药物基因组学在丙泊酚心血管敏感性方面的个体差异。
Pharmacogenomic strain differences in cardiovascular sensitivity to propofol.
机构信息
Anesthesia Research, The Medical College of Wisconsin and The Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226, USA.
出版信息
Anesthesiology. 2011 Dec;115(6):1192-200. doi: 10.1097/ALN.0b013e318238f445.
INTRODUCTION
A pharmacogenomic approach was used to further localize the genetic region responsible for previously observed enhanced cardiovascular sensitivity to propofol in Dahl Salt Sensitive (SS) versus control Brown Norway (BN) rats.
METHODS
Propofol infusion levels that decreased blood pressure by 50% were measured in BN.13(SS) rats (substitution of SS chromosome 13 into BN) and in five congenic (partial substitution) strains of SS.13(BN). The effect of superfused 2,6 diisopropylphenol on small mesenteric arterial vascular smooth muscle transmembrane potential was measured in congenic strains before and during superfusion with Rp-adenosine-3',5'-cyclic monophosphorothioate and 2.5 μM (Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate, inhibitors of protein kinase A and G, respectively. The genetic locus and potential role of the renin gene in mediating vascular smooth muscle sensitivity to propofol were determined in three selected subcongenic SS.BN¹³ strains.
RESULTS
A 30-32% smaller propofol infusion rate reduced blood pressure by 50% in BN.13(SS) compared with BN and the SS.13(BN) congenic containing an 80 BN gene substitution. Compared with the 80 BN gene-containing SS.13(BN) congenic, SS exhibited greater protein kinase A dependent vascular smooth muscle hyperpolarization in response to propofol. Using subcongenics, the increased propofol-induced cardiovascular sensitivity and hyperpolarization was further localized to an eight-gene region (containing the BN renin gene). Blockade of angiotensin receptors with losartan in this subcongenic increased propofol-induced hyperpolarization by threefold to that observed in SS.
CONCLUSIONS
Enhanced cardiovascular sensitivity to propofol in SS (compared with BN) is caused by an altered renin gene. Through modified second messenger function, this differentially regulates vascular smooth muscle contractile state and reduces vascular tone, thereby exacerbating cardiovascular depression by propofol.
简介
采用药物基因组学方法进一步定位负责先前观察到的达荷美盐敏感（SS）与对照棕色挪威（BN）大鼠对异丙酚心血管敏感性增强的遗传区域。
方法
测量 BN.13（SS）大鼠（SS 染色体 13 取代 BN）和五个部分取代 SS.13（BN）的同基因（部分取代）株中降低血压 50%的异丙酚输注水平。在 SS 同基因株中，测量了超灌注 2,6-二异丙基苯酚对小肠系膜动脉血管平滑肌跨膜电位的影响，并用蛋白激酶 A 和 G 的抑制剂 Rp-腺苷-3'，5'-环单磷酸硫代酯和 2.5 μM（Rp）-8-（对氯苯硫代）鸟苷-3'，5'-环单磷酸硫代酯进行超灌注。在三个选定的亚同基因 SS.BN¹³ 株中确定了肾素基因在介导血管平滑肌对异丙酚敏感性中的遗传位置和潜在作用。
结果
与 BN 相比，BN.13（SS）中的异丙酚输注率降低 30-32%，血压降低 50%，而含有 80 BN 基因取代的 SS.13（BN）同基因则降低了 50%。与含有 80 BN 基因的 SS.13（BN）同基因相比，SS 表现出更大的蛋白激酶 A 依赖性血管平滑肌超极化反应对异丙酚的反应。使用亚同基因，进一步将增加的异丙酚诱导的心血管敏感性和超极化作用定位到一个包含 8 个基因的区域（包含 BN 肾素基因）。在该亚同基因中用氯沙坦阻断血管紧张素受体，使异丙酚诱导的超极化作用增加三倍，达到 SS 观察到的水平。
结论
与 BN 相比，SS 对异丙酚的心血管敏感性增强是由改变的肾素基因引起的。通过改变第二信使功能，这会调节血管平滑肌的收缩状态并降低血管张力，从而加重异丙酚引起的心血管抑制。
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