cGMP becomes a drug target

Cyclic guanosine 3′,5′-monophosphate (cGMP) serves as a second messenger molecule, which regulates pleiotropic cellular functions in health and disease. cGMP is generated by particulate or soluble guanylyl cyclases upon stimulation with natriuretic peptides or nitric oxide, respectively. Furthermore, the cGMP concentration is modulated by cGMP-degrading phosphodiesterases. Several targets of cGMP are utilized to effect its various cellular functions. These effector molecules comprise cGMP-dependent protein kinases, ion channels, and phosphodiesterases. During the last decade, it emerged that cGMP is a novel drug target for the treatment of pulmonary and cardiovascular disorders. In this respect, several drugs were developed, which are now in clinical phase studies for, e.g., pulmonary hypertension or cardiovascular diseases. These new drugs act NO-independently with/without heme on soluble guanylyl cyclases or induce subtypes of particular guanylyl cyclases and thereby lead to new therapeutic concepts and horizons. In this regard, the fifth cGMP meeting held in June 2011 in Halle, Germany, comprised the new therapeutic challenges with the novel functional and structural concepts of cGMP generating and effector molecules. This report summarizes the new data on molecular mechanisms, (patho)physiological relevance, and therapeutic potentials of the cGMP signaling system that were presented at this meeting

Oxygen carrying capacity of salvaged blood in patients undergoing off-pump coronary artery bypass grafting surgery : a prospective observational study

BACKGROUND: Intraoperative cell salvage (ICS), hereby referred to ‘mechanical red cell salvage’, has been widely used and proven to be an effective way to reduce or avoid the need for allogeneic red blood cells (RBCs)transfusion and its associated complications in surgeries involving major blood loss. However, little is known about the influence of this technique on the functional state of salvaged RBCs. Furthermore, there are no articles that describe the change of free hemoglobin (fHb) in salvage blood during storage, which is a key index of the quality control of salvaged blood. Therefore, in this study, the influence of ICS on the function of salvaged RBCs and the changes of salvaged RBCs during storage were studied with respect to the presence of oxyhemoglobin affinity (recorded as a P(50) value) and the level of 2, 3-diphosphoglycerate (2, 3-DPG) and fHb by comparing salvaged RBCs with self-venous RBCs and 2-week-old packed RBCs. METHODS: Fifteen patients undergoing off-pump coronary artery bypass grafting (OPCAB) surgery were enrolled. Blood was collected and processed using a Dideco Electa device. The level of P(50), 2, 3-DPG and fHB from salvaged RBCs, venous RBCs and 2-week-old packed RBCs was measured. We also measured the changes of these indicators among salvaged RBCs at 4 h (storage at 21–24 °C) and at 24 h (storage at 1–6 °C). RESULTS: The P(50) value of salvaged RBCs at 0 h (28.77 ± 0.27 mmHg) was significantly higher than the value of venous RBCs (27.07 ± 0.23 mmHg, p = 0.000) and the value of the 2-week-old packed RBCs (16.26 ± 0.62 mmHg, p = 0.000). P(50) value did not change obviously at 4 h (p = 0.121) and 24 h (p = 0.384) compared with the value at 0 h. The 2, 3-DPG value of salvaged RBCs at 0 h (17.94 ± 6.91 μmol/g Hb) was significantly higher than the value of venous RBCs (12.73 ± 6.52 mmHg, p = 0.007) and the value of the 2-week-old packed RBCs (2.62 ± 3.13 mmHg, p = 0.000). The level of 2, 3-DPG slightly decreased at 4 h (p = 0.380) and 24 h (p = 0.425) compared with the value at 0 h. Percentage of hemolysis of the salvaged blood at 0 h(0.51 ± 0.27 %) was significantly higher than the level of venous blood (0.07 ± 0.05 %, p = 0.000) and the value of 2-week-old packed RBCs (0.07 ± 0.05 %, p = 0.000), and reached 1.11 ± 0.42 % at 4 h (p = 0.002) and 1.83 ± 0.77 % at 24 h (p = 0.000). CONCLUSIONS: The oxygen transport function of salvaged RBCs at 0 h was not influenced by the cell salvage process and was better than that of the venous RBCs and 2-week-old packed RBCs. At the end of storage, the oxygen transport function of salvaged RBCs did not change obviously, but percentage of hemolysis significantly increased

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Nitric Oxide Scavenging by Red Blood Cell Microparticles and Cell-Free Hemoglobin as a Mechanism for the Red Cell Storage Lesion

Background-Intravascular red cell hemolysis impairs nitric oxide (NO)-redox homeostasis, producing endothelial dysfunction, platelet activation, and vasculopathy. Red blood cell storage under standard conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or microparticles and hemolysis, which we hypothesized could impair vascular function and contribute to the putative storage lesion of banked blood. Methods and Results-We now find that storage of human red blood cells under standard blood banking conditions results in the accumulation of cell-free and microparticle-encapsulated hemoglobin, which, despite 39 days of storage, remains in the reduced ferrous oxyhemoglobin redox state and stoichiometrically reacts with and scavenges the vasodilator NO. Using stopped-flow spectroscopy and laser-triggered NO release from a caged NO compound, we found that both free hemoglobin and microparticles react with NO about 1000 times faster than with intact erythrocytes. In complementary in vivo studies, we show that hemoglobin, even at concentrations below 10 mu mol/L (in heme), produces potent vasoconstriction when infused into the rat circulation, whereas controlled infusions of methemoglobin and cyanomethemoglobin, which do not consume NO, have substantially reduced vasoconstrictor effects. Infusion of the plasma from stored human red blood cell units into the rat circulation produces significant vasoconstriction related to the magnitude of storage-related hemolysis. Conclusions-The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis. (Circulation. 2011; 124: 465-476.

Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion

Bacground-: Intravascular red cell hemolysis impairs nitric oxide (NO)-redox homeostasis, producing endothelial dysfunction, platelet activation, and vasculopathy. Red blood cell storage under standard conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or microparticles and hemolysis, which we hypothesized could impair vascular function and contribute to the putative storage lesion of banked blood. METHODS AND RESULTS-: We now find that s