慢性缓激肽B2受体阻断对清醒Dahl盐抵抗大鼠血压的影响。

Effect of chronic bradykinin B2 receptor blockade on blood pressure of conscious Dahl salt-resistant rats.

作者信息

Mukai H, Fitzgibbon W R, Ploth D W, Margolius H S

机构信息

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA.

出版信息

Br J Pharmacol. 1998 May;124(1):197-205. doi: 10.1038/sj.bjp.0701797.

DOI:10.1038/sj.bjp.0701797

PMID:9630360

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565358/

Abstract

In this study 3 protocols were utilized to determine the role of endogenous kinins in the resistance of the inbred Dahl (Rapp) salt-resistant (SR/Jr) rats to high salt diet-induced blood pressure elevation. 2. The bradykinin B2 receptor antagonist, Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) at doses of either 10-20 or 20-40 nmol day(-1) (subcutaneously (s.c), via osmotic minipumps, for either 1 or 3 weeks during a high (8%) salt diet) effectively blocked or attenuated the hypotensive responses to 100-1000 ng of bradykinin. 3. In the first protocol, 5 week old SR/Jr rats treated with Hoe 140 (10-20 nmol day(-1), n = 9, s.c., via osmotic minipumps) for 3 weeks and concomitantly fed high (8%) NaCl diet had significantly higher conscious tail cuff blood pressures (BPc) at 1 and 3 weeks when compared with rats treated with vehicle (0.9% NaCl, n = 6). The differences in BPc between the 2 groups were 13 mmHg (P < 0.001) after 1 week and 8 mmHg (P < 0.05) after 3 weeks of treatment. 4. In the second protocol, 5 week old SR/Jr rats were treated with Hoe 140 (20-40 nmol day(-1), n = 8, s.c., via osmotic minipumps) or vehicle (n = 8) for 3 weeks. During the first week of treatment the rats were fed normal (0.8%) NaCl diet. The rats were then switched to 8% NaCl for 2 remaining weeks of the protocol. The mean BPc of Hoe 140-treated rats was not significantly different from that of the vehicle-treated rats when fed 0.8% NaCl diet. In contrast, rats treated with Hoe 140 and concomitantly fed high (8%) NaCl diet had significantly increased BPc (123+/-2 vs 111 +/- 1 mmHg, P < 0.001 for the Hoe 140- and vehicle-treated rats, respectively). 5. In the third protocol, treatment with Hoe 140 (20 40 nmol day(-1), s.c., via osmotic minipumps) during high salt diet did not increase BPc in rats that were pre-exposed to the high salt diet for 2 weeks. 6. At the end of 3 weeks of study, blood pressure was measured via an arterial catheter during pentobarbitone-induced anaesthesia. Rats treated with Hoe 140 for 1 or 3 weeks had significantly lower mean arterial blood pressures than the vehicle-treated rats. 7. Our findings suggest that in SR/Jr rats, kinin activation of bradykinin B2 receptors at least partially contributes to early regulatory mechanisms that resist an increase in blood pressure following exposure to a high salt diet. The mechanism underlying the decreased blood pressure during pentobarbitone anaesthesia of SR/Jr rats chronically treated with Hoe 140 has yet to be elucidated.

摘要

在本研究中，采用了3种方案来确定内源性激肽在近交系达尔（拉普）抗盐（SR/Jr）大鼠对高盐饮食诱导的血压升高的抵抗中的作用。2. 缓激肽B2受体拮抗剂Hoe 140（D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-缓激肽），剂量为10 - 20或20 - 40 nmol·天⁻¹（皮下注射，通过渗透微型泵，在高（8%）盐饮食期间持续1或3周）能有效阻断或减弱对100 - 1000 ng缓激肽的降压反应。3. 在第一个方案中，5周龄的SR/Jr大鼠用Hoe 140（10 - 20 nmol·天⁻¹，n = 9，皮下注射，通过渗透微型泵）处理3周，并同时喂食高（8%）NaCl饮食，与用赋形剂（0.9% NaCl，n = 6）处理的大鼠相比，在1周和3周时清醒状态下尾袖血压（BPc）显著更高。治疗1周后两组BPc的差异为13 mmHg（P < 0.001），治疗3周后为8 mmHg（P < 0.05）。4. 在第二个方案中，5周龄的SR/Jr大鼠用Hoe 140（20 - 40 nmol·天⁻¹，n = 8，皮下注射，通过渗透微型泵）或赋形剂（n = 8）处理3周。在治疗的第一周，大鼠喂食正常（0.8%）NaCl饮食。然后在方案的剩余2周将大鼠转换为8% NaCl饮食。喂食0.8% NaCl饮食时，用Hoe 140处理的大鼠的平均BPc与用赋形剂处理的大鼠无显著差异。相反，用Hoe 140处理并同时喂食高（8%）NaCl饮食的大鼠BPc显著升高（分别为123±2 vs 111±1 mmHg，Hoe 140处理组和赋形剂处理组大鼠P < 0.001）。5. 在第三个方案中，在高盐饮食期间用Hoe 140（20 - 40 nmol·天⁻¹，皮下注射，通过渗透微型泵）处理，对预先暴露于高盐饮食2周的大鼠的BPc没有升高作用。6. 在研究3周结束时，在戊巴比妥诱导的麻醉期间通过动脉导管测量血压。用Hoe 140处理1或3周的大鼠的平均动脉血压显著低于用赋形剂处理的大鼠。7. 我们的研究结果表明，在SR/Jr大鼠中，缓激肽对缓激肽B2受体的激活至少部分有助于抵抗高盐饮食后血压升高的早期调节机制。长期用Hoe 140处理的SR/Jr大鼠在戊巴比妥麻醉期间血压降低的潜在机制尚待阐明。