Mervaala E M, Malmberg L, Teräväinen T L, Laakso J, Vapaatalo H, Karppanen H
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Br J Pharmacol. 1998 Jan;123(2):195-204. doi: 10.1038/sj.bjp.0701591.
1 In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg(-1) day(-1) in the food) and a calcium channel blocker felodipine (0.4 mg kg(-1) day(-1) subcutaneously via an osmotic minipump). 2 Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. 3 The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. 4 Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the alpha-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet. 5 Ramipril and felodipine in combination increased plasma renin activity by 1.9-3.2 fold without affecting serum aldosterone levels. 6 Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium-dependent and endothelium-independent vascular relaxation responses and attenuated alpha-adrenoceptor-mediated vascular contractile responses.
1 在自发性高血压大鼠（SHR）中，我们在4周的时间内研究了对照低钠饮食、高盐饮食（食物干重中氯化钠含量为6%）和一种新型高矿盐饮食（添加了钾、镁和L-赖氨酸的矿盐，添加量比10.5%高75%，以产生相同的6%氯化钠浓度）对血管紧张素转换酶抑制剂雷米普利（食物中0.25 mg·kg⁻¹·天⁻¹）和钙通道阻滞剂非洛地平（通过渗透微型泵皮下注射0.4 mg·kg⁻¹·天⁻¹）低剂量联合用药所产生的心血管效应的影响。2 高盐饮食而非矿盐饮食加速了SHR高血压的发展，并诱导了左心室和肾脏肥大。高盐饮食和矿盐饮食均未显著影响心率。3 雷米普利和非洛地平联合用药可降低收缩压，并在高盐饮食期间有效预防左心室肥大的发展，且对心率无显著影响。低钠饮食或用矿盐替代饮食中的高盐可改善该药物联合用药的心血管效应。4 在为期四周的研究结束时，检测了体外完整内皮肠系膜动脉环的反应。雷米普利和非洛地平联合用药显著改善了对照饮食和高盐饮食的SHR对乙酰胆碱的内皮依赖性血管舒张反应，并增强了对硝普钠的非内皮依赖性血管舒张反应。用矿盐替代饮食中的高盐可改善对乙酰胆碱的内皮依赖性血管舒张反应。在高盐饮食期间，该药物联合用药减弱了α-肾上腺素能受体介导的对去甲肾上腺素的血管收缩反应。5 雷米普利和非洛地平联合用药使血浆肾素活性增加了1.9 - 3.2倍，而不影响血清醛固酮水平。6 我们的研究结果表明，在高盐摄入期间，雷米普利和非洛地平低剂量联合用药的心血管效应得以维持。然而，限制盐摄入或用富含钾和镁的矿盐替代饮食中的高盐可改善该药物联合用药的心血管效应。在高钠摄入情况下，该药物联合用药的部分有益心血管效应显然是通过改善内皮依赖性和非内皮依赖性血管舒张反应以及减弱α-肾上腺素能受体介导的血管收缩反应来介导的。
