Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myocardial ischaemia followed by reperfusion (I/R) is associated with impaired endothelial function including diminished release and/or effects of nitric oxide (NO) which may contribute to the development of I/R injury. The aim of the present study was to investigate the role of the L-arginine/NO pathway in myocardial I/R injury. In isolated rat hearts subjected to global ischaemia followed by reperfusion L-arginine and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), but not D-arginine, significantly enhanced the recoveries of mycardial performance and coronary flow, and reduced the area of no-reflow and creatine kinase outflow. The NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the protective effects of L-arginine. Endothelium-dependent vasodilatation after I/R was preserved in L-arginine treated but not in vehicle hearts. Following I/R Ca2+-dependent NO synthase activity was reduced by 90% in comparison with non-ischaemic hearts. L-arginine but not D-arginine significantly increased NO synthase activity. In anaesthetized pigs, L-arginine given by local coronary venous retroinfusion reduced myocardial infarct size induced by 45 min of coronary artery ligation and 4 h of reperfusion to 35% of the area at risk from 76% in controls. The protective effect of L-arginine was blocked by L-NNA. Acetylcholine-induced coronary vasodilatation following I/R was attenuated in controls but not in L-arginine treated pigs. It is concluded that L-arginine or the NO donor SNAP reduces I/R-induced myocardial and endothelial injury. The protective effect of L-arginine seems to be mediated through maintained production of NO by preserving the function of Ca2+-dependent NO synthase in the heart.
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PMID:The role of the L-arginine/nitric oxide pathway in myocardial ischaemic and reperfusion injury. 1057 51

The effects of ischemia and reperfusion on the coronary endothelium and myocardium as well as tolerance to ischemia/reperfusion injury were assessed using isolated retrogradely perfused rat hearts. Repeated brief episodes of myocardial ischemia followed by reperfusion is known to have a protective effect against subsequent myocardial infarction. However, no studies have been performed with perfusion in the absence of blood cells to determine the effect of repeated ischemia and reperfusion on the coronary endothelium and myocardium. Using the Langendorff perfusion technique, rat hearts were subjected to a 30-, 10-, 5-, or 2-min period of low-flow perfusion by reducing the coronary flow to 3 ml/min followed by reperfusion at 20 ml/min for the same period of time. Control perfusion was then performed at a constant flow rate of 20 ml/ min for 60 min. Acetylcholine-induced coronary vasodilation was significantly (P < 0.05) lower in hearts subjected to 30 min of ischemia and 30 min of reperfusion when compared with the control hearts. Myocardial creatinine kinase (CK) activity was significantly reduced (P < 0.01) in hearts subjected to ischemia and reperfusion for either 30, 10, or 5 min. To assess the effect of repeated episodes of ischemia and reperfusion, the following protocols were used: a control study with constant perfusion for 60 min (group A), 30 min of ischemia and 30 min of reperfusion (group B), three 10-min episodes of ischemia and reperfusion (group C), six 5-min episodes of ischemia and reperfusion (group D), and 15 2-min episodes of ischemia and reperfusion (group E). Acetylcholine-induced coronary vasodilation was significantly inhibited in group B (80% +/- 12%, P < 0.05) and group C (70% +/- 13%, P < 0.01), but did not change significantly in either group D (123% +/-19%) or group E (142% +/- 15%), compared with the control group (group A; 127% +/- 15%, mean +/-SEM). Nitroglycerin-induced coronary vasodilation was not altered by ischemia/reperfusion in any group. In contrast, myocardial CK activity was significantly lower in group B (3.6 +/- 0.6IU/mg protein, P < 0.01), group C (3.2 +/- 0.1 IU/mg protein, P < 0.01), and group D (3.3 +/- 0.21U/mg protein, P < 0.01) than in group A (47 +/- 6.7 IU/mg protein). The myocardial CK activity of group E was not significantly different from that of group A, but was significantly higher than in groups B, C, and D (P < 0.01). In isolated perfused rat hearts, both the coronary endothelium and myocardium are damaged by repeated episodes of ischemia and reperfusion. However, the coronary endothelium is more resistant to such damage than is the myocardium.
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PMID:Effects of repeated brief episodes of ischemia and reperfusion in isolated perfused rat hearts. 1077 4

1. We investigated the effects of JTV-519 (4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4, 5-tetrahydro-1,4-benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K(+) currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of JTV-519 on experimental atrial fibrillation (AF) in isolated guinea-pig hearts. 2. In atrial cells stimulated at 0.2 Hz, JTV-519 in concentrations of 0.3 and 1 microM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration-dependent manner. 3. The muscarinic acetylcholine receptor-operated K(+) current (I(K.ACh)) was activated by the extracellular application of carbachol (1 microM), adenosine (10 microM) or by the intracellular loading of GTP gamma S (100 microM). JTV-519 inhibited the carbachol-, adenosine- and GTP gamma S-induced I(K.ACh) with the IC(50) values of 0.12, 2.29 and 2.42 microM, respectively, suggesting that the drug may inhibit I(K.ACh) mainly by blocking the muscarinic receptors. 4. JTV-519 (1 microM) inhibited the delayed rectifier K(+) current (I(K)). Electrophysiological analyses indicated that the drug preferentially inhibits I(Kr) (rapidly activating component) but not I(Ks) (slowly activating component). 5. In isolated hearts, perfusion of carbachol (1 microM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV-519 (1 microM) inhibited the induction of AF by prolonging MAP and ERP. 6. We conclude that JTV-519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K(+) currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease.
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PMID:Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. 1109 Jan 8

Alterations in the flow of blood to and from the penis are thought to be the most frequent causes of male erectile dysfunction and, therefore, the present review focuses on the penile vasculature. In the flaccid state, tonic noradrenaline release from the sympathetic nerves contracts penile arterial and corporal smooth muscle through activation of postjunctional alpha(1)-adrenoceptors, both by increasing intracellular calcium and by enhancing the sensitivity of the contractile apparatus for calcium. In addition, noradrenaline inhibits vasodilatatory neurotransmitter release by prejunctional alpha(2)-adrenoceptors. The exact role of the sympathetic neurotransmitters, neuropeptide Y and adenosine 5'-triphosphate, in erection is largely unknown. Penile vasodilatation during erection is mediated by nitric oxide (NO) through activation of guanylyl cyclase in the smooth muscle layer, followed by increases in cyclic guanosine monophosphate lowering of intracellular calcium and desensitisation of the contractile apparatus for calcium. Acetylcholine, vasoactive intestinal peptide as well as peptides in sensory nerves probably also play a role in penile vasodilation. Increased flow through the penile arteries stimulates the endothelium leading to release of NO, prostanoids and a non-NO non-prostanoid factor, and as such enhances the vasodilatation, while the role of endothelium-derived contractile factors in penile vasoconstriction is not clear. Erectile dysfunction shares arterial risk factors with ischaemic heart disease, and diabetes, age, and hypercholesterolaemia are associated with impairment of both neurogenic and endothelium-dependent vasodilator mechanisms in corpus cavernosum. Only few studies have investigated the impact of these risk factors on the penile vasculature, although recent evidence suggests that arterial insufficiency precedes changes in corpus cavernosum leading to erectile dysfunction.
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PMID:Penile arteries and erection. 1218 19

Type 2 diabetes mellitus (T2-DM) markedly increases the incidence of ischemic heart disease (IHD) and, consequently, mortality. However, the underlying mechanisms leading to IHD in T2-DM are not completely understood. We hypothesized that in T2-DM the regulation of coronary microvascular resistance by local mechanisms is altered. Thus, in coronary arterioles (diameter: approximately 80 microm) isolated from male mice with T2-DM (C57BL/KsJ-db/db) and control littermates, responses to changes in intraluminal pressure, flow, and agonists with known mechanisms of action were studied. Increases in pressure (from 20 to 120 mmHg) resulted in similar myogenic responses of coronary arterioles of control and db/db mice, whereas dilations in response to cumulative concentrations of ACh and the nitric oxide (NO) donor NONOate were significantly decreased compared with those of control vessels. On the other hand, responses to adenosine were not different between vessels of control and db/db mice. Increases in flow (0-20 microl/min) resulted in dilations of control vessels (maximum: 38 +/- 4%) that were inhibited by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). In contrast, arterioles of db/db mice exhibited greatly reduced dilations to flow (maximum: 4 +/- 6%) that were unaffected by L-NAME. In carotid arteries of db/db mice, superoxide dismutase (SOD)-sensitive, enhanced superoxide production was detected by dihydroethydine staining and lucigenin enhanced chemiluminescence. Correspondingly, intraluminal administration of SOD significantly augmented flow-, ACh-, and NONOate-induced dilations of diabetic arterioles, and then flow- and ACh-induced responses could be inhibited by L-NAME. Collectively, these findings suggest that in T2-DM, due to an enhanced superoxide production, NO mediation of agonist- and flow-induced dilations of coronary arterioles is reduced. This alteration in the regulation of coronary microvascular resistance may contribute to the development of IHD in T2-DM.
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PMID:Superoxide-NO interaction decreases flow- and agonist-induced dilations of coronary arterioles in Type 2 diabetes mellitus. 1280 26

Endothelial cell dysfunction (ECD) is emerging as the common denominator for diverse and highly prevalent cardiovascular diseases. Recently, an increased number of procoagulant circulating endothelial microparticles (EMPs) has been identified in patients with acute myocardial ischemia, preeclampsia, and diabetes, which suggests that these particles represent a surrogate marker of ECD. Our previous studies showed procoagulant potential of endothelial microparticles and mobilization of microparticles by PAI-1. The aim of this study was to test the effects of isolated EMPs on the vascular endothelium. EMPs impaired ACh-induced vasorelaxation and nitric oxide production by aortic rings obtained from Sprague-Dawley rats in a concentration-dependent manner. This effect was accompanied by increased superoxide production by aortic rings and cultured endothelial cells that were coincubated with EMPs and was inhibited by a SOD mimetic and blunted by an endothelial nitric oxide synthase inhibitor. Superoxide was also produced by isolated EMP. In addition, p22(phox) subunit of NADPH-oxidase was detected in EMP. Our data strongly suggest that circulating EMPs directly affect the endothelium and thus not only act as a marker for ECD but also aggravate preexisting ECD.
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PMID:Endothelium-derived microparticles impair endothelial function in vitro. 1507 74

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease in general including acute coronary syndromes, especially in the Japanese population. The vascular endothelium has been reported to be a multifunctional organ whose integrity is essential for normal vascular physiology. Vascular endothelial dysfunction can be a critical factor in the pathogenesis of ischemic heart disease. Acetylcholine and methacholine cause vasodilation by endothelium-derived relaxing factor when the endothelium is functioning normally, whereas they cause vasoconstriction when the endothelium is removed or damaged. Coronary spasm can be induced by a variety of stimuli with different mechanisms of action, including acetylcholine and methacholine. Patients with coronary spasm may have a disturbance in endothelial function as well as local hyperreactivity of the coronary arteries.
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PMID:Endothelial function and coronary spastic angina. 1575 Feb 67

Although hypothermia is one of the most powerful modulators that can reduce ischemic injury, the effects of hypothermia on the function of the cardiac autonomic nerves in vivo are not well understood. We examined the effects of hypothermia on the myocardial interstitial norepinephrine (NE) and ACh releases in response to acute myocardial ischemia and to efferent sympathetic or vagal nerve stimulation in anesthetized cats. We induced acute myocardial ischemia by coronary artery occlusion. Compared with normothermia (n = 8), hypothermia at 33 degrees C (n = 6) suppressed the ischemia-induced NE release [63 nM (SD 39) vs. 18 nM (SD 25), P < 0.01] and ACh release [11.6 nM (SD 7.6) vs. 2.4 nM (SD 1.3), P < 0.01] in the ischemic region. Under hypothermia, the coronary occlusion increased the ACh level from 0.67 nM (SD 0.44) to 6.0 nM (SD 6.0) (P < 0.05) and decreased the NE level from 0.63 nM (SD 0.19) to 0.40 nM (SD 0.25) (P < 0.05) in the nonischemic region. Hypothermia attenuated the nerve stimulation-induced NE release from 1.05 nM (SD 0.85) to 0.73 nM (SD 0.73) (P < 0.05, n = 6) and ACh release from 10.2 nM (SD 5.1) to 7.1 nM (SD 3.4) (P < 0.05, n = 5). In conclusion, hypothermia attenuated the ischemia-induced NE and ACh releases in the ischemic region. Moreover, hypothermia also attenuated the nerve stimulation-induced NE and ACh releases. The Bezold-Jarisch reflex evoked by the left anterior descending coronary artery occlusion, however, did not appear to be affected under hypothermia.
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PMID:Hypothermia reduces ischemia- and stimulation-induced myocardial interstitial norepinephrine and acetylcholine releases. 1708 72

Diabetes is a risk factor of ischemic heart disease, cerebral ischemia, and atherosclerosis, in which endothelial dysfunction plays a role in the pathogenesis. We examined vascular responses in the aorta of pre-diabetic db/db mice with normoglycemia, hyperlipidemia, and hyperinsulinemia (6 weeks old), and diabetic db/db mice with hyperglycemia, hyperlipidemia, and hyperinsulinemia (11 weeks old) in comparison with age-matched non-diabetic db/+ mice. Prostaglandin F2alpha (PGF2alpha)-induced contraction was significantly enhanced in the aorta of diabetic but not pre-diabetic db/db mice compared to age-matched non-diabetic db/+ mice. Acetylcholine (ACh), adenosine-5'-diphosphate (ADP), NaF, a G protein activator and A-23187, a Ca-ionophore, caused endothelium-dependent and nitric oxide (NO)-mediated relaxation, and sodium nitroprusside (SNP), an NO donor, caused endothelium-independent relaxation in the pre-contracted aorta of db/db mice. Maximal endothelium-dependent ACh-induced relaxation was reduced in diabetic but not pre-diabetic db/db mice compared to age-matched db/+ mice, while maximal SNP-induced relaxation was not different between diabetic and non-diabetic mice. ACh-induced relaxation in diabetic db/db mice was not affected by ozagrel, a thromboxane A2 (TXA2) synthetase inhibitor, or acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor, suggesting no involvement of endogenous TXA2 or prostanoids in the reduction of relaxation. Maximal endothelium-dependent ADP-, A-23187-, and NaF-induced relaxation was not reduced in diabetic db/db mice. EC50 values for ACh- and SNP-induced relaxation were increased in diabetic but not pre-diabetic db/db mice, suggesting decreases in sensitivity to NO in diabetic mice. Two-week treatment with KV-5070, a PPARgamma agonist, lowered plasma glucose, triglyceride (TG), and insulin but not cholesterol, and reversed the reduced ACh-induced relaxation. In conclusion, ACh-induced endothelium-dependent relaxation is impaired in diabetic db/db mice, probably due to the dysfunction of ACh receptors and/or receptor-G protein coupling. Endothelial dysfunction was not genetic and was considered to be initiated primarily by hyperglycemia, and was improved by anti-diabetic treatment with a PPARgamma agonist.
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PMID:Impairment of endothelium-dependent ACh-induced relaxation in aorta of diabetic db/db mice--possible dysfunction of receptor and/or receptor-G protein coupling. 1822 1

Vagal nerve stimulation (VS) has been reported to improve the survival after both acute and chronic myocardial infarction through the release of neurotransmitter ACh. However, the precise mechanism behind its beneficial effect is still unknown. In this study, we demonstrate the upregulation of tumor necrosis factor-alpha (TNF-alpha) and its cell survival TNF receptor-2 (TNFR2) as the mechanism behind VS induced myocardial protection. We investigated the effects of efferent VS on myocardial ischemic injury with in vivo and in vitro mouse models. In in vivo hearts VS significantly increased the expression of TNF-alpha both at the messenger and protein level after 3-hours of myocardial ischemia. In the in vitro studies ACh treatment before hypoxia, induced a significant upregulation of TNF-alpha compared to the untreated cardiomyocytes. Immunofluorescence analysis confirmed the synthesis of TNF-alpha by cardiomyocytes both in vivo and in vitro. VS also significantly reduced the myocardial infarct size (23.9+/-5.7% vs. 56+/-1.9%) and activated the cell survival Akt cascade system. Further, ACh upregulated the cell survival TNFR2 expression, while downregulating the cell destructive TNF receptor 1 (TNFR1) expression. These results were confirmed using the TNF receptors deficient mice, where the VS mediated protection was lost both in vivo and in vitro in TNFR2 (TNFR2(-/-)) and TNF receptors double knock out (TNFR1(-/-)2(-/-)) mice. VS and ACh protects the heart against acute ischemia or hypoxic injury by differentially regulating the TNF receptor subtypes.
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PMID:Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury. 2030 76


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