Prostacyclin-induced hypothermia: Involvement of central histamine H2-receptors

Some of the biological activities of prostacyclin (PGI₂) are known to be mediated through cyclic AMP (cAMP). The purpose of this study was to assess the involvement of histamine and serotonin receptors as well as cAMP in the PGI₂-induced hypothermia in conscious guinea pig. Intracerebroventricular administration of 50–500 μg/kg PGI₂ produced a dose-related hypothermia, whereas its stable metabolite 6-keto prostaglandin F₁α had an insignificant effect. Low central doses (10–50 μg/kg) of dibutyryl cAMP (DBC) were hyperthermic, but high doses (100–500 μg/kg) caused hypothermia. Theophylline and low doses of DBC given centrally attenuated the PGI₂-induced hypothermia. Mepyramine and methysergide did not antagonize the effects of PGI₂ or DBC. However, central administration of metiamide (10–100 μg/kg) attenuated the hypothermic responses to both PGI₂ and DBC. These results suggest that histamine H₂-receptors are involved in the hypothermia induced by PGI₂.     

Mast cell histamine release induced by Portuguese man-of-war (Physalia) venom

Nematocyst venom from Portuguese Man-of War ($\text{Physalia}$ sp.) tentacles causes isolated rat peritoneal mast cells to release histamine. Extent of histamine release is dose-dependent (K_0.5 = 6.1 μg venom/ml) and attains 100% at high doses of venom. Release is independent of intra- and extracellular calcium levels and does not depend upon a cellular supply of ATP. The rate of histamine release is temperature-dependent and the extent of release is maximized broadly over the range of 10–30°C. The cytoplasmic marker lactate dehydrogenase, is released concomitantly with histamine but is more sensitive to the venom (K_0.5 = 2.1 μg/ml). Antimycin A, while it does not significantly affect venom-induced histamine release, increases the sensitivity of lactate dehydrogenase release (K_0.5 = 0.2 μg/ml). We conclude that $\text{Physalia}$ nematocyst venom induces the release of histamine from mast cells by a cytolytic mechanism and that this action is antagonized by an intracellular, energy-requiring process.     

Histamine paw edema of mice was increased and became H2-antagonist sensitive by co-injection of nitric oxide forming agents,but serotonin paw edema was decreased

Nitric oxide (NO) suprisingly caused the opposite effect on histamine and serotonin edema. The local injection of acidified nitrite (0.3–30 μg /paw which correspond to 10 μg−1mg/kg) increased histamine edema of mice up to 45±4% and suppressed serotonin edema to 90±3%. Other NO-generators (nitroprusside sodium and hydroxylamine) showed similar effects. These results were in accordance with our previous data on endogenous NO. Methylene blue (MB, 30ng/paw which corresponds to 1 μg/kg) suppressed histamine edema (62±3%) and increased serotonin edema (43±3%) in normal mice, being reversed by acidified nitrite. This suggests the involvement o of guanosine 3′, 5′ -cyclic monophosphate (cGMP) formation for the action of NO. Histamine edema became sensitive to H₂-antagonist, cimetidine, by co-injection of 30 μg/paw (which corresponds to 1mg/kg) acidified nitrite (ED₅₀=30 μg/kg versus ⪢ 1mg/kg). NO seemed to modify the histamine receptor(s) or tautomeric form of histamine. NO, O₂⁻ and other oxyradicals might finely control the vascular permeability together with inflammatory mediators.     

Infusions of chemicals into the brain and the development of sustained elevations of blood pressure in the rat

Osmotic minipumps were used to infuse carbachol chloride (1.23 μg/hr), echothiophate iodide (0.5 μg/hr), histamine dihydrochloride (10 μg/hr), prostaglandin E₂ (1.0 μg/hr) and thyrotropin-releasing hormone (0.5 and 5.0 μg/hr) solutions into the cerebral ventricles of unanesthetized rats and blood pressure was measured by the tail-cuff method. Histamine dihydrochloride, prostaglandin E₂ and thyrotropin-releasing hormone produced an initial rise in blood pressure, but were not effective in producing sustained elevations in blood pressure. Carbachol infusions elevated blood pressure throughout the 7-day infusion period when results were compared to saline-infused animals. Infusions of echothiophate iodide, an anticholinesterase agent, produced an initial rise in blood pressure but these pressor effects were not sustained. In animals infused with echothiophate for 7 days, the pressor response to a challenge dose of echothiophate was diminished.     

The role of the central arachidonic acid-thromboxane A2 cascade in cardiovascular regulation during hemorrhagic shock in rats

The aim of the current study was to elucidate the underlying central mechanism(s) of the cardiovascular effects evoked by centrally injected melittin and arachidonic acid (AA) in hemorrhaged hypotensive condition, specifically, from central AA release from the cell membrane under the influence of phospholipase A₂ (PLA₂) to central thromboxane A₂ (TXA₂) signaling via the cyclooxygenase (COX) pathway. As the main control of the study, melittin (3 μg) or AA (150 μg) was injected intracerebroventricularly (i.c.v.) after the hemorrhage procedure, which was performed by withdrawing a total volume of 2.2 ml of blood/100 g body weight over a period of 10 min. Both treatments generated a pressor response and abolished the hypotension-induced hemorrhage. Pretreatment with the PLA₂ inhibitor mepacrine (500 μg; i.c.v.) completely blocked the pressor response to melittin in the hemorrhagic hypotensive state. Pretreatments with the nonselective COX inhibitor indomethacin (200 μg; i.c.v.) or the TXA₂ synthesis inhibitor furegrelate (250 or 500 μg; i.c.v.) were made to test the role of central COX activity and, subsequently, the TXA₂ signaling pathway in the melittin- or AA-mediated reversal of hemorrhagic hypotension. Indomethacin completely prevented the pressor response to melittin and AA in the hemorrhaged, hypotensive state, but furegrelate did so only partially.In conclusion, these findings suggest that central COX activity and, subsequently, the central TXA₂ signaling pathway, are, at least in part, involved in the melittin- or AA-induced reversal effect during hemorrhagic shock.     

The Magnitude and Duration of Itch Produced by Intracutaneous Injections of Histamine

The magnitude and duration of itch sensation produced by intracutaneous injection of histamine were determined for humans with the procedure of magnitude estimation scaling. Thirteen subjects received a 10-μ1 intracutaneous injection of histamine at doses of 0.0001, 0.001, 0.01, 0.1, 1, and 10 μg into the volar forearm; eight of these subjects also received a 100-μg dose. One subject received multiple injections over several weeks to determine the reliability of the magnitude estimates of itch. Following each injection, the area of flare and duration of itch were also determined.

Intracutaneous injection of histamine produced a pure sensation of itch, without pain. The magnitude of itch increased in a dose-dependent fashion. The lowest histamine dose that produced itch greater than the itch produced by vehicle was 0.01 μg. The greatest itch was produced by the 100-μg dose. A power function fitted to the mean magnitude estimates had an exponent of 0.17, indicating a negatively accelerating relation between the magnitude of itch and histamine dose. The one subject who received histamine over several weeks gave fairly reproducible estimates of itch magnitude.

The duration of itch and the area of flare also increased in a dose-dependent fashion. The lowest dose of histamine that produced a duration of itch longer than the itch produced by the vehicle was 0.1 μg, while the 100-μg dose produced the longest duration of itch. Although the area of flare increased with each increase in dose from 0.1 to 10 μg, the areas of flare produced by 10 and 100 μg of histamine did not differ.

These results indicate that humans can scale the magnitude of itch produced by histamine in a dose-dependent manner. In addition, the duration of itch and the area of flare produced by histamine are dose-dependent, confirming results of previous investigators. Intracutaneous histamine is easily quantifiable and may thus be a useful stimulus in neurophysiological studies of the peripheral neural mechanisms of itch.     

Histamine H2 receptors and cyclic AMP in brain

The intravenous injection of histamine to 2–3 day old chicks resulted in a rapid and marked increase in the cyclic AMP content of the cerebral hemispheres that had been removed and frozen within 0.5s using a freeze-blowing technique. This response was not antagonized by pretreatment of the chicks with the histamine H₁-receptor antagonists mepyramine and diphenhydramine but was blocked by the H₂-receptor antagonists burimamide and metiamide. Parallel $\text{in vitro}$ experiments on slices of chick cerebral hemispheres demonstrated that the H₁ antagonists only produced a weak and non-competitive antagonism of the effects of histamine on cyclic AMP production. On the other hand the H₂ antagonists at low concentrations competitively blocked the histamine response. It is suggested that increased cyclic AMP formation in chick cerebral hemispheres can be mediated through stimulation of histamine H₂-receptors.     

Direct actions of prostaglandins E1, A1, and F2α on myocardial contraction

The inotropic and chronotropic actions of prostaglandin (PG) types PGE₁, PGA₁, and PGF_2α were studied in isolated guinea pig right and left atria, and papillary muscles; rabbit atria; and toad ventricular strips in order to more completely define the cardiac contractile properties of PG. All three prostaglandins, in muscle bath concentrations of 10μg/ml, exerted positive inotropic and chronotropic actions on guinea pig atrium. These contractile effects were persistent after removal of PG from the muscle bath and appeared to limit the relative response to a subsequent dose of PG. The inotropic action of PGE₁ was present over a wide range of bath calcium concentrations (1.1 to 4.4 mM/L). Beta adrenergic receptor blockade, histamine blockade, and pretreatment with reserpine failed to significantly affect the inotropic actions of PG. Norepinephrine and histamine produced more potent inotropic and chronotropic effects on guinea pig atria than did PG and these contractile effects did not exhibit persistence or tachyphylaxis. The prostaglandins did not significantly affect dose response curves for norepinephrine inotropic and chronotropic actions. The prostaglandins had no effect on the force or frequency of contraction in rabbit atria. PGE₁ exerted a positive inotropic effect on toad ventricular myocardium whereas PGA₁ had no effect and PGF_2α had a negative inotropic action.     

Thromboxane A2 analogue contracts predominantly the hepatic veins in isolated canine liver

Thromboxane A₂ (TxA₂) is a potent vasoconstrictor and has been implicated as a mediator of liver diseases such as ischemic-reperfusion injury. We determined the effects of TxA₂ and the well-known hepatic venoconstrictor histamine, on the vascular resistance distribution and liver weight in isolated canine livers perfused with blood via the portal vein. The stable TxA₂ (STA₂; 20 μg, n=5) and histamine (5 μg, n=6) similarly increased the hepatic total vascular resistance, 2.5- and 2.4-fold, respectively. The increase in the hepatic venous resistance was significantly greater than that of the portal resistance (threefold vs. 1.9-fold for STA2; threefold vs. 1.8-fold for histamine). Predominant hepatic venoconstriction induced by both agents was confirmed in livers perfused in a reverse direction from the hepatic vein to the portal vein, as shown by marked precapillary vasoconstriction. STA2 transiently increased liver weight loss (−3.6 g/100g liver weight), followed by a gradual weight gain (9.0 g/100 g). Histamine caused a progressive weight gain (9.1 g/100 g). In conclusion, similar to histamine, TxA₂ constricts predominantly the hepatic vein in isolated canine livers.     

Effects of beta-endorphin and D-alanine2 enkephalinamide on urine production and urinary electrolytes in the rat.

The intracerebro-ventricular administration of human β-Endorphin (β-EP, 0.1–3 μg/rat) or D-alanine₂ methionine enkephalinamide (D-ala, 0.3–30 μg/rat) caused a dose dependent reduction in the urine volume. The oliguria was associated with a decrease in the concentration of Na⁺ and K⁺ in the urine of rats previously hydrated by oral administration with 25 ml/kg tap water plus 50 ml/kg 0.5% NaCl. On a molar basis, β-EP proved to be about 5–7 times more potent than D-ala. The effects caused by the peptides were antagonized by the simultaneous intraperitoneal administration of 1 mg/kg naloxone. In rats treated chronically with morphine, no cross-tolerance was demonstrated to the antidiuretic effect of β-EP, but clear cross-tolerance was evident to the changes in urine electrolytes induced by β-EP. Results suggest that morphine and the opiate peptides share a similar mechanism of action.     

Urocortin 1 administered into the hypothalamic supraoptic nucleus inhibits food intake in freely fed and food-deprived rats

Peptides of the corticotropin-releasing hormone/Urocortin (CRH/Ucn) family are known to suppress appetite primarily via CRH₂ receptors. In the rat hypothalamic supraoptic nucleus (SON), synthesis of both Ucn1 and CRH₂ receptors has been reported, yet little is known about the effects of Ucn1 in the SON on feeding behaviour. We first established the dose-related effects of Ucn1 injected into the SON on the feeding response in both freely fed and 24-h food-deprived rats. A conditioned taste avoidance paradigm was performed to investigate possible generalised effects of local Ucn1 treatment. Administration of Ucn1 into the SON at doses equal to or higher than 0.5 μg significantly decreased food intake in both freely fed and food-deprived rats. The Ucn1-mediated suppression of food intake was delayed in freely fed as compared to food-deprived animals. Conditioning for taste aversion to saccharine appeared at 0.5 and 1 μg of Ucn1. Both the early and the delayed onset of anorexia observed after intra-SON injection of Ucn1 under fasting and fed conditions, respectively, suggest the possible involvement of different CRH receptor subtypes in the two conditions, while the conditioned taste aversion seems to be responsible for the initial latency to eat the first meal in these animals.     

Estrogen induced changes in uterine sensitivity for the decidual cell reaction: Interactions between prostaglandin E2 and histamine or bradykinin

In rats receiving high doses of estrogen along with progesterone, the uterus is desensitized and does not respond to artificial stimuli with increased endometrial vascular permeability or decidualization. In addition, prostaglandin E₂ (PGE₂), the putative mediator of endometrial vascular permeability changes in sensitized uteri, is ineffective when given into the uterine lumen. The possibility that this inability of PGE₂ to increase endometrial vascular permeability may be related to the unavailability of hitamine of bradykinin was investigated. Rats were differentially sensitized for the decidual cell reaction by the daily injection of 2 mg progesterone with either 0.5 of 10 μg estrone for the 3 days preceding the unilateral intra-uterine injection of 50 μl phosphate buffered saline containing gelatin with or without 10 μg PGE₂ and with or without 1 mg histamine or 1 μg bradykinin. Prior to the intrauterine injection, all rats were treated with indomethacin to inhibit endogenous prostaglandin production. Endometrial vascular permeability changes were determined 8 h later by determining radioactivity levels in injected and non-injected uterine horns 15 min after the i.v. injection of ¹²⁵I-labelled bovine serum albumin. PGE₂ increased endometrial vascular permeability in rats receiving 0.5 μg estrone, but not in those receiving 10 μg. Histamine or bradykinin, alone or with PGE₂, did not affect endometrial vascular permeability in rats receiving either estrogen dose. The data suggest that the unresponsiveness of uteri from rats treated with high doses of estrogen is not simply due to the unavailability of bradykinin or histamine.     

Effect of N-salicyloyltryptamine (STP), a novel tryptamine analogue, on parameters of cell viability, oxidative stress, and immunomodulation in RAW 264.7 macrophages

Immunomodulatory actions exerted by some classes of tryptamines, such as benzoyltryptamine analogues, suggest these molecules as promising candidates to develop new therapies to treat conditions associated to acute and chronic pain and inflammation. N-salicyloyltryptamine (STP) was observed to act as an anticonvulsive agent and exert antinociceptive effects in mouse. In the present work, we performed a screening of cytotoxic, cytoprotective, immunomodulatory, and redox properties of STP in RAW 264.7 macrophages challenged with hydrogen peroxide and LPS. Our results show that STP presents no cytotoxicity in the range of 0.001 to 1 μg/mL, but doses of 50 and 100 μg/mL caused loss of cell viability (IC₅₀?=?22.75 μg/mL). Similarly, STP at 0.001 to 1 μg/mL did not cause oxidative stress to RAW 264.7 cells, although it did not prevent cell death induced by H₂O₂ 0.5 mM. At 1 μg/mL, STP reversed some redox and inflammatory parameters induced by LPS. These include thiol (sulfhydryl) oxidation, superoxide dismutase activation, and morphological changes associated to macrophage activation. Besides, STP significantly inhibited LPS-induced TNF-α and IL-1β release, as well as CD40 and TNF-α protein upregulation. Signaling events induced by LPS, such as phosphorylation of ERK 1/2 and IκBα and p65 nuclear translocation (NF-kB activation) were also inhibited by STP. These data indicate that STP is able to modulate inflammatory parameters at doses that do not interfere in cell viability.     

Central mechanism underlying pressor and bradycardic effect of intracerebroventricularly injected arachidonic acid

The aim of the current study was to determine the central cyclooxygenase (COX) pathway and central thromboxane signaling in the cardiovascular effects evoked by arachidonic acid (AA). As a main control for the study, different doses of AA (75, 150, or 300?μg) were administered intracerebroventricularly (i.c.v.). Centrally injected AA dose- and time-dependently increased mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. The maximal cardiovascular effects of AA were observed at min 10 of the injection and lasted almost 30?min. To investigate the central mechanism of the AA-induced cardiovascular effect in conscious normotensive animals, pretreatment with nonselective COX inhibitor indomethacin (200?μg; i.c.v.), thromboxane A2 (TXA2) synthesis inhibitor furegrelate (250 or 500?μg; i.c.v.), or TXA2 receptor antagonist SQ-29548 (8 or 16?μg; i.c.v.) was carried out 15?min before AA (150?μg; i.c.v.) injection. While indomethacin completely prevented the pressor and bradycardic responses to AA, furegrelate and SQ-29548 attenuated these effects in part in awake normotensive rats. In conclusion, these findings suggest that the pressor and bradycardic cardiovascular effects of centrally injected AA are dependent on COX activity being totally central and the TXA2 signaling pathway being subsequently central, at least in part.     

Specific activation of cyclic AMP-dependent protein kinase(s) by H2-histamine agonists in isolated gastric mucosal cells from guinea-pig

Histamine stimulated cyclic AMP-dependent protein kinase activity in dispersed mucosal cells from guinea-pig gastric fundus (K_a = 5 μM). The H₂-agonists dimaprit and impromidine produced similar effects, while the H₁-agonist 2-(2-pyridyl) ethylamine had only a weak one. The H₂-antagonist cimetidine competitively inhibited 0.1 mM histamine stimulation (K_i = 2 μM). In contrast, the H₁-antagonist diphenhydramine had no effect up to 1 mM.     

Bicyclic and tricyclic heterocycle derivatives as histamine H3 receptor antagonists for the treatment of obesity

A novel series of non-imidazole bicyclic and tricyclic histamine H₃ receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.     

Activation of histamine H3 receptors inhibits renal noradrenergic neurotransmission in anesthetized dogs

To investigate the possible involvement of histamine H(3) receptors in renal noradrenergic neurotransmission, effects of (R)alpha-methylhistamine (R-HA), a selective H3-receptor agonist, and thioperamide (Thiop), a selective H3-receptor antagonist, on renal nerve stimulation (RNS)-induced changes in renal function and norepinephrine (NE) overflow in anesthetized dogs were examined. RNS (0.5-2.0 Hz) produced significant decreases in urine flow and urinary sodium excretion and increases in NE overflow rate (NEOR), without affecting renal hemodynamics. When R-HA (1 microg x kg(-1) x min(-1)) was infused intravenously, mean arterial pressure and heart rate were significantly decreased, and there was a tendency to reduce basal values of urine flow and urinary sodium excretion. During R-HA infusion, RNS-induced antidiuretic action and increases in NEOR were markedly attenuated. Thiop infusion (5 microg x kg(-1) x min(-1)) did not affect basal hemodynamic and excretory parameters. Thiop infusion caused RNS-induced antidiuretic action and increases in NEOR similar to the basal condition. When R-HA was administered concomitantly with Thiop infusion, R-HA failed to attenuate the RNS-induced antidiuretic action and increases in NEOR. However, in the presence of pyrilamine (a selective H1-receptor antagonist) or cimetidine (a selective H2-receptor antagonist) infusion, R-HA attenuated the RNS-induced actions, similarly to the case without these antagonists. Thus functional histamine H3 receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of renal noradrenergic neurotransmission.     

Evaluation of used Purslane extracts in Tris extenders on cryopreserved goat sperm

This study aimed to evaluate the comparative effects of Purslane aqueous extract (PAE), Purslane methanolic extract (PME) and Purslane ethanolic extract (PEE on the quality of frozen-thawed goat spermatozoa. Collected semen with motility >75% and sperm concentration >1.0 × 10⁹ sperm/ml was pooled and divided into 10 equal aliquots and supplemented by basic extender containing 25, 50 or 100 μg/ml of Purslane aqueous extract (PAE_25μg/ml, PAE_50μg/ml, PAE_100μg/ml, respectively), basic extender containing 25, 50 or 100 μg/ml of Purslane methanolic extract (PME_25μg/ml, PME_50μg/ml, PME_100μg/ml, respectively), basic extender containing 25, 50 or 100 μg/ml of Purslane ethanolic extract (PEE_25μg/ml, PEE_50μg/ml, PEE_100μg/ml, respectively). Control diluent contained no additives. For the determination of sperm quality, frozen straws were thawed and then the sperm characteristics were assessed. Results indicated that higher (P < 0.05) percentages of total motility, viability, mitochondrial activity and lower percentages of malondialdehyde (MDA) for PAE_50μg/ml, PME_50μg/ml and PEE_50μg/ml than those of the control. In addition, PME_50μg/ml resulted in the highest) P < 0.05) total motility and the lowest (P < 0.05) MDA levels compared to other treatments. Compared to the control group, PME_50μg/ml resulted in higher integrity (P < 0.05) of plasma membranes and in lower amounts of apoptotic and dead spermatozoa. PME_50μg/ml and PAE_50μg/ml showed higher (P < 0.05) percentages of progressive motility, DNA integrity and live post-thawed spermatozoa than those of the control. No significant differences in the motility, viability, mitochondrial activity and number of live sperms were observed between PME_50μg/ml and PAE_50μg/ml treatments. In conclusion, the results of this study indicated that 50 μg/ml purslane extracts could be used for the cryopreservation. However, the results of methanolic extract was more beneficial compared to other extracts.     

Bronchoconstriction by histamine and bradykinin in guinea pigs: Relationship to thromboxane A2 generation and the effect of aspirin

Histamine 2.5, 5, 10 or 20 μg/kg i.v. induce a pronounced bronchospasm in guinea-pigs, accompanied by a dose-related increase of TXA₂ in arterial blood, as revealed by contraction of rabbit isolated aorta and by radioimmunoassay. Aspirin 10 mg/kg prevented formation of TXA₂ like material without significantly modifying the severity of the bronchospasm. Bradykinin 0.5, 1 or 2 μg/kg i.v. acted similarly, except that pretreatment with aspirin blocked both the increased airway resistance and release of TXA₂. Aspirin also blocked the increase in blood pressure and heart rate caused by histamine or bradykinin.