The role of the central thromboxane A2 in cardiovascular effects of a phospholipase A2 activator melittin administrated intracerebroventricularly in normotensive conscious rats

Yalçın, Murat; Ak, Fusun; Ertürk, Melih

doi:10.1016/j.npep.2006.01.003

Cited by 22 publications

(13 citation statements)

References 22 publications

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“…Furthermore, a recent report demonstrated that i.c.v. administration of melittin, a PLA 2 activator, affects the cardiovascular system and increases BP in both normal 11–13 and hypotensive settings 13 . In the present study, the pressor response induced by centrally injected AA is in agreement with the results of previous studies reporting that i.c.v.…”

Section: Discussionsupporting

confidence: 93%

“…administration of melittin, a PLA 2 activator, affects the cardiovascular system and raises blood pressure under both normal 11–13 and hypotensive conditions 13 . Activation of central TXA 2 receptors contributes to these effects of melittin 11 and increases in plasma catecholamine, vasopressin and renin activity mediate the cardiovascular responses to melittin under both conditions 13 . Taken together, the results of these studies suggest that activation of PLA 2 by melittin may increase AA levels in target cells, leading to increased synthesis of PGs, including TXA 2 .…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular Effects of Centrally Administered Arachidonic Acid in Haemorrhage‐induced Hypotensive Rats: Investigation of a Peripheral Mechanism

Yalçın

Aydin

2009

Clin Exp Pharma Physio

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1. The aims of the present study were to determine the cardiovascular effects of arachidonic acid (AA) and to investigate the peripheral mechanisms mediating these effects in haemorrhage-induced hypotensive rats. 2. Acute haemorrhage was induced by withdrawing a total volume of 2.2 mL blood/100 g bodyweight over a period of 10 min. Rats were then injected with 75-300 microg, i.c.v., AA and cardiovascular changes were monitored over the next 60 min. Plasma catecholamine and vasopressin levels, as well as plasma renin activity (PRA), were measured 10 min after injection of 150 microg AA in haemorrhage-induced hypotensive awake rats. In addition, rats were pretreated with saline (1 mL/kg, i.v.), the vasopressin V(1) receptor antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1),O-Me-Tyr(2),Arg(8)]-vasopressin (10 microg/kg, i.v.), the alpha(1)-adrenoceptor antagonist prazosin (500 microg/kg, i.v.), the non-specific angiotensin II receptor antagonist saralasin (250 microg/kg, i.v.) or a combination of these three antagonists 5 min before injection of AA (150 microg, i.c.v.). The effects of these antagonists on responses to AA were determined. 3. Arachidonic acid caused dose- and time-dependent increases in mean arterial pressure and heart rate and reversed hypotension in haemorrhaged rats. Haemorrhage itself produced an increase in plasma catecholamine and vasopressin levels, as well as PRA; injection of AA produced further increases in these parameters, ranging from 39-123%, under hypotensive conditions. Under hypotensive conditions, pretreatment of rats with all three receptor antagonists produced similar partial blockade of the pressor response to AA, but not the increase in heart rate. Moreover, combined administration of all three receptor antagonists prior to the i.c.v. injection of 150 microg AA completely abolished the pressor response to AA in haemorrhage-induced hypotensive rats. 4. These results indicate that centrally administered AA reverses hypotension by increasing blood pressure and heart rate in the hypotensive setting. The observed increases in plasma catecholamine and vasopressin levels, as well as PRA, mediate the pressor response to AA in haemorrhage-induced hypotensive rats.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Cardiovascular Effects of Centrally Administered Arachidonic Acid in Haemorrhage‐induced Hypotensive Rats: Investigation of a Peripheral Mechanism

Yalçın

Aydin

2009

Clin Exp Pharma Physio

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“…Melittin is a powerful PLA2 activator [22, 23] and releases arachidonic acid from plasma membrane [24, 25]. It is most likely that topical application of melittin caused the release of COX/LOX metabolites such as prostaglandins and HPETEs by activating the PLA2-COX/LOX pathway.…”

Section: Discussionmentioning

confidence: 99%

Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways

Xiao

et al. 2011

Biochemical and Biophysical Research Communications

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Previous studies demonstrated that melittin, the main peptide in bee venom, could cause persistent spontaneous pain, primary heat and mechanical hyperalgesia, and enhance the excitability of spinal nociceptive neurons. However, the underlying mechanism of melittin-induced cutaneous hypersensitivity is unknown. Effects of melittin applied topically to acutely dissociated rat dorsal root ganglion neurons were studied using whole-cell patch clamp and calcium imaging techniques. Melittin induced intracellular calcium increases in 60% of small (<25 µm) and medium (<40 µm) diameter sensory neurons. In current clamp, topical application of melittin evoked long-lasting firing in 55% of small and medium-sized neurons tested. In voltage clamp, melittin evoked inward currents in sensory neurons in a concentration-dependent manner. Repeated application of melittin caused increased amplitude of the inward currents. Most melittin-sensitive neurons were capsaicin-sensitive, and 65% were isolectin B4 positive. Capsazepine, the TRPV1 receptor inhibitor, completely abolished the melittin-induced inward currents and intracellular calcium transients. Inhibitors of signaling pathways showed that phospholipaseA2, but not phospholipase C, was involved in producing the melittin-induced inward currents. Inhibitors of cyclooxygenases (COX) and lipoxygenases (LOX), two key components of the arachidonic acid metabolism pathway, each partially suppressed the inward current evoked by melittin. Inhibitors of protein kinase A (PKA), but not of PKC, also abolished the melittin-induced inward currents. These results indicate that melittin can directly excite small and medium-sized sensory neurons at least in part by activating TRPV1 receptors via PLA2-COXs/LOXs cascade pathways.

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“…Its effects on the cardiovascular system [12] and insulin secretion [13] have also been demonstrated and attributed to the activation of phospholipase A 2 . However, MLT is extremely cytotoxic and potentially immunogenic [14] and thus not clinically used.…”

Section: Introductionmentioning

confidence: 99%

“…An amphipathic molecule with a hydrophobic N-terminal region (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and a hydrophilic C-terminus (21)(22)(23)(24)(25)(26), MLT has a random coil conformation in dilute aqueous solutions [2]. MLT has two regions of a-helix separated by a proline 'hinge' in aqueous solutions at high concentrations or in hydrophobic environments, such as alcohols or lipid bilayers [3].…”

Section: Introductionmentioning

confidence: 99%

PEGylation of Melittin: Structural Characterization and Hemostatic Effects

Peng

Huang

Shek

et al. 2010

Journal of Bioactive and Compatible Polymers

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To promote and understand the structure-property relationship for hemostasis, we modified melittin (MLT) using a four-arm poly(ethylene glycol) (PEG) with N-hydroxysuccinimide ester. The PEGylation was characterized by FTIR, MALDI-MS, NMR, a bicinchoninic acid assay, circular dichroism, hemolysis assay, and thromboelastography. Changes in the reaction conditions affected the extent of the modification, the numbers of MLT conjugated to PEG arms, and possible PEGylation sites. The reaction at pH 9.2 with a high MLT/PEG ratio, resulted in the highest modification. Reactions in dimethylsulfoxide (DMSO) resulted in more multi-arm coupled MLT, reaching a maximum of four MLT per PEG. The helicity of the modified peptide, relative to the native peptide, was essentially maintained in DMSO, but substantially lost at pH 9.2. PEGylation reduced the hemolytic effects of MLT and subsequently changed its coagulation profiles. The overall hemostatic effects of MLT modified in DMSO indicate that this may be a convenient approach to the PEGylation of biomolecules for biomedical applications.

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The role of the central thromboxane A2 in cardiovascular effects of a phospholipase A2 activator melittin administrated intracerebroventricularly in normotensive conscious rats

Cited by 22 publications

References 22 publications

Cardiovascular Effects of Centrally Administered Arachidonic Acid in Haemorrhage‐induced Hypotensive Rats: Investigation of a Peripheral Mechanism

Cardiovascular Effects of Centrally Administered Arachidonic Acid in Haemorrhage‐induced Hypotensive Rats: Investigation of a Peripheral Mechanism

Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways

PEGylation of Melittin: Structural Characterization and Hemostatic Effects

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