Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physiological and pathophysiological roles of K(ATP) channels have been clarified recently in genetically engineered mice. The Kir6.2-containing K(ATP) channels in pancreatic ss-cells and the hypothalamus are essential in the regulation of glucose-induced insulin secretion and hypoglycemia-induced glucagon secretion, respectively, and are involved in glucose uptake in skeletal muscles, thus playing a key role in the maintenance of glucose homeostasis. Disruption of Kir6.1-containing K(ATP) channels in mice leads to spontaneous vascular spasm mimicking vasospastic (Prinzmetal) angina in humans, indicating that the Kir6.1-containing K(ATP) channels in vascular smooth muscles participate in the regulation of vascular tonus, especially in coronary arteries. Together with protective roles of K(ATP) channels against cardiac ischemia and hypoxia-induced seizure propagation, it is now clear that K(ATP) channels, as metabolic sensors, are critical in the maintenance of homeostasis against acute metabolic changes.
J Mol Cell Cardiol 2005 Jun
PMID:Roles of KATP channels as metabolic sensors in acute metabolic changes. 1591 Aug 76

Transient episodes of angina preceding acute myocardial infarction may both, protect the myocardium by ischemic preconditioning or damage it when associated with coronary microembolization. We now studied the potential loss of ischemic preconditioning with coronary microembolization. Anesthetized pigs (group 1; n=8) were subjected to 90 min sustained low-flow ischemia. Group 2 (n=8) was subjected to coronary microembolization (i.e. microspheres; 42 microm slashed circle; 3000 per ml min-1 inflow) 35 min before sustained ischemia. In group 3, coronary microembolization was followed 10 min later by one cycle of ischemic preconditioning (10 min ischemia/15 min reperfusion) before subsequent sustained ischemia. Infarct size was determined after 2 h reperfusion by triphenyl tetrazolium chloride staining. Infarct size after sustained ischemia alone (group 1) was 19.4+/-3.4% of the area at risk (mean+/-S.E.M.). With coronary microembolization before sustained ischemia (group 2) infarct size was only slightly larger (23.6+/-4.6%, ns). In group 3 with microembolization followed by ischemic preconditioning, infarct size was reduced to 12.7+/-3.0% (P<0.05 vs. group 2). The relationships between infarct size and transmural blood flow in groups 1 and 3 were not different, giving the impression that ischemic preconditioning failed to protect microembolized myocardium. However, additional coronary microembolization shifted the relationship between infarct size and blood flow upwards to a larger infarct size at any given blood flow. Thus when comparing the relationship of group 3 to its true control (group 2), it was shifted downwards (P<0.05; analysis of covariance (ANCOVA)) indicating persistent protection of microembolized myocardium by ischemic preconditioning. Coronary microembolization induces additional infarction when superimposed on sustained ischemia but does not interfere with the endogenous protection by ischemic preconditioning.
J Mol Cell Cardiol 2005 Aug
PMID:Preinfarction angina: no interference of coronary microembolization with acute ischemic preconditioning. 1591 44

To assess the value of serial C-reactive protein (CRP), serum amyloid A (SAA), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) evaluation in the risk stratification in patients undergoing percutaneous coronary intervention. The study was designed as a prospective cohort trial with a 1-year follow-up. Eighty patients (70 with stable angina, 10 with unstable angina) were enrolled. Blood samples were collected before the procedure and after 6 and 24 h, and 1 month. Clinical follow-up visits were performed (*with exercise test) 7 days* and 1*, 3, 6* and 12 months after the procedure. Any symptoms of restenosis were verified angiographically. Multivariate logistic regression analysis identified increased preprocedural TNF-alpha and CRP levels and elevated CRP concentrations evaluated 24 h after the procedure as significant predictors of both clinical restenosis and major adverse cardiac events (MACE), while high SAA values at 24 h accurately predicted clinical restenosis. Patients, who were in the highest tertile of, either, baseline TNF-alpha and/or baseline CRP/CRP at 24 h, were more prone to develop restenosis and MACE than stratified only on the basis of a single marker. Our data indicate that combined analysis of CRP and TNF-alpha might be an effective approach to the clinical restenosis and MACE prediction. Additionally, long-term outcome is markedly influenced by the periprocedural activation of inflammation.
Int J Mol Med 2005 Jul
PMID:Combined periprocedural evaluation of CRP and TNF-alpha enhances the prediction of clinical restenosis and major adverse cardiac events in patients undergoing percutaneous coronary interventions. 1594 95

Since its first description in 1979 (Brown et al., 1979. Nature 280, 235-236), extensive work on the I(f) current has amply demonstrated its role in the generation and neurotransmitter-induced modulation of pacemaker activity in heart (DiFrancesco, 1993. Annual Review of Physiology 55, 455-472). At pacemaker voltages, I(f) is an inward current activated by negative voltage and by intracellular cAMP. Moderate beta-receptor stimulation accelerates, and vagal stimulation slows, cardiac rate by increasing and decreasing, respectively, I(f) at diastolic potentials via changes in cAMP level. Cloning of four isoforms of hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels in the late 1990s has shown their correlation to native f-channels. Comparison of the properties of native pacemaker channels with those of HCN channels has provided information concerning the composition and molecular features of native channels in different cardiac regions. The relevance of I(f) to pacemaker generation and modulation makes f-channels a natural target of drugs aiming to control pharmacologically heart rate. Agents selectively reducing heart rate have been developed which act by specific inhibition of I(f), such as ivabradine; these drugs have a high potential for treatment of diseases where heart rate reduction is beneficial, such as angina and heart failure. Knowledge of the molecular properties of HCN clones will help the development of drugs specifically interacting with cardiac, rather than neuronal pacemaker channels. Devices able to replace electronic pacemakers and based on the delivery of a cellular source of pacemaker channels to non-pacing tissue (biological pacemakers) are likely to be developed in the near future for use in therapies for diseases of heart rhythm.
Prog Biophys Mol Biol
PMID:Serious workings of the funny current. 1597 37

Current theories suggest that atherosclerosis, plaque rupture, stroke, and restenosis after angioplasty may involve defective apoptotic mechanisms in vascular cells. Prior work has demonstrated that cells from human atherosclerotic lesions, and cells from the aorta of aged rats, exhibit functional resistance to apoptosis induced by TGF-beta and glucocorticoids. The present studies demonstrate that human lesion-derived cells (LDC) are also resistant to apoptosis induced by fas ligation compared to cells derived from the adjacent media, and that in vitro expansion of LDC causes acquired resistance to apoptosis. Microarray profiling of fas-resistant versus sensitive cells identified a set of genes including STATs, caspase 1, cyclin D1, Bcl-xL, VDAC2, and BAD. The STAT proteins have been implicated in resistance to apoptosis, potentially via their ability to modulate caspase 1 (ICE), Bcl-xL, and cyclin D1 expression. Western blot analysis of sensitive and resistant LDC clonal lines confirmed increases in cyclin D1, STAT6, Bcl-xL, and BAD, with decreased expression of caspase 1. Thus, transcript profiling has identified a potential pathway of apoptotic regulation in subsets of lesion cells. The resistant phenotype may contribute to plaque stability and excessive vascular repair, while sensitive cells may be involved in plaque rupture and infarction. The data suggests both genetic interventions and novel small-molecule inhibitors that may be effective modulators of apoptosis in atherosclerosis, angina, and in-stent restenosis.
J Mol Cell Cardiol 2005 Sep
PMID:Genomic profiling of acquired resistance to apoptosis in cells derived from human atherosclerotic lesions: potential role of STATs, cyclinD1, BAD, and Bcl-XL. 1600 68

Therapeutic activation of the vascular NO/cGMP pathway is induced by a variety of stimuli/mediators including physical activity, supplementation with the precursor L-arginine and organic nitrates which generate NO in the vasculature. The necessity of an enzymatic reduction for NO generation from these drugs as well as differences in the activity of the NO/cGMP pathway within the vascular tree determine the unique hemodynamic changes elicited by organic nitrates. These changes include preferential venodilation, vessel-size specific arterial dilation and improvement of the aortic distensibility and Windkessel-function. Some animal experiments and clinical investigations suggest that nitrates may also be endowed with cardioprotective and/or vasoprotective effects. "Early entry" therapy with nitrates do not significantly improve survival in myocardial infarction but increases the beneficial effects of the ACE-inhibitor enalapril by 50%. Furthermore, nitrates have been shown to improve survival in heart failure, but prognostic effects in stable angina pectoris are unknown. Short-term experimental and clinical investigations suggest that nitrate tolerance induced by nitroglycerin is associated with toxic effects in the vasculature, but this is not true for pentaerythrityl tetranitrate and isosorbide mononitrate. The observed endothelial dysfunction induced by a continuous treatment with nitroglycerin may be an additional risk for patients who receive continuous nitroglycerin to treat conditions such as unstable angina and acute heart failure. In general, nitrates are remarkably safe drugs and are well tolerated. Appropriate clinical trials are needed to answer the question whether nitrates can do more than symptomatic relief in cardiovascular disease.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 05
PMID:Organic nitrates in cardiovascular disease. 1619 99

Dihydropyridines (DHPs) are an important class of drugs, used extensively in the treatment of angina pectoris, hypertension, and arrhythmia. The molecular mechanism by which DHPs modulate Ca(2+) channel function is not known in detail. We have found that DHP binding is allosterically coupled to Ca(2+) binding to the selectivity filter of the skeletal muscle Ca(2+) channel Ca(V)1.1, which initiates excitation-contraction coupling and conducts L-type Ca(2+) currents. Increasing Ca(2+) concentrations from approximately 10 nM to 1 mM causes the DHP receptor site to shift from a low-affinity state to a high-affinity state with an EC(50) for Ca(2+) of 300 nM. Substituting each of the four negatively charged glutamate residues that form the ion selectivity filter with neutral glutamine or positively charged lysine residues results in mutant channels whose DHP binding affinities are decreased up to 10-fold and are up to 150-fold less sensitive to Ca(2+) than wild-type channels. Analysis of mutations of amino acid residues adjacent to the selectivity filter led to identification of Phe-1013 and Tyr-1021, whose mutation causes substantial changes in DHP binding. Thermo-dynamic mutant cycle analysis of these mutants demonstrates that Phe-1013 and Tyr-1021 are energetically coupled when a single Ca(2+) ion is bound to the channel pore. We propose that DHP binding stabilizes a nonconducting state containing a single Ca(2+) ion in the pore through which Phe-1013 and Tyr-1021 are energetically coupled. The selectivity filter in this energetically coupled high-affinity state is blocked by bound Ca(2+), which is responsible for the high-affinity inhibition of Ca(2+) channels by DHP antagonists.
Mol Pharmacol 2006 Aug
PMID:Allosteric interactions required for high-affinity binding of dihydropyridine antagonists to Ca(V)1.1 Channels are modulated by calcium in the pore. 1667 61

Chronic diabetes precipitates ischaemic heart disease (IHD) and many other disorders. IHD inturn is shown in the form of angina initially. According to EUROPA study, the incidence of angina is high in type II diabetics. Gliclazide, a second generation sulphonylurea derivative is widely used in the treatment of type-II diabetes and is known to release insulin by K(+) channel inhibition. Nicorandil, a newer antianginal drug widely used now a days acts by opening potassium channels in the cardiac muscle cell and also by releasing nitric oxide. However its action on pancreatic cell K(+) channel is not known. Since there is possibility for drug interaction leading to decreased activity of gliclazide the present study was conducted to evaluate the effect of the combination. Studies in normal and alloxan induced diabetic rats were conducted with oral doses of 2 mg/kg bd. wt. of gliclazide, 1.8 mg/kg bd. wt. of nicorandil and their combination with adequate washout periods in between treatments. Studies in normal rabbits were conducted with 5.6 mg/1.5 kg bd. wt. of gliclazide, 1.4 mg/1.5 kg bd. wt. of nicorandil and their combination given orally. Blood samples were collected in rats from retro orbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h and by marginal ear vein puncture in rabbits at 0, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. All the blood samples were analysed for glucose by GOD/POD method. The blood samples of rabbits were analysed by HPLC for gliclazide. Gliclazide produced hypoglycaemic/antidiabetic activity in normal and diabetic rats with peak activity at 1 h and 8 h and hypoglycaemic activity in normal rabbits at 3 h, while nicorandil alone produced significant hyperglycaemia at 4 h and reduced the effect of gliclazide with no significant change in pharmacokinetics when administered in combination. The interaction observed appears to be pharmacodynamic at the receptor level as expected.
Mol Cell Biochem 2006 Oct
PMID:Influence of nicorandil on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits. 1671 84

The etiology of coronary spastic angina (CSA) remains uncertain. Mice lacking the gene encoding the inwardly rectifying K(+) channel Kir6.1 were developed as an animal model of CSA. We investigated whether mutation in the coding region of the Kir6.1 gene is detected in Japanese patients with CSA. The study population included 19 Japanese patients with CSA (10 men and 9 women with a mean age of 61+/-14 years). Mutational analysis of the coding region of Kir6.1 was performed by direct sequencing. We found no missense or nonsense mutations in these samples, but we found in one female CSA patient, a single base substitution (C to T) at nucleotide position 111 in exon 2 of the coding region, which was heterozygous and did not cause amino acid substitution (Ile37Ile, silent mutation). In the remaining 18 patients, no base substitution was detected in the coding region of the Kir6.1 gene. No mutation that alters primary structure of Kir6.1 was detected in Japanese patients with CSA. The results indicate that abnormality in the primary structure of Kir6.1 may not be involved in the genetic pathogenesis of CSA in humans.
Int J Mol Med 2006 Oct
PMID:Mutational analysis of Kir6.1 in Japanese patients with coronary spastic angina. 1696 9

An increasing amount of basic scientific data indicates that adhesion molecules may be involved in the pathogenesis of vessel re-narrowing in patients undergoing coronary angioplasty. Furthermore, inflammation is suggested to be a pivotal mechanism linking atherosclerosis and restenosis. The aim of this study was to assess if periprocedural evaluation of soluble P-selectin (sP-selectin) and E-selectin (sE-selectin) possesses any additive value in the restenosis prediction to C-reactive protein (CRP) measurement. One hundred and nine stable angina patients were consecutively enrolled into the prospective cohort study. All participants were treated with single vessel coronary bare metal stenting. sP-selectin, sE-selectin and CRP were measured in peripheral venous blood samples collected before and 6, 24 h and 1 month after the procedure. Clinical follow-up visits were held 7 days(*), 1(*), 3, 6(*), and 12 months ((*)with an exercise test) after stenting. Any symptoms of restenosis were verified angiographically. Clinical restenosis occurred in 18 subjects. Concentrations of sP-selectin and sE-selectin did not differ between patients with and without clinical restenosis at any measuring point. In the latter group a decrease in sP-selectin and sE-selectin levels was observed 6 h after stenting. These findings when considered in all of the investigated subjects had no impact on the subsequent incidence of restenosis. An inflammatory response assessed as an increase in CRP level with the peak values at 24 h was noted in the whole population. However, it was significantly more pronounced in the restenosis group. Application of the Cox's proportional hazard model revealed a high CRP level 24 h after stenting and the history of coronary angioplasty concerning a nontarget lesion to be the only independent predictors of clinical restenosis. To conclude, the periprocedural evaluation of sP-selectin and sE-selectin in peripheral venous blood in patients undergoing elective coronary stenting provides no prognostic information in terms of clinical restenosis prediction, and the magnitude of the systemic inflammatory response triggered by coronary angioplasty assessed as an increase in CRP level and the history of coronary angioplasty concerning nontarget stenosis remain independent predictors of lesion re-narrowing.
Int J Mol Med 2007 Jan
PMID:Periprocedural soluble P- and E-selectin levels fail as predictors of clinical restenosis in patients treated with elective coronary stenting. 1714 64


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