Increased Susceptibility to Deoxycorticosterone Acetate-Salt-Induced Hypertension in Endothelin-B-Receptor-Deficient Rats
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.Journal of Cardiovascular Pharmacology (Impact Factor: 2.14). 12/2000; 36(5 Suppl 1):S86-9. DOI: 10.1097/00005344-200036051-00028
We evaluated the role of endothelin-B- (ET(B)) receptor-mediated action in the development and maintenance of deoxycorticosterone acetate (DOCA)-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting lethal (sl) rat which carries a naturally occurring deletion in the ET(B)-receptor gene. Homozygous (sl/sl) rats exhibit abnormal development of the neural crest-derived epidermal melanocytes and the enteric nervous system (ENS), and do not live beyond 1 month because of intestinal aganglionosis and resulting intestinal obstruction. Therefore, the dopamine-beta-hydroxylase (D betaH) promoter was used to direct ET(B) transgene expression in sl/sl rats to support normal ENS development. D betaH-ET(B) sl/sl rats live into adulthood and are healthy, expressing ET(B)-receptor in adrenals and other adrenergic neurons. When homozygous (sl/sl) and wild-type (WT) (+/+) rats, all of which were transgenic, were treated with DOCA and salt for 4 weeks, the homozygous rats exhibited significantly earlier and higher increases in systolic blood pressure than WT rats. The daily oral administration of ABT-627, a selective ET(A)-receptor antagonist, almost completely suppressed the DOCA-salt-induced hypertension in both groups. Renal dysfunction and histological damage induced by DOCA-salt treatment were more severe in homozygous than in WT rats. Increased and marked vascular hypertrophy of the aorta was also observed in homozygous rats, compared with WT rats. Renal and vascular injuries induced by DOCA and salt were significantly improved by ABT-627 administration. We propose that ET(B)-receptor-mediated actions are protective factors in the pathogenesis of DOCA-salt-induced hypertension. ET(A)-mediated actions are at least partly responsible for the increased susceptibility to DOCA-salt-induced hypertension and related tissue injuries in ET(B)-receptor-deficient rats.
- [Show abstract] [Hide abstract]
ABSTRACT: Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.Biological & Pharmaceutical Bulletin 12/2001; 24(11):1219-30. DOI:10.1248/bpb.24.1219 · 1.83 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Vascular endothelin (ET) type B (ET(B)) receptors exert dilator and constrictor actions in a complex interaction with ET(A) receptors. We aimed to clarify the presence and relative importance of nitric oxide (NO) and other mechanisms underlying the dilator effects of ET(B) receptors in rat kidneys. Complete inhibition of NO production with Nomega-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg iv) enhanced the renal vasoconstriction elicited by ET-1 injected into the renal artery from -15 to -30%. Additional infusion of the NO donor nitroprusside (NP) into the renal artery did not reverse this effect (-29%) but effectively buffered ANG II-mediated vasoconstriction. Similarly, ET-1 responses were enhanced after a smaller intrarenal dose of L-NAME (-22 vs. -15%) and were unaffected by subsequent NP infusion (-21%). These results indicate that the responsiveness to ET-1 is buffered by ET(B) receptor-stimulated phasic release of NO, rather than its static mean level. Infusion of the ET(B) receptor antagonist BQ-788 into the renal artery further enhanced the ET-1 constrictor response to NP+L-NAME (-92 vs. -49%), revealing an NO-independent dilator component. In controls, vasoconstriction to ET-1 was unaffected by vehicle (-27 vs. -20%) and markedly enhanced by BQ-788 (-70%). The same pattern was observed when indomethacin (Indo) was used to inhibit cyclooxygenase (-20% for control, -22% with Indo, and -56% with ET(B) antagonist) or methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MS-PPOH) or miconazole+Indo was used to inhibit epoxygenase alone (-10% for control, -11% with MS-PPOH, and -35% with ET(B) antagonist) or in combination (-14% for control, -20% with Indo + miconazole, and -43% with ET(B) antagonist). We conclude that phasic release of NO, but not its static level, mediates part of the dilator effect of ET(B) receptors and that an NO-independent mechanism, distinct from prostanoids and epoxyeicosatetraenoic acids, perhaps ET(B) receptor clearance of ET-1, plays a major buffering role.AJP Regulatory Integrative and Comparative Physiology 06/2005; 288(5):R1168-77. DOI:10.1152/ajpregu.00550.2004 · 3.11 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We used patch-clamp electrophysiology to investigate regulation of the epithelial Na+ channel (ENaC) by endothelin-1 (ET-1) in isolated, split-open rat collecting ducts. ET-1 significantly decreases ENaC open probability by about threefold within 5 min. ET-1 decreases ENaC activity through basolateral membrane ETB but not ETA receptors. In rat collecting duct, we find no role for phospholipase C or protein kinase C in the rapid response of ENaC to ET-1. ET-1, although, does activate src family tyrosine kinases and their downstream MAPK1/2 effector cascade in renal principal cells. Both src kinases and MAPK1/2 signaling are necessary for ET-1-dependent decreases in ENaC open probability in the split-open collecting duct. We conclude that ET-1 in a physiologically relevant manner rapidly suppresses ENaC activity in native, mammalian principal cells. These findings may provide a potential mechanism for the natriuresis observed in vivo in response to ET-1, as well as a potential cause for the salt-sensitive hypertension found in animals with impaired endothelin signaling.American journal of physiology. Renal physiology 08/2008; 295(4):F1063-70. DOI:10.1152/ajprenal.90321.2008 · 3.25 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.