Tropical Peatland Hydrology Simulated With a Global Land Surface Model.

Tropical peatlands are among the most carbon-dense ecosystems on Earth, and their water storage dynamics strongly control these carbon stocks. The hydrological functioning of tropical peatlands differs from that of northern peatlands, which has not yet been accounted for in global land surface models (LSMs). Here, we integrated tropical peat-specific hydrology modules into a global LSM for the first time, by utilizing the peatland-specific model structure adaptation (PEATCLSM) of the NASA Catchment Land Surface Model (CLSM). We developed literature-based parameter sets for natural (PEATCLSMTrop,Nat) and drained (PEATCLSMTrop,Drain) tropical peatlands. Simulations with PEATCLSMTrop,Nat were compared against those with the default CLSM version and the northern version of PEATCLSM (PEATCLSMNorth,Nat) with tropical vegetation input. All simulations were forced with global meteorological reanalysis input data for the major tropical peatland regions in Central and South America, the Congo Basin, and Southeast Asia. The evaluation against a unique and extensive data set of in situ water level and eddy covariance-derived evapotranspiration showed an overall improvement in bias and correlation compared to the default CLSM version. Over Southeast Asia, an additional simulation with PEATCLSMTrop,Drain was run to address the large fraction of drained tropical peatlands in this region. PEATCLSMTrop,Drain outperformed CLSM, PEATCLSMNorth,Nat, and PEATCLSMTrop,Nat over drained sites. Despite the overall improvements of PEATCLSMTrop,Nat over CLSM, there are strong differences in performance between the three study regions. We attribute these performance differences to regional differences in accuracy of meteorological forcing data, and differences in peatland hydrologic response that are not yet captured by our model.

Overriding water table control on managed peatland greenhouse gas emissions.

Global peatlands store more carbon than is naturally present in the atmosphere1,2. However, many peatlands are under pressure from drainage-based agriculture, plantation development and fire, with the equivalent of around 3 per cent of all anthropogenic greenhouse gases emitted from drained peatland3-5. Efforts to curb such emissions are intensifying through the conservation of undrained peatlands and re-wetting of drained systems6. Here we report eddy covariance data for carbon dioxide from 16 locations and static chamber measurements for methane from 41 locations in the UK and Ireland. We combine these with published data from sites across all major peatland biomes. We find that the mean annual effective water table depth (WTDe; that is, the average depth of the aerated peat layer) overrides all other ecosystem- and management-related controls on greenhouse gas fluxes. We estimate that every 10 centimetres of reduction in WTDe could reduce the net warming impact of CO2 and CH4 emissions (100-year global warming potentials) by the equivalent of at least 3 tonnes of CO2 per hectare per year, until WTDe is less than 30 centimetres. Raising water levels further would continue to have a net cooling effect until WTDe is within 10 centimetres of the surface. Our results suggest that greenhouse gas emissions from peatlands drained for agriculture could be greatly reduced without necessarily halting their productive use. Halving WTDe in all drained agricultural peatlands, for example, could reduce emissions by the equivalent of over 1 per cent of global anthropogenic emissions.

Preconditioning in rat hearts is independent of mitochondrial F1F0 ATPase inhibition.

Mitochondrial F1F0 adenosinetriphosphatase (ATPase) is responsible for the majority of ATP synthesis during normoxic conditions, but under ischemic conditions it accounts for significant ATP hydrolysis. A previous study showed that preconditioning in isolated rat hearts is mediated by inhibition of this ATPase during ischemia. We tested this hypothesis in our isolated rat heart model of preconditioning. Preconditioning was accomplished by three 5-min periods of global ischemia separated by 5 min of reperfusion. This was followed by 20 min of global ischemia and 30 min of reperfusion. Preconditioning significantly enhanced reperfusion contractile function and reduced lactate dehydrogenase release but paradoxically reduced the time to onset of contracture during global ischemia. Myocardial ATP was depleted at a faster rate during the prolonged ischemia in preconditioned than in sham-treated hearts, which is consistent with the reduced time to contracture. ATP during reperfusion was repleted more rapidly in preconditioned hearts, which is consistent with their enhanced contractile function. Preconditioning significantly reduced lactate accumulation during the prolonged ischemia. We were not able to demonstrate that mitochondrial F1F0 ATPase (measured in submitochondrial particles) was inhibited by preconditioning before or during the prolonged ischemia. The mitochondrial ATPase inhibitor oligomycin significantly conserved ATP during ischemia and increased the time to the onset of contracture, which is consistent with inhibition of the mitochondrial ATPase. Our results show that preconditioning in rat hearts can be independent of mitochondrial ATPase inhibition as well as ATP conservation.

Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448.

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.

Cardioselective antiischemic ATP-sensitive potassium channel (KATP) openers. 5. Identification of 4-(N-aryl)-substituted benzopyran derivatives with high selectivity.

This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4. showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.

Lack of a pharmacologic interaction between ATP-sensitive potassium channels and adenosine A1 receptors in ischemic rat hearts.

OBJECTIVES: An interaction between adenosine A1 receptors and ATP-sensitive potassium channels (KATP) has been hypothesized to mediate preconditioning in several species. Unlike other species tested, KATP blockers and A1 antagonists do not abolish preconditioning in rat hearts. The purpose of this study was to determine if KATP and A1 receptors are pharmacologically linked in rat hearts as they are in other species. METHODS: Isolated rat hearts were given 0.03-1.00 microM R-PIA (adenosine A1 receptor agonist) with or without concomitant 0.3 microM glyburide starting 10 min pre-ischemia. After 25 min global ischemia, the hearts were reperfused for 30 min. Rat hearts were also treated with 1-30 microM cromakalim in the presence of 10 microM DPCPX (adenosine A1 antagonist). RESULTS: R-PIA produced a concentration-dependent bradycardia before ischemia which was blocked by DPCPX. R-PIA increased the time to onset of contracture in a concentration-dependent manner (EC25 = 0.13 microM) and this was unaffected by 0.3 microM glyburide (EC25 = 0.20 microM). This concentration of glyburide completely abolished the protective effects of 10 microM cromakalim. R-PIA also significantly enhanced post-ischemic recovery of function and reduced LDH release, and glyburide did not alter these responses. Cromakalim significantly increased the time to onset of contracture (EC25 = 4.5 microM) and 10 microM DPCPX had no effect on this (EC25 = 5.6 microM). Cromakalim also significantly enhanced post-ischemic recovery of function and reduced LDH release. DPCPX did not alter these cardioprotective effects while glyburide completely abolished the cardioprotective effects of cromakalim. CONCLUSIONS: While both cromakalim and R-PIA are cardioprotective in isolated rat hearts, they are not pharmacologically linked, possibly explaining why preconditioning may be different in this species.

Cardioselective antiischemic ATP-sensitive potassium channel openers. 4. Structure-activity studies on benzopyranylcyanoguanidines: replacement of the benzopyran portion.

The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassium channel (KATP) opener (4) are described. Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally simpler acyclic analog (8) with slightly lower antiischemic potency than the lead compound 4. Further structure-activity studies on the acyclic analog 8 provided the 2-phenoxy-3-pyridylurea analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners is not mandatory for antiischemic activity and cardiac selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relationships for the antiischemic and vasorelaxant activities of KATP openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve KATP opening as their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.

Cardioselective anti-ischemic ATP-sensitive potassium channel openers. 3. Structure-activity studies on benzopyranyl cyanoguanidines: modification of the cyanoguanidine portion.

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.

The KATP blocker sodium 5-hydroxydecanoate does not abolish preconditioning in isolated rat hearts.

Blockers of ATP-sensitive K+ channels (KATP) abolish preconditioning in several species. Glyburide does not abolish preconditioning in rat hearts, but this may be due to a loss of its activity during ischemia. We determined the effect of a KATP blocker, which is more active during ischemia (sodium 5-hydroxydecanoate, 5-HD), on preconditioning in isolated rat hearts. Rat hearts were subjected to 4 periods of 5 min global ischemia followed by 30 min of global ischemia and reperfusion. Preconditioning significantly enhanced post-ischemic recovery of function and reduced lactate dehydrogenase (LDH) release vs. sham. 5-HD (100 microM) did not abolish preconditioning. Cromakalim (20 microM) was protective in this ischemic model and this was abolished by 5-HD. This is further evidence that KATP opening is not the mechanism of preconditioning in rats.

Endogenous catecholamines are not necessary for ischaemic preconditioning in the isolated perfused rat heart.

OBJECTIVE: The mechanism of the protective effect of ischaemic preconditioning in the myocardium is not yet known. The aim of this study was to test the hypothesis that endogenous myocardial catecholamines may be mediators of preconditioning. METHODS: To test whether endogenous catecholamines are involved in preconditioning, experiments were performed in hearts from rats which had been catecholamine depleted with either reserpine or 6-hydroxydopamine. Experiments were also done to determine if noradrenaline can mimic preconditioning. RESULTS: Catecholamine depletion with either reserpine or 6-hydroxydopamine had no effect on preischaemic coronary flow or cardiac function. Ischaemic preconditioning (four episodes of 5 min global ischaemia and 5 min reperfusion) resulted in a significant increase in postischaemic cardiac function and a 50% decrease in lactate dehydrogenase (LDH) release following 30 min ischaemia and 30 min reperfusion compared with non-preconditioned hearts. Reserpine pretreatment did not affect the response to ischaemia or to preconditioning, although LDH release tended to be greater than in normal hearts, especially in the non-preconditioned group. Although 6-hydroxydopamine significantly increased postischaemic cardiac function in the preconditioned group, no other index of ischaemic damage (for example, LDH release, left ventricular end diastolic pressure) was affected. Further studies showed that 10 nmol.min-1 noradrenaline did not affect the severity of ischaemia, indicating that it does not mimic preconditioning. CONCLUSIONS: Endogenous catecholamines are not necessary for ischaemic preconditioning in isolated rat hearts and play little or no role in the functional responses to ischaemia.

Inhibition of nitric oxide synthesis does not affect ischemic preconditioning in isolated perfused rat hearts.

Endothelium-derived nitric oxide (NO) has recently been reported to be a mediator of ischemic preconditioning in dog hearts. The aim of the present study was to determine the role of NO in ischemic preconditioning in isolated perfused rat hearts. Rat hearts were perfused at either constant pressure (80 mmHg) or constant flow. After aerobic perfusion (37 degrees C) for 10 min, hearts were treated with N omega-nitro-L-arginine methyl ester (L-NAME; 30 microM), which is an inhibitor of NO synthase, or vehicle. Ten minutes later, the hearts were preconditioned (4 episodes of 5 min of global ischemia and 5 min of reperfusion) or perfused normally before a 30-min global ischemic period. All hearts were reperfused for 30 min. Coronary flow or perfusion pressure plus heart rate and contractile function were measured continuously. Hearts perfused at constant pressure and treated with 30 microM L-NAME, a concentration that effectively inhibits endogenous NO synthesis, exhibited decreased coronary flow after 10 min, and flow remained decreased throughout the experiment. Ischemic preconditioning before 30 min of global ischemia resulted in a doubling of contractile function and a reduction of lactate dehydrogenase release at the end of the 30-min reperfusion period compared with nonpreconditioned hearts. The protective effect of preconditioning was not different in L-NAME-treated hearts. In addition, inhibition of NO synthase had no effect on the severity of ischemia in nonpreconditioned hearts. Similar results were obtained in preconditioned hearts that were perfused at constant flow, indicating that the flow reductions caused by L-NAME did not influence the results.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cromakalim on skeletal muscle function and blood flow in the ferret ischemic hindlimb.

Cromakalim, an agent that opens ATP-modulated potassium channels, has recently been reported to reduce skeletal muscle contractile force during anoxia in vitro. To determine whether this activity occurs in vivo, cromakalim was tested for its ability to influence muscle function and blood flow in a model of skeletal muscle ischemia. In anesthetized ferrets the muscles of the hindlimb were stimulated electrically via the sciatic nerve and isometric force of contraction was measured. Under normal perfusion conditions, contractile force peaked (324 +/- 33 g) within 1 or 2 min and gradually declined to about 85% of the peak over 20 min. Following this initial period, the abdominal aorta was partially occluded to reduce femoral blood pressure to 35-40 mm Hg, and infusion of cromakalim or vehicle was started. After 60 min of treatment, a second exercise challenge was performed. In the vehicle-treated group, peak force was reduced by 33% (p < 0.05), and over the 20-min stimulation period, the area under the force-time curve (AUC) was 22.8 +/- 2.6% of that seen during the normal flow period. Compared to vehicle, cromakalim infusions of 1.33 or 3.0 micrograms/kg/min reduced mean arterial blood pressure by 7 and 45%, but had no significant effect on either peak force or AUC. Although the higher dose of cromakalim significantly reduced vascular resistance in resting, normally perfused skeletal muscle of the forelimbs, neither dose affected blood flow in the ischemic skeletal muscles of the hindlimb during exercise. These results suggest that cromakalim does not influence skeletal muscle blood flow or function during an acute ischemic insult.

Effect of in vivo inhibition of neutrophil adherence on skeletal muscle function during ischemia in ferrets.

Neutrophils are reported to play an important role in the genesis of tissue damage during reperfusion after periods of ischemia in a variety of organs and may also be involved in loss of tissue function during ischemia. To test this hypothesis, the monoclonal antibody, MoAb 60.3, which prevents the adhesion of ferret neutrophils to cultured human endothelial cells at a concentration of 30 micrograms/ml, was tested in a model of peripheral vascular disease to determine whether it would preserve skeletal muscle function during ischemia. In an anesthetized ferret the muscles of the hindlimb were stimulated electrically to contract isometrically and the force of contraction was measured. Under normal perfusion conditions the contractile force peaked within 1 or 2 min of initiation of stimulation and gradually declined to approximately 80% of peak force after 20 min. When femoral arterial pressure was reduced to 45 mmHg by partial occlusion of the abdominal aorta, peak force was reduced by 25 +/- 7%, and within 5 min the force decayed to approximately 20% of the original peak, resulting in an area under the force-time curve (AUC) of 32 +/- 5% of that seen during the normal flow period. During ischemia after treatment with MoAb 60.3 (2 mg/kg iv), peak force was 94 +/- 3% and AUC was 49 +/- 5% of that observed during the normal flow period, a significant protective effect compared with the untreated control group (P = 0.0294). When the nonneutrophil-directed monoclonal antibody, L6, was tested in this model, no protective effects were evident.(ABSTRACT TRUNCATED AT 250 WORDS)