br In patients with type I diabetes mellitus poor
In patients with type I diabetes mellitus poor management causes/INS; a drastic rise in glucose levels resulting in diabetic ketoacidosis (DKA). About 1% of DKA episodes can be complicated by cerebral edema. ET and its receptors are involved in the regulation of /INS;cerebral blood flow. We studied the effect of ETA receptor antagonists in a rat model of DKA. DKA was produced by streptozotocin (150mg/kg, ip). Group 1: Control (non-diabetic) animals administered citrate. Animals that developed DKA were divided in five additional groups. Group II: DKA animals without treatment; Group III: DKA animals given saline; Group IV: DKA animals given saline and insulin of /INS;1.5u/kg/h/INS;; Group V: DKA animals given saline, insulin of /INS;1.5u/kg/h/INS; and BMS-182874 (9mg/kg);/INS; and Group VI: DKA animals given saline, insulin of /INS;1.5u/kg/h/INS; and BQ123 (1mg/kg). Blood glucose and ketones markedly increased by day 4 in DKA rats. Saline/insulin treatment in DKA rats increased the plasma and Bafilomycin A1 ET-1 levels which were not affected by BMS-182874 or BQ123 treatment. There was /INS;no change in the expression of ETB receptors in the brain, however, ETA receptor expression increased in DKA rats and was not altered following treatment with insulin, BMS-182874 or BQ123. Animals in insulin/saline group showed a significant increase (160%) in cerebral blood perfusion compared to baseline. This increase in cerebral perfusion was attenuated by BQ123 or BMS-182874. Treatment with BQ123 also improved blood pH and ketones in DKA rats. It can be concluded that ETA receptor antagonists maybe of therapeutic use in the management of DKA and its complications.
Introduction Following the discovery of endothelin (Yanagisawa et al., 1988), functional characterization of the three endothelin isoforms (endothelin-1, endothelin-2 and endothelin-3) predicts that at least two mammalian receptor subtypes are present: endothelin ETA receptor that is selective for endothelin-1, and endothelin ETB receptor that has equal affinity for the three isoforms (Opgenorth, 1995). The existence of the two distinct high-affinity endothelin receptor subtypes has been confirmed by cloning. Unique cDNAs that code for proteins belonging to the G-protein-linked heptahelical receptor superfamily are identified in bovine and rat tissues (Arai et al., 1990; Sakurai et al., 1990). Human endothelin ETA and ETB receptors have also been cloned and found to have ∼90% deduced amino acid homology with the bovine or rat receptor and ∼60% identity with each other (Arai et al., 1993; Elshourbagy et al., 1993). While pharmacological studies suggest that there may be more endothelin receptor subtypes (Bax and Saxena, 1994), no additional homologous mammalian cDNAs have been identified. In tissues and cells, endothelin binding initiates a complex signal transduction cascade (Simonson, 1993). Endothelin-1 binding activates phospholipases C and D, causing increases in inositol 1,4,5-trisphosphate and neutral 1,2-diacylglycerol which are associated with a biphasic increase in the intracellular Ca2+ concentration and activation of various kinase-mediated pathways involved in mitogenic responses (Wu-Wong et al., 1997b; Wu-Wong and Opgenorth, 1998). Recent evidence suggests that endothelin may play a role in modulating apoptosis of endothelial and smooth muscle cells (Wu-Wong et al., 1997b; Shichiri et al., 1998). Thus, in addition to the potent vasoconstricting activity and its involvement in cardiovascular diseases, endothelin-1 may play a pivotal role in the pathogenesis of cell growth disorders such as cancer, restenosis, and benign prostatic hyperplasia (Webb et al., 1998). A major advance was made in the endothelin field with the development of endothelin receptor antagonists. In particular, BQ-123 (cyclo (d-Trp–d-Asp–Pro–d-Val–Leu)) (Ihara et al., 1991) and FR139317 ((R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-+++methylpentanoyl] amino-3-[3-(1-methyl-1H-indoyl)]propionyl]amino-3-(2-pyridyl) propionic acid) (Sogabe et al., 1993) have been important tools in the investigation of endothelin-mediated pathophysiology. Both are endothelin ETA receptor-selective, but are peptidic compounds and have poor pharmacokinetics with limited utility as therapeutic agents. Following the peptidic compounds, many pharmaceutical companies reported the discovery of a number of non-peptide antagonists with greatly improved pharmacokinetics, such as Ro 47–0203 (4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2-bipyrimidin-4-yl]-benzenesulfonamide, bosentan), SB 217242 ((+)-(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid), PD 156707 (sodium 2-benzo(1,3ioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-but-2-enoate), etc. (see Table 1). Some of these antagonists are being investigated in human clinical trials.