Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To examine responses of the beta-adrenoceptor guanine nucleotide protein (G protein)/adenylyl cyclase complex to acute myocardial ischemia, we measured adenylyl cyclase activity stimulated at the beta-adrenoceptor and postreceptor levels and compared crude homogenates prepared from ischemic and nonischemic rabbit myocardium obtained after 30 minutes of coronary artery occlusion. Basal adenylyl cyclase activity was unchanged, but enzyme activity stimulated by the guanosine triphosphate analog guanyl-5'-imidodiphosphate (GppNHp) at 10 mumol/L was depressed 63% by ischemia (n = 16, p = 0.001). In contrast, adenylyl cyclase activity stimulated by 1 mumol/L (-)-isoproterenol in the presence of 10 mumol/L GppNHp was not significantly reduced (n = 10), a finding that indicates relative preservation of beta-adrenoceptor-mediated adenylyl cyclase activity in ischemia. The ratio of (-)-isoproterenol-stimulated to GppNHp-stimulated adenylyl cyclase activity increased fourfold in ischemic myocardium (n = 6, p = 0.001), consistent with more efficient beta-adrenergic signal transduction via less functional stimulatory G protein (Gs). These data could not be explained by augmented beta-adrenoceptor density or agonist affinity or by a reduction in inhibitory G protein-mediated inhibition of adenylyl cyclase. Forskolin (1 mmol/L) and Mn2+ (1 mmol/L), agents that directly stimulate the catalytic subunit of adenylyl cyclase, each increased enzyme activity significantly more in ischemic than in nonischemic myocardium. We conclude that preservation of (-)-isoproterenol-mediated adenylyl cyclase activity during acute myocardial ischemia in the rabbit results at least in part from enhanced function of the catalytic subunit of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Preserved beta-adrenoceptor-mediated adenylyl cyclase activity despite receptor and postreceptor dysfunction in acute myocardial ischemia. 807 18

Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the beta-adrenergic receptor (beta AR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the beta AR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery. 5 wk later, after ameroid closure, flow and function were normal in the ischemic bed, but flow (P = 0.001) and function (P < 0.03) were abnormal when metabolic demands were increased. The ischemic bed showed a reduction in myocardial beta AR number (P < 0.005). Despite regional downregulation of myocardial beta AR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Gi alpha 2, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gs alpha, was increased in endocardial sections from the ischemic bed (P = < 0.05). Decreased Gi alpha 2 content was associated with decreased inhibition of adenylyl cyclase. Reduced Gi alpha 2 content, in conjunction with increased Gs alpha content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia.
 ...
PMID:Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia. 825 20

The effects of 1 h of coronary arterial occlusion (CAO) followed by 15 min reperfusion (CAR) were examined in nine conscious dogs. Ischemia was verified by decreased regional blood flow (radioactive microspheres) and loss of systolic regional wall motion in the ischemic zone. beta-Adrenergic receptor density assessed by 125I-labeled cyanopindolol binding in a crude membrane fraction tended to decrease but was not significantly different. However, adenylyl cyclase activity and the guanine nucleotide stimulatory protein (Gs) were reduced in ischemic subendocardium compared with nonischemic subendocardium. The fraction of beta-adrenergic receptors binding agonist with high affinity increased in ischemic subendocardial and subepicardial layers. Compared with prior data in experiments with 1 h CAO without CAR, the increase in beta-adrenergic receptor density that occurs with myocardial ischemia is rapidly reversed with CAR of 15 min duration, while the decreased fraction of receptors binding agonist with high affinity was reversed to an increase in high-affinity receptors. The global decreases in adenylyl cyclase and Gs, which have been observed with simple CAO, persist but are observed selectively in the previously ischemic subendocardium after CAR. Thus both CAO and CAR affect beta-adrenergic receptors and adenylyl cyclase differently. During CAR, increased numbers of beta-adrenergic receptors binding agonist with high affinity occur potentially as a compensatory mechanism in the face of persistent reductions in adenylyl cyclase activity and Gs.
 ...
PMID:Effects of coronary arterial reperfusion on beta-adrenergic receptor-adenylyl cyclase coupling. 838 10

Reduction of cAMP has been implicated in the protection of ischemic preconditioning (IP), but until now, this possibility has not been directly addressed. In this study, we found that in the in vivo rabbit heart 10 to 30 minutes of sustained regional ischemia was accompanied by a nearly twofold rise in cAMP levels. This increase in cAMP was attenuated when sustained ischemia was preceded by IP induced with a single cycle of transient ischemia and reperfusion (TI/R) and prevented when ischemia was preceded by three cycles of TI/R. The mechanism of cAMP reduction by IP does not involve activation of protein kinase C (PKC), since the PKC inhibitor polymyxin B (24 mg/kg) did not raise cAMP levels during sustained ischemia in IP hearts. Furthermore, this effect is also not mediated by reduced responsiveness of the beta-adrenergic effector pathway, since both nonischemic hearts and hearts subjected to three cycles of TI/R exhibited similar increases in cAMP in response to 5 micrograms/kg isoproterenol. However, propranolol (0.75 mg/kg) abolished the rise in cAMP levels observed during sustained ischemia in control hearts but did not reduce cAMP levels further in IP hearts. These data indicate that the ischemia-induced rise in cAMP levels in control hearts was mediated by activation of the beta-adrenergic receptor. Taken together with data demonstrating that beta-adrenergic responsiveness was not affected by IP, these data support the conclusion that the lack of elevation in cAMP levels observed during sustained ischemia in IP hearts is mediated by an attenuation of norepinephrine release. To examine whether the protection of IP against necrosis was mediated by the lack of elevation in cAmp levels, we determined whether the infarct size-limiting effect of IP could be blocked by NKH477, an activator of adenylyl cyclase. Four groups or rabbits were subjected to 30 minutes of in vivo regional ischemia and 90 minutes of reperfusion. Control hearts (n = 10) had 53.6 +/- 5.5% infarction of the area at risk. IP with three cycles of transient ischemia limited infarct size to 3.2 +/- 1.3% (N = 13, p < .0001). NKH477 (45 micrograms/kg) increased average cAMP levels in IP hearts during sustained ischemia to levels similar to those in untreated control hearts. However, NKH477 did not block IP (50.2 +/- 7.7% of the area at risk was infarcted in the control +NKH477 group [n = 10] versus 10.0 +/- 5.9% in the IP + NKH477 group [n = 7], P < .05). Therefore, we conclude that although IP lowers cAMP levels during sustained ischemia, this effect is not necessary for its protection against necrosis, since raising cAMP does not block this protection of IP.
 ...
PMID:Effect of ischemic preconditioning of the myocardium on cAMP. 860 96

The recently cloned G protein-coupled adenosine A3 receptor has been proposed to play a role in the pathophysiology of cerebral ischemia. Because phospholipase C activation occurs as a very early response to brain ischemia, we evaluated the ability of A3- selective and nonselective adenosine analogues to elicit phosphoinositide hydrolysis. In myo-[3H]inositol-labeled rat striatal and hippocampal slices, A3 agonists stimulated formation of [3H]inositol phosphates in a concentration-dependent manner. In striatum, the potency order was 2-chloro-N6-(3-iodobenzyl)- adenosine-5'-N-methyluronamide > or = N6-(3-iodobenzyl)- adenosine-5'-N-methyluronamide >> N-methyl-1,3-di-n-butylxanthine-7-beta-D-ribofuronamide > or = 5'-N-ethylcarboxamidoadenosine > or = N6-2-(4-aminophenyl)-ethyladenosine > N6-(p-sulfophenyl)-adenosine = 1,3-dibutylxanthine-7- riboside, which is identical to the potency order in binding studies at cloned rat A3 receptors. Stimulation of phospholipase C activity was abolished by guanosine-5'-O-(2-thiodiphosphate), confirming the involvement of a G protein-coupled receptor. Activation of phospholipase C was higher in the striatum than in the hippocampus, consistent with A3 receptor densities. Stimulation of phospholipase C activity by adenosine analogues was only modestly antagonized by xanthine derivatives and at much higher concentrations than needed for blocking adenosine A1, A2A, and A2b receptors. In the presence of an A1/A2 antagonist, a selective A3 in rat striation. Thus, stimulation of phospholipase C activity agonist only weakly inhibited forskolin-stimulated adenylyl cyclase activity represents a principal transduction mechanism for A3 receptors in mammalian brain, and perhaps A3 receptor-mediated increases of inositol phosphates in the ischemic brain contribute to neurodegeneration by raising intracellular calcium levels.
 ...
PMID:G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain. 884 3

Adenosine exerts most of its cardiac effects via direct interaction with sympathetic neurotransmission: Release of norepinephrine is inhibited in presynaptic neurons, and catecholamine-induced activation of adenylyl cyclase is inhibited in postsynaptic effector cells. While presynaptic effects fade rapidly during ischemia, postsynaptic antagonism to catecholamines remains an important protective element during sustained ischemia.
 ...
PMID:[Interactions of adenosine with sympathetic neurotransmission in the heart]. 906 62

In order to examine the mechanisms of ischemia-reperfusion induced changes in beta-adrenoceptor-linked signal transduction pathway, isolated rat hearts perfused in the absence or presence of superoxide dismutase (SOD) plus catalase (CAT) were made ischemic for 30 min and then reperfused for 60 min. The left ventricular developed pressure as well as the rare of contraction and rate of relaxation were markedly decreased, whereas the left ventricular end-diastolic pressure increased in the ischemic hearts. A significant increase in the density and affinity of beta 1-adrenoceptors without any changes in the characteristics of beta 2-adrenoceptors was evident in cardiac membranes obtained from the ischemic hearts. The recovery of contractile abnormalities in the ischemic heart was depressed upon reperfusion; the ischemic-reperfused hearts also showed attenuated inotropic responses to isoproterenol. The affinities and densities of beta- and beta-adrenoceptors were decreased in the ischemic-reperfused hearts; the magnitude of changes in beta 1-adrenoceptors was greater than that in beta 2-adrenoceptors. The isoproterenol-stimulated adenylyl cyclase activity was depressed in both ischemic hearts and ischemic-reperfused hearts. The basal and forskolin-stimulated adenylyl cyclase activities were unaltered due to ischemia but were increased upon reperfusion. The NaF- and 5'-Guanylyl-imidodiphosphate[Gpp(NH)p]-stimulated adenylyl cyclase activities were depressed in the ischemic hearts and increased in the ischemic reperfused hearts. Cholera toxin (CT)-stimulated adenylyl cyclase as well as the CT-catalysed ADP-ribosylation activity and stimulatory G protein (Gs protein) immunoreactivity were decreased in the ischemic hearts and increased in the reperfused hearts. Pertussis toxin (PT)-stimulated adenylyl cyclase activity was unaltered in both ischemic and ischemic-reperfused hearts, whereas the PT-catalysed ribosylation and inhibitory G protein (Gi protein) immunoactivity were slightly increased in the reperfused myocardium. Thus the inability of isoproterenol to stimulate adenylyl cyclase in the ischemic-reperfused hearts may be due to alterations mainly in the characteristics of beta 1-adrenoceptors including density, affinity and coupling with the adenylyl cyclase. Scavenging of oxyradicals by the addition of SOD plus CAT in the perfusion medium prevented the reperfusion-induced changes in contractile function, inotropic responses of the heart to isoproterenol, activation of adenylyl cyclase by isoproterenol, as well as densities and affinities of beta-adrenoceptors in cardiac membranes. These results suggest that the depressed contractile activity and the attenuated inotropic responses of ischemic-reperfused hearts to isoproterenol as well as the defects in beta-adrenoceptor-linked signal transduction may be due to the formation of oxyradicals in the myocardium.
 ...
PMID:Beta-adrenoceptor-linked signal transduction in ischemic-reperfused heart and scavenging of oxyradicals. 914 Aug 14

In view of the accumulation of H2O2 in the myocardium due to ischemia-reperfusion and changes in beta-adrenoceptor mechanisms in the ischemic-reperfused heart, we investigated the effects of H2O2 on the beta-adrenoceptor, G-protein and adenylyl cyclase complex. Rat hearts were perfused with 1 mM H2O2 for 10 min before isolating membranes for measuring the biochemical activities. The stimulation of adenylyl cyclase by different concentrations of isoproterenol was depressed upon perfusing hearts with H2O2. Both the affinity and density of beta1-adrenoceptors as well as the density of the beta2-adrenoceptors were decreased whereas the affinity of beta2-adrenoceptors was increased by H2O2 perfusion. Competition curves did not reveal any effect of H2O2 on the proportion of coupled receptors in the high affinity state. The basal as well as forskolin-, NaF- and Gpp(NH)p-stimulated adenylyl cyclase activities were depressed by perfusing the heart with H2O2. Catalase alone or in combination with mannitol was able to significantly decrease the magnitude of alterations due to H2O2. The positive inotropic effect of 1 microM isoproterenol was markedly attenuated upon perfusing hearts with 200-500 microM H2O2 for 10 min. These results suggest that H2O2 may depress the beta1-adrenoceptor, Gs-proteins and catalytic subunit of the adenylyl cyclase enzyme and thus may play an important role in attenuating the beta-adrenoceptor linked signal transduction due to ischemia-reperfusion injury.
 ...
PMID:Role of H2O2 in changing beta-adrenoceptor and adenylyl cyclase in ischemia-reperfused hearts. 977 90

Nitric oxide (NO) donors given during ischemia possibly protect the myocardium by increasing tissue cyclic guanosine monophosphate (cGMP) and decreasing cytosolic Ca2+ levels. However, NO donors also elevate ischemic cyclic adenosine monophosphate (cAMP) levels, which exacerbates ischemic-reperfusion injury. The authors propose that suppression of this NO donor-induced increase in cAMP would improve the cardioprotective properties of these compounds. Langendorff perfused rat hearts were treated with sodium nitroprusside (SNP, 0.1 mM ) or glyceryl trinitrate (GTN, 1.0 microM ) and/or adenylyl cyclase (SQ, 50 microM ) or guanylyl cyclase (ODQ, 30-300 microM ) inhibitors during 40-min low-flow (0.2 ml/min) ischemia. Control reperfusion rate-pressure product (RPP) recoveries were 47 +/- 3% (n = 9) and improved to 59 +/- 1% (n = 11) (p < 0.05) with SNP treatment. Ischemic ODQ treatment decreased RPP recovery to 33 +/- 3% (n = 10) (p < 0.05). ODQ eliminated the cardioprotective effects of SNP (RPP recovery: 40 +/- 5% [n = 7] vs. 59 +/- 1% [p < 0.05]). Adenylyl cyclase inhibition improved RPP recovery from 59 +/- 1% (SNP) to 72 +/- 4% (SNP + SQ) (n = 11) (p < 0.05). The authors conclude that (a) suppression of the NO donor-induced elevations in ischemic cGMP levels (ODQ) worsened reperfusion RPP, (b) suppression of the NO donor-induced elevation in ischemic cAMP levels (SQ) further improved reperfusion RPP in NO donor-treated hearts, and (c) the severity of ischemic-reperfusion injury in the NO donor-treated heart was inversely related to ischemic-tissue cGMP levels and often directly related to the ischemic-tissue cAMP-to-cGMP ratio.
 ...
PMID:Relation of cyclic nucleotide ratios to ischemic and reperfusion injury in nitric oxide-donor treated rat hearts. 1158 23

Renal proximal tubule cells are particularly vulnerable to injury following ischemia and reperfusion due to their marginal blood supply and high metabolic demand. Renal adenosine receptor (AR) modulations preserve renal function following ischemic-reperfusion injury in vivo. Numerous intracellular proteins have been shown to be pivotal in the signal transduction of adenosine-mediated protection in vivo. However, characterization of the expression and function of ARs and intracellular proteins mediating protection in human proximal tubular cells is lacking. Therefore, we studied the ARs in an immortalized human renal proximal tubular cell (HK-2) line to determine if this cell line could function as an in vitro model of AR coupling. Immunoblotting with AR subtype specific antibodies detected all 4 subtypes of ARs (A(1), A(2a), A(2b) and A(3)), several isoforms of protein kinase C (alpha, delta, and epsilon and several heterotrimeric G-protein isoforms (G(i)alpha, G(s)alpha and G(q)alpha). The A(1) and A(3) ARs inhibited forskolin- stimulated adenylyl cyclase activity. The A(1) ARs also activated 42/44-kD ERK mitogen-activated protein kinases via G(i)- and tyrosine kinase-dependent pathways. The A(2a) ARs stimulated adenylyl cyclase activity and activated the protein kinase A-->CREB pathway. Chronic (48 h) treatment with a nonselective AR antagonist (8-phenyltheophylline) upregulated A(1), A(2a) ARs and G(i)alpha. Conversely, chronic stimulation of HK-2 ARs with a nonselective AR agonist (N-ethylcarbamoyladenosine) downregulated all 4 subtypes of ARs and G(s)alpha. Based on these findings, HK-2 cells are a useful in vitro model to study the signaling cascades of AR-mediated renal protection.
 ...
PMID:Characterization of adenosine receptors in human kidney proximal tubule (HK-2) cells. 1238 23


<< Previous 1 2 3 4 5 Next >>