Stabilization of Delphinidin in Complex with Sulfobutylether-ß-Cyclodextrin Allows for Antinociception in Inflammatory Pain.

Aims: Delphinidin (DEL) is a plant-derived antioxidant with clinical potential to treat inflammatory pain but suffers from poor solubility and low bioavailability. The aim of the study was to develop a well-tolerated cyclodextrin (CD)-DEL complex with enhanced bioavailability and to investigate the mechanisms behind its antinociceptive effects in a preclinical model of inflammatory pain. Results: CD-DEL was highly soluble and stable in aqueous solution, and was nontoxic. Systemic administration of CD-DEL reversed mechanical and heat hyperalgesia, while its local application into the complete Freund's adjuvant (CFA)-induced inflamed paw dose-dependently reduced mechanical hyperalgesia, paw volume, formation of the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE), and tissue migration of CD68+ macrophages. CD-DEL also directly prevented 4-HNE-induced mechanical hyperalgesia, cold allodynia, and an increase in the intracellular calcium concentration into transient receptor potential ankyrin 1 expressing cells. Both 4-HNE- and CFA-induced reactive oxygen species (ROS) levels were sensitive to CD-DEL, while its capacity to scavenge superoxide anion radicals (inhibitory concentration 50 [IC50]: 70 ± 5 µM) was higher than that observed for hydroxyl radicals (IC50: 600 ± 50 µM). Finally, CD-DEL upregulated heme oxygenase 1 that was prevented by HMOX-1 siRNA in vitro. Innovation:In vivo application of DEL to treat inflammatory pain is facilitated by complexation with CD. Apart from its antioxidant effects, the CD-DEL has a unique second antioxidative mechanism involving capturing of 4-HNE into the CD cavity followed by displacement and release of the ROS scavenger DEL. Conclusion: CD-DEL has antinociceptive, antioxidative, and anti-inflammatory effects making it a promising formulation for the local treatment of inflammatory pain.

Association of increased myocardial contractility and elevated end-diastolic wall tension with short-term myocardial ischemia: a pressure-volume analysis.

OBJECTIVE: Critical myocardial oxygen imbalance as indicated by elevated interstitial lactate levels may occur in cases of rapidly elevated end-diastolic myocardial wall tension during elevated myocardial contractility in the intact myocardium. Simultaneous administration of beta-adrenergic receptor agonist and antagonist reliably allows for investigating the myocardial response. DESIGN: Experimental using an in vivo animal model. SETTING: Research institution. PARTICIPANTS: Animal model. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Fifteen minipigs were investigated in an open-chest model. After a midline sternotomy, a thin dialysis tube was implanted into the LV midmyocardium. Extracellular lactate in perfusate was analyzed every 5 minutes. End-systolic time-varying elastance and end-diastolic wall tension were measured. After a stable period, dobutamine (10 microg/kg/min) was administered to 8 animals. After 20 minutes, esmolol (0.5-mg/kg bolus, repetitively) was added until heart rate decreased to <100 beats/min. For 20 minutes, esmolol was infused at a rate of 3 mg/kg/h, and then dobutamine alone was continued for 10 minutes. With dobutamine, the lactate level did not change, but wall tension decreased and contractility increased. Simultaneous esmolol initially (in the first 10 minutes) increased lactate, whereas LV end-diastolic wall tension and contractility both increased; but after 10 minutes, lactate and contractility decreased significantly. Lactate again increased within 10 minutes after stopping esmolol. A group of 7 animals received esmolol for 20 minutes and showed no changes in lactate; myocardial wall tension increased and contractility decreased. CONCLUSION: Results suggest that oxygen demand/supply is balanced until both end-diastolic wall tension and myocardial contractility are elevated to critical levels.

How to distinguish between ischemic and nonischemic postsystolic thickening: a strain rate imaging study.

Ongoing myocardial thickening after aortic valve closure (postsystolic thickening = epsilonPST) is an established marker for the presence of segmental ischemia. However, epsilonPST may also be present in late activated segments and can be induced by pharmacological interventions or left ventricular pressure overload. The aim of this study was to determine if it is possible to distinguish between ischemic and nonischemic epsilonPST. In an experimental pig-model (n = 11) regional radial deformation was measured in the inferolateral wall during either normal perfusion or regional ischemia using ultrasonic strain rate imaging. Ischemia was induced by active hypoperfusion of the circumflex coronary artery territory. Measurements were made at 1. baseline, and during 2. theodrenalin infusion, 3. dobutamine infusion 4. esmolol infusion and 5. during a preload increase induced by saline infusion. In all segments where thickening was ongoing after aortic valve closure, the amount of epsilonPST was calculated as the difference of maximal strain minus systolic strain. In addition, peak strain rate during the isovolumetric relaxation period was extracted. During normal coronary perfusion, 73% of all segments (n = 40) developed epsilonPST. This physiological epsilonPST averaged 5 +/- 2% and was most frequently induced during the esmolol infusion (n = 11). Peak isovolumetric strain rate averaged -2.1 +/- 0.5 s(-1) in segments with physiological epsilonPST. During coronary hypoperfusion, 96% of the "at risk" segments developed epsilonPST. EpsilonPST in the ischemic segments averaged 14 +/- 3%, and was highest during the dobutamine infusion (25 +/- 4%) and lowest during the esmolol infusion (5 +/- 1%). In contrast to normally perfused segments, peak isovolumetric strain rate was positive in the ischemic segments and averaged 2.0 +/- 0.5 s(-1) in these pathologic segments with postsystolic strain. Using a cut-off value of > or = 0 s(-1) for isovolumetric strain rate, pathologic epsilonPST was detected with a sensitivity of 100% and a specificity of 87%. These experimental findings were confirmed by a subsequent clinical study with 6 patients with acute myocardial infarction (ischemic group) and 6 patients with arterial hypertension or aortic stenosis (nonischemic group). Ischemic and nonischemic postsystolic thickening can be precisely differentiated by extracting the polarity of the peak isovolumetric strain curve.

Determination of preload-recruitable stroke work and elastance by the relationship of arterial blood flow velocity to left ventricular area.

OBJECTIVE: The authors investigated the feasibility of an online sampling and display of LV flow-area loops for the determination of LV elastance and preload-recruitable stroke work (PRSW). Automated LV area measurements by echocardiography may be combined with flow velocity measurements in the internal carotid artery to construct LV flow-area loops as estimates of the systolic pressure-volume relationship. SETTING: University hospital. DESIGN: Open chest model. PARTICIPANTS: Eight anesthetized minipigs. INTERVENTIONS: Inferior vena cava occlusion was performed to simultaneously obtain parameters of the LV flow-area relationship and the LV pressure-area relationship. MEASUREMENTS AND MAIN RESULTS: Parameters were obtained at baseline and during sequential administration of dobutamine (5 microg/kg/min) and halothane (0.8 vol%). Linear regression analysis and analysis of variance were performed to investigate an underlying linear relationship between the corresponding variables. Highly linear elastance and PRSW curves were derived from the flow-area and pressure-area loops (n = 24, R >/= 0.85). Changes of the curve slopes indicated inotropic changes as well as model independent dP/dt(max). Elastance from the pressure-area relationship was expressed by elastance from the flow-area relationship by the term y = 0.52 + 0.04. x (R(2) = 0.84; p < 0.0001). Linear regression of PRSW as derived from the flow-area relationship with PRSW as derived from the pressure-area relationship was expressed by y = 0.43 + 0.02. x (R(2) = 0.77; p < 0.0001). CONCLUSION: Indices of the LV pressure-area relationship can be derived from real-time loops constructed from arterial flow velocity and LV area.