Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation

Tissue kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that tissue kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of tissue kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, tissue kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester abolished kallikrein's effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that tissue kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.     

钾通道阻滞剂对糖尿病伴冠心病患者Warm-up现象的影响

目的:观察钾通道阻滞剂格列本脲对冠心病伴糖尿病患者发生Warm-up现象的影响.方法:选择47例运动试验阳性和经冠状动脉造影证实.至少单支冠状动脉狭窄程度为70%～90%的慢性稳定型心绞痛伴糖尿病患者作为研究对象.根据其血糖控制方式分为格列本脲治疗组(治疗组.22例)与节食对照组(对照组,25例),通过间隔15 min的连续运动试验来观察2组2次运动中心电图上反映缺血情况的指标变化.结果:治疗组2次运动相比除ST段压低0.1 mV出现的时间有所后延外,余指标均未见明显缺血减轻的改变(P＞0.05);对照组则在第2次运动后发生了明显的Warm-up效应(P＜0.05).缺血阈值和极量运动时的ST段压低最大值在第2次运动后的改善情况2组间比较,差异有统计学意义(P＜0.05).结论:以节食方式控制血糖良好的稳定型心绞痛并发糖尿病患者可以发牛Warm-up现象,格列本脲能阻断Warm-up现象的发生.     

Potent and selective activation of the pancreatic beta-cell type KATP channel by two novel diazoxide analogues

Aims/hypothesis We investigated the pharmacological properties of two novel ATP sensitive potassium (K_ATP) channel openers, 6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC 55-0118) and 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414), on the cloned cardiac (Kir6.2/SUR2A), smooth muscle (Kir6.2/SUR2B) and pancreatic beta cell (Kir6.2/SUR1) types of K_ATP channel.Methods We studied the effects of these compounds on whole-cell currents through cloned K_ATP channels expressed in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes.Results In HEK 293 cells, NNC 55-0118 and NN414 activated Kir6.2/SUR1 currents with EC₅₀ values of 0.33 µmol/l and 0.45 µmol/l, respectively, compared with that of 31 µmol/l for diazoxide. Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes, nor did they activate Kir6.2 expressed in the absence of SUR. Current activation was dependent on the presence of intracellular MgATP, but was not supported by MgADP.Conclusion/interpretation Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of K_ATP channel with a higher potency than diazoxide, by interaction with the SUR1 subunit. The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial.Abbreviations K_ATP channel ATP-sensitive potassium channel - SUR sulphonylurea receptor - KCO K⁺ channel opener - Kir inwardly rectifying K⁺ channel - TEVC two electrode voltage clamp - HEK293 cell Human Embryonic Kidney 293 cell     

Antimycin A induced cardioprotection is dependent on pre-ischemic p38-MAPK activation but independent of MKK3

To examine the role of mitogen-activated protein kinase kinase 3 (MKK3) and p38 mitogen-activated protein kinase (p38-MAPK) in the cardioprotection afforded by antimycin A. Langendorff perfused murine hearts exposed to antimycin A or vehicle prior to global ischemia with p38-MAPK and HSP27 phosphorylation examined in the presence and absence of SB203580 or the presence (mkk3(+/+)) and absence (mkk3(-/-)) of MKK3. Infarct size was determined after 30 or 40 min of global ischemia and 2 h reperfusion. p38-MAPK dual phosphorylation in response to antimycin A was attenuated by co-administration of the antioxidant mercaptopropyonyl-glycine but unaffected by the absence of MKK3 or the presence of SB203580 at a concentration that inhibited the downstream phosphorylation of HSP27. Pre-ischemic exposure to antimycin A caused a significant reduction in subsequent infarction (I:R%) compared to vehicle on both the mkk3(-/-) and mkk3(+/+) background (23.7+/-2.9 and 22.8+/-4.6 compared to 50.7+/-4.0 and 49.6+/-5.4 P=0.001, respectively). In C57Bl6 mice, antimycin A prior to ischemia reduced infarct size compared to vehicle (22.8 +/- 6.1 vs. 48.3+/-5.2 P=0.01, respectively), an effect abolished by coincident SB203580. The cardiac protection initiated by antimycin A is dependent on the activation of p38-MAPK which occurs, at least in part, in response to oxygen-derived free radicals. The mechanism of this protective form of p38-MAPK activation is independent of the upstream kinase MKK3 and does not involve autophosphorylation.     

Post-infarction treatment with simvastatin reduces myocardial no-reflow by opening of the KATP channel

Simvastatin can prevent cardiac remodelling after myocardial infarction, though the exact mechanisms are uncertain. Myocardial no-reflow is associated with progressive cardiac remodelling. However, it remains unknown whether post-infarction treatment with simvastatin can also reduce myocardial no-reflow for which suppression of adenosine triphosphate-sensitive K+ (K(ATP)) channel opening is an important mechanism. METHODS: Area at risk and the area of no-reflow were determined by myocardial contrast echocardiography (MCE) and by pathology in 45 mini-swine randomised into 5 groups: 10 control, 9 simvastatin, 9 glibenclamide, 9 simvastatin plus glibenclamide and 8 sham-operated. A myocardial infarction and reperfusion model was created by 3-h occlusion of the coronary artery followed by 4 weeks of reperfusion. RESULTS: Compared with the control group, simvastatin significantly increased coronary blood volume (P<0.01) and decreased the area of no-reflow measured by MCE (78.5+/-4.5% to 43.7+/-4.3%) and pathological evaluation (82.3+/-1.9% to 45.2+/-3.8%) of area at risk (P<0.01). Simvastatin also increased the levels of K(ATP) channel proteins (SUR2 and Kir6.2) (P<0.05), but had no effect on necrosis area. The combination of simvastatin and glibenclamide had no significant effect on the above parameters. CONCLUSIONS: Post-infarction treatment with simvastatin can reduce myocardial no-reflow. This beneficial effect is due to activation of the K(ATP) channel.     

Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein

OBJECTIVE: Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress. Previous studies have revealed that activation of the beta-adrenergic system and consecutive elevation of the intracellular cAMP concentration regulate HERG channels via protein kinase A-mediated phosphorylation of the channel protein and via direct interaction with the cAMP binding site of HERG. In contrast, the influence of the alpha-adrenergic signal transduction cascade on HERG currents as suggested by recent reports is less well understood. The aim of the present study was to elucidate the biochemical pathways of the protein kinase C (PKC)-dependent regulation of HERG currents. METHODS: HERG channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. RESULTS: Application of the phorbol ester PMA, an unspecific protein kinase activator, shifted the voltage dependence of HERG activation towards more positive potentials. This effect could be mimicked by activation of conventional PKC isoforms with thymeleatoxin. Coexpression of HERG with the beta-subunits minK or hMiRP1 did not alter the effect of PMA. Specific inhibition of PKC abolished the PMA-induced activation shift, suggesting that PKC is required within the regulatory mechanism. The PMA-induced effect could still be observed when the PKC-dependent phosphorylation sites in HERG were deleted by mutagenesis. Cytoskeletal proteins such as actin filaments or microtubules did not affect the HERG activation shift. CONCLUSION: In addition to the known effects of PKA and cAMP, HERG channels are also modulated by PKC. The molecular mechanisms of this PKC-dependent process are not completely understood but do not depend on direct PKC-dependent phosphorylation of the channel.     

Effect of pressure overload on cardioprotection of mitochondrial KATP channels and GSK-3beta: interaction with the MPT pore

BACKGROUND: The mitochondrial permeability transition (MPT) pore may serve as the end-effector of cardioprotective mechanisms, namely the mitochondrial K(ATP) channels and glycogen synthase kinase-3beta (GSK-3beta). We recently showed that augmented MPT pore induction contributes to pressure overload-induced exacerbation of infarct size. This study tests the hypotheses that (i) elevation in perfusion pressure attenuates cardioprotection associated with activation of mitochondrial KATP channels or inhibition of GSK-3beta and (ii) perfusion pressure modulates the regulation of the MPT pore by mitochondrial KATP channels and/or GSK-3beta. METHODS: Langendorff-perfused hearts were subjected to a regional ischemia-reperfusion insult at a perfusion pressure of either 80 or 160 cm H2O. The perfusion medium contained no drug, diazoxide (80 micromol/l; mitochondrial KATP channel opener), lithium chloride (LiCl, 1 mmol/l; nonselective inhibitor of GSK-3beta), SB-216763 (3 micromol/l; selective inhibitor of GSK-3beta), cyclosporine A (0.2 micromol/l; inhibitor of MPT pore induction), glibenclamide (50 micromol/l; inhibitor of KATP channels), and the combination of cyclosporine A and glibenclamide or the combination of glibenclamide and LiCl. RESULTS: The increase in perfusion pressure in the absence of a drug caused larger infarcts, an effect associated with poorer recovery of function following ischemia reperfusion. Treatment with either diazoxide or cyclosporine A reduced infarct size at both perfusion pressures but in contrast to diazoxide, cyclosporine A was more protective at the higher pressure. On the other hand, LiCl and SB-216763 reduced infarct size at both pressures, with the effect more marked at the higher perfusion pressure. Glibenclamide did not affect infarct size but eliminated the cardioprotective effect of cyclosporine A while having no effect on LiCl-induced cardioprotection. CONCLUSION: Perfusion pressure primarily affects GSK-3beta-mediated regulation of MPT pore formation in the ischemic reperfused heart.     

Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide.

Nitric oxide (NO) has been implicated in the "second-window" of ischemic preconditioning (PC). However, the identity of the end effector after initiation of preconditioning by NO is not known. It is likely that NO is involved in opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. We hypothesized that NO is an important trigger for the opening of mitoK(ATP) channels in the late phase of preconditioning and inducible nitric oxide synthase (iNOS) up-regulation via NF kappa B plays a critical role in diazoxide-induced cardioprotection. To examine this, diazoxide (7 mg/kg) was administered to wild-type (WT) mice and mice lacking the gene 24 hours before 40 minutes of global ischemia. Hearts were perfused in a Langendorff mode and effects of activation of mitoK(ATP) channel and other interventions on functional, biochemical and pathological changes in ischemic hearts were assessed. In hearts from WT mice treated diazoxide, left-ventricular-developed pressure, end-diastolic pressure and coronary flow were significantly improved after ischemia/reperfusion (I/R); lactate dehydrogenase (LDH) release was also significantly decreased, while ATP contents were significantly higher. Administration of 5-HD, a specific blocker of mitoK(ATP) channel or l -NAME, an inhibitor of iNOS before I/R, during diazoxide-pretreatment completely blocked the late cardioprotection against ischemia. Late cardioprotection was also blocked by inhibition of either PKC- delta by rottlerin or NF kappa B by DDTC before diazoxide pretreatment. Diazoxide pretreatment significantly increased nuclear translocation of p65 which was blocked by protein kinase C (PKC) or nitric oxide synthase (NOS) inhibition. Diazoxide was totally inefffective in iNOS knockout mice. These results suggest that diazoxide activates NF kappa B via PKC signaling pathway and that leads to iNOS up-regulation after 24 hours. NO which is generated upon ischemic stress triggers the opening of mitoK(ATP)channel as an end effector of cardioprotection during late PC.     

Delayed cardioprotection in a human cardiomyocyte-derived cell line: the role of adenosine, p38MAP kinase and mitochondrial KATP

Evidence of delayed preconditioning (PC) in man is limited. Adenosine is proposed as a trigger via action on the A₁ receptor in many species and the mitochondrial K_ATP channel is a likely end effector. We examined the ability of a brief, simulated ischemic episode on day one to provide delayed cardioprotection against lethal, simulated ischemia on day two in a human cardiac cell line with reference to the role of adenosine, the p38MAP kinase signalling pathway and mitochondrial K_ATP channel. Results: PC and adenosine administered on day 1 protected against cell death on day 2 as measured by LDH release and propidium iodide (PI) exclusion: (%LDH release: PC: 12.1 ± 1.1%, ADO: 11.9 ± 2.0% vs control: 36.4 ± 1.1%, %PI positive: PC: 14.6% ± 1.4%, ADO: 17.9 ± 2.0% vs control: 34.4 ± 2.0% respectively). This protection is abolished by treatment with SB203580 prior to the protective stimulus on day 1: [PC + SB (%LDH release 28.6 ± 2.8%, %PI positive 34.7 ± 2.2%) and ADO + SB (%LDH release 25.3 ± 2.9%; %PI positive 33.7 ± 7.3%)]. Similarly 5-hydroxydecanoate abolished protection, when given immediately prior to lethal simulated ischemia on day 2: [PC + 5-HD; (%LDH release 31.9 ± 4.8%; %PI positive 29.5 ± 2.0%) and ADO + 5-HD (%LDH release 36.9 ± 4.0%; %PI positive 34.8 ± 2%)]. Conclusion: In this model delayed PC can be mimicked by adenosine and involves the p38MAP kinase pathway and the mitochondrial K_ATP channel. Received: 2 November 1999, Returned for revision: 24 November 1999, Revision received: 23 December 1999, Accepted: 20 January 2000     

Thromboxane A2 receptor and MaxiK-channel intimate interaction supports channel trans-inhibition independent of G-protein activation

Large conductance voltage- and calcium-activated potassium channels (MaxiK, BK_Ca) are well known for sustaining cerebral and coronary arterial tone and for their linkage to vasodilator β-adrenergic receptors. However, how MaxiK channels are linked to counterbalancing vasoconstrictor receptors is unknown. Here, we show that vasopressive thromboxane A2 receptors (TP) can intimately couple with and inhibit MaxiK channels. Activation of the receptor with its agonist trans-inhibits MaxiK independently of G-protein activation. This unconventional mechanism is supported by independent lines of evidence: (i) inhibition of MaxiK current by thromboxane A2 mimetic, U46619, occurs even when G-protein activity is suppressed; (ii) MaxiK and TP physically associate and display a high degree of proximity; and (iii) Förster resonance energy transfer occurs between fluorescently labeled MaxiK and TP, supporting a direct interaction. The molecular mechanism of MaxiK–TP intimate interaction involves the receptor''s first intracellular loop and C terminus, and it entails the voltage-sensing conduction cassette of MaxiK channel. Further, physiological evidence of MaxiK–TP physical interaction is given in human coronaries and rat aorta, and by confirming TP role (with antagonist SQ29,548) in the U46619-induced MaxiK inhibition in human coronaries. We propose that vasoconstrictor TP receptor and MaxiK-channel direct interaction facilitates G-protein–independent TP to MaxiK trans-inhibition, which would promote vasoconstriction.     

The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel

ATP-binding cassette (ABC) proteins are highly conserved and widely expressed throughout nature and found in all organisms, both prokaryotic and eukaryotic. They mediate myriad critical cellular processes, from nutrient import to toxin efflux using the energy derived from ATP hydrolysis. Most ABC proteins mediate transport of substances across lipid membranes. However, there are atypical ABC proteins that mediate other processes. These include, but are not limited to, DNA repair (bacterial MutS), ion transport (cystic fibrosis transmembrane receptor), and mRNA trafficking (yeast Elf1p). The sulfonylurea receptor (SUR) is another atypical ABC protein that regulates activity of the potassium ATP channel (K(ATP)). K(ATP) is widely expressed in nearly all tissues of higher organisms and couples cellular energy status to membrane potential. K(ATP) is particularly important in the regulation of insulin secretion from pancreatic beta-cells and in regulating action potential duration in muscle cells. SUR is indispensable for normal channel function, and mutations in genes encoding SURs increase the susceptibility to diabetes, myocardial infarction, and heart failure. Here, we review the structure and function of ABC proteins and discuss SUR, its regulation of the K(ATP) channel, and its role in cardiovascular disease.     

NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells

The proteasome has been successfully targeted for the treatment of multiple myeloma and mantle cell lymphoma; however, in other hematologic malignancies, bortezomib has been less effective as a single agent. Here, we describe effects of NPI-0052, a novel proteasome inhibitor, in leukemia model systems. In cell lines, NPI-0052 inhibits all 3 proteolytic activities associated with the proteasome: chymotrypsin-, trypsin-, and caspase-like. NPI-0052 also induces DNA fragmentation in leukemia lines and in mononuclear cells from a Ph + acute lymphoblastic leukemia (ALL) patient. Caspase-3 activation by NPI-0052 was seen in wild-type Jurkat cells, but was significantly lessened in Fas-associated death domain (FADD)-deficient or caspase-8-deficient counterparts. NPI-0052-induced apoptosis was further probed using caspase-8 inhibitors, which were more protective than caspase-9 inhibitors. N-acetyl cysteine (NAC) also conferred protection against NPI-0052-induced apoptosis, indicating a role for oxidative stress by NPI-0052. In support of the drug's in vitro activities, biweekly treatment with NPI-0052 lessened total white blood cell (WBC) burden over 35 days in leukemic mice. Interestingly, combining NPI-0052 with either MS-275 or valproic acid (VPA) induced greater levels of cell death than the combination of bortezomib with these histone deacetylase inhibitors (HDACi). These effects of NPI-0052, alone and in combination with HDACi, warrant further testing to determine the compound's clinical efficacy in leukemia.     

Chronic low-dose lipid infusion in healthy patients induces markers of endothelial activation independent of its metabolic effects

Elevated plasma triglyceride/free fatty acid (FFA) levels and insulin resistance may promote atherosclerosis through endothelial activation (ie, increased expression of intercellular adhesion molecule 1 [ICAM-1]/vascular adhesion molecule 1 [VCAM-1], and endothelin-1 [ET-1]) in patients with the metabolic syndrome, but this has never been directly tested. The authors measured endothelial activation and insulin sensitivity (euglycemic insulin clamp with [3-(3)H]-glucose) after a 4-day low-dose lipid infusion that elevated plasma FFA to levels observed in the metabolic syndrome in 20 lean, non-diabetic insulin-resistant subjects with a strong family history of type 2 diabetes mellitus (FH(+)) and 10 insulin-sensitive volunteers without a family history of type 2 diabetes mellitus (FH(-)). Low-dose lipid infusion reduced insulin sensitivity by approximately 25% in insulin-sensitive FH(-)controls but did not worsen preexisting insulin resistance in FH(+). Low-dose lipid infusion elevated plasma ICAM and VCAM levels similarly in both groups (approximately 12%-18%; P<.01 vs baseline), while plasma ET-1 levels increased more in FH(+)vs FH(-)(46% vs 10%; P=.005). Increased plasma FFA levels closely correlated with elevated ICAM (r=0.60; P<.01), VCAM, and ET-1 levels (r=0.39 and r=0.42, respectively; P<.05). Low-dose lipid infusion induces endothelial activation in both lean insulin-resistant (FH(+)) and insulin-sensitive (FH(-)) healthy patients, regardless of changes in insulin sensitivity. These results prove that even a modest lipid oversupply may be sufficient to trigger a deleterious endothelial response.     

The effect of K(atp)channel activation on myocardial cationic and energetic status during ischemia and reperfusion: role in cardioprotection

The role of cation and cellular energy homeostasis in ATP-sensitive K(+)(K(ATP)) channel-induced cardioprotection is poorly understood. To evaluate this, rapidly interleaved(23)Na and(31)P NMR spectra were acquired from isolated rat hearts exposed to direct K(ATP)channel activation from nicorandil or pinacidil. Nicorandil attenuated ATP depletion and intracellular Na(+)(Na(+)(i)) accumulation, delayed the progression of acidosis during zero-flow ischemia and prevented ischemic contracture. The K(ATP)channel inhibitor 5-hydroxydecanoate abolished these effects. Pinacidil did not alter Na(+)(i)accumulation, ATP depletion or pH during ischemia under the conditions employed. Both agonists greatly improved the post-ischemic functional recovery. Both agonists also dramatically improved the rate and extent of the reperfusion recoveries of Na(+)(i), PCr and ATP. The Na(+)(i)and PCr reperfusion recovery rates were tightly correlated, suggesting a causal relationship. Separate atomic absorption tissue Ca(2+)measurements revealed a marked reperfusion Ca(2+)uptake, which was reduced two-fold by pinacidil. In conclusion, these results clearly indicate that while K(ATP)channel-induced metabolic alterations can vary, the functional cardioprotection resulting from this form of pharmacological preconditioning does not require attenuation of acidosis, cellular energy depletion, or Na(+)(i)accumulation during ischemia. Rather than preservation of cationic/energetic status during ischemia, the cardioprotective processes may involve a preserved capability for its rapid restoration during reperfusion. The enhanced reperfusion Na(+)(i)recovery may be enabled by the improved reperfusion cellular energy state. This accelerated Na(+)(i)recovery could play an important cardioprotective role via a potential causal relationship with the reduction of reperfusion tissue Ca(2+)uptake and resultant reperfusion injury.     

Growth hormone-induced blood pressure decrease is associated with increased mRNA levels of the vascular smooth muscle KATP channel

Growth hormone (GH) deficiency is associated with abnormal vascular reactivity and development of atherosclerosis. GH treatment in GH deficient states restores systemic vascular resistance, arterial compliance, endothelium-dependent and endothelium-independent vasodilation, and may reverse markers of early atherosclerosis. However, very little is known about the molecular mechanisms underlying these effects. In the present study, male Sprague Dawley rats were hypophysectomized and treated for two weeks with GH (recombinant human GH, 2 mg/kg/day) or saline as s.c. injections twice daily. GH decreased aortic systolic blood pressure compared with saline-treated animals, while the diastolic blood pressure was not significantly changed. GH treatment increased cardiac output as determined by Doppler-echocardiography and the calculated systemic vascular resistance was markedly reduced. In order to identify GH-regulated genes of importance for vascular function, aortic mRNA levels were analyzed by the microarray technique and correlated to the systolic blood pressure levels. Using this approach, we identified 18 GH-regulated genes with possible impact on vascular tone and atherogenesis. In particular, mRNA levels of the inwardly rectifying potassium channel Kir6.1 and the sulfonylurea receptor 2B, which together form the vascular smooth muscle ATP-sensitive potassium channel, were both up-regulated by GH treatment and highly correlated to systolic blood pressure. Our findings establish a major role for GH in the regulation of vascular physiology and gene expression. Increased expression of the ATP-sensitive potassium channel, recently shown to be crucial in the regulation of vascular tone, constitutes a possible mechanism by which GH governs vascular tone.