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PubMed1990

Prostaglandin deficiency.

Healthy cells from virtually all tissues synthesize a variety of prostaglandins, autacoids which can significantly alter cellular functions. An absolute or relative deficiency of prostaglandins has now been demonstrated in many diseases or clinical conditions. These include 'natural' disorders such as peptic ulcer disease and diabetes mellitus. These also include 'acquired' or iatrogenic conditions such as cyclosporine nephrotoxicity and the gastropathy induced by nonsteroidal anti-inflammatory drugs. We believe that the diversity of the disorders associated with prostaglandin deficiency may be wider and of greater pathogenetic importance than is currently recognized. We propose: 1) that prostaglandin deficiency will be demonstrated in many abnormalities which are now described as of uncertain etiology; and 2) that adverse effects from many commonly prescribed drugs may also be related to an unrecognized and unfavorable alteration in prostaglandin synthesis, disposal, or activity.

Humans↗
PubMed2003

Phosphoinositide 3-kinase gamma-deficient hearts are protected from the PAF-dependent depression of cardiac contractility.

OBJECTIVES: Following an ischemic insult, cardiac contractile recovery might be perturbed by the release of autacoids, like platelet-activating factor (PAF), that depress heart function by acting through G protein-coupled receptors (GPCRs). The signaling events downstream the PAF receptor that lead to the negative inotropic effect are still obscure. We thus investigated whether the GPCR-activated phosphoisositide 3-kinase gamma (PI3Kgamma) could play a role in the cardiac response to PAF. METHODS: The negative inotropic effect of PAF was studied ex vivo, in isolated electrically driven atria and in Langendorff-perfused whole hearts derived from wild-type and PI3Kgamma-null mice. Postischemic recovery of contractility was analyzed in normal and mutant whole hearts subjected to 30 min of ischemia and 40 min of reperfusion in the presence or absence of a PAF receptor antagonist. RESULTS: While wild-type hearts stimulated with PAF showed increased nitric oxide (NO) production and a consequent decreased cardiac contractility, PI3Kgamma-null hearts displayed reduced phosphorylation of nitric oxide synthase 3 (NOS3), blunted nitric oxide production and a complete protection from the PAF-induced negative inotropism. In addition, Langendorff-perfused PI3Kgamma-null hearts showed a better contractile recovery after ischemia/reperfusion, a condition where PAF is known to be an important player in depressing contractility. In agreement with a role of PI3Kgamma in this PAF-mediated signaling, postischemic contractile recovery in PI3Kgamma-null mice appeared overlapping with that of normal hearts treated with the PAF receptor antagonist WEB 2170. CONCLUSION: These data indicate a novel PAF-dependent signaling pathway that, involving PI3Kgamma and NOS3, contributes to postischemic contractile depression.

Animals↗
PubMed2004

The bronchodilators 8-iso-prostaglandin E2 and prostaglandin E2 induce K+ current suppression via thromboxane A2 receptors in porcine tracheal smooth muscle.

We examined relaxations and changes in K(+) current evoked by 8-iso-prostaglandin E(2) and prostaglandin E(2) in porcine tracheal smooth muscle. Both autacoids completely reversed cholinergic tone; blockade of thromboxane A(2) receptors had no effect on relaxations to either compound. 8-iso-prostaglandin E(2) and prostaglandin E(2) suppressed outward K(+) currents while the thromboxane A(2) receptor agonist U46619 (9, 11-dideoxy-9a,11a-methanoepoxy prostaglandin F(2alpha)) had no significant effect. During thromboxane A(2) receptor antagonism, however, 8-iso-prostaglandin E(2) markedly augmented K(+) currents while prostaglandin E(2) no longer suppressed K(+) currents, indicating that the inhibition of K(+) currents by both compounds was thromboxane A(2) receptor-mediated. Furthermore, the observation that K(+) currents were augmented by 8-iso-prostaglandin E(2) but not by prostaglandin E(2) suggests that the salutory effect is not exerted through a prostaglandin E receptor. Additionally, our observations argue against any causal role for K(+) current activation in mediating relaxations evoked by isoprostanes or by prostaglandin E(2). We conclude that 8-iso-prostaglandin E(2) relaxes porcine tracheal smooth muscle independent of K(+) current activity, and that 8-iso-prostaglandin E(2) may also act at a non-thromboxane A(2)/non-prostaglandin E receptor to augment K(+) currents.

Animals↗
PubMed2004

Secretion of interleukin-6 and prostaglandin E2 during uveal melanoma-monocyte in vitro interactions.

Host-tumor interactions in uveal melanoma are not well understood. It is believed that the cytokine interleukin-6 and the lipid mediator autacoid prostaglandin E2 are involved in tumor growth, proliferation, tumor cell survival, and angiogenesis. These cytokines have been shown to be poor prognostic markers in uveal and cutaneous melanoma. In this study, we investigated the levels of interleukin-6 and prostaglandin E2 in monocyte and uveal melanoma conditioned medium. Five human uveal melanoma cell lines (92.1, MKT-BR, OCM-1, SP6.5 and UW-1), and one monocyte cell line (28SC) were seeded in 6 well plates at a concentration of 1 x 10(6)cells ml(-1). After 18 hr melanoma conditioned medium was placed on the monocyte cell line and monocyte conditioned medium was placed on each uveal melanoma cell line. Tumor cells and monocytes incubated in fresh medium after 18 hr were used as controls. Interleukin-6 and prostaglandin E2 levels were determined by immunoassays prior to media transfer and 6, 12, 24, and 36 hr thereafter. In the absence of conditioned medium, neither product showed baseline levels of expression. Interleukin-6 but not prostaglandin E2, which remained undetectable for the duration of the study, showed up-regulation of expression after incubation in conditioned medium. 28SC incubated in melanoma conditioned medium expressed higher levels of interleukin-6 than did uveal melanoma cells incubated in monocyte conditioned medium. In addition each cell line exhibited a distinct pattern of expression with individual cell lines exhibiting peak levels of cytokine production at different time points. The results of this study offer insight into the mechanism by which interleukin 6 may be involved in tumor-host interactions potentially favoring tumor growth, survival, and proliferation.

Cell Communication↗
PubMed2006

The role of the mast cell in the pathophysiology of asthma.

There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma.

Animals↗
PubMed2005

Bradykinin B2 type receptor activation regulates fluid and electrolyte transport in the rabbit kidney.

Bradykinin is an important autacoid produced in the kidney, regulating both renal function and blood pressure. In vivo studies in anesthetized rabbits, revealed that BK induced diuresis (UV), natriuresis (U(Na)V) and was not associated with renal hemodynamic changes. These diuretic and natriuretic effects were blocked by the BK-B2 antagonist HOE-140. BK also inhibits vasopressin (AVP)-stimulated water flow (L(p)) in microperfused rabbit cortical collecting ducts (rCCD), in a concentration-dependent fashion, consistent with its in vivo diuretic effects. BK-B1 antagonist Leu8-des-Arg9-BK did not alter the effect of BK on Lp, but HOE-140 completely blocked the inhibitory effects of BK on Lp. While BK did not increase [Ca2+]i in fura-2 loaded freshly microdissected rCCD, BK increased [Ca2+]i in immortalized cultured rCCD cells demonstrating different signaling mechanisms are activated by BK in microdissected versus cultured rCCD. In microperfused rCCD, neither the protein kinase C inhibitor staurosporine nor the phospholipase C (PLC) inhibitor U-73,122 attenuated the BK response arguing against activation of PLC/PKC by BK in rCCD. We conclude: (1) BK induces UV and U(Na)V by a BK-B(2) receptor; (2) BK inhibits AVP-stimulated Lp by a BK-B2 receptor suggesting that its effects on Lp are not via a PLC/PKC; (3) finally, BK raises [Ca2+]i in rCCD cells by a BK-B2 receptor mechanism.

Animals↗
PubMed2004

Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation.

Prostaglandins are lipid-derived autacoids that modulate many physiological systems including the CNS, cardiovascular, gastrointestinal, genitourinary, endocrine, respiratory, and immune systems. In addition, prostaglandins have been implicated in a broad array of diseases including cancer, inflammation, cardiovascular disease, and hypertension. Prostaglandins exert their effects by activating rhodopsin-like seven transmembrane spanning G protein-coupled receptors (GPCRs). The prostanoid receptor subfamily is comprised of eight members (DP, EP1-4, FP, IP, and TP), and recently, a ninth prostaglandin receptor was identified-the chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). The precise roles prostaglandin receptors play in physiologic and pathologic settings are determined by multiple factors including cellular context, receptor expression profile, ligand affinity, and differential coupling to signal transduction pathways. This complexity is highlighted by the diverse and often opposing effects of prostaglandins within the immune system. In certain settings, prostaglandins function as pro-inflammatory mediators, but in others, they appear to have anti-inflammatory properties. In this review, we will discuss the pharmacology and signaling of the nine known prostaglandin GPCRs and highlight the specific roles that these receptors play in inflammation and immune modulation.

Humans↗
PubMed2006

Attenuated cardioprotective response to bradykinin, but not classical ischaemic preconditioning, in DOCA-salt hypertensive left ventricular hypertrophy.

Hypertensive left ventricular hypertrophy (LVH) co-exists frequently with ischaemic heart disease. While ischaemic preconditioning (IPC) is known to protect against ischaemia-reperfusion injury in LVH, it is not known if other cardioprotective manoeuvres are effective. Bradykinin, a key autacoid mediator in IPC, is protective in normal hearts but its ability to protect against ischaemia-reperfusion injury in LVH is unknown. Hypertensive LVH was induced in male rats by 4 weeks treatment with deoxycorticosterone acetate (DOCA) and salt drinking fluid. Hearts were Langendorff perfused, subjected to 35 min coronary artery occlusion and 120 min reperfusion, and infarct size (AN/RZ %) was determined by tetrazolium staining. The effects of IPC with 2 x 5 min cycles of global ischaemia or 10 min pretreatment with bradykinin were assessed. DOCA-salt rats were markedly hypertensive and left ventricle/body weight ratio was 26% greater than in normotensive controls. Baseline coronary flow and risk zone/LV ratio were similar in normotensive hearts and DOCA-salt hearts, and infarct size was similar (AN/RZ 50.6+/-3.2% and 47.0+/-3.1%, respectively). IPC was equally protective in normotensive and DOCA-salt hearts (AN/RZ 18.6+/-3.3% and 18.4+/-2.3%, respectively, P < 0.01 versus corresponding control). Bradykinin 0.1, 0.2 or 0.5 microM pretreatment produced concentration-dependent infarct limitation in normotensive hearts (bradykinin 0.5 microM AN/RZ, 9.5+/-3.6%, P < 0.01 versus normotensive control), but the effect in DOCA-salt hearts was attenuated (bradykinin 0.5 microM AN/RZ, 23.4+/-3.8%). Further, the pre-ischaemic coronary vasodilator response to bradykinin was abrogated in DOCA-salt hypertensive hearts. We conclude that the cardioprotective action of bradykinin is markedly attenuated in moderate LVH and coronary vasodilator effect is lost. The reasons for reduced sensitivity to bradykinin in the hypertensive heart are unknown but these findings may have implications for the application of preconditioning-mimetic interventions in LVH.

Animals↗
PubMed2003

COX-3 the enzyme and the concept: steps towards highly specialized pathways and precision therapeutics?

Cyclooxygenases (COXs) catalyse the key rate-limiting step in prostanoid and thromboxane biosynthesis and are targets of non-steroidal anti-inflammatory drugs (NSAIDs). Until recently, the presence of only two isoforms-COX-1 and COX-2-remained in question because the potent anti-pyretic and analgesic effects of acetaminophen (paracetamol, tylenol ben-u-ron) could not be explained by either COX-1 or COX-2 blockades. A novel COX-1 splice variant termed COX-3, sensitive to acetaminophen, was recently discovered by Simmons et al., and is considered to play a key role in the biosynthesis of prostanoids known to be important mediators in pain and fever. Drugs that preferential block COX-1 also appear to act at COX-3. However the existence of COX-3 at the nucleotide sequence level in humans has been called to question. A functional COX-3 in humans is still to come underlining that the concept of COX-3 is still attractive. Here, we discuss some of the implications drawn from the identification of additional functional cyclooxygenase members in the generation of bioactive autacoids.

Acetaminophen↗
PubMedDate not supplied

Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX.

Endogenous chemical mediators or autacoids play key roles in controlling inflammation and its programmed resolution. Among them, it is known that lipoxins (LX) and aspirin-triggered LX (ATL) evoke bioactions in a range of physiologic and pathophysiologic processes and serve as endogenous lipid/chemical mediators that stop neutrophilic infiltration and initiate resolution. LXA4, ATL and their metabolic stable analogs elicit cellular responses and regulate PMN in vivo via interacting with their specific receptor, namely ALX. ALX is the first cloned and identified lipoxygenase-derived eicosanoid receptor with cell type-specific signaling pathways. Also, ALX could regulate PMN by interacting with each class of ligands (lipid vs. peptide) within specific phases of an inflammatory response. Together LX, ATL and ALX may provide new opportunities to design "resolution-targeted" therapies with high degree of precision in controlling inflammation. In this chapter, we give an overview and update of the current actions for LX and ATL, the identification of ALX and their novel anti-inflammatory and pro-resolving signals.

Amino Acid Sequence↗
PubMed2005

Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals.

Endocannabinoids have analgesic/anti-inflammatory properties. The biology of endocannabinoids, their receptors, signalling mechanisms and role in the regulation of physiological processes have been extensively reviewed. This review focuses on the role of palmitoylethanolamide (PEA), an endogenous fatty acid amide analogue of the endocannabinoid anandamide, in tissue protective mechanisms. PEA was first identified almost five decades ago in lipid extracts of various natural products, and its anti-inflammatory and antinociceptive effects were established later. Evidence exists that PEA is synthesised during inflammation and tissue damage and a number of beneficial effects, including the relief of inflammation and pruritus, have been shown to be useful in the control of neurogenic and neuropathic pain. The postulated hypotheses as to the mode of action of PEA include a possible local autacoid-like mediator activity regulating mast-cell activity and putative activation of cannabinoids and vanilloid TRPV1 receptors via "entourage" effects. The large number of scientific investigations into the effects of PEA and PEA-related compounds has given rise to new therapeutic opportunities. In spite of the multitude of therapies currently employed to control inflammation, pain, pruritus and tissue damage, the possibility of using a natural compound, such as PEA to manipulate endogenous protective mechanisms may be considered a beneficial novel therapeutic strategy in veterinary medicine.

Amides↗
PubMed1988

Consideration of conduit and resistance vessels in regulation of blood flow.

In heart failure the maximal capacity for dilation, especially in skeletal muscle arteries, is reduced. This may be due to changes in sympathetic tone, in hormonal stimulation (both by circulating and intramurally released compounds like angiotensin II with additional presynaptic effects) or in endothelium mediated vasodilation. The loss of endothelium-mediated, flow-dependent dilation in large arteries may originate from endothelial impairment induced by, e.g., chronic hypoxia or hypercholesterolemia. Similar effects result from suppressed local dilator autacoid release brought about, e.g., by circulating atrial natriuretic factor in the presence of a fully functioning endothelium. Finally, attenuated augmentations in flow may be secondary to changes in muscular metabolism, and an increased alpha-adrenergic neurogenic constriction may be present. This may be further enhanced by a local, beta-receptor-mediated angiotensin II release. An impaired dilation at the level of resistance vessels may result from a combination of the mechanisms listed above.

Animals↗
PubMed1997

Attenuation of epinephrine-induced dysrhythmias by bradykinin: role of nitric oxide and prostaglandins.

Cardiac dysrhythmias are common during anesthesia and surgery. An important precipitating factor of clinically relevant arrhythmias is the introoperative use of epinephrine. Bradykinin acts as an endogenous cardioprotective substance because it suppresses ventricular dysrhythmias induced by ischemia. In this study, we investigated whether bradykinin has a protective effect, preventing the development of dysrhythmias after epinephrine infusion in rats. Because kinins are potent stimulators of the release of nitric oxide and prostaglandins from the endothelium, we investigated whether the protective effect of bradykinin is mediated by these 2 autacoids. Male Sprague-Dawley rats anesthetized with sodium pentobarbital had catheters placed into a carotid artery and both jugular veins. Arterial blood pressure and lead II of the electrocardiogram (ECG) were continuously monitored and recorded. After a steady state was achieved, 1 mg/kg enalapril, an inhibitor of angiotensin I-converting enzyme/kininase II, was given intravenously to all groups except the one treated with losartan. Bradykinin was infused at the initial rate of 0.5 microg/kg per min. Cardiac arrhythmia was induced with 7.5 microg/kg epinephrine intravenously. Dysrhythmia was assessed by counting the number of premature ventricular contractions (PVCs), runs of ventricular tachycardia (V Tach), and missing beats during the first minute after epinephrine. In untreated, control rats, epinephrine caused 10.8 +/- 2.7 PVCs, 0.8 +/- 0.2 runs of V tach, and 11.6 +/- 7.4 missing beats/min. In rats pretreated with bradykinin, the same dose of epinephrine elicited 1.2 +/- 0.5 PVCs, no runs of V tach, and 0.4 +/- 0.4 missing beats/min. This beneficial effect of bradykinin was partially reversed by N-nitro-L-arginine methyl ester (L-NAME) or indomethacin, and completely by L-NAME plus indomethacin or icatibant, but it was not affected by des-Arg9[Leu8]-bradykinin. We conclude that bradykinin, acting on the B2 receptor, attenuates epinephrine-induced dysrhythmia via a mechanism that involves the release of NO and prostaglandins. Although the mechanism is not clear, NO and prostaglandins may prevent epinephrine-induced dysrhythmia and protect the myocardium via a direct action on cardiac neurons.

Adrenergic beta-Antagonists↗
PubMed1999

Broad-spectrum cardioprotection with adenosine.

Ischemia-reperfusion results in contractile dysfunction, necrosis, and vascular injury. This postischemic injury is mediated in part by superoxide radical production, neutrophils, dysfunction to ionic pumps, and edema formation. Adenosine is an autacoid released tonically by myocytes, endothelium, and neutrophils; the release of adenosine from the myocyte compartment into the interstitium is increased during ischemia. The major effects of adenosine are mediated by specific receptors identified as A1, A2a, A2b, and A3. Each receptor subtype contributes to physiological responses that influence ischemia-reperfusion injury. Adenosine has potent cardioprotective properties exerted during three major windows of opportunity: pretreatment, ischemia, and reperfusion. The cardioprotective effects exerted during pretreatment and ischemia may involve metabolic changes and hyperpolarization via K(ATP)-channel activation, mediated through A1 receptor mechanisms. The cardioprotective mechanisms exerted during reperfusion involve inhibition of neutrophils directly (superoxide anion generation, expression of adhesion molecules), and by inhibiting activation of the endothelium through A2 receptor-mediated mechanisms, thereby preventing neutrophil-endothelial cell interactions, which initiate the inflammatory-like component of reperfusion injury. Activation of the newly identified A3 receptor has been shown to be cardioprotective partially by inhibition of neutrophil adherence to endothelium and by neutrophil-independent mechanisms. These mechanisms of cardioprotection have been suggested to play major roles in the reduction of infarction and apoptosis after myocardial ischemia, cardioplegic arrest, and subsequent reperfusion. Adenosine has been used as an adjunct to both crystalloid and blood cardioplegia, but its potential as a cardioprotective agent has not been fully explored.

Adenosine↗
PubMed1988

Role of platelet-activating factor (PAF) in the bronchopulmonary alterations and beta-adrenoceptor function induced by endotoxin.

The possibility that PAF is implicated in the alterations of the beta-adrenoceptor function observed during endotoxemia was investigated. Lung parenchymal strips (LPS) from endotoxin-treated guinea-pig demonstrated specific desensitization to low doses of PAF whereas the contractions induced by histamine and leukotriene D4 were slightly affected. In addition, histamine-contracted LPS from endotoxin-injected animals exhibited decreased responsiveness to isoproterenol, a phenomenon not observed with guinea-pigs also treated with the specific PAF antagonist, BN 52021. No alteration of the sensitivity to isoproterenol of LPS preincubated with PAF was noted, suggesting an indirect effect of the autacoid on beta-adrenoceptor function.

Animals↗
PubMed2002

Human histamine N-methyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5'-flanking region single nucleotide polymorphism (SNP).

Histamine N-methyltransferase (HNMT) catalyzes one of two major metabolic pathways for histamine. The levels of HNMT activity and immunoreactive protein in human tissues are regulated primarily by inheritance. Previous studies of HNMT identified two common single nucleotide polymorphisms (SNPs), including a functionally significant nonsynonymous coding SNP (cSNP), (C314T, Thr105Ile), but that polymorphism did not explain all of the phenotypic variation. In the present study, a genotype-to-phenotype strategy was used to search for additional genetic factors that might contribute to the regulation of human HNMT activity. Specifically, we began by resequencing the human HNMT gene using 90 ethnically anonymous DNA samples from the Coriell Cell Repository and identified a total of eight SNPs, including the two that had been reported previously. No new nonsynonymous cSNPs were observed, but three of the six novel SNPs were located in the 5'-flanking region (5'-FR) of the gene-including a third common polymorphism with a frequency of 0.367 (36.7%). That observation directed our attention to possible genetic effects on HNMT transcription. As a first step in testing that possibility, we created and studied a series of reporter gene constructs for the initial 1kb of the HNMT 5'-FR. The core promoter and possible regulatory regions were identified and verified by electrophoresis mobility shift assays. We then studied the possible functional implications of the new common HNMT 5'-FR SNP. However, on the basis of reporter gene studies, that SNP appeared to have little effect on transcription. Phenotype-genotype correlation analysis performed with 112 human kidney biopsy samples that had been phenotyped for their level of HNMT activity confirmed that the common 5'-FR SNP was not associated with the level of HNMT activity in vivo. In summary, this series of experiments resulted in the identification of several novel HNMT polymorphisms, identification of the HNMT core promoter, and a comprehensive functional genomic study of a common HNMT 5'-FR SNP. These results represent an additional step in the definition of molecular genetic mechanisms involved in the regulation of this important autacoid-metabolizing enzyme in humans.

5' Flanking Region↗
PubMed1999

The cardiovascular effects and implications of peroxynitrite.

Nitric oxide is an endogenous autacoid produced primarily by the vascular endothelium. Under basal conditions, nitric oxide undergoes a rapid biradical reaction with superoxide anions to form peroxynitrite. This reaction, and hence the formation of peroxynitrite is augmented in inflammatory-like conditions such as ischemia-reperfusion injury when both substrates are present in high concentrations. Peroxynitrite has been implicated as a physiologically active toxic metabolite of nitric oxide leading to vascular and myocardial dysfunction. Recent evidence, however, has suggested that peroxynitrite may actually have beneficial properties under in vivo biological conditions when thiol-containing agents (glutathione, albumin, cysteine) agents are available to convert the peroxynitrite anion to nitrosothiols and related products demonstrating antineutrophil and cardioprotective properties. The dichotomy of physiologically relevant properties of peroxynitrite has important clinical applications with respect to nitric oxide therapy for cardiac, vascular, cerebral and pulmonary disease states. This review summarizes the biological properties of peroxynitrite relevant to the cardiovascular system.

Animals↗
PubMed2001

Kinin receptors in pain and inflammation.

Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.

Animals↗