irl-1620 and Body-Weight

IRL-1620, a potent endothelin B receptor agonist, enhanced the efficacy of paclitaxel in a breast tumor model, but its effect in prostate cancer is not known. The present study was conducted to evaluate the effect of IRL-1620 on tumor perfusion, uptake of [(14)C]-doxorubicin in the tumor and efficacy of doxorubicin (DOX), and 5-flurouracil (5-FU) in a rat prostate tumor model.. JHU-4 (Mat-Lu) cells inoculated prostate tumor model in Copenhagen rats was used for the study.. Administration of IRL-1620 (3 nmol/kg, i.v) significantly increased (102.8%) prostate tumor perfusion and tumor uptake of [(14)C]-doxorubicin (115%) compared to vehicle treated rats. Results of the efficacy study demonstrate that IRL-1620 administration 15 min prior to DOX (5 mg/kg) or 5-FU (50 mg/kg) on every third day for a total of four doses significantly reduced tumor volume compared to vehicle treated rats.. IRL-1620 significantly enhanced the uptake and efficacy of anticancer agents in prostate cancer.

Topics: Animals; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Biological Transport; Body Weight; Doxorubicin; Endothelins; Fluorouracil; Male; Peptide Fragments; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Receptor, Endothelin B; Vasodilation; Vasodilator Agents

We investigated the mechanisms involved in the enhancement of endothelin (ET)-1 vascular reactivity induced by ethanol consumption. Ethanol intake for 2, 6, and 10 weeks enhanced the ET-1-induced contractile response of endothelium-intact but not endothelium-denuded rat carotid rings independently of the treatment duration. Conversely, phenylephrine-induced contraction was not affected by ethanol intake. The contraction induced by IRL1620 [succinyl-(Glu(9),Ala(11,15))-ET-1-(8-21)], a selective ET(B) agonist, was increased after treatment with ethanol in endothelium-intact but not in endothelium-denuded carotid rings. Moreover, ET-1- and IRL1620-induced relaxation was reduced in endothelium-intact phenylephrine-precontracted rings from ethanol-treated rats. Acetylcholine-induced relaxation was not affected by ethanol treatment. N(G)-Nitro-l-arginine methyl ester, 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one, indomethacin, and tetraethylammonium reduced the relaxation induced by IRL1620 in carotid glands from control but not ethanol-treated rats. The mRNA levels for ET(A) and ET(B) receptors were not altered by ethanol consumption. However, ethanol treatment reduced the protein expression of ET(B) receptors. Furthermore, immunohistochemical assays showed reduced immunostaining for endothelial ET(B) receptors after treatment with ethanol. We conclude that ethanol consumption enhances ET-1-induced contraction in the rat carotid and that this response is not different among the three periods of treatment used in this study. Finally, the potentiation of ET-1-induced vascular reactivity is probably caused by reduced expression of relaxing endothelial ET(B) receptors.

Topics: Acetylcholine; Animals; Blood Glucose; Blotting, Western; Body Weight; Carotid Arteries; Central Nervous System Depressants; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Ethanol; Immunohistochemistry; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Phenylephrine; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; Vasoconstrictor Agents; Vasodilator Agents

Several neurotransmitter mechanisms have been proposed to play a role in the actions of morphine. We reported that centrally administered endothelin A (ETA) receptor antagonists potentiate morphine analgesia in rats. It has also been reported that ETB agonist, IRL1620, has antinociceptive action mediated through opiate receptors in the periphery. The present study was conducted to determine if central ETB receptors are involved in analgesic actions of morphine. The effect of intracerebroventricular (i.c.v.) administration of ETB receptor agonist, IRL1620, on morphine-induced analgesia and hyperthermia was determined in the rat. Morphine (4 mg/kg, s.c.) produced a significant increase (84%) in tail-flick latency compared to the control group and the analgesic response lasted for 4 h. IRL1620 (30 microg, i.c.v.) did not produce any increase (16%) in tail-flick latency over the 5-hour observation period in vehicle-treated rats. Pretreatment with IRL1620 (3, 10, and 30 microg, i.c.v.) did not have any significant effect on the intensity and duration of morphine (4 mg/kg, s.c.)-induced analgesia. Morphine (4 mg/kg, s.c.) administration produced an increase in body temperature compared to the control group. In vehicle-pretreated rats, IRL1620 (30 microg, i.c.v.) did not produce any change in body temperature. The morphine-induced hyperthermic effect was not altered in IRL1620-pretreated rats. These studies demonstrate that IRL1620, a specific ETB receptor agonist, did not affect the morphine-induced analgesic and hyperthermic effect in rats. It can be concluded that central ETB receptors are not involved in modulation of pharmacological actions of morphine.

Topics: Analgesia; Analgesics, Opioid; Animals; Area Under Curve; Body Temperature; Body Weight; Drug Interactions; Endothelins; Injections, Intraventricular; Male; Morphine; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B

We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu,(9)Ala(11,15)]-ET-1(8-21) (IRL-1620), an ET(B) agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ET(B) responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-1 and ET(A/B) receptors was evaluated in mesenteric arteries by reverse transcription-polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620-induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620-induced vasodilation. Removal of the ovaries increased ET-1 mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ET(B) receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ET(B) receptor expression in the DOCA group. A greater blood pressure-lowering effect of bosentan (ET(A)/ET(B) blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ET(B) receptor-mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ET(B) receptor vascular responses/expression in DOCA-salt hypertension.

Topics: Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Endothelin-1; Endothelins; Estradiol; Female; Hypertension; In Vitro Techniques; Mesenteric Arteries; Organ Size; Ovariectomy; Peptide Fragments; Potassium, Dietary; Progesterone; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Chloride, Dietary; Time Factors; Uterus; Vasoconstriction

1. The aim of the study was to visualize endothelin-1 (ET-1)-mediated constriction in renal vessels of cortical and juxtamedullary glomeruli in the split hydronephrotic rat kidney in vivo and to functionally characterize the ET receptor subtypes involved. 2. ET-1 (10(-9) M) constricted preglomerular vessels (by 6-18%) and efferent arterioles (by 11-13%), and decreased glomerular blood flow (GBF, by 55%) of cortical and juxtamedullary glomeruli. 3. The ETA antagonist BQ-123 (10(-6) M), as well as the ETB antagonist BQ-788 (2 x 10(-7) M) and IRL 1038 (10(-6) M), shifted the concentration-response curve of GBF for ET-1 to the right by one order of magnitude. While BQ-123 antagonized ET-1 constriction only in preglomerular vessels, BQ-788 and IRL 1038 were effective both in preglomerular vessels and efferent arterioles. 4. The ETB agonist IRL 1620 (10(-8) M) reduced GBF by 50% and constricted efferent arterioles (by 20-33%) about two times more than preglomerular vessels (by 6-14%). 5. Our results suggest that in renal cortical and juxtamedullary vessels of rats, ET-1-induced preglomerular vasoconstriction is mediated by ETA and ETB receptors, while efferent vasoconstriction is predominantly mediated by ETB receptors, which might have important consequences for the regulation of glomerular filtration pressure by ET.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Glomerular Filtration Rate; Kidney; Kidney Glomerulus; Microcirculation; Nephrosis; Peptide Fragments; Peptides, Cyclic; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstriction