of negative charges on the membrane surface, which induces aggregation of mitochondria, thus enhancing light scattering and creating the illusion of mitochondrial swelling.

Nitric oxide as a target for the hypotensive and vasorelaxing effects induced by (Z)-ethyl 12-nitrooxy-octadec-9-enoate in rats

The cardiovascular effects induced by a new organic nitrate were investigated in rats. The (Z)-ethyl 12-nitrooxy-octadec-9-enoate (NCOE) was synthesized from ricinoleic acid, the major compound of the castor oil. NCOE induced significant and dose-dependent hypotension and bradycardia in normotensive rats. In rats pretreated with NCOE (60mg/kg, i.v., once a day) for 4 consecutive days, hypotension induced by the nitrate was similar to that observed in rats that were not pretreated with the compound. The vasorelaxation induced by the compound was concentration-dependent (10−10–10−3M) in rat mesenteric artery rings, pre-contracted with phenylephrine (1μM), with or without endothelium. Pre-incubation with PTIO (300μM), a free radical form of NO (NO) scavenger, attenuated the NCOE vasorelaxation potency. However, in the presence of l-cysteine (3mM), a reduced form of NO (NO−) scavenger, NCOE response was potentiated. NCOE effect was not changed in the presence of an inhibitor of cytochrome P450, proadifen (10μM). On the other hand, the vasodilation was reduced in the presence of mitochondrial aldehyde dehydrogenase inhibitor (mtALDH), cyanamide (1mM); soluble guanylyl cyclase inhibitor (sGC), ODQ (10μM); and non-selective K+ channels blocker, TEA (3mM). In addition the NCOE-induced vasorelaxation was reduced by BKCa (iberiotoxin, 100nM) and KATP selective (glibenclamide, 10μM) blockers, however the effect was not modified by a KV blocker (4-aminopyridine, 1mM). Furthermore, NCOE increased NO levels in rat aortic smooth muscle cultured cells, detected by NO-sensitive probe DAF-2DA, by flow cytometry. These results together suggest that NCOE induces short-lasting hypotension and bradycardia, and promotes vasorelaxation due to NO release through the compound metabolism via mtALDH and consequent sGC, KATP and BKCa activation. Furthermore, the compound was not able to induce tolerance.

Antihypertensive effect of a standardized aqueous extract of Cecropia glaziovii Sneth in rats: An in vivo approach to the hypotensive mechanism

Cecropia glaziovii Sneth is a common tree at the Southeastern Brazilian coast. As many other species of the genus, it shares the reputed folk use to treat heart failure, cough, asthma and bronchitis. The plant has been cultivated under controlled conditions and the 2% aqueous extract (AE) prepared with the dried leaves was standardized by its chemical contents on catechins, flavonoids and procyanidins. The present paper reports the antihypertensive activity of AE and of n-butanol fraction (BuF), an enriched semi-purified butanolic fraction used to isolate the main chemical constituents. Oral administration of AE and BuF induced hypotension in normotensive rats. The effect of AE (0.5 g/kg/bi, p.o.) was time and dose-dependent peaking at 2-3 weeks after daily administration. BuF was faster but not more active than AE. Both extracts decreased the hypertension of spontaneous hypertensive rats, the hypertension induced in rats by L-NAME treatment and that induced by constriction of one renal artery. The antihypertensive effect was maintained for as long as 60 days of treatment and was reversible upon drug washout at the same rate of its establishment. Acute i.v. administration of BuF to anesthetized rats induced a fast short-lasting hypotension and inhibited the pressor responses to noradrenaline, angiotensin I and angiotensin II by 40%. These results were indirect indications that the hypotension induced by AE is not related to ACE inhibition, increased NO synthesis, or specific blockade of alpha1 and AT1 receptors. It can be suggested that BuF interferes with the calcium handling mechanisms in smooth muscle cells and neurons. Intravenous injection of five out of nine compounds isolated from BuF produced immediate but short-lasting hypotension that does not correlate with the onset of the hypotension after oral treatment. This finding suggests that they may not be the compounds directly responsible for the delayed and sustained hypotension after per os administration of AE. The many compounds isolated from AE are under evaluation to determine its pharmacokinetics, mechanisms of action and interactions necessary to yield the plant effect. Although its mechanism is still unknown, AE seems to be an effective and safe antihypertensive phytomedicine.

The effects of neurotoxic insecticides on central cholinergicallymediated hypertension

Malathion by itself produced a double-phased blood pressure response in the anaesthetized rat. Immediately after intravenous injection of malathion there was a shortlasting hypotension (up to 90 sec), followed by a prolonged hypertension similar to that observed after intravenous injection of phisostigmine to rats. The hypotensive response is probably due to accumulation of acetylcholine after cholinesterase inhibition by malathion. The hypertensive response to malathion is due to secondary activation of adrenergic mechanisms in the central nervous system. Malathion coused dose-dependent inhibition of the central cholinergically mediated hypertension in rats produced by intravenous injection of physostigmine. Both the degree and duration of hypertension were equally depressed. These experiments indicate that development of central cholinergically-mediated hypertension is possible only in the presence of functionally competent cholinesterase. Both lindan and permethrine also depress the central cholinergically mediated hypertension produced by intravenous injection of physostigmine. Thus, all the three neurotoxic insecticides can inhibit transmitter interaction which is the basis of central cholinergically mediated hypertension, but not necessarily by the same mechanisms.

Hemodynamic effects and histamine release elicited by the selective adenosine A 3 receptor agonist 2-Cl-IB-MECA in conscious rats

The hemodynamic effects of the novel, selective adenosine A 3 receptor agonist 2-chloro- N 6-(3-iodobenzyl)adenosine-5′- N-methylcarboxamide (2-Cl-IB-MECA) were investigated in conscious rats. Intravenous administration of 200 μg/kg 2-Cl-IB-MECA resulted in a short-lasting hypotension, which was accompanied by a 50–100-fold increase in plasma histamine concentrations. Administration of a second dose of 2-Cl-IB-MECA did not elicit any hemodynamic effects. Also no histamine release was observed after the second dose. The observation of rapid tachyphylaxis in combination with histamine release suggests that mast cell mediator release plays a key role in the hemodynamic effects of adenosine A 3 receptor agonists.

The effect of Phoneutria nigriventer (armed spider) venom on arterial blood pressure of anaesthetised rats

The changes induced in the mean arterial blood pressure of anaesthetised rats following the administration of armed spider ( Phoneutria nigriventer) venom have been investigated. The intravenous injection of Phoneutria nigriventer venom (0.1 mg/kg) evoked a brief and reversible decrease in the mean arterial blood pressure whereas a higher dose of venom (0.3 mg/kg) caused a biphasic response characterized by a short-lasting hypotension followed by a sustained and prolonged hypertension (40–50 min). These changes were accompanied by tachycardia, salivation, fasciculations, defecation and respiratory disturbances. Pretreatment of the animals with atropine (10 mg/kg), propranolol (100 mg/kg), phenoxybenzamine (100 mg/kg) and indomethacin (4 mg/kg) did not significantly affect the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. Similarly, the bradykinin B 2 receptor antagonist Hoe 140 ( d-Arg-[Hyp 3,Thi 5, dTic 7,Oic 8]-bradykinin) (0.6 mg/kg), the PAF receptor antagonist WEB 2086 (3-(4-(2-chlorophenyl)-9-methyl-6 H-thieno-(3,2 f) (1,2,4)-triazolo-(4,3- a) (1,4)-diazepine-2-yl)-(4-morpholinyl)-1-propanone) (20 mg/kg), the tachykinin NK 1 receptor antagonist SR 140333 (( S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenyl acetyl) piperidin-3-yl] ethyl}-4-phenyl-1-azoniabicyclo[2.2.2] octane, chloride) (0.5 mg/kg), the tachykinin NK 2 receptor antagonist SR 48968 ( (S)-N-methyl- N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide) (0.5 mg/kg) and the nitric oxide synthase inhibitor N ω-nitro- l-arginine methyl ester (10 mg/kg) had no significant effect on the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. The increase in the blood pressure induced by Phoneutria nigriventer venom was also not significantly affected by either the angiotensin II receptor antagonist losartan (10 mg/kg) or the endothelin ET A receptor antagonist FR 139317 (( R)2-[( R)-2-[[1-(hexahydro-1 H-azepinyl]carbonyl]amino-4-methyl-pentanoyl]amino-3-[3-(1-methyl-1 H-indoyl)]propionyl] amino-3-(2-propionyl] amino-3-(2-pyridyl) propionic acid) (30 mg/kg). The ATP-dependent K + channel antagonist glibenclamide (50 mg/kg) reduced by 40% the hypotension induced by Phoneutria nigriventer venom without affecting the hypertensive response. Pretreatment of the animals with L-type Ca 2+ channel antagonists such as verapamil (10–100 μg/kg/min), diltiazem (40–120 μg/kg/min) and nifedipine (0.3–10 mg/kg) markedly attenuated the hypertension induced by Phoneutria nigriventer venom. Verapamil (30 μg/kg/min) and diltiazem (120 μg/kg/min) also promptly reversed the established hypertension induced by Phoneutria nigriventer venom when infused 8 min after venom injection. Our results indicate that the brief decrease of blood pressure induced by Phoneutria nigriventer venom is partially due to ATP-dependent K + channel activation. The prolonged hypertension seems to result from direct Ca 2+ entry into vascular and/or cardiac muscles.

Cardiovascular Effects of Serotonin Agonists and Antagonists

The effects of serotonin (5-hydroxytryptamine; 5-HT) on the cardiovascular system are complex. These effects, consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilation or vasoconstriction are mediated by three main sets of receptors called 5-HT1-like, 5-HT2, and 5-HT3. In addition, recent findings suggest the participation of a putative 5-HT4 receptor. Though selective 5-HT1A receptor agonists can lower heart rate (and arterial blood pressure), 5-HT usually lowers heart rate by eliciting an initial short-lasting hypotension due to bradycardia (von Bezold-Jarisch-like reflex) via 5-HT3 receptors located on sensory vagal nerve endings in the heart. Once this bradycardia reflex is suppressed--for example, during deep anesthesia, vagotomy, or spinal section--5-HT can increase heart rate in different species by a variety of mechanisms. Myocardial 5-HT1-like, 5-HT2, and 5-HT4 receptors appear to be involved in the cat, rat, and pig, respectively. 5-HT-induced tachycardia in the dog and rabbit is due mainly to release of catecholamines and involves 5-HT2 receptors on the adrenal medulla and 5-HT3 receptors on postganglionic cardiac sympathetic nerve fibers. Recently, 5-HT3 receptors also have been implicated in the 5-HT-induced tachycardia in the conscious dog. The blood pressure response to 5-HT is usually triphasic and consists of a von Bezold-Jarisch-like reflex, a middle pressor phase, and a longer-lasting hypotension. The pressor response is a consequence of vasoconstriction mediated via 5-HT2 receptors; however, vasoconstriction in the dog saphenous vein and cephalic arteries and arteriovenous anastomoses is due to stimulation of 5-HT1-like receptors. The depressor response exclusively involves 5-HT1-like receptors located at four different sites: (a) central nervous system (decrease in sympathetic and increase in vagal nervous activity), (b) sympathetic nerve terminals (reduction of transmitter release), (c) vascular smooth muscle (vasodilatation), and (d) vascular endothelium (release of a relaxant factor, probably nitric oxide). Arteriolar dilatation, together with the constriction of arteriovenous anastomoses, leads to an increase in nutrient (tissue; capillary) blood flow. The 5-HT1-like receptors are heterogeneous in nature; however, apart from the resemblance of the central nervous system 5-HT1-like receptor causing hypotension and bradycardia to the 5-HT1A binding subtype, the relationship of the other 5-HT1-like receptors to 5-HT1 binding subtypes is still debatable.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiovascular effects from stimulation of 5-hydroxytryptamine receptors.

The cardiovascular effects of 5-hydroxytryptamine (5-HT), consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, are mediated by three main types of receptors called 5-HT1-like, 5-HT2, and 5-HT3. In intact animals 5-HT elicits a short-lasting bradycardia, accompanied by hypotension, via stimulation of 5-HT3 receptors located on sensory vagal nerve endings in the heart (Bezold-Jarisch reflex). The nature of 5-HT receptors mediating tachycardiac responses is species-dependent. Myocardial 5-HT1-like and 5-HT2 receptors subserve tachycardia in the cat and rat, respectively. Tachycardia in the dog and rabbit is due to a release of catecholamines effected via the 5-HT2 receptors on the adrenal medulla and the 5-HT3 receptors on postganglionic cardiac sympathetic nerve fibres, respectively. The receptors mediating tachycardia in the pig are unique as they do not resemble any of the three 5-HT receptors characterized so far. The blood pressure response to 5-HT is usually triphasic: initial short-lasting hypotension due to reflex bradycardia (via 5-HT3 receptors), a middle pressor phase (via 5-HT2 receptors), and a longer-lasting hypotension (via 5-HT1-like receptors). Vascular contraction by 5-HT is generally mediated by 5-HT2 receptors (located primarily on the large conducting vessels), though in some instances (e.g., dog saphenous vein, dog and human basilar artery, and porcine arteriovenous anastomoses) the contractile response is (also) mediated via 5-HT1-like receptors. Venous dilatation and arteriolar dilatation (leading to increased capillary ['nutrient'] blood flow) occur via 5-HT1-like receptors located mainly on the vascular smooth muscles but also on the endothelium; the smooth muscle and endothelial 5-HT1-like receptors seem to be heterogeneous. In addition, 5-HT can elicit vasodilatation and hypotension as a result of decreased sympathetic nervous tone by acting within the central nervous system and by inhibiting noradrenaline release by a presynaptic action. Both these effects also involve 5-HT1-like receptors that do not appear to be identical. Last, knowledge of the cardiovascular effects of 5-HT and the nature of the receptors involved should be helpful in developing 5-HT-related compounds that may be useful in the treatment of hypertension, migraine, and peripheral vascular diseases.

Studies on the vascular and hematological changes induced by ellagic acid in rats.

We compared the major changes induced by ellagic acid (EA), a Hageman factor activator, in normal rats and in kininogen-deficient Brown Norway rats. In normal rats, large doses of EA induced a congestion of lymph nodes, spleen and liver, a prolongation of activated partial thromboplastin time, the consumption of prekallikrein, high molecular weight kininogen and fibrinogen, as well as the stimulation of platelets with their accumulation in lungs, liver and spleen. A systemic hypotension of long duration was also observed. The fibrinogen consumption, the thrombocytopenia and the lengthening of activated partial thromboplastin time were dose-dependent. In kininogen-deficient rats, EA induced only a minimal congestion of lymphoid tissues, the accumulation of platelets in lungs, a decrease of plasma fibrinogen and a short-lasting hypotension. It is concluded that the vascular changes induced by blood coagulation with ellagic acid resulted mainly from kinin formation.

κ-Opiate-induced diuresis and changes in blood pressure: Demonstration of receptor stereoselectivity using (+)- and (−)-tifluadom

(+)-Tifluadom injected i.p. produced a biphasic response of urine output: within the first hour of its administration the drug produced antidiuresis followed by a diuretic phase. In contrast, the (−) isomer produced a modest reduction in urine output as compared to the output of the saline-treated rats. In addition, (+)-tifluadom markedly reduced the output of urinary Na + and K +. The effects of (+)-tifluadom were blocked by 7.5 mg/kg naloxone but not by 10 mg/kg of the benzodiazepine antagonist Ro 15-1788. Parallel experiments demonstrated that the i.v. administration of (+)-tifluadom to non-anesthetized rats caused a dose-related pressor response that lasted for at least 15 min. This effect of (+)-tifluadom was blocked and antagonized by naloxone. In contrast, (−)-tifluadom was either inactive on the cardiovascular system or produced short-lasting hypotension. In pentobarbital-anesthetized rats, 100 μg/kg (+)-tifluadom caused a precipitous hypotension that was reversed by naloxone but not by Ro 15-1788.

Exaggerated hypotension by N-formylmethionylleucyl-phenylalanine in indomethacin pretreated rats. Role of toxic oxygen.

In pentobarbital anaesthetized rats the intravenous administration of the oligopeptide N-formyl-Met-Leu-Phe (FMLP) is shown to produce a short-lasting hypotension. When the animals have been pretreated with indomethacin, FMLP induces a marked and sustained blood pressure fall. This exaggerated hypotensive response to FMLP is absent in rats which have received a low dose of endotoxin at the day before, and is greatly reduced in animals treated with ascorbic acid or dimethylsulfoxide. In addition, the duration of hypotension is shortened in rats which have been partially depleted of leukocytes by daily methotrexate dosages, or which simultaneously receive drug treatments known to enhance vessel wall cyclic AMP levels like isoprenaline, glucagon or theophylline. The results suggest that after the FMLP administration toxic oxygen species generated by leukocytes contribute to the development of the cardiovascular dysfunction. Endothelial cAMP is suggested to control the sensitivity of the cardiovascular system to these reactive species.

The triple effect ineuced by Δ9-tetrahydrocannabinol on the rat blood pressure

The intracenous injection of Δ 9-trans-tetrahydrocannobinol (2–10 mg/kg) produced dose-related changes in the rat blood pressure. Three efefcts were detected: )1) an immediate and short-lasting hypotension related to brady-cardia, blocked after atropine, vagotomy hexamethonium an dpitching; (2) A rise in blood pressure 30 seconds after injection, insective to yohimbine, hexamethonium, pithing and reserpine treatment; (3) a slow and persistent hypotension, 5 min later, insensitive to atropine and vagotomy but inhibited by hexamethonium, pithing and reserpine treatment. It was concluded that intravenous injection of THC in rats may induced vagal stimualtion and hypptension. This effect was reversed and followed by hypertension due to direct vasoconstriction not dependent on sympathetic activity. After this action a centyral decrease in sympathetic tonus led to a persistent hypotension an effect which is commonly reeported for mammals.

The Origin of the Hypertensive Effect of Arecoline in Rats

Arecoline, injected intravenously in rats, causes a short-lasting hypotension followed by a hypertension of long duration. The hypertensive effect of arecoline results mainly from its stimulating action on the sympathetic ganglia. Arecoline activates atropine-sensitive receptors in these ganglia, thus producing the release of catecholamines from adrenergic terminals.