Gohlke P, Kuwer I, Schnell A, Amann K, Mall G, Unger T
Department of Pharmacology, Christian-Albrechts University of Kiel, Germany.
Hypertension. 1997 Jan;29(1 Pt 2):478-82. doi: 10.1161/01.hyp.29.1.478.
We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B2-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B2-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577 +/- 279, n = 11 and 3988 +/- 300 mm/mm3; n = 10; P < .05) compared with vehicle-treated animals (2935 +/- 137 mm/mm3; n = 13). These effects were abolished by chronic bradykinin B2-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429 +/- 309 mm/mm3; n = 7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B2-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.
我们研究了血管紧张素转换酶（ACE）抑制剂诱导心脏毛细血管长度密度增加的作用机制。对易患中风的自发性高血压大鼠在产前及直至20周龄时用ACE抑制剂雷米普利（每天口服0.01和1毫克/千克）和AT1受体拮抗剂氯沙坦（每天口服30毫克/千克）进行治疗。通过在6至20周龄时与缓激肽B2受体拮抗剂依卡替班（每天0.5毫克/千克，通过渗透微型泵皮下注射）联合治疗，评估内源性缓激肽增强对ACE抑制剂作用的贡献。在治疗期结束时，使用定向仪方法通过体视学测量心脏毛细血管长度密度。高剂量而非低剂量的雷米普利可预防高血压和左心室肥厚的发展，且不受慢性缓激肽B2受体阻断的影响。与用赋形剂处理的动物（2935±137毫米/立方毫米；n = 13）相比，低剂量和高剂量雷米普利显著增加了心脏毛细血管长度密度（3577±279，n = 11和3988±300毫米/立方毫米；n = 10；P <.05）。这些作用被慢性缓激肽B2受体阻断所消除。单独的缓激肽拮抗剂对心脏毛细血管长度密度无影响。氯沙坦可预防高血压和左心室肥厚，但未显著改变心脏毛细血管长度密度（3429±309毫米/立方毫米；n = 7）。我们的结果表明，在易患中风的自发性高血压大鼠中，慢性ACE抑制剂治疗可独立于血压降低或左心室肥厚而增加心脏毛细血管长度密度。这种作用与ACE抑制剂诱导的内源性缓激肽增强有关，因为它被慢性缓激肽B2受体阻断所预防，且在用AT1受体拮抗剂氯沙坦进行抗高血压治疗后未观察到。
