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PubMed1999

NO: the primary EDRF.

Since the discovery of an endothelium-derived relaxing factor (EDRF) by Furchgott and Zawadzki (Furchgott and Zawadzki. 1980), which was later identified as nitric oxide (NO) (Ignarro et al., 1987; Palmer et al., 1987; Furchgott, 1988), it has become clear that there are a number of additional endothelium-derived vasodilator and vasoconstrictor autacoids (endothelin-1, prostaglandin H2, and the endothelium-derived hyperpolarizing factor: EDHF). None of these autacoids play such a central role in the regulation of vascular tone and homeostasis as the primary EDRF, the free radical NO, which is generated via a live-electron oxidation of a guanidino nitrogen from L-arginine by an NO synthase (NOS).

Animals↗

PubMed2006

Vascular endothelium and blood flow.

Major advances have been made over the last decade towards the elucidation of the molecular mechanisms involved in the endothelium-dependent regulation of vascular tone and blood flow. While the primary endothelium-derived vasodilator autacoid is nitric oxide, it is clear that epoxyeicosatrienoic acids and other endothelium-derived hyperpolarising factors, as well as endothelin-1 and reactive oxygen species, play a significant role in the regulation of vascular tone and gene expression. This review is intended as an overview of the signalling mechanisms that link haemodynamic stimuli (such as shear stress and cyclic stretch) and endothelial cell perturbation to the activation of enzymes generating vasoactive autacoids.

Animals↗

PubMed1989

Physiologic role of the peripheral enkephalinergic system in regulating cardiovascular homeostasis: evidence of interactions with the renin-angiotensin and kallikrein-kinin systems.

On isolated heart preparation, it was found that Leu5-Enkephalin (Leu5-ENK) did not influence the cardiac function. On the other hand, Leu5-ENK induced a specific dose-related inhibition, in the cardiac perfusate, of the activities of kininase II (KII) and angiotensin converting enzyme (ACE) (but not of kininase I-KI). Instead no detectable alterations of the above enzymatic activities with the used concentrations of Leu5-ENK were observed in vitro. This opioid also increased specifically the effects induced by some of the autacoids, related to both renin-angiotensin and kallikrein-kinin systems, on the KII and ACE activities. A specific correlation between these Leu5-ENK-induced modifications and the functional responses of the heart to the same autacoids was observed. Naloxone (NAL) and more significantly ICI 174864 (ICI) opposed or reversed the inhibitory effect of the used opioid whereas they had neither inhibitory nor synergic effect on both KII and ACE activity by themselves. The possible physiologic role of the enkephalins in regulating cardiovascular function by acting peripherally on some humoral systems through modulatory mechanism was discussed.

Animals↗

PubMed1988

Fendiline and calmidazolium enhance the release of endothelium-derived relaxant factor and of prostacyclin from cultured endothelial cells.

We investigated the effects of fendiline, calmidazolium and trifluoperazine, compounds described as calmodulin antagonists, on the release of the endothelial autacoids prostacyclin (PGI2) and endothelium-derived relaxant factor (EDRF). Cultured bovine aortic endothelial cells were grown on microcarrier beads and continuously superfused with Tyrode's solution. Samples collected from the superfusate were assayed for PGI2 concentration (6-keto PGF1 alpha radioimmunoassay) and for EDRF activity (stimulation of soluble guanylate cyclase in vitro). Stimulation of endothelial cells by ATP (3 microM) resulted in a 6.9 +/- 1.4-fold increase of PGI2 concentration in the superfusate (p less than 0.01) and an 8.6 +/- 3.4-fold enhanced guanylate cyclase activity (p less than 0.01). In the presence of calmidazolium (10 microM), the basal values of PGI2 concentration increased 28-fold (p less than 0.01) and the guanylate cyclase activity 10-fold (p less than 0.01). Further enhancement of both was observed after additional administration of ATP. Fendiline (30 microM) did not affect autacoid release by non-stimulated cells. However, the ATP-induced release of PGI2 and EDRF was more than doubled (p less than 0.01) in the presence of this drug compared to ATP-stimulation alone. Trifluoperazine (10 microM) had no enhancing effect on EDRF release, and the ATP-induced release of PGI2 was even significantly attenuated by 84 +/- 12% (p less than 0.01). Calmidazolium and fendiline were also applied to endothelial cells loaded with the fluorescent indicator of free calcium concentration (Ca2i+), indo-1. However, effects of calmidazolium on Ca2i+ could not be quantified since calmidazolium caused some leakage of indo-1 out of the cells. A smaller leakage was observed during the combined application of fendiline and ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1988

Effects of the specific platelet-activating factor antagonists, BN 52021 and BN 52063, on various experimental gastrointestinal ulcerations.

Platelet-activating factor (PAF) has been shown recently to induce gastrointestinal damage similar to that evoked by endotoxin, suggesting that the autacoid could be implicated in other types of gastrointestinal damage. Thus, the effects of BN 52021 and BN 52063, two specific PAF antagonists, were investigated in various experimental models of gastrointestinal damage in rats. BN 52021 and BN 52063, markedly reduced both the PAF- and endotoxin-induced alterations of the mucosa, suggesting a role for the autacoid in the latter process. BN 52021 and another unrelated PAF antagonist, triazolam, partially reduced the restraint-stress-induced gastric damage in young female, but not male, rats. Similar partial protection was obtained in rats with ethanol-induced gastric damage. In contrast with atropine and ranitidine, BN 52021 did not affect the gastric hypersecretion in pylorus-ligated rats nor the aspirin-induced gastric ulcerations. The present results indicate that PAF plays a major role in the gastric damage induced by endotoxin and may also partially contribute to the gastric lesions induced by ethanol and stress. The results suggest that there is a potential therapeutic use for PAF antagonists in certain types of gastrointestinal lesions in man.

Animals↗

PubMed1996

N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation.

Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides ('ALIAmides') represent novel therapeutic agents useful in the management of inflammatory disease conditions.

Amides↗

PubMed1993

Electrophysiological properties and chemosensitivity of guinea pig nodose ganglion neurons in vitro.

Conventional intracellular recording techniques were employed to obtain information on the electrophysiological and pharmacological characteristics of C-type neurons in the guinea pig nodose ganglia. Approximately 90% of the cell bodies gave rise to axons with conduction velocities consistent with C-fibers (0.9-1.1 m/s). The average resting membrane potential and input impedence was about -60 mV and 45 M sigma, respectively. Orthodromic electrical stimulation of the vagus nerve 20-30 mm caudal to the ganglion produced overshooting action potentials in the nodose neurons. The falling phase of the action potential was followed by a transient (50-300 ms) fast hyperpolarization (AHPfast). In 20% of C-type neurons the AHPfast was followed by a slowly developing, long-lasting afterhyperpolarization (AHPslow) that limited the ability of the neuron to fire action potentials at high frequency. The AHPslow magnitude was dependent on the number of spikes, had a reversal potential of -87 mV, and was abolished by 100 microM cadmium chloride, suggesting that it is produced by a calcium-dependent potassium current. In about 30% of the nodose neurons, hyperpolarizing current steps from resting potential produced a time- and voltage-dependent anomalous rectification in the electrotonic potential. External cesium (1 mM), but not barium (100 microM) reversibly blocked this effect. Single-electrode voltage-clamp measurements revealed a slowly developing inward current in these neurons that grows in magnitude with step hyperpolarizations from resting potential, and has an estimated reversal potential of about -44 mV. These properties suggest that this current is analogous to IH observed in many peripheral and central neurons. Autacoids including serotonin, histamine, several prostanoids, peptidoleukotriene, and bradykinin, were examined for their ability to affect the excitability of the nodose neurons. Serotonin was the only autacoid capable of depolarizing the membrane potential to action potential firing threshold. The serotonin-induced membrane depolarization was associated with a significant increase in input conductance. Histamine depolarized the membrane potential of the C-type neurons in 28/30 neurons. Bradykinin, prostacyclin, and leukotriene C4 were found to cause membrane depolarizations in a subset (73%, 31%, and 50%, respectively) of nodose neurons. The AHPslow was virtually abolished by bradykinin, prostacyclin, and in a subset of neurons, leukotriene C4. Inhibition of the AHPslow was accompanied by a change in the accommodative properties of the neurons, reflected by the increased frequency at which the neuron could successfully elicit repetitive action potentials.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1988

Inhibition of prostaglandin E1-induced activation of adenylate cyclase in human blood platelet membrane.

Activation of human blood platelet adenylate cyclase is initiated through the binding of prostaglandin E1 to the membrane receptors. Incubation of platelet membrane with [3H]prostaglandin E1 at pH 7.5 in the presence of 5 mM MgCl2 showed that the binding of the autacoid was rapid, reversible and highly specific. The binding was linearly proportional to the activation of adenylate cyclase. Although the membrane-bound radioligand could not be removed either by GTP or its stable analogue 5'-guanylylimido diphosphate, 150 nM cyclic AMP displaced about 40% of the bound agonist from the membrane. Scatchard analyses of the binding of the prostanoid to the membrane in the presence or absence of cyclic AMP showed that the nucleotide specifically inhibited the high-affinity binding sites without affecting the low-affinity binding sites. Incubation of the membrane with 150 mM cyclic AMP and varying amounts of prostaglandin E1 (25 nM to 1.0 microM) showed that the percent removal of the membrane-bound autacoid was similar to the percent inhibition of adenylate cyclase at each concentration of the agonist. At a concentration of 25 nM prostaglandin E1, both the binding of the agonist and the activity of adenylate cyclase were maximally inhibited by 40%. With the increase of the agonist concentration in the assay mixture, the inhibitory effects of the nucleotide gradually decreased and at a concentration of 1.0 microM prostaglandin E1 the effect of the nucleotide became negligible. These results show that cyclic AMP inhibits the activation of adenylate cyclase by low concentrations of prostaglandin E1 through the inhibition of the binding of the agonist to high-affinity binding sites.

Adenylyl Cyclases↗

PubMed1994

The nitric oxide-cyclic GMP signal transduction system for intracellular and intercellular communication.

From our work and that of others, it is now quite apparent that the NO-cGMP system can function as an intracellular or intercellular signal transduction system (Murad et al., 1988, 1990; Murad, 1989a,b; Ishii et al., 1989, 1991). If a specific cell possesses both NO synthase and an isoform of guanylyl cyclase that is activatable with NO, then cGMP levels in that cell can be regulated by agents that alter NO synthase activity and NO formation (Fig. 1). NO, or a complex of NO which is liberated from the producing or donor cell, can also activate guanylyl cyclase in a neighboring or perhaps a distant cell to increase cGMP synthesis. In the latter scenario, NO or its carrier complex behaves as a paracrine substance, autacoid, or hormone. Interestingly, the liberated extracellular NO can also feed back and increase cGMP synthesis in the cell of origin. This is best demonstrated by the inhibitory effects of hemoglobin on agonist-induced cGMP accumulation in homogeneous cell culture systems where the hormone or agonist effects on cGMP are mediated by NO. Presumably, hemoglobin would not be permeable and could only trap or scavenge extracellular NO to account for its ability to decrease hormonally induced cGMP increases in homogeneous cell populations. There is no direct evidence that NO can act as an endocrine substance to increase cGMP synthesis in a distant target cell population. However, complexes or carrier states of NO that would liberate NO at a distant site could most certainly be viewed as endocrinological agents (hormones or autocoids). We suspect that appropriately designed experiments in the future will also support this role for NO as an endocrinological agent that can also function at a distance similar to classical hormones. Indeed, we believe that NO should be added to the list of agents that can function as a neurotransmitter, paracrine substance, and autacoid or hormone. It can also be viewed as an intracellular, as well as intercellular, messenger. To date, no substance has played such a diverse role in intracellular and intercellular signal transduction. Thus, NO appears to be a unique and simple molecule with diverse functions in signal transduction.

Amino Acid Oxidoreductases↗

PubMed1992

The presence of platelet-activating factor binding sites in human myometrium and their role in uterine contraction.

It has recently been suggested that platelet-activating factor is involved in a number of processes associated with reproductive biology. We have demonstrated a critical role for this autacoid in the initiation and maintenance of parturition both in animals and man. In the present investigation, it has been demonstrated that platelet-activating factor affects contraction in strips of human myometrium at concentrations as low as 10(-10) mol/L. A platelet-activating factor receptor has been identified and characterized in human myometrium. Platelet-activating factor acts to cause an increase in intracellular Ca2+ concentration of isolated myometrial smooth muscle cells in culture and an increase in the phosphorylation of the 20 kd light chain of myosin in a concentration-dependent fashion. The presence of platelet-activating factor receptors in human myometrium, the observed increase in Ca2+ concentration and phosphorylation of myosin light chain in the presence of platelet-activating factor provide further support for the importance of this autacoid in the initiation of parturition.

Binding Sites↗

PubMed1996

Characterization of histamine receptors in the ureter of the dog.

We investigated the effects of histamine on the motility of isolated segments from canine ureters and characterized pharmacologically the histamine receptors involved. We also evaluated the effects of various autacoids (5-HT, carbachol, noradrenaline, thromboxane, prostaglandin F2alpha) on the motility of canine ureters. Histamine as well as the H1 receptor agonist 2-(2-pyridyl)ethylamine elicited a concentration-dependent contraction. This contractile response was antagonized by dimethindene, causing a rightward shift (pA2 8.30) and a reduction of the slope and the maximal effect (pD'2 6.01) of the concentration-response curve. The histamine H2 receptor antagonist cimetidine in a concentration of 10(-5) mol/l was ineffective concerning the concentration-response curve for histamine. After precontraction of the ureter segments (5-HT, carbachol, prostaglandin F2alpha), a concentration-dependent relaxant effect was evaluated in the presence of histamine or the histamine H2 receptor agonist impromidine. The histamine H2 receptor antagonist cimetidine attenuated the relaxant response, causing a rightward shift of the concentration-response curve. All autacoids except thromboxane were capable of increasing contractility in canine ureters. Comparing the absolute contractile force in the presence of prostaglandin F2alpha, 5-HT, carbachol, noradrenaline and potassium, we found that histamine exhibits the most marked effect on this parameter in the canine ureter. It is concluded that there are two types of histamine receptors modulating contractile activity in the canine ureter: histamine H1 receptors, which mediate contraction, and histamine H2 receptors, which mediate relaxation (in the precontracted tissue).

Animals↗

PubMed2001

Urinary adrenomedullin is related to ET-1 and salt intake in patients with mild essential hypertension. Salt Sensitivity Group of Italian Society of Hypertension.

Adrenomedullin (ADM) infusion increases salt excretion in the rat. However, there is no evidence that this substance is related to changes in salt intake in humans. In this study we sought whether the urinary excretion rate of this autacoid is related to salt intake and by the expected changes in arterial pressure in patients with mild essential hypertension. The influence of salt intake on the renal excretion of ADM was investigated in 55 hypertensive patients in a double blind, randomized and crossover study comparing a 2-week 50 mmol/day salt intake period with a 150 mmol/day salt intake period. Twenty-four-hour ADM and endothelin-1 (ET-1) excretion rate were measured by radioimmunoassay on preextracted urinary samples (intraassay confidence variable <8%). The antibodies used in these assays had minimal ADM-ET-1 cross-reactivity (<1%). Twenty-four-hour microalbuminuria was measured by nephelometry. On univariate analysis changes in urinary ADM were significantly related to those in salt excretion (r = 0.33, P = .01) as well as to changes in urinary ET-1 (r = 0.56, P = .0001). Furthermore, changes in urinary albumin excretion were related to those in urinary ET-1 (r = 0.26, P = .05), but were independent of those in urinary ADM (P = .19). In a multiple regression model including age, sex, body mass index, and changes in systolic pressure, plasma renin activity and plasma aldosterone and urine volume, salt excretion resulted as the stronger independent predictor of urinary ADM (r = 0.33, P = .01). However, changes in urinary salt lost prediction power (P = .11) for urinary ADM when urinary ET-1 was introduced into the model. In this model (multiple r = 0.31) urinary ET-1 resulted to be the only independent predictor of urinary ADM (beta = 0.56, P = .0001). This study is the first to show that the renal excretion of ADM is related to changes in salt intake and that it is tightly linked to that of ET-1. The data support the notion that these autacoids play a role in the regulation of sodium metabolism in patients with mild hypertension. The intercorrelations between ET-1, ADM, and microalbuminuria are compatible with the hypothesis that ET-1 is involved in a salt-induced increase in glomerular pressure and suggest that ADM may act as a counterregulatory factor in this situation.

Adrenomedullin↗

PubMed1998

Effects of prostaglandin E2 on growth, morphology, morphometry and keratin pattern of bovine corneal epithelial cells cultured in vitro.

In this work the relationship between the proliferation of bovine corneal epithelial cells and PGE2 has been studied. Our data indicate that PGE2 plays an important role in the growth of corneal epithelial cells. Actually, epithelial cells cultured on a keratocyte feeder-layer and exposed to indomethacin, a cyclooxygenase inhibitor, have shown a decrease in growth rate at drug concentrations which otherwise did not induce a reduction in the viability of the keratocytes as well as in epithelial cells in separate cultures. This effect has been reversed by an exogenous PGE2 addition to the culture media. Moreover, significant increases have been found in the growth of epithelial cells cultured in the presence of keratocytes, with basal medium and with conditioning medium after adding exogenous PGE2 at concentrations equal to or lower than 10(-6) M. Significant decreases in the dimensions of the corneal epithelial cells have been found only when PGE2 has been added to basal and to conditioning medium, suggesting that the autacoid maintains cell dimension and morphology. The appearance of keratins with high molecular weight (54 and 57 kDa) coupled with the tendency to stratification of the cells cultivated with media supplemented with PGE2, indicates that the autacoid could favour cell differentiation. The action of PGE2 on the corneal epithelial cells does not seem to be influenced by the presence of the fibroblasts and their products, since PGE2 has induced increases in cell growth and morphological variations, independent of cultural conditions and therefore also only in the presence of basal medium.

Animals↗

PubMed2002

Update on ascites and hepatorenal syndrome.

Ascites is the most common complication occurring during liver cirrhosis. Even if a significant decrease in renal clearance may be observed in the first step of chronic active liver disease, renal impairment, at times complicated by the typical signs of hepatorenal syndrome, occurs only in patients with ascites, especially when tense and refractory. Experimental and clinical data seem to suggest a primary sodium and water retention in the pathogenesis of ascites, in the presence of an intrahepatic increase of hydrostatic pressure, which, by itself, physiologically occurs during digestion. Abnormal sodium and water handling leads to plasma volume expansion, followed by decreased peripheral vascular resistance and increased cardiac output. This second step is in agreement with the peripheral arterial vasodilation hypothesis, depicted by an increase in total blood volume, but with a decreased effective arterial blood volume. This discrepancy leads to the activation of the sympathetic nervous and renin-angiotensin-aldosterone systems associated with the progressive activation of the renal autacoid systems, especially, that of the arachidonic acid. During advanced cirrhosis, renal impairment becomes more sustained and renal autacoid vasodilating substances are less available, possibly due to a progressive exhaustion of these systems. At the same time ascites becomes refractory inasmuch as it is no longer responsive to diuretic treatment. Various pathogenetic mechanisms leading to refractory ascites are mentioned. Finally, several treatment approaches to overcome the reduced effectiveness of diuretic therapy are cited. Paracentesis, together with simultaneous administration of human albumin or other plasma expanders is the main common approach to treat refractory ascites and to avoid a further decrease in renal failure. Other effective tools are: administration of terlipressin together with albumin, implantation of the Le Veen shunt, surgical porto-systemic shunting or transjugular intrahepatic portosystemic stent-shunt, or orthotopic liver transplantation, according to the conditions of the individual patient.

Ascites↗

PubMed2001

Efferent arteriole tubuloglomerular feedback in the renal nephron.

BACKGROUND: Afferent and efferent arteriole resistance exerts critical and opposite actions in the regulation of glomerular capillary pressure (PGC) and glomerular filtration rate (GFR). Tubuloglomerular feedback (TGF) plays an important role in the regulation of afferent arteriole resistance; however, the role of TGF in the regulation of efferent arteriole resistance is less well established. We hypothesized that TGF caused by increased NaCl in the tubular fluid stimulates the macula densa to initiate a cascade of events resulting in efferent arteriole vasodilation, mediated by adenosine via its A2 receptor. METHODS: Rabbit efferent arterioles and adherent tubular segments with macula densa were simultaneously microperfused in vitro while changing NaCl concentration at the macula densa. To study whether autacoids produced by the glomerulus participate in the effect of TGF on efferent arterioles, they were perfused orthograde or retrograde. To eliminate the hemodynamic influence of the afferent arteriole during orthograde perfusion, the perfusion pipette was advanced to the distal end of the afferent arteriole, and the tip of the pressure pipette was placed beyond the afferent arteriole; for retrograde perfusion, the efferent arteriole was perfused from its distal end. RESULTS: In efferent arterioles perfused orthograde and preconstricted with norepinephrine (NE), increasing NaCl concentration at the macula densa increased the diameter by 33%. In preconstricted efferent arterioles perfused retrograde, increasing NaCl at the macula densa increased the diameter by 33%. Efferent arteriole vasodilation was completely blocked by a selective adenosine A2 receptor antagonist (3, 7-dimethyl-1-propargylxanthine) but not by an adenosine A1 receptor antagonist (FK838). CONCLUSIONS: Our data show that in vitro, preconstricted efferent arterioles dilate in response to increased macula densa NaCl, and this process is mediated by activation of adenosine A2 receptors. Thus, TGF changes efferent arteriole resistance in the opposite direction from the afferent arteriole, possibly amplifying TGF regulation of PGC and GFR. In vivo efferent arteriole TGF may only buffer the signals that cause efferent arteriole resistance to parallel changes in afferent arteriole resistance. Effects of TGF on efferent arterioles perfused orthograde or retrograde were similar, suggesting that glomerular autacoids do not participate in this process.

Animals↗

PubMed1995

Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.

Mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play important roles in tissue inflammation and in neuroimmune interactions. Very little is known about endogenous molecules and mechanisms capable of modulating mast cell activation. Palmitoylethanolamide, found in peripheral tissues, has been proposed to behave as a local autacoid capable of downregulating mast cell activation and inflammation. A cognate N-acylamide, anandamide, the ethanolamide of arachidonic acid, occurs in brain and is a candidate endogenous agonist for the central cannabinoid receptor (CB1). As a second cannabinoid receptor (CB2) has been found in peripheral tissues, the possible presence of CB2 receptors on mast cells and their interaction with N-acylamides was investigated. Here we report that mast cells express both the gene and a functional CB2 receptor protein with negative regulatory effects on mast cell activation. Although both palmitoylethanolamide and anandamide bind to the CB2 receptor, only the former downmodulates mast cell activation in vitro. Further, the functional effect of palmitoylethanolamide, as well as that of the active cannabinoids, was efficiently antagonized by anandamide. The results suggest that (i) peripheral cannabinoid CB2 receptors control, upon agonist binding, mast cell activation and therefore inflammation; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for the CB2 receptor on mast cells; (iii) modulatory activities on mast cells exerted by the naturally occurring molecule strengthen a proposed autacoid local inflammation antagonism (ALIA) mechanism; and (iv) palmitoylethanolamide and its derivatives may provide antiinflammatory therapeutic strategies specifically targeted to mast cells ("ALIAmides").

Amides↗

PubMed1990

Endothelium-dependent modulation of vascular tone and platelet function.

Endothelial cells exert potent effects on vascular tone and platelet activity by the release of autacoids. One of the functionally most important autacoids is the endothelium-derived relaxant factor (EDRF). It inhibits platelet and vascular smooth muscle activation by cGMP-dependent attenuation of the agonist-induced rise of intracellular free Ca2+. Recent experiments suggest that EDRF has a physiologic role in the control of the vascular tone of large arteries and resistance vessels. Furthermore, there is evidence that an impairment of EDRF release may be a significant pathophysiologic factor in myocardial ischaemia. Coronary vascular tone might be also affected by the endothelium-derived vasoconstrictor peptide, endothelin, but its significance for the control of coronary blood flow remains to be elucidated.

Endothelins↗

PubMed1992

Clinical relevance of endothelium-derived relaxing factor (EDRF).

1. In addition to metabolic and neurohumoral factors endothelium-derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L-arginine by a Ca2+/calmodulin-dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium-dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L-arginine supplementation is effective in a few instances.

Animals↗