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U K Decking

Publications and source records attributed to U K Decking.

At least 19 recordsLinked to original sources
PubMed2001

Myoglobin: A scavenger of bioactive NO.

The present study explored the role of myoglobin (Mb) in cardiac NO homeostasis and its functional relevance by employing isolated hearts of wild-type (WT) and myoglobin knockout mice. (1)H NMR spectroscopy was used to measure directly the conversion of oxygenated Mb (MbO(2)) to metmyoglobin (metMb) by reaction with NO. NO was applied intracoronarily (5 nM to 25 microM), or its endogenous production was stimulated with bradykinin (Bk; 10 nM to 2 microM). We found that infusion of authentic NO solutions dose-dependently (>/= 2.5 microM NO) increased metMb formation in WT hearts that was rapidly reversible on cessation of NO infusion. Likewise, Bk-induced release of NO was associated with significant metMb formation in the WT (>/=1 microM Bk). Hearts lacking Mb reacted more sensitively to infused NO in that vasodilatation and the cardiodepressant actions of NO were more pronounced. Similar results were obtained with Bk. The lower sensitivity of WT hearts to changes in NO concentration fits well with the hypothesis that in the presence of Mb, a continuous degradation of NO takes place by reaction of MbO(2) + NO to metMb + NO(3)(-), thereby effectively reducing cytosolic NO concentration. This breakdown protects myocytic cytochromes against transient rises in cytosolic NO. Regeneration of metMb by metMb reductase to Mb and subsequent association with O(2) leads to reformation of MbO(2) available for another NO degradation cycle. Our data indicate that this cycle is crucial in the breakdown of NO and substantially determines the dose-response curve of the NO effects on coronary blood flow and cardiac contractility.

Animals↗
PubMed1999

Disruption of myoglobin in mice induces multiple compensatory mechanisms.

Myoglobin may serve a variety of functions in muscular oxygen supply, such as O(2) storage, facilitated O(2) diffusion, and myoglobin-mediated oxidative phosphorylation. We studied the functional consequences of a myoglobin deficiency on cardiac function by producing myoglobin-knockout (myo(-/-)) mice. To genetically inactivate the myoglobin gene, exon 2 encoding the heme binding site was deleted in embryonic stem cells via homologous recombination. Myo(-/-) mice are viable, fertile, and without any obvious signs of functional limitations. Hemoglobin concentrations were significantly elevated in myo(-/-) mice. Cardiac function and energetics were analyzed in isolated perfused hearts under resting conditions and during beta-adrenergic stimulation with dobutamine. Myo(-/-) hearts showed no alteration in contractile parameters either under basal conditions or after maximal beta-adrenergic stimulation (200 nM dobutamine). Tissue levels of ATP, phosphocreatine ((31)P-NMR), and myocardial O(2) consumption were not altered. However, coronary flow [6.4 +/- 1.3 ml.min(-1).g(-1) [wild-type (WT)] vs. 8.5 +/- 2.4 ml.min(-1).g(-1) [myo(-/-)] [and coronary reserve [17.1 +/- 2.1 (WT) vs. 20.8 +/- 1.1 (myo(-/-) ml. min(-1).g(-1) were significantly elevated in myo(-/-) hearts. Histological examination revealed that capillary density also was increased in myo(-/-) hearts [3,111 +/- 400 mm(-2) (WT) vs. 4,140 +/- 140 mm(-2) (Myo(-/-)]. These data demonstrate that disruption of myoglobin results in the activation of multiple compensatory mechanisms that steepen the pO(2) gradient and reduce the diffusion path length for O(2) between capillary and the mitochondria; this suggests that myoglobin normally is important for the delivery of oxygen.

Adenosine↗
PubMed1999

Purinogen is not an endogenous substrate used in endothelial cells during substrate deprivation.

Porcine aortic endothelial cells (PAEC) are known to be metabolically robust. They are capable of surviving extended periods of complete lack of exogenous substrate, and purine release has been shown to be significantly up-regulated. The endogenous substrates used during substrate deprivation, as well as the sources responsible for the increased purine release, have not been completely identified. We tested the possibility that a phosphoglyceroyl-ATP-containing polymer, purinogen, might support PAEC hibernation induced by lack of exogenous substrate. This involved isolation of the acid-insoluble fraction of PAEC, which was presumed to contain purinogen, and analysis by HPLC and 31P NMR. No evidence supporting the presence of triphosphate-containing compounds (purinogen) was found. Similar results were obtained in the rat heart. The majority of the products in the acid-insoluble, alkaline-treated fraction were identified as RNA degradation products (2'- and 3'-nucleoside monophosphates). A [14C]adenosine labelling experiment showed that incorporation of adenosine into the acid-insoluble fraction was almost completely prevented after inhibition of RNA synthesis with actinomycin D. Furthermore, RNA isolated from PAEC and subsequently treated with alkali showed a profile that was almost identical with the HPLC profile of the acid-insoluble fraction. Finally, substrate-free incubation of the cells did not quantitatively or qualitatively influence the distribution of acid-insoluble derivatives. We conclude that PAEC survival during the absence of exogenous substrate is not supported by purinogen but rather by some other, yet-to-be-identified, endogenous substrate.

Adenosine Triphosphate↗
PubMed1999

Contribution of NO to ischemia-reperfusion injury in the saline-perfused heart: a study in endothelial NO synthase knockout mice.

The contribution of endogenous NO to ischemia-reperfusion injury was studied in isolated perfused hearts of wild-type (WT) and endothelial NO synthase knockout (eNOS-) mice. The hearts were subjected to a 16-min period of global no-flow ischemia and were subsequently reperfused for 1 h. Cardiac contractile function was evaluated and 31P-NMR spectroscopy was used to monitor myocardial energy status and the intracellular pH. During both baseline and ischemia, there were neither significant differences in mechanical function nor in energetic parameters between the two groups, for example at baseline left ventricular developed pressure (LVDP) was 56.5+/-5.4 mmHg in WT and 58.7+/-5.2 mmHg in eNOS-and phosphocreatine (PCr) level was 12.9+/-1.3 m m in WT and 12.7+/-1.7 m m in eNOS-. In reperfusion, however, a significant improvement of the post-ischemic functional and metabolic recovery became apparent in the eNOS-hearts. While in the WT group, LVDP recovered only to 38. 4+/-5.3 mmHg, LVDP in the eNOS-group attained 49.4+/-5.5 mmHg at the end of 60 min reperfusion (P<0.05, n=8). Similarly, the recovery of PCr was significantly enhanced in the transgenic hearts as compared to WT (10.4+/-1.6 vs 8.1+/-1.3 m m, P<0.05). eNOS-hearts also showed a better restoration of dP/d t and a significant lower left ventricular enddiastolic pressure. In an additional series of wild-type hearts, the NO synthase inhibitor NG-monomethyl-L-arginine methyl ester (100 microm) also tended to improve the recovery of both LVDP (43.8+/-6.8 mmHg) and PCr (9.5+/-1.6 m m) in reperfusion (1 h), but the restoration of functional and metabolic parameters was less pronounced when compared with eNOS-. The results provide clear evidence that endogenously formed NO significantly contributes to ischemia-reperfusion injury in the saline-perfused mouse heart, most likely by peroxynitrite formation from NO.

Animals↗
PubMed1999

Blocking Na(+)-H+ exchange by cariporide reduces Na(+)-overload in ischemia and is cardioprotective.

In myocardial ischemia, rapid inactivation of Na(+)-K(+)-ATPase and continuing influx of sodium induce Na(+)-overload which is the basis of Ca(2+)-overload and irreversible tissue injury following reperfusion. The Na(+)-H(+)-exchanger of subtype 1 (NHE-1) is assumed to play a major role in this process, but previously available inhibitors were non-specific and did not allow to verify this hypothesis. Cariporide (HOE 642) is a recently synthesized NHE-1 inhibitor. We have investigated its effects on Na+ homeostasis (23Na NMR spectroscopy), cardiac function and energy metabolism (31P NMR) in ischemia and reperfusion. In the well-oxygenated, isolated guinea-pig heart, cariporide (10 microM) had no effect on intracellular Na+, pH or cardiac function. NHE-1 inhibition by cariporide was demonstrated using the NH4Cl prepulse technique. When hearts were subjected to 15 min of ischemia, cariporide markedly inhibited intracellular Na(+)-accumulation (1.3 +/- 0.1 vs 2.1 +/- 0.1-fold rise) but had no effect on the decline in pH. In reperfusion, NHE-1-blockade significantly delayed pH recovery. With longer periods of ischemia (36 min), cariporide delayed the onset of contracture, reduced ATP depletion, Na(+)-overload and again had no effect on pH. In reperfusion, hearts treated with cariporide showed an improved recovery of left ventricular pressure (60 +/- 1 vs 16 +/- 8 mmHg): end-diastolic pressure was normalized and phosphocreatine fully recovered, while there was only a partial recovery in controls. The data demonstrate that Na(+)-H(+)-exchange is an important port of Na(+)-entry in ischemia and contributes to H(+)-extrusion in reperfusion. By reducing Na(+)-overload in ischemia and prolonging acidosis in reperfusion, NHE-blockade represents a promising cardioprotective principle.

Adenosine Triphosphate↗
PubMed1999

Metabolic adaptation of endothelial cells to substrate deprivation.

Endothelial cells are known to be metabolically rather robust. To study the mechanisms involved, porcine aortic endothelial cells (PAEC), cultured on microcarrier beads, were perfused with glucose (10 mM) or with substrate-free medium. Substrate-free perfusion for 2 h induced an almost complete loss of nucleoside triphosphates (31P-NMR) and decreased heat flux, a measure of total energy turnover, by >90% in parallel microcalorimetric measurements. Heat flux and nucleoside triphosphates recovered after addition of glucose. Because protein synthesis is a major energy consumer in PAEC, the rate of protein synthesis was measured ([14C]leucine incorporation). Reduction or blockade of energy supply resulted in a pronounced reduction in the rate of protein synthesis (up to 80% reduction). Intracellular triglyceride stores were decreased by approximately 60% after 2 h of substrate-free perfusion. Under basal perfusion conditions, PAEC released approximately 30 pmol purine. mg protein-1. min-1, i.e., 16% of the cellular ATP per hour, while ATP remained constant. Substrate deprivation increased the release of various purines and pyrimidines about threefold and also induced a twofold rise in purine de novo synthesis ([14C]formate). These results demonstrate that PAEC are capable of recovering from extended periods of substrate deprivation. They can do so by a massive downregulation of their energy expenditure, particularly protein synthesis, while at the same time using endogenous triglycerides as substrates and upregulating purine de novo synthesis to compensate for the loss of purines.

Adaptation, Physiological↗
PubMed1998

Coronary hemodynamics in endothelial NO synthase knockout mice.

For the specific analysis of endothelial NO synthase (eNOS) function in the coronary vasculature, we generated a mouse homozygous for a defective eNOS gene (eNOS-/-). Western blot as well as immunohistochemical staining revealed the absence of eNOS protein in eNOS-/- mice. Aortic endothelial cells derived from eNOS-/- mice displayed only background levels of NOx formation compared with wild-type (WT) cells (88 versus 1990 pmol NOx x h-1/mg protein-1). eNOS-/- mice were hypertensive (mean arterial pressure, 135 +/- 15 versus 107 +/- 8 mm Hg in WT) without the development of cardiac hypertrophy. Coronary hemodynamics, analyzed in Langendorff-perfused hearts, showed no differences either in basal coronary flow or in maximal and repayment flow of reactive hyperemia. Acute NOS inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME) in WT hearts substantially reduced basal flow and reactive hyperemia. The coronary response to acetylcholine (ACh) (500 nmol/L) was biphasic: An initial vasoconstriction (flow, -35%) in WT hearts was followed by sustained vasodilation (+190%). L-NAME significantly reduced vasodilation in WT hearts (+125%) but did not alter the initial vasoconstriction. In eNOS-/- hearts, the initial vasoconstriction was augmented (-70%), whereas the ACh-induced vasodilation was not affected. Inhibition of cyclooxygenase with diclofenac converted the ACh-induced vasodilation into vasoconstriction (-49% decrease of basal flow). This effect was even more pronounced in eNOS-/- hearts (-71%). Our results demonstrate that (1) acute inhibition of eNOS reveals a role for NO in setting the basal coronary vascular tone as well as participation in reactive hyperemia and the response to ACh; (2) chronic inhibition of NO formation in eNOS-/- mutant mice induces no changes in basal coronary flow and reactive hyperemia, suggesting the activation of important compensatory mechanisms; and (3) prostaglandins are the main mediators of the ACh-induced vasodilation in both WT and eNOS-/- mice.

Animals↗
PubMed1998

Cardioprotective actions of KC 12291. I. Inhibition of voltage-gated Na+ channels in ischemia delays myocardial Na+ overload.

To characterize KC 12291 (1-(5-phenyl-1,2, 4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N-[2-(3,4-dimethoxy phenyl) ethyl] amino] propane hydrochloride), a newly synthezised inhibitor of voltage-gated Na+ channels, the effects of the agent on Na+ current and ischemia-induced Na+ overload were investigated in isolated cardiomyocytes, atria and saline-perfused hearts. As measured by the patch clamp technique, KC 12291 (1 microM) significantly reduced peak Na+ current after activation of voltage-gated Na+ channels in rat cardiomyocytes. Partial depolarization enhanced the inhibitory effects during steady state conditions of the channel. In isolated guinea pig atria, 1 microM KC 12291 had no effect on contractility under basal conditions but effectively delayed the onset and reduced the extent of anoxic contracture. The concentration-response curve was clearly shifted to the left when atria were partially depolarized by increased extracellular K+. As measured by 23Na NMR spectroscopy in isolated perfused guinea pig hearts, intracellular Na+ rose more than four-fold in a linear fashion during 60 min of low-flow ischemia. KC 12291 (1 microM) prevented Na+ overload within the initial 12 min of ischemia; thereafter the slope of Na+ accumulation was identical to controls. Electrical excitability of hearts, evaluated by intracardial ECG, completely ceased within 15 min after the onset of ischemia. KC 12291 (1 microM) accelerated this process by more than 6 min. The data provide first evidence that KC 12291 reduces Na+ influx through voltage-gated Na+ channels during ischemia and thus delays Na+ overload by enhancing the inexcitability of the heart.

Animals↗
PubMed1998

Cardioprotective actions of KC 12291. II. Delaying Na+ overload in ischemia improves cardiac function and energy status in reperfusion.

The novel blocker of voltage-gated Na+ channels KC 12291 (1-(5-phenyl-1,2,4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N- [2-(3,4-dimethoxyphenyl)ethyl] amino] propane hydrochloride) delays myocardial Na+ overload in ischemia. To test whether KC 12291 displays cardioprotective properties in the intact heart, cardiac function, energy status and intracellular pH (31P NMR) as well as ion homeostasis (23Na NMR) were investigated during low-flow ischemia (100 microl/min for 36 min) followed by reperfusion. In the well-oxygenated, isolated perfused guinea pig heart, KC 12291 (1 microM) had no effect on left ventricular developed pressure (LVDP; 54+/-19 mmHg). KC 12291 delayed the onset and decreased the extent of ischemic contracture and markedly improved the recovery of LVDP in reperfusion [39+/-14 mmHg (n=4) vs 2+/-2 mmHg in controls (n=5)]. KC 12291 did not influence the rapid drop in phosphocreatine (PCr) following onset of ischemia but attenuated the decline in ATP. It also diminished the ischemia-induced fall in intracellular pH [6.39+/-0.2 (n=6) vs 6.18+/-0.20 in controls (n=6)]. In reperfusion, KC 12291 remarkably enhanced the recovery of PCr (84.8+/-9.6% vs 51.1+/-8.8% of baseline) and ATP (38.2+/-12.9% vs 23.7+/-9.3% of baseline). It also accelerated the recovery of intracellular pH. KC 12291 not only reduced the extent of ischemia-induced Na+ overload, but also enhanced Na+ recovery. It is concluded that KC 12291 delays contracture and reduces ATP depletion and acidosis in ischemia, and markedly improves the functional, energetic and ionic recovery in reperfusion. Blocking voltage-gated Na+ channels in ischemia to delay Na+ overload may thus constitute a promising therapeutic approach for cardioprotection.

Adenosine Triphosphate↗
PubMed1998

Spatial heterogeneity of myocardial perfusion and metabolism.

Left ventricular myocardium is characterized by a substantial spatial heterogeneity of both perfusion and metabolism. Under resting conditions, the transmural gradient of myocardial oxygen consumption (MVO2) from the subepi- to the subendocardial layer exceeds that of coronary flow, resulting in a lower subendocardial PO2, altered kinetics of oxidative phosphorylation, and enhanced free cytosolic adenosine. Within each layer, there is a major spatial variability of perfusion: Local flow rates in individual myocardial samples (200 mg) range from 20-250% of the mean myocardial blood flow. Low flow areas (< 50% of mean flow) display a rather low uptake of fatty acids and glucose; the uptake of these substrates increases in proportion to local flow. There is also a close relationship between local perfusion and the local turnover of the tricarboxylic acid cycle and, thus, MVO2 as was recently demonstrated using 13C NMR techniques. Consequently, within the well perfused left ventricular myocardium local MVO2 and, thus, energy turnover varies more than 3-fold between low and high flow areas. Low flow areas are not ischemic, since local lactate, adenosine, and ATP are comparable to mean flow areas. When coronary perfusion pressure is reduced, the transmural perfusion gradient reverses resulting in impaired energy status and enhanced adenosine predominantly in the subendocardium. This rise in local adenosine or lactate requires a decrease of the individual local flow by more than 50% of its preischemic value. It, thus, appears that not the absolute level of local flow predicts the impact of ischemia but its relative change.

Adenosine Triphosphate↗
PubMed1997

Decrease of ischemic injury to the isolated perfused rat liver by loop diuretics.

Recent studies suggest a major role played by sodium in the pathogenesis of ischemic liver injury: in these studies, sodium-free media have been shown to offer protection against hypoxic injury to isolated hepatocytes. As sodium-free perfusions of the isolated rat liver proved impossible because of extensive vasoconstriction, we assessed the effects of two inhibitors of the Na+-K+-2Cl- cotransporter, the loop diuretics furosemide and bumetanide, on ischemic liver injury. In untreated control livers lactate dehydrogenase (LDH) efflux immediately after reperfusion after 60 minutes of ischemia at 37 degrees C was 1666 +/- 473 U/L. When livers were pretreated with furosemide or bumetanide before the ischemic period, LDH efflux was only 773 +/- 292 U/L and 702 +/- 183 U/L respectively (P < .01). LDH activity in the effluent of the pretreated livers remained significantly below the values of ischemic control livers for the whole reperfusion period of 90 minutes. Bile flow in the postischemic phase was improved by pretreatment with furosemide or bumetanide. The increase in intracellular sodium, as measured by 23Na-NMR, was attenuated from 193% +/- 71% during 60 minutes of ischemia in controls to 148% +/- 80% after bumetanide application (P < .05). Also, after 120 minutes of warm ischemia, LDH and aspartate aminotransferase release were significantly decreased and bile flow increased by pretreatment with bumetanide. Thus, both furosemide and bumetanide showed a clear benificial effect on rat livers subjected to warm ischemia. These data suggest that one means by which sodium ions are accumulated during liver ischemia might be the Na+-K+-2Cl- cotransporter, which is blocked by furosemide and bumetanide.

Animals↗
PubMed1997

Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation.

OBJECTIVE: It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such as dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduction of cardiac contractility has not been clearly established so far. Therefore, we studied the effects of authentic NO on left ventricular function and myocardial energy status in the isolated heart. METHODS: In 43 isolated perfused guinea pig hearts quantitative and kinetic changes in coronary flow (CF), left ventricular developed pressure (LVDP), the cardiac release of adenosine, lactate, cyclic GMP, and norepinephrine were measured during infusion of authentic NO. In parallel, myocardial phosphocreatine (PCr), ATP and the free energy change of ATP-hydrolysis (delta GATP) were measured using 31P nuclear magnetic resonance spectroscopy. RESULTS: At low concentrations (0.01 to 1.0 mumol/L) NO increased CF only; at higher concentrations (1 to 100 mumols/L) CF remained elevated and LVDP was significantly reduced. Onset and offset of changes in LVDP occurred always within 2 to 5 s after start and cessation of NO infusion. Contractile dysfunction was significantly correlated to a pronounced increase in adenosine formation (> 70-fold), a significant decrease in myocardial PCr (-78%), ATP (-25%) and a decrease in delta G(ATP) from -61.76 kJ/mol to -50.75 kJ/mol. This was paralleled by a significant decrease in myocardial oxygen consumption (-65%) and a tenfold increase in lactate production. Coronary vasodilation (NO: 0.001 to 1.0 mumol/L) significantly correlated with the increase in cGMP release, whereas at negative inotropic concentrations (NO: 10 to 100 mumols/L) a clear quantitative and kinetic dissociation between NO-induced changes in cGMP and LVDP was observed. Contractile dysfunction was not related to cardiac release of norepinephrine. CONCLUSIONS: In the isolated heart NO can potently depress myocardial energy generation thus being an effective modulator of cardiac contractility. This effect of NO may be of pathophysiological significance in cardiac muscle disorders in vivo.

Adenosine↗
PubMed1997

Dissociation between adenosine release, MVO2, and energy status in working guinea pig hearts.

Rapid adaptation of ATP formation and coronary flow is required when cardiac work is altered. Cardiac energy status was proposed to control both oxygen consumption (MVO2) and release of vasoactive adenosine (AR). To investigate the hypothesis of a linear relation between free AMP and AR, we employed 31P nuclear magnetic resonance (NMR) in a newly elaborated guinea pig heart performing pressure-volume work. Under basal conditions, MVO2 was 7.8 +/- 1.0 mumol.min-1.g-1, free AMP 297 +/- 189 nM and AR 226 +/- 179 pmol.min-1.g-1 (n = 29). Decreasing arterial PO2 by 50% reduced MVO2 and increased free AMP by 29%; however, AR rose threefold (n = 5). Doubling oxygen content of the perfusion medium (fluorocarbon emulsion) did not alter MVO2, free AMP, or AR (n = 6). When afterload was doubled, MVO2 increased (+45%) and AR decreased (-60%) despite no change in ADP or AMP (n = 6). Dobutamine increased MVO2 (+50%) and AMP (-98%); however, AR rose more than five times (n = 8). Switching substrates from glucose + pyruvate to glucose diminished MVO2 and increased ADP twofold and AMP fourfold, whereas AR remained constant (n = 6). Our findings demonstrate that cardiac energy status is also not the prime regulator of oxidative phosphorylation in the isolated heart. Changes in the oxygen supply-to-demand ratio induced a rise in AR that exceeded by far the increase in free AMP. Thus, additional factors, possibly inhibition of adenosine kinase, influence the release of vasoactive adenosine.

Adenosine↗
PubMed1997

Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release.

To elucidate the physiological role of the AMP-adenosine metabolic cycle and to investigate the relation between AMP and adenosine formation, the O2 supply of isolated guinea pig hearts was varied (95% to 10% O2). The net adenosine formation rate (AMP-->adenosine) and coronary venous effluent adenosine release rate were measured; free cytosolic AMP was determined by 31P-nuclear magnetic resonance. Switching from 95% to 40% O2 increased free AMP and adenosine formation 4-fold, whereas free cytosolic adenosine and venous adenosine release rose 15- to 20-fold. In the AMP range from 200 to 3000 nmol/L, there was a linear correlation between free AMP and adenosine formation (R2 = .71); however, adenosine release increased several-fold more than formation. At 95% O2, only 6% of the adenosine formed was released; however, this fraction increased to 22% at 40% O2, demonstrating reduced adenosine salvage. Selective blockade of adenosine deaminase and adenosine kinase indicated that flux through adenosine kinase decreased from 85% to 35% of adenosine formation in hypoxia. Mathematical model analysis indicated that this apparent decrease in enzyme activity was not due to saturation but to the inhibition of adenosine kinase activity to 6% of the basal levels. The data show (1) that adenosine formation is proportional to the AMP substrate concentration and (2) that hypoxia decreases adenosine kinase activity, thereby shunting myocardial adenosine from the salvage pathway to venous release. In conclusion, because of the normal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induced inhibition of adenosine kinase causes the amplification of small changes in free AMP into a major rise in adenosine. This mechanism plays an important role in the high sensitivity of the cardiac adenosine system to impaired oxygenation.

Adenosine↗
PubMed1996

Cloning of the rat P2u receptor and its potential role in coronary vasodilation.

We cloned and sequenced the cDNA as well as the genomic DNA of the P2u receptor gene from the rat. The coding region of the gene is not interrupted by introns. P2u is expressed in a variety of rat organs with pronounced differences of expression intensities. Highest expression was found in liver and testis, while no expression could be detected in the brain. High P2u expression was found in primary microvascular endothelial cells from the rat heart, but not in cardiac myocytes. By in situ analysis, we localized P2u expression in epithelial cells of esophagus and bronchi. Functional analysis revealed that, in isolated perfused rat hearts, the P2u ligands UTP and ATP induce a pronounced vasodilation of coronary blood vessels. In contrast, UMP and uridine, the degradative products of UTP, act as potent vasoconstrictors. Our experiments suggest that, in the rat heart, endothelial P2u receptors are involved in the ATP/UTP-mediated vasodilation of coronary blood vessels.

Adenosine Triphosphate↗