Gohlke P, Linz W, Schölkens B A, Wiemer G, Unger T
Department of Pharmacology, Christian-Albrechts University Kiel, Germany.
Hypertension. 1996 Sep;28(3):397-402. doi: 10.1161/01.hyp.28.3.397.
In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.
在先前针对易患中风的自发性高血压大鼠（SHRSP）的研究中，我们证明，即使是亚降压剂量的早期发作、长期血管紧张素转换酶抑制剂治疗也能改善心脏功能和代谢，并增加主动脉环磷酸鸟苷（cGMP）含量。用依替巴肽阻断缓激肽2（B2）受体可预防这些作用。在本研究中，我们研究了长期口服血管紧张素1（AT1）受体拮抗剂氯沙坦（每天30 mg/kg）对产前及随后至20周龄的SHRSP心脏功能和生化参数以及主动脉cGMP含量的影响。氯沙坦可预防高血压和左心室肥厚的发生。在离体灌注心脏中进行的体外心脏功能测量显示有所改善，左心室压力显著增加（22.4%）、左心室压力变化率（dP/dtmax）显著增加（35.1%）以及冠状动脉血流量显著增加（38%）就证明了这一点。细胞内酶乳酸脱氢酶、肌酸激酶以及乳酸向冠状动脉流出液中的释放分别减少了46.4%、47.2%和63.6%。在心肌组织中，糖原以及富含能量的磷酸盐三磷酸腺苷（ATP）和磷酸肌酸的浓度分别增加了43.2%、33.1%和42.4%，而乳酸减少了57.0%。主动脉组织中的cGMP含量增加了五倍。我们的结果表明，氯沙坦对AT1受体的长期阻断改善了SHRSP的心脏功能和代谢，并增加了主动脉cGMP含量，其程度与先前在同等降压剂量下长期使用血管紧张素转换酶抑制剂治疗后观察到的相似。本文讨论了预防高血压和心脏肥大以及对非AT1受体的刺激，以解释氯沙坦的心脏和血管作用。
