Otoxic, causing ventricular remodeling. 2ARs couple first to Gs then to
Otoxic, causing ventricular remodeling. 2ARs couple first to Gs then to inhibitory G protein (Gi). Continuous 2AR activation may protect the heart from continuous 1AR stimulation. Distribution of cAMP within myocytes differs after 1AR stimulation relative to 2AR stimulation. 1AR activation results in a global increase in cAMP while 2AR activation generates an increase only within restricted cellular subdomains. Phosphodiesterase 4D (PDE4D) degrades cAMP and is recruited to activated 2ARs after agonist-induced internalization of the receptors. In cultured myocytes, inhibition of PDE4D leads to a global rise in cAMP levels after 2AR stimulation and causes 2AR signaling to resemble that of the 1AR. Hypothesis We hypothesized that mice with disruption of both 1AR and PDE4D (1/PDE4D DKO) would experience myocardial remodeling similar to that associated with continuous 1AR stimulation. Methods Seven 1/PDE4D DKO, 11 2KO, and seven wild-type mice were evaluated. The wild-type PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/25112874 and 2KO mice received 14-day infusions of the AR agonist isoproterenol. ECG-gated magnetic resonance imaging was used to determine the left ventricle end diastolic volume (LVEDV), left ventricle end systolic volume, and heart rate. The stroke volume and cardiac output were calculated. Results See Fig. 1. Conclusions Disruption of PDE4D causes 2ARs to behave like 1ARs in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27385778 vivo, just as it does in vitro.Figure 1 (abstract 235)P236 Long-term alcoholic patients have decreased perioperative cAMP levelsH Schoenfeld1, R Franke1, C von Heymann1, U Doepfmer1, A Blaicher2, S Ziemer1, C Spies1 1Charite-Universitaetsmedizin Berlin, Charite Campus Mitte, Berlin, Germany; 2Medical University of Vienna, Austria, Vienna Critical Care 2006, 10(Suppl 1):P236 (doi: 10.1186/cc4583) Background Patients with chronic alcohol misuse have an increased risk of postoperative bleeding complications compared with non-alcoholic individuals [1]. Serotonin increases [2], and cAMP and cyclic guanosine monophosphate (cGMP) decrease, platelet aggregation [3]. The aim of our study was to examine platelet-rich plasma levels of the mentioned substances in longterm alcoholic patients undergoing surgery. Methods We included 33 consecutive patients with chronic alcohol misuse scheduled for tumor resections of the upper digestive tract and postoperative intensive care. We defined longterm alcoholic patients as having a daily alcohol intake of at least 60 g and fulfilling the DSM-IV criteria of the American Psychiatric Association for alcohol abuse or dependence. Blood samples were collected before and 1 day after surgery. Serotonin was measured by ELISA, cAMP and cGMP by radioimmunoassay. Additionally, we measured SCH 530348MedChemExpress SCH 530348 standard coagulation tests and determined platelet aggregation induced by ADP, collagen, epinephrine and ristocetin before and after surgery. Statistics: Mann hitney U test. Results Basic patient characteristics and platelet aggregation responses induced by the mentioned agonists did not significantly differ. Data are presented in Table 1.Table 1 (abstract P236) Parameter Alcoholics Nonalcoholics P valuecAMP preoperatively (nmol/l) 1.8 (1.6?.6) 3.2 (2.2?.3) <0.01 cAMP postoperatively (nmol/l) 1.8 (1.5?.3) 2.7 (2.1?.9) 0.03 cGMP preoperatively (nmol/l) 4.0 (2.3?.8) 5.6 (1.6?4.4) 0.77 cGMP postoperatively (nmol/l) 2.9 (2.3?.8) 3.7 (1.4?.3) 0.94 Serotonin preoperatively 381 (194?73) 386 (180?05) 0.98 (ng/109 platelets) Serotonin postoperatively 288 (193?80) 460 (225?23) 0.10 (ng/109 platelets) Data presented.