Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
 15,705 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently demonstrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 microm) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium.
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PMID:Role of STAT3 in ischemic preconditioning. 1170 38

The renin-angiotensin (RAS) and the alpha1 sympathetic nervous system (SNS) interact at different levels in cardiovascular regulation. Concurrent use of angiotensin-converting enzyme (ACE) inhibitors and alpha1 receptor antagonists result in a synergistic antihypertensive action and is of wide utility in cardiovascular therapy. We examined the impact of concurrent inhibition of RAS (captopril or losartan) and the SNS (prazosin) before and after acute nitric oxide (NO) synthase inhibition with L-nitro-L-arginine methyl ester (L-NAME) on renal cortical perfusion (RCF) and blood pressure (MAP) in healthy and acute ischemic renal failure (ARF) rats (n = 6). Captopril or losartan reduced MAP and increased RCF more in healthy (p < 0.001) and ARF rats (p < 0.02). Prazosin alone reduced both MAP and RCF (p < 0.001). The combination of prazosin with captopril or losartan caused an additive fall in MAP, and mitigated the fall in RCF. Captopril + prazosin caused a profound fall in RCF following L-NAME, in healthy but not ARF rats (p < 0.001). Acetylcholine (Ach), a vasodilator which stimulates endogenous NO production caused a profound paradoxical fall in RCF in ARF, but not in healthy rats (p < 0.001 ANOVA). These results indicate a significant interaction between angiotensin II and phenylephrine in renal vasomotion. It establishes that endogenous NO homeostatically opposes angiotensin II-alpha1-mediated renal vasoconstriction, and that the vasodilator role of NO is diminished in ARF. The paradoxical fall in RCF induced by Ach in ARF is speculated to result, at least in part, from the formation of peroxynitrite (ONOO-), which acts as a renal vasoconstrictor, following the combination of ischemia-generated super oxide anion (O-2), with endothelial NO released by Ach.
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PMID:Interactions of the renin-angiotensin system and alpha-1 adrenoceptors on renal hemodynamics in healthy and acute renal failure rats: the role of nitric oxide. 1180 63

Progesterone modulates gamma-aminobutyric acid and excitatory amino acid neurotransmitter systems and has neuroprotective properties in models of hypoxia-ischemia. This study examined the in vitro effects of allopregnanolone, the active progesterone metabolite, in models of N-methyl-D-aspartate (NMDA)-induced necrosis and apoptosis. Cultured NT2 neurons were exposed to 1 mM NMDA. Lactate dehydrogenase (LDH) release was measured 24 h later. NMDA at a concentration of 1 mM produced a 39 +/- 19% release of total LDH. Exposure to 10 microM allopregnanolone prior to NMDA exposure reduced LDH release by 51% (P = 0.0028). NMDA stimulated apoptotic cell changes defined by terminal dUTP nick-end labeling (TUNEL) and 5,5', 6,6'-tetrachloro-1,1,3,3'-tetra ethlybenzimidazolycarbocyanide iodide staining were reduced to baseline values by both 10 microM allopregnanolone and 100 microM MK-801. Pretreatment with allopregnanolone (0-10 microM) reduced the percentage of TUNEL-positive cells in a dose-dependent manner (EC(50) = 2.7 +/- 0.1 nM). Physiologic concentrations of allopregnanolone provided protection against both necrotic and apoptotic injury induced by NMDA excitotoxicity.
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PMID:Allopregnanolone attenuates N-methyl-D-aspartate-induced excitotoxicity and apoptosis in the human NT2 cell line in culture. 1212 53

The aim of the present study was to assess the veno-arterial difference in pCO2 (delta pCO2) as an indicator of ischemia compared to the arteriovenous O2 difference (AVDO2). Staircase cerebral blood flow (CBF) reductions were obtained in seven domestic pigs by inducing intracranial hypertension: CBF 100%, 50-60% of baseline, 20-30% of baseline. ICP, MAP, CPP and CBF (Laser-Doppler method) were continuously recorded. The superior sagittal sinus was punctured to determine AVDO2 and delta pCO2. AVDO2 was 5.9 (+/- 1.78, range 3.3-7.4), 7.01 (+/- 1.31, range 5-8.9) and 8.17 (+/- 1.51, range 6.0-11.3) ml/100 ml in the three CBF steps (p = 0.001). CBF impairment was accompanied by the following increases in delta pCO2: from 10 (+/- 4, range 4-15) mmHg to 14.5 (+/- 4.11, range 10-27) mmHg, and to 31.2 (+/- 9.0, range 17-39) mmHg (p < 0.001). When CBF declines AVDO2 increases, indicating greater extraction of O2 to satisfy the aerobic metabolism. However, this mechanism can no longer compensate once a critical CBF threshold is reached. delta pCO2 rises slowly during moderate CBF reduction because of defective washout; the rise is impressive during marked CBF impairment when anaerobic metabolism takes place with proton buffering in CO2 and H2O. Therefore, when the brain's ability to compensate for low blood flow is exceeded, CO2 production outweighs O2 extraction.
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PMID:Cerebral veno-arterial pCO2 difference as an estimator of uncompensated cerebral hypoperfusion. 1216 4

Because end-organ injury can occur with reperfusion following hemorrhage or ischemia, we hypothesized that aggressive intravenous fluid resuscitation would aggravate tissue injury in a fixed-volume model of hemorrhagic shock. Unanesthetized chronically prepared male rats were hemorrhaged 33-36 mL/kg for 2.5 h. Then Lactated Ringers Solution (3x hemorrhage volume) was infused over 5 min (FAST), 20 min (MEDIUM), 180 min (SLOW), or not at all (NO RESUS). Plasma ornithine carbamoyltransferase (OCT), lactate, and creatinine were measured as indices of hepatocellular injury, anaerobic metabolism, and renal function, respectively. At 1 h post-resuscitation (PR), MAP was greater after SLOW and MEDIUM treatment (tx) than after other txs (P < 0.05). OCT increased earliest after FAST tx to values greater than those after other txs from 30 min to 24 h PR (P < 0.01). Plasma lactate was elevated immediately before resuscitation in all groups (P < 0.01) and returned to baseline at 3 h PR after SLOW tx compared to 5 h PR after FAST tx (P < 0.05). Creatinine at 5 h PR was less in the groups treated with intravenous fluid compared to the NO RESUS group, P < 0.05. Survival at 72 h was reduced in the FAST (57%) and NO RESUS (58%) groups compared to the SLOW (87%) and MEDIUM (85%) groups (P < 0.05). Thus, overly aggressive fluid tx accelerates hepatocellular injury, is no better than lesser rates of resuscitation at correcting plasma lactate and preserving renal function, and provides no overall survival benefit.
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PMID:Detrimental effects of rapid fluid resuscitation on hepatocellular function and survival after hemorrhagic shock. 1235 25

There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 +/- 2 to 22 +/- 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 +/- 2 to 91 +/- 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 +/- 4 to 59 +/- 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug x exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.
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PMID:Effect of morphine on sympathetic nerve activity in humans. 1238 64

Ischemia followed by reperfusion has a number of clinically significant consequences. A number of pathophysiological processes appear to be involved in ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK) are integral components of the parallel MAP kinase cascades activated in response to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory cytokines. Many studies suggest that members of the MAP kinase family in particular Jun N-terminal kinase (JNK) are activated in kidney following ischemia/reperfusion of this tissue. The present study underlines the therapeutic potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage during renal ischemia/reperfusion injury. Our previous results showed that 90 min of ischemia followed by reperfusion caused very severe injury and that the untreated animals had 100% mortality after the 3rd day whereas there was improved renal function and 100% survival of animals in the three drug combination treatment group. The present study, mainly on tissue sections, further supports the protection provided by the triple drug therapy. A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three classes of MAPK and ameliorates AP-1 whereas individual or a combination of any two drugs is not as effective.
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PMID:Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon. 1248 68

A variety of seemingly unrelated clinical conditions manifest the same effects on the heart. These effects include: (1) reversible myocardial dysfunction, (2) beta-adrenergic desensitization, and (3) activation of inflammatory mediators. We provide evidence supporting a role for cytokines, mitogen activated protein kinases (MAP kinases), and nitric oxide (NO) as common mediators of reversible myocardial dysfunction and beta-adrenergic desensitization. Data from animal models and human studies support a pathogenic role for these inflammatory mediators in ischemic as well as non-ischemic myocardial dysfunction. It is suggested that compensatory cellular programs are activated to provide short-term protection from brief periods of ischemia and infection. Continuous activation of these compensatory pathways leads to cardiomyopathy and chronic (congestive) heart failure. Elucidating the signaling pathways involved has the potential to provide the opportunity to exploit the cardioprotective advantages of these agents without bearing the burden of excessive stimulation.
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PMID:Inflammatory mediators and reversible myocardial dysfunction. 1259 3

During ischemia/reperfusion (I/R), cardiomyocytes are exposed to sudden lack of nutrients and successively to radical oxygen species (ROS). In the present study, we used the HL-5 cardiac atrial myocyte cell line exposed to serum/glucose depletion added or not in H(2)O(2) to mimic ROS during ischemia, then replaced in their standard culture medium to simulate reperfusion. We investigated the effects of serum/glucose depletion combined or not to ROS exposure on AKT and MAP kinases activation to address the role of each event with respect to apoptosis. We demonstrate that serum/glucose depletion per se did not induce apoptosis when compared to ROS exposure. In particular, ROS recruited p38MAPK and JNK pathways. SB202190 preventing p38MAPK activity, partially protected HL-5 from apoptosis while blocking JNK, thanks to JNKI, further enhanced apoptosis. Blocking phosphatidylinositol (PI) 3-kinase with LY294002 or ERKs with U0126 was without consequence on apoptosis. Finally, BCL-2 and BCL-X(L/S) expression levels were analyzed in cells exposed to 1 h ischemia followed by 12-h reperfusion in the presence or not of SB202190; BCL-2, but not BCL-X(L/S), expression was decreased in ROS treated cells but SB202190 failed to restore BCL-2 level. Our data suggest that p38MAPK activation primarily mediates ROS-induced apoptosis while concomitant JNK activation would represent a scavenger pathway for cells trying to escape apoptosis.
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PMID:Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model. 1259 6

In cardiac myocytes of new-born rats, the degree of intercellular communication through gap junctional channels closely depends on the metabolic state of the cells. In contrast, in stably transfected HeLa cells expressing rat cardiac connexin43 (Cx43, the main channel-forming protein present in ventricular myocytes), a major part of junctional communication persisted in ATP-depleted conditions, in the presence of a metabolic inhibitor (KCN) or of a broad spectrum inhibitor of protein kinases (H7). However, another metabolic inhibitor, antimycin A, which like cyanide inhibits electron transfer in the respiratory chain, totally interrupted cell-to-cell communication between Cx43-HeLa cells, even in whole-cell conditions, when ATP (5 mM) was present. Antimycin A caused a modest increase in cytosolic calcium concentration; however, junctional uncoupling still occurred when this rise was prevented. Conditions of ischemic insult (e.g. ischemia or chemical hypoxia) frequently cause the activation of protein kinases, particularly of Src and MAP kinases, and such activations are known to markedly disrupt gap junctional communication. Antimycin-induced junctional uncoupling occurred even in the presence of inhibitors of these kinases. Antimycin A appears able to cause junctional uncoupling either through the ATP depletion it induces as a metabolic poison or via a direct action on gap junction constituents.
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PMID:The metabolic inhibitor antimycin A can disrupt cell-to-cell communication by an ATP- and Ca(2+)-independent mechanism. 1450 27


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