Role of endothelin receptors in the hypertensive state of kinin B(2) knockout mice subjected to a high-salt diet.
Mice with disruption of the kinin B(2) receptor (B(2)KO mice) are sensitive to salt-rich diets, which causes hypertension. The aim of the study was to assess the role of endothelin-1 (ET-1) and angiotensin-II in hypertensive B(2)KO mice on a salt-rich diet. We also wanted to verify if there is an upregulation of the mRNA expression of the precursors or receptors for these hormones. Two groups of B(2)KO mice (20-25 g) were investigated. The first group received an 8% NaCl diet with 1% NaCl in drinking water (HS) and the second was fed with normal food with tap water (NS). The antagonists tested were the ET(A) receptor antagonist BQ-123 (1 and 5 mg/kg), the ET(B) receptor antagonist BQ-788 (0.25 and 1 mg/kg), the angiotensin receptor type 1 antagonist losartan (10 mg/kg) and the angiotensin-converting enzyme inhibitor captopril (3 mg/kg). These were injected intraperitoneally 30 min prior to blood pressure measurement by the tail-cuff method. We also studied the level of expression of preproET-1, ET-1 receptors, angiotensinogen and angiotensin receptors by RNA extraction from the heart and kidneys of these mice followed by reverse transcriptase (RT)-PCR. B(2)KO mice (HS) were hypertensive after 8 weeks compared with B(2)KO mice on normal diet (HS, 93.4+/-1.5 mmHg, n=7; NS, 61.4+/-2.7 mmHg, n=7). In the HS group, the mean arterial blood pressure was significantly reduced by BQ-123 (5 mg/kg) to 61.9+/-1.8 mmHg (n=7), by BQ-788 (1 mg/kg) to 58.8+/-2.6 mmHg (n=6), by losartan (10 mg/kg) to 73.2+/-1.7 mmHg (n=8) and by captopril (3 mg/kg) to 86.0+/-2.3 mmHg (n=8). The expression studied by RT-PCR did not show any difference (either in precursors or receptors expression) between hypertensive and normal mice. The four antagonists used seemed to reverse the hypertension. These results suggest that ET-1 and angiotensin-II are probably involved in the mechanism that leads to hypertension since the effect of these hormones is probably not compensated by kinins in B(2)KO mice. Further studies are necessary to understand the implication of the cross-talk between these hormones in the hypertensive state.
Department of Pharmacology, Institute of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4.
Isabelle
I
Brochu
Julie
J
Labonté
Ghassan
G
Bkaily
Pedro
P
D'Orléans-Juste
D000804:Angiotensin II / Q000235:genetics; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D016232:Endothelins / Q000235:genetics; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009842:Oligopeptides / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D043782:Receptor, Bradykinin B2; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011945:Receptors, Angiotensin / Q000235:genetics; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; D017466:Receptors, Endothelin; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; C086539:BQ 788; D002216:Captopril; D019808:Losartan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)