title: Blood pressure modulation following activation of mast cells by cationic cell penetrating peptides.
abstract: Short cell penetrating peptides (CPP) are widely used in vitro to transduce agents into cells. But their systemic effect has not been yet studied in detail. We studied the systemic effect of the cell penetrating peptides, penetratin, transportan and pro-rich, on rat hemodynamic functions. Intra-arterial monitoring of blood pressure showed that injection of the positively charged penetratin and transportan in a wide range of concentrations (2.5-320 μg/kg) caused highly significant transient decrease in the systolic and diastolic blood pressure in a dose dependent manner (p<0.01). Pretreatment with histamine receptors blockers or with cromolyn, a mast cell stabilizing agent, significantly attenuated this effect. Furthermore, in vitro incubation of these both peptides with mast cells line, LAD2, caused a massive mast cell degranulation. In vitro studies showed that these CPP in a wide range of concentrations were not cytotoxic without any effect on the survival of LAD2 mast cell line. In contrast, the less positively charged and proline-rich CPP, pro-rich, had no systemic effects with no effect on mast cell degranulation. Our results indicate that intravenously administrated positively charged CPP may have deleterious consequences due to their induced BP drop, mediated by mast cell activation. Therefore, the major effect of mast cell activation on BP should be considered in developing possible future drug therapies based on the injection of membrane-permeable and positively charged CPP. Nevertheless, lower levels of such CPP may be considered as a treatment of systemic high BP through moderate systemic mast cell activation.
authors.affiliation: Laboratory of Biotechnology and Radiobiology, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Maamoun
authors.initials: M
authors.lastname: Basheer
authors.forename: Herzl
authors.initials: H
authors.lastname: Schwalb
authors.forename: Irit
authors.initials: I
authors.lastname: Shefler
authors.forename: Lilia
authors.initials: L
authors.lastname: Levdansky
authors.forename: Yoseph A
authors.initials: YA
authors.lastname: Mekori
authors.forename: Raphael
authors.initials: R
authors.lastname: Gorodetsky
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D015550:Cell Degranulation; D002460:Cell Line; D002470:Cell Survival; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019004:Galanin / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D006439:Hemodynamics; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D055672:Static Electricity / Q000009:adverse effects; D014862:Wasp Venoms / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D011993:Recombinant Fusion Proteins; D014862:Wasp Venoms; C110068:transportan; D019004:Galanin; C414409:penetratin