ABNORMALITY OF THE ATP-SENSITIVE POTASSIUM CHANNEL IN HYPERTENSION

有证据表明，ATP敏感的K+(KATP)通道是 抗高血压K+通道激动剂的作用已引起广泛关注 关注该通道在血管平滑肌中的作用 功能。这些特征的调查和阐明 不同的血管类型可能有助于深入了解这些因素的作用 通道正常，血管平滑肌功能正常。在高血压中，三磷酸腺苷 这个通道的灵敏度似乎降低了。这项研究建议 这笔赠款旨在检验以下假设：1) 血管平滑肌KATP通道对ATP敏感性的改变 高血压中的细胞是血管适应性反应的一部分 高血压伴肥厚；2)敏感性改变 表示与此不同的一种基因的表达 频道。具体目标：1)描述具体目标的影响 KATP通道的激动剂和拮抗剂 激动剂刺激的血管平滑肌收缩反应 高血压大鼠和正常血压大鼠；2)测定单次 离体血管平滑肌膜片上的KATP通道 来自高血压和正常血压大鼠的细胞；3)防止 药物对高血压大鼠血压的升降作用 方法或动脉阻塞，然后确定这样的效果 治疗：a)特定激动剂和拮抗剂的作用 KATP通道对基础和激动剂刺激的心肌收缩反应的影响 来自高血压大鼠和正常血压大鼠的血管平滑肌，b) 大鼠心肌细胞膜片上单个KATP通道的特性 高血压和正常血压来源的血管平滑肌细胞 大鼠；5)确定单个KATP通道的特性是否改变 当高血压大鼠和正常血压大鼠的血管平滑肌细胞 是在原代细胞培养中生长的；6)确定是否有敏感性 在一种非遗传模型中，KATP通向ATP的通道的 7)确定高血压患者对三磷酸腺苷敏感性的改变 KATP通道与膜环境的改变有关 (翻译后效果)或更改是否代表该表达式 这个通道的另一种形式(翻译前效应)。这个 拟议的实验将在分离的血管节段上进行 和细胞(颈动脉、尾动脉、肠系膜动脉和冠状动脉) 易卒中的自发性高血压大鼠和正常血压大鼠 标准肌浴技术和膜片钳技术在Wistar-京都大鼠中的应用 技术。青蛙血管平滑肌细胞基因表达的研究 卵母细胞将指示KATP通道的基因表达是否 在高血压中发生改变。澄清两国之间的关系 KATP通道激动剂的更大效力及其改变的性质 高血压的经络可能有助于更好地理解这一现象 对血管肥大和对发展更有效和更好 用于治疗这种疾病的耐受性药理药剂。

Evidence that the ATP-sensitive K+(KATP) channel is the specific site of action of the antihypertensive K+ channel activators has focussed a great deal of attention on the role of this channel in vascular smooth muscle function. Investigation and elucidation of these characteristics in a variety of blood vessel types may provide insight into the role of these channels in norm,al smooth muscle function. In hypertension, the ATP sensitivity of this channel appears to be decreased. The studies proposed in this grant are designed to test the following hypotheses: 1) the altered sensitivity to ATP of the KATP channel of vascular smooth muscle cells in hypertension is part of the adaptive response to the vascular hypertrophy associated with high blood pressure; 2) the altered sensitivity to ATP is indicative of the genetic expression of a different from this channel. Specific aims: 1) To characterize the effects of specific agonists and antagonists of the KATP channel on basal and agonist-stimulated contractile responses in vascular smooth muscle from hypertensive and normotensive rats;2) To determine the properties of single KATP channels in membrane patches from isolated vascular smooth muscle cells derived from hypertensive and normotensive rats; 3) To prevent the rise in or lower blood pressure in hypertensive rats by pharmacological means or arterial obstruction and then determine the effect of such treatment on:a) the actions of specific agonists and antagonists of the KATP channel on basal and agonist-stimulated contractile responses in vascular smooth muscle from hypertensive and normotensive rats,b) the properties of single KATP channels in membrane patches from isolated vascular smooth muscle cells derived from hypertensive and normotensive rats; 5) To determine if the properties of single KATP channels are altered when vascular smooth muscle cells from hypertensive and normotensive rats are grown in primary cell culture; 6) To determine whether the sensitivity of the KATP channel to ATP is altered in a non-genetic model of hypertension; 7) To determine whether the change in ATP sensitivity of the KATP channel is associated with a change in the membrane environment (posttranslational effect) or whether the change represents the expression of a different form of this channel (pretranslational effect). The proposed experiments will be performed on isolated blood vessel segments and cells (carotid, tail, mesenteric and coronary arteries) from the stroke-prone strain of the spontaneously hypertensive rat and normotensive Wistar-Kyoto rats using standard muscle bath technique and the patch clamp technique. The expression of vascular smooth muscle cell mRNA in frog oocytes will indicate whether the genetic expression of the KATP channel is altered in hypertension. Elucidation of the relationship between the greater potency of KATP channel agonists and the altered properties of this channel in hypertension may lead a better understanding of the phenomenon of vascular hypertrophy and to the development of more effective and better tolerated pharmacological agents for the treatment of this disease.