ATP敏感性钾通道SUR2B/Kir6.1亚型选择性开放剂纳他卡林的心血管药理学作用特征

目的研究SUR2B/Kir6.1亚型KATP通道开放剂纳他卡林的心血管药理学作用。方法(1)血流动力学测定:戊巴比妥钠腹腔注射麻醉大鼠,从颈总动脉插管至左心室,连接八导生理记录仪记录心功能的变化。(2)制备大鼠离体工作心脏,观察纳他卡林对其心功能的影响。(3)制备大鼠尾动脉血管条,用去甲肾上腺素预收缩后,观察累积给予纳他卡林对血管张力的影响。结果纳他卡林10-8～10-4mol.L-1对大鼠离体工作心脏功能无影响;对大鼠尾动脉血管条具有内皮细胞依赖性舒张作用。麻醉大鼠,纳他卡林0.5、2、8mg.kg-1静脉注射可剂量依赖性降低血压,纳他卡林8mg.kg-1抑制心脏的收缩和舒张功能,其效应可被格列苯脲和L-NAME拮抗。结论纳他卡林对心脏无直接作用,可通过舒张血管降低血压;纳他卡林的心血管药理学作用与其选择性开放KATP通道、促进内皮细胞释放NO有关。     

Distinct role of adrenoceptor subtypes in cardiac adaptation to chronic pressure overload

1. With the generation of gene knockout (KO) or transgenic overexpression (TG) mouse models targeting adrenoceptors (AR), recent studies in vivo have investigated the role of AR subtypes in pressure overload-induced left ventricular (LV) hypertrophy and remodelling. 2. Although subjecting alpha(1B)-KO mice to transverse aortic constriction (TAC) did not reveal significant phenotype differences compared with controls, mice deficient in both alpha(1A)- and alpha(1B)-AR responded to TAC with poor survival, increased cardiomyocyte apoptosis, more severe fibrosis and dysfunction, but a similar degree of LV hypertrophy, compared with wild-type littermates. Following TAC, alpha(1B)-TG mice developed more severe hypertrophy, interstitial fibrosis and LV dysfunction. In contrast, overexpression of alpha(1A)-AR preserved cardiac function and reduced death from heart failure without affecting the degree of LV hypertrophy. Thus, alpha(1A)- and alpha(1B)-adrenoceptor signalling impacts differently on myocardial adaptation to pressure overload. 3. The absence of both beta(1)- and beta(2)-AR significantly suppressed pressure overload-evoked hypertrophy, fibrosis and expression of inflammatory or fibrogenic genes. Conversely, studies on beta(2)-TG mice with TAC revealed adverse consequences, including accelerated development of heart failure, poor survival and more severe interstitial fibrosis, but a comparable degree of hypertrophy compared with wild-type littermates. 4. Collectively, these findings suggest that the effect of ARs on pressure overload-induced myocardial adaptation is subtype specific. Whereas activation of alpha(1B)-AR or beta(2)-AR contributes to maladaptation and the onset of heart failure, activation of alpha(1A)-AR or inactivation of beta(2)-AR is beneficial in the setting of chronic pressure overload.     

新型K_(ATP)开放剂埃他卡林对慢性低氧诱导大鼠体内肺动脉平滑肌K_(ATP)通道mRNA表达变化的影响

目的研究慢性低氧对大鼠肺动脉平滑肌KATP通道mRNA表达的影响及新型KATP开放剂埃他卡林(Iptakalim,IPT)的作用。方法将清洁级SD大鼠30只随机分成对照组、低氧组、IPT组,每组10只。将低氧组与IPT组放入常压低氧舱制备动物模型;采用右心导管测量大鼠肺动脉压;用实时荧光定量PCR检测(Real time PCR)技术分析各组肺动脉平滑肌KATP通道Kir6.1与SUR2B mRNA表达。结果低氧组大鼠肺动脉平均压高于对照组和IPT组(P<0.05),低氧组SUR2B亚基mRNA水平低于对照组(P<0.05),IPT可逆转慢性低氧对SUR2B的作用,各组Kir6.1亚基mRNA表达水平无差异(P>0.05)。结论慢性缺氧导致大鼠肺动脉平滑肌KATP通道SUR2B mRNA表达减少,IPT能拮抗慢性缺氧对KATP通道SUR2B mRNA基因表达的抑制作用。     

Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels

Many mammalian cells have two distinct types of ATP-sensitive potassium (K(ATP)) channels: the classic ones in the surface membrane (sK(ATP)) and others in the mitochondrial inner membrane (mitoK(ATP)). Cardiac mitoK(ATP) channels play a pivotal role in ischemic preconditioning, and thus represent interesting drug targets. Unfortunately, the molecular structure of mitoK(ATP) channels is unknown, in contrast to sK(ATP) channels, which are composed of a pore-forming subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of mitoK(ATP) channels, we compared the pharmacology of native cardiac mitoK(ATP) channels with that of molecularly defined sK(ATP) channels expressed heterologously in human embryonic kidney 293 cells. Using mitochondrial oxidation to index mitoK(ATP) channel activity in rabbit ventricular myocytes, we found that pinacidil and diazoxide open mitoK(ATP) channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoK(ATP) channels. Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B. P-1075 activated all the K(ATP) channels, except Kir6.1/SUR1 channels. Glybenclamide potently blocked all sK(ATP) channels, but 5HD only blocked channels formed by SUR1/Kir6.1 or Kir6.2 (IC(50)s of 66 and 81 microM, respectively). This potency is similar to that for block of mitoK(ATP) channels (IC(50) = 95 microM). In addition, HMR-1098 potently blocked Kir6.2/SUR2A channels (IC(50) = 1.5 microM), but was 67 times less potent in blocking Kir6.1/SUR1 channels (IC(50) = 100 microM). Our results demonstrate that mitoK(ATP) channels closely resemble Kir6.1/SUR1 sK(ATP) channels in their pharmacological profiles.     

Tissue Angiotensin-converting enzyme activity plays an important role in pressure overload-induced cardiac fibrosis in rats

It has been widely assumed that the cardiac angiotensin-generating system plays an important role in the development and maintenance of cardiac remodeling caused by pressure overload. The roles of angiotensin-converting enzyme (ACE) in pressure overload-induced cardiac hypertrophy and fibrosis in rats were investigated. Pressure overload was achieved by constricting the abdominal aorta above the renal arteries. After they underwent surgery, the rats were treated with a low or high dose of the ACE inhibitor imidapril (0.07 and 0.7 mg/kg/d s.c.) with an osmotic pump for 4 weeks. High-dose imidapril prevented the increase in blood pressure, cardiac hypertrophy, and fibrosis. Low-dose imidapril inhibited only cardiac fibrosis. ACE activity in the myocardium, but not in serum, was significantly increased in the rats with the banded aorta, and ACE immunoreactivity was increased in the areas of fibrosis. These changes were markedly reduced by both doses of imidapril. These results suggest that the increased local ACE expression contributes to the development of pressure overload-induced cardiac fibrosis but is not responsible for hypertrophy in rats.     

雷米普利对大鼠高血压并发左心室心肌肥厚伴心肌舒张功能不全和血管纤维化的作用

目的探讨雷米普利对舒张性心力衰竭的治疗作用。方法45只雄性Spargue-Dawley大鼠随机分为假手术组、心肌肥厚模型组和雷米普利治疗组。采用腹主动脉缩窄手术制备心肌肥厚模型,造模12周后ig给予雷米普利1mg·kg-1,每天1次,连续12周。颈动脉插管法测定大鼠左心室舒张末压(LVEDP)、左心室收缩压(LVSP)和左心室压变化速率最大值(±dp/dtmax);测定心脏重量指数和左心室重量指数(LVMI);Van Gieson染色法测定心肌间质和心肌血管纤维化程度;实时PCR法测定胶原Ⅰ型和胶原Ⅲ型mRNA表达。结果与假手术组相比,模型组大鼠LVEDP和LVSP分别升高了103.9%和37.7%;LVMI、心肌间质和血管纤维化分别增加了35.5%,306.3%和104.1%;胶原Ⅰ型和胶原Ⅲ型mRNA表达分别上调2.1倍和4.4倍。与模型组大鼠比较,雷米普利组大鼠LVEDP,LVSP和LVMI分别降低了62.5%,27.4%和18.6%;大鼠心肌间质和心肌血管的纤维化分别降低了44.9%和55.6%;心肌组织胶原Ⅰ型和胶原Ⅲ型mRNA表达分别降低了44.8%和67.0%。结论雷米普利能改善高血压并发左心室心肌肥厚伴心肌舒张功能不全大鼠的心肌舒张功能,可能与其延缓心肌纤维化的病理进程有关,提示雷米普利对舒张性心力衰竭可能有一定的治疗作用。     

Block of human aorta Kir6.1 by the vascular KATP channel inhibitor U37883A.

1. A human aorta cDNA library was screened at low stringency with a rat pancreatic Kir6.1 cDNA probe and a homologue of Kir6.1 (hKir6.1) was isolated and sequenced. 2. Metabolic poisoning of Xenopus laevis oocytes with sodium azide and application of the K+ channel opener drug diazoxide induced K+ channel currents in oocytes co-injected with cRNA for hKir6.1 and hamster sulphonylurea receptor (SUR1), but not in oocytes injected with water or cRNA for hKir6.1 or SUR1 alone. 3. K+ channel currents due to hKir6.1+SUR1 or mouse Kir6.2+SUR1 were strongly inhibited by 1 microM glibenclamide. K+-current carried by hKir6.1+SUR1 was inhibited by the putative vascular-selective KATP channel inhibitor U37883A (IC50 32 microM) whereas current carried by Kir6.2+SUR1 or Shaker K+ channels was unaffected. 4. The data support the hypothesis that hKir6.1 is a component of the vascular KATP channel, although the lower sensitivity of hKir6.1+SUR1 to U37883A compared with native vascular tissues suggests the need for another factor or subunit. Furthermore, the data suggest that pharmacology of KATP channels can be determined by the pore-forming subunit as well as the sulphonylurea receptor and point to a molecular basis for the pharmacological distinction between vascular and pancreatic/cardiac KATP channels.     

黄芪注射液对压力过载性左心室肥厚大鼠心肌胶原蛋白Ⅰ、Ⅲ表达的影响

目的:观察黄芪注射液对大鼠压力过载性心肌肥厚的逆转作用,并探讨胶原蛋白Ⅰ、Ⅲ在肥厚心肌中的表达变化及黄芪注射液对其的影响。方法:采用缩窄大鼠腹主动脉建立心肌肥厚模型,术后12周开始给药,连续12周。测定大鼠左心室质量指数(LVWI),观察黄芪注射液对大鼠心肌组织病理变化的影响;检测大鼠左心室组织胶原蛋白Ⅰ、Ⅲ的表达。结果:黄芪注射液呈剂量依赖性抑制模型大鼠左心室LVWI的增加,其中高剂量黄芪注射液与卡托普利作用相似。黄芪注射液和卡托普利均能减轻模型大鼠心肌胞外基质过多沉积,改善心肌细胞受压萎缩或空泡变性的程度;均能抑制心衰大鼠左心室组织中胶原蛋白I的表达,而胶原蛋白Ⅲ的表达无显著变化。结论:黄芪注射液对压力过载所致大鼠左心室肥厚有抑制作用,其机制可能与下调心肌组织胶原蛋白I的表达有关。     

丹参酮ⅡA对压力负荷增加的大鼠TNF-α表达的影响

目的观察TNF-α在压力负荷增加大鼠血清中的表达,并探讨其对心肌纤维化的作用机制。方法 32只成年雄性SD大鼠,随机分成四组(n=8),假手术组(Sham组)、模型组(Model组)、Tan II A组(Tan II A组,20 mg.kg-1.d-1)及阳性对照药物卡托普利组(Captopril组,100 mg.kg-1.d-1)。除Sham组外,其余3组大鼠均行肾上方腹主动脉缩窄术制备压力负荷增加心肌纤维化模型,Sham组仅分离腹主动脉而不结扎。术后4周成功造模并开始给药,疗程为4周。8周后检测左室重量指数、心肌组织病理学、心肌羟脯氨酸(HYP)含量、血清TNF-α蛋白的含量。结果与Model组比较,Tan II A组能明显抑制心肌纤维化大鼠心肌组织的病理改变,降低心肌肥厚指数、心肌羟脯氨酸含量以及血清TNF-α蛋白浓度(P0.01)。结论压力负荷增加大鼠血清TNF-α蛋白表达明显升高,表明促炎细胞因子TNF-α在压力负荷增加大鼠心肌纤维化中起着重要的作用;TanII A对心肌纤维化的保护作用可能部分与下调促炎细胞因子表达有关。     

Comparison of the angiotensin II type 1-receptor antagonist YM358 and the angiotensin-converting enzyme inhibitor enalapril in rats with cardiac volume overload.

We evaluated the effects of chronic oral administration of an angiotensin II type 1 (AT1)-receptor antagonist YM358 and an angiotensin converting enzyme inhibitor enalapril on hemodynamics and cardiac hypertrophy in rats with volume overload-induced heart failure. We assessed changes of cardiac hemodynamics and cardiac hypertrophy at 2 and 4 weeks after administration of YM358 (3, 30 mg/kg per day) or enalapril (30 mg/kg per day) in abdominal aortocaval shunt rats. YM358 (30 mg/kg) attenuated increases of left ventricle (LV)/body weight (BW), left atrium (LA)/BW, right ventricle (RV)/BW and heart/BW ratios, but did not affect cardiac hemodynamics in shunt rats. Enalapril also reduced the increased LV/BW and heart/BW ratios together with significant reductions of systolic blood pressure, left ventricular systolic pressure and the first derivative of left ventricular pressure. These data suggest that the effects on attenuation of the development of cardiac hypertrophy are not different for YM358 and enalapril, although the effects on cardiac hemodynamics are different for the same dosages. The attenuating action of YM358 on cardiac hypertrophy was independent of the action on hemodynamics and indicated the direct action of the AT1 receptor on the heart.     

Nitric oxide inhibits isoprenaline-induced positive inotropic effects in normal, but not in hypertrophied rat heart

Evidence has accumulated that, in the rat heart, nitric oxide (NO) inhibits β-adrenoceptor-mediated positive inotropic effects. The aim of this study was to investigate whether this effect of NO may be altered in cardiac hypertrophy. For this purpose we studied the effects of the NO-donor SNAP (S-nitroso-N-acetyl-D,L-penicillamine) on isoprenaline-induced positive inotropic effects in left ventricular strips from three models of cardiac hypertrophy: a) 12–16 weeks old male spontaneously hypertensive rats (SHR) vs. age-matched normotensive Wistar-Kyoto (WKY) rats, b) six weeks old male Wistar WKY-rats subtotally nephrectomized (SNX) 7 weeks after SNX vs. sham-operated rats (SOP) and c) four weeks old male Wistar WKY-rats supra-renal aortic-banded (AOB, band diameter 1.0 mm) 8 weeks after AOB vs. SOP. In all three models of cardiac hypertrophy the heart weight/body weight ratio was significantly higher than in their respective controls. On isolated electrically driven ventricular strips isoprenaline (10^–10–10^–5 M) caused concentration-dependent increases in force of contraction. Maximal increases (E_max) were similar in SHR vs. WKY-rats, but reduced in SNX- (2.9±0.29 vs. 5.1±0.34 mN, p<0.01) and AOB-rats (2.3±0.37 vs. 4.2±0.33 mN, p<0.01). In control rats (WKY and the respective SOP) the NO-donor SNAP (10^–5 M) caused a significant rightward-shift of the concentration-response curve for isoprenaline; this rightward-shift could be inhibited by methylene blue (10^–5 M). In ventricular strips of SHR, SNX- and AOB-rats, however, 10^–5 M SNAP failed to significantly affect isoprenaline-induced positive inotropic effect. We conclude that in cardiac hypertrophy effects of NO are attenuated. Such an impairement of the NO-system could contribute to the development and/or maintenance of cardiac hypertrophy. Received: 16 February 1998 / Accepted: 11 March 1998     

Iptkalim inhibits cocaine challenge—induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up—regulating Kir6.1 and Kir6.2 mRNA expression

目的:研究钾通道开放剂埃他卡林对急慢性可卡因应用引起的伏隔核、纹状体和额叶皮层的多巴胺和谷氨酸水平变化的影响及其机制。方法:采用高效液相色谱与电化学检测、荧光检测联用的方法测定各脑区谷氨酸和多巴胺的含量;采用半定量逆转录聚合酶链反应(RT-PCR)研究ATP敏感性钾通道亚单位Kir6.1、Kir6.2、SUR1和SUR2 mRNA表达的变化。结果:埃他卡林不影响急性可卡因应用引起纹状体和伏隔核中多巴胺和谷氨酸水平的增高(P>0.05),能够逆转激发剂量可卡因诱导的慢性成瘾大鼠纹状体和伏隔核的多巴胺含量增高(P<0.05),对激发后皮层和伏隔核谷氨酸水平增高有降低趋势但差异无显著性(P>0.05)。激发剂量可卡因能提高可卡因预处理组和埃他卡林预处理组纹状体和伏隔核的Kir6.1和Kir6.2 mRNA表达以及皮层的Kir6.2 mRNA表达,而且IPT预处理组的升高幅度显著高显著高于可卡因慢性处 理组。结论:埃他卡林通过上调Kir6.1和Kir6.2 mRNA表达抑制可卡因激发引起的纹状体和伏隔核的多巴胺水平的增高。     

An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in rats

1. To assess the involvement of volume overload in the development of cardiac hypertrophy during treatment with an antidiabetic thiazolidinedione, changes in cardiac anatomy and parameters of cardiac volume overload were evaluated in female Sprague-Dawley rats treated with the thiazolidinedione derivative T-174. 2. Two week administration of T-174 (13 and 114 mg/kg per day) increased absolute and relative heart weights by 11-24%, demonstrating the development of cardiac hypertrophy. There was no evidence of oedema in hearts from treated rats. 3. Both plasma and blood volumes were increased in T-174-treated rats without any changes in systolic blood pressure and heart rate, whereas haematocrit was decreased. In accordance with the existence of volume overload, both left ventricular end-diastolic pressure and right atrial pressure were increased. Morphometric analysis of hearts revealed that T-174 induced eccentric heart hypertrophy, as characterized by a small increase in wall thickness and a large increase in the chamber volume, which is characteristic of volume overload. Volume overload is suggested as the possible trigger mechanism because blood volume expansion preceded cardiac hypertrophy and there was a high correlation between heart weight and blood volume. 4. T-174-treated streptozotocin-induced diabetic rats also exhibited blood volume expansion and cardiac hypertrophy. 5. These findings suggest that cardiac volume overload is induced by plasma volume expansion and contributes to the development of eccentric cardiac hypertrophy during treatment with antidiabetic thiazolidinediones. Although thiazolidinediones are insulin-sensitizing agents, these cardiac effects are likely to be mediated independently of insulin.     

Decreased expression of aortic KIR6.1 and SUR2B in hypertension does not correlate with changes in the functional role of K(ATP) channels

ATP-dependent potassium (K(ATP)) channels are the target of multiple vasoactive factors and drugs. Changes in the functional role of ATP-dependent (K(ATP)) potassium channels in hypertension are controversial. The aim of the present study was to analyze the possible changes of ATP-sensitive potassium channels (K(ATP)) expression and function during hypertension. For this purpose, we used endothelium-denuded aorta segments from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) to analyze the 1) expression of K(ATP) subunits Kir6.1, Kir6.2 and SUR2B by immunohistochemistry and Western blot, 2) the K(ATP) currents recorded in the whole cell configuration of the patch-clamp technique and 3) the vasodilator response to the K(ATP) channel openers, pinacidil and cromakalim. Kir6.1 and SUR2B were expressed in the medial layer of the aorta from WKY rats and SHR rats, while Kir6.2 was not detected in aorta from either strain. Kir6.1 and SUR2B expression were decreased in hypertension. However, the vasodilator responses of pinacidil and cromakalim were similar in WKY rats and SHR rats. Moreover, pinacidil induced increase in K+ currents was also similar in WKY rats and SHR rats and also similarly inhibited by glybenclamide. Our data demonstrate for the first time direct evidence of decreased aortic Kir6.1/SUR2B subunit expression in hypertension, but preserved functional responses to K(ATP) channel openers.     

Molecular and functional diversity of ATP-sensitive K+ channels: the pathophysiological roles and potential drug targets

ATP-sensitive K(+) (K(ATP)) channels comprise the pore-forming subunit (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptors (SUR1 or SUR2). K(ATP) channels with different combinations of these subunits are present in various tissues and regulate cellular functions. From the analysis of mouse models with targeted deletion of the gene encoding the pore-forming subunit Kir6.1 or Kir6.2, functional roles of K(ATP) channels in various organs have been clarified. Kir6.1(-/-) mice showed sudden death associated with ST elevation and atrioventricular block in ECG, a phenotype resembling Prinzmetal angina in humans. Kir6.2(-/-) mice were more susceptible to generalized seizure during hypoxia than wild-type (WT) mice, suggesting that neuronal K(ATP) channels, probably composed of Kir6.2 and SUR1, play a crucial role for the protection of the brain against lethal damage due to seizure. In Kir6.2(-/-) mice lacking the sarcolemmal K(ATP) channel activity in cardiac cells, ischemic preconditioning failed to reduce the infarct size, suggesting that sarcolemmal K(ATP) channels play an important role in cardioprotection against ischemia/reperfusion injuries in the heart. Mitochondrial K(ATP) channels have been also proposed to play a crucial role in cardioprotection, although the molecular identity of the channel has not been established. Nicorandil and minoxidil, K(+) channel openers activating mitochondrial K(ATP) channels, decreased the mitochondrial membrane potential, thereby preventing the Ca(2+) overload in the mitochondria of guinea-pig ventricular cells. SURs are the receptors for K(+) channel openers and the activating effects on sarcolemmal K(ATP) channels in cardiovascular tissues could be modulated by the interaction of nucleotides. Due to the molecular diversity of the accessory and pore subunits of K(ATP) channels, there would be considerable differences in the tissue selectivity of K(ATP) channel-acting drugs. Studies of Kir6.1 and Kir6.2 knockout mice indicate that K(ATP) channels are involved in the mechanisms of the protection against metabolic stress. Further clarification of physiological as well as pathophysiological roles of K(ATP) channels may lead to a new therapeutic strategy to improve the quality of life.     

Phosphodiesterase 5A as a target in cardiac disease

Cardiac hypertrophy and doxorubicin cardiotoxicity are causes of heart failure. Recently, studies have been undertaken to ascertain whether or not raising cGMP levels by targeting phosphodiesterase 5A (PDE5A) for inhibition with sildenafil may be useful in these conditions. In two animal models of cardiac hypertrophy (pressure overload in mice, isoprenaline-induced in rats), sildenafil pretreatment has been shown to prevent the development of hypertrophy. More importantly, sildenafil was shown to reverse existing cardiac hypertrophy in the pressure overload model. In mouse electrocardiography, increases in ST-interval duration correlate with doxorubicin-induced cardiotoxicity, and this increase was not observed when the mice were treated with both doxorubicin and sildenafil. Doxorubicin treatment decreased heart rate and left ventricular developed pressure, and these decreases were inhibited by pretreatment with sildenafil. As experiments, in animal models of cardiac hypertrophy and doxorubicin-induced cardiomyopathy, with the PDE5A inhibitor sildenafil have shown beneficial effects, this clearly establishes PDE5A as a target in cardiac disease.     

Role of vascular K(ATP) channels in blood pressure variability after sinoaortic denervation in rats

Aim:

To investigate the role of ATP-sensitive potassium (K_ATP) channels on blood pressure variability (BPV) in sinoaortic denervated (SAD) rats.

Methods:

SAD was performed on male Sprague-Dawley rats 4 weeks before the study. mRNA expression of Kir6.1, Kir6.2 and SUR2 in aorta and mesenteric artery was determined using real-time quantitative polymerase chain reaction, and confirmed at the protein level using Western blotting and laser confocal immunofluorescence assays. Concentration-response curves of isolated aortic and mesenteric arterial rings to adenosine and pinacidil were established. Effects of K_ATP channel openers and blocker on BPV were examined in conscious SAD rats.

Results:

Aortic SUR2 expression was significantly greater, while Kir6.1 was lower, in SAD rats than in sham-operated controls. In contrast, in the mesenteric artery both SUR2 and Kir6.1 expression were markedly lower in SAD rats than controls. For both arteries, Kir6.2 expression was indistinguishable between sham-operated and SAD rats. These findings were confirmed at the protein level. Responses of the aorta to both adenosine and pinacidil were enhanced after SAD, while the mesenteric response to adenosine was attenuated. Pinacidil, diazoxide, nicorandil, and glibenclamide significantly decreased BPV.

Conclusion:

These findings indicate that expression of vascular K_ATP channels is altered by chronic SAD. These alterations influence vascular reactivity, and may play a role in the increased BPV in chronic SAD rats.