Activation of β_2-Adrenergic Receptor Induced by Three Catecholamine Agonists:a Docking and Molecular Dynamics Study

We studied the activation of β2-adrenergic receptor（β2AR） by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics（MD） simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions（TMs）, in the mo- lecular switches, and in the conserved DRY（Aspartic acid, Arginine and Tyrosine） motif. This study provides detailed information concerning the structure ofβ2AR during activation process.

Benefit of prophylactic bronchodilator withβ2 adrenergic agonist in ischemia-reperfusion-induced lung injury

Primary lung graft dysfunction could significantly attribute to ischemia-reperfusion lung injury(IRLI)during transplantation surgery.β2-adrenergic agonists were one of the bronchodilators that had been well-established in the management of asthma and chronic obstructive pulmonary disease(COPD)with anti-inflammatory potency.By applying the model of isolated rat lung,we evaluated the efficacy of short-actingβ2-agonist inhalation to ameliorate ischemia-reperfusion damage.The experiment protocol was 180 min of global ischemia and then reperfusion for 60 min.In theβ2-agonist inhalation group,aerosolized albuterol was administrated prior ischemia procedure.Increased weight ratios of wet to dry lung and microvascular permeability were characterized in the IRLI group.In contrast,pre-inhaledβ2-agonist significantly mitigated the severity of pulmonary edema.Bronchoalveolar lavage from theβ2-agonist group presented decreased leukocyte counts and cytokines production,including interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),and macrophage inflammatory protein 2(MIP-2).Devastating oxidative stress was widely recognized during the ischemia-reperfusion process,whileβ2-agonist pretreatment revealed subsided H2O2,myeloperoxidase(MPO),and the cleavage of caspase-3.Western blotting from lung homogenates identified the blockade of NF-κB and MAPK activation in theβ2-agonist inhalation group.Currently,there was no specific pharmacotherapy in IRLI management.Our results elucidated the protective effect ofβ2-agonist bronchodilator against ischemia-reperfusion induced oxidative stress,inflammation reaction,and pulmonary edema.

Effects of α-methylnorepinephrine on cardiac function and myocardium at early stage of resuscitation in rabbits

BACKGROUND： Recent studies have shown that α2-adrenergic agonists can reduce postresuscitation myocardial injury. This study was undertaken to observe changes of hemodynamics, myocardial injury markers cTnT and cardiac morphology by establishing a cardiopulmonary resuscitation model with rabbits, and to detect whether a-methyl norepinephrine （α-MNE） can reduce the myocardial injury after CPR and improve cardiac function.METHODS： Eighteen health rabbits, weighing 2.5-3.5 kg, both male and female, were provided by the Lanzhou Institute of Veterinary Medicine. After setting up a rabbit model of cardiopulmonary resuscitation, 18 rabbits were randomly divided into three groups. The rabbits in group A as an operation-control group were subjected to anesthesia, endotracheal intubation, and surgery without induction of ventricular fibrillation. The rabbits in group B as an epinephrine group were administered with 30 μg/kg epinephrineduring CPR. The rabbits in group C as a MNE group were administered with 100 μg/kg a-MNE during CPR. The left ventricular end-diastolic pressure （LVEDP）, left ventricular pressure rise and fall rate （＋dp/dt） and serum concentrations of BNP were measured. Statistical package of SPSS 10.0 was used for data analysis and significant differences between means were evaluated by ANOVA.RESULTS： Compared to group A, the LVEDP of other two groups increased respectively （P〈0.01 all）, and peak±dp/dt decreased in the other two groups （P〈0.01）. The increase of LVEDP was lower in group C than in group B （P〈0.05）, whereas peak±dp/dt was higher in group C than in group B （P〈0.05） at the same stage. Compared to group A, the cTnT of the remaining two groups increased, respectively （P〈0.01）, and peaked at 30 minutes, cTnT was less elevated in group C than in group B （P〈0.05） during the same period. In groups B and C, myocardial injury was seen under a light microscope, but the injury in group C was lighter than that in group B.CONCLUSION：Methylnorepinephrine can lessen myocardial dysfunction after CPR.

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Adipose tissue is a promising target for treating obesity and metabolic diseases.However,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese subjects.We have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells.We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue.Using an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and FGF21.Additionally,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy.In light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it.Thus,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.