scholarly journals Effect of Rho-Kinase and Autophagy on Remote Ischemic Conditioning-Induced Cardioprotection in Rat Myocardial Ischemia/Reperfusion Injury Model

2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Jie Gao ◽  
Feng Min ◽  
Shasha Wang ◽  
Heng Lv ◽  
Huan Liang ◽  
...  
Keyword(s):  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Light Chain ◽  
Kinase Inhibitor ◽  
Ischemia Reperfusion ◽  
Rho Kinase ◽  
Beclin 1 ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning

Objective. Remote ischemic conditioning (RIC) is a cardioprotective method in ischemia/reperfusion (I/R) injury. This study investigated the mechanism of Rho-kinase-mediated autophagy in RIC. Methods. Sixty male Sprague–Dawley rats were randomly divided into six groups: sham, I/R, RIC, I/R+fasudil, RIC+wortmannin, and RIC+fasudil+wortmannin. Throughout the experiment, mean arterial pressure and heart rate were continuously monitored. Histopathology and ultrastructure and myocardial enzymes’ expression were evaluated to determine the degree of cardiac injury. The protein expression of the Rho-kinase substrates myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1), autophagy-related protein light chain 3-II (LC3-II) and Beclin 1, and protein kinase B (AKT) was measured in the myocardial tissue. Results. Compared with the sham group, the mean arterial pressure and heart rate were decreased, myocardial enzyme levels were increased, and myocardial damage was aggravated in the I/R group; however, RIC improved these alterations. The expression of phosphorylated MLC and MYPT1 was lower, while LC3-II, Beclin 1, and phospho-AKT expression levels were higher in the RIC group compared with the I/R group. Obviously, treatment of the I/R group rats with fasudil, a Rho-kinase inhibitor, significantly ameliorated the I/R effects, whereas treatment of the RIC group rats with wortmannin, a phosphatidylinositol-3 kinase (PI3K) inhibitor, inhibited the RIC protective effects. Moreover, the rats in the RIC+fasudil+wortmannin group showed similar changes to those in the RIC+wortmannin group. Conclusion. These results showed that RIC protected the myocardium from I/R injury by suppressing Rho-kinase and the underlying mechanism may be related to enhancing autophagy via the PI3K/AKT pathway.

scholarly journals Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation

2001 ◽  
Vol 91 (3) ◽  
pp. 1269-1273 ◽  
Author(s):  
Thomas M. Mills ◽  
Kanchan Chitaley ◽  
Christopher J. Wingard ◽  
Ronald W. Lewis ◽  
R. Clinton Webb
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Nature Medicine ◽  
Rho Kinase ◽  
Vasodilatory Effect ◽  
Rho Kinase Inhibitor ◽  
Erectile Response ◽  
Kinase Pathway

A recent report from this laboratory (Chitaley K, Wingard C, Webb R, Branam H, Stopper V, Lewis R, and Mills T. Nature Medicine 7: 119–122, 2001) showed that inhibition of Rho-kinase increased the erectile response (intracavernosal pressure and mean arterial pressure) by a process that does not require nitric oxide or cGMP. The present study investigated whether vasoconstrictor agents, which are active in the penis, act via the Rho-kinase pathway. Western analysis revealed RhoA and Rho-kinase protein in the penis. Treatment with the selective Rho-kinase inhibitor Y-27632 significantly increased the magnitude of the erectile response. Intracavernous administration of endothelin-1 (ET-1; 50 pmol) or methoxamine (10 μg/kg) reduced the erectile response to autonomic stimulation. If Y-27632 was given before ET-1 or methoxamine, the vasoconstrictor effect was reduced, and intracavernosal pressure and mean arterial pressure remained elevated. However, when given after methoxamine, Y-27632 had a reduced vasodilatory effect, and Y-27632 had no vasodilatory effect when given after ET-1. These findings suggest that ET-1 and methoxamine increase Rho-kinase activity in the cavernous circulation and support the hypothesis that the vasoconstriction that maintains the penis in the nonerect state is mediated, in part, by the Rho-kinase pathway.

scholarly journals Effect of Dexmedetomidine on Perioperative Stress Response and Immune Function in Patients With Tumors

2020 ◽  
Vol 19 ◽  
pp. 153303382097754
Author(s):  
Lihong Zheng ◽  
Juan Zhao ◽  
Likun Zheng ◽  
Shuangfeng Jing ◽  
Xiaoting Wang
Keyword(s):  
Heart Rate ◽  
Stress Response ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Immune Function ◽  
Spontaneous Respiration ◽  
General Anesthetics ◽  
Ifn Γ ◽  
Group D ◽  
Perioperative Stress

Objective: This study aims to investigate the effect of dexmedetomidine on perioperative stress response and immune function in patients with tumors. Methods: Sixty patients who underwent selective radical gastrectomy for cancer were randomly divided into 3 groups: remifentanil group (group R), dexmedetomidine group (group D), and sufentanil group (group S). Remifentanil, dexmedetomidine, and sufentanil were used as general anesthetics. Endotracheal intubation and mechanical ventilation were performed after the spontaneous respiration disappeared. Then, the data were recorded, and blood samples were collected at all time points. Results: The heart rate significantly increased ( P < 0.05) at T1 in group S, and both heart rate and mean arterial pressure significantly increased ( P < 0.05) in group R when compared to group D. The heart rate significantly increased ( P < 0.05) at T2 in group S and group R. Furthermore, the heart rate significantly increased ( P < 0.05) at T3 and T4 in group S and group R. Intra-group comparison: The heart rate at T1–T4 and mean arterial pressure at T1–T4 significantly increased ( P < 0.05) in group S, and the heart rate at T1 and T4, and mean arterial pressure at T2–T4 significantly increased ( P < 0.05) in group R when compared to T0. The serum IL-6, IFN-γ, and β-EP significantly increased ( P < 0.05) at T0’ in group S and group R when compared to group D. Blood glucose, and serum IL-10, IFN-γ, and β-EP significantly increased ( P < 0.05), while IL-18 significantly decreased ( P < 0.05) at T1’ in group S and group R. Conclusion: Continuous infusion of dexmedetomidine in combination with the inhalation of sevoflurane is superior to sevoflurane + remifentanil or sufentanil in patients undergoing tumor surgery.

scholarly journals Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine

2018 ◽  
Vol 129 (5) ◽  
pp. 970-988 ◽  
Author(s):  
John J. Savarese ◽  
Hiroshi Sunaga ◽  
Jeff D. McGilvra ◽  
Matthew R. Belmont ◽  
Matthew T. Murrell ◽  
...  
Keyword(s):  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Neuromuscular Blockade ◽  
Blocking Agent ◽  
Neuromuscular Blocking ◽  
Neuromuscular Blocking Agent ◽  
Duration Of Action ◽  
Short Acting ◽  
Circulatory Effects

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Structure–activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by l-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. Methods Adduction of CW 1759-50 with l-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee–approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by l-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. Results The half-time of adduction of l-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of l-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. Conclusions CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by l-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

scholarly journals A Novel Regulatory Mechanism of Myosin Light Chain Phosphorylation via Binding of 14-3-3 to Myosin Phosphatase

2008 ◽  
Vol 19 (3) ◽  
pp. 1062-1071 ◽  
Author(s):  
Yasuhiko Koga ◽  
Mitsuo Ikebe
Keyword(s):  
Light Chain ◽  
Myosin Light Chain ◽  
Regulatory Mechanism ◽  
Kinase Inhibitor ◽  
Myosin Ii ◽  
Critical Role ◽  
Rho Kinase ◽  
Myosin Phosphatase ◽  
Dependent Cell ◽  
Direct Binding

Myosin II phosphorylation–dependent cell motile events are regulated by myosin light-chain (MLC) kinase and MLC phosphatase (MLCP). Recent studies have revealed myosin phosphatase targeting subunit (MYPT1), a myosin-binding subunit of MLCP, plays a critical role in MLCP regulation. Here we report the new regulatory mechanism of MLCP via the interaction between 14-3-3 and MYPT1. The binding of 14-3-3β to MYPT1 diminished the direct binding between MYPT1 and myosin II, and 14-3-3β overexpression abolished MYPT1 localization at stress fiber. Furthermore, 14-3-3β inhibited MLCP holoenzyme activity via the interaction with MYPT1. Consistently, 14-3-3β overexpression increased myosin II phosphorylation in cells. We found that MYPT1 phosphorylation at Ser472 was critical for the binding to 14-3-3. Epidermal growth factor (EGF) stimulation increased both Ser472 phosphorylation and the binding of MYPT1-14-3-3. Rho-kinase inhibitor inhibited the EGF-induced Ser472 phosphorylation and the binding of MYPT1-14-3-3. Rho-kinase specific siRNA also decreased EGF-induced Ser472 phosphorylation correlated with the decrease in MLC phosphorylation. The present study revealed a new RhoA/Rho-kinase–dependent regulatory mechanism of myosin II phosphorylation by 14-3-3 that dissociates MLCP from myosin II and attenuates MLCP activity.

Hypotensive and Regional Haemodynamic Effects of Exercise, Fasted and after Food, in Human Sympathetic Denervation

1998 ◽  
Vol 94 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Sharmini Puvi-Rajasingham ◽  
Gareth D. P. Smith ◽  
Adeola Akinola ◽  
Christopher J. Mathias
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Superior Mesenteric Artery ◽  
Vascular Resistance ◽  
Mesenteric Artery ◽  
Autonomic Failure ◽  
Sympathetic Denervation ◽  
Stroke Distance

1. In human sympathetic denervation due to primary autonomic failure, food and exercise in combination may produce a cumulative blood pressure lowering effect due to simultaneous splanchnic and skeletal muscle dilatation unopposed by corrective cardiovascular reflexes. We studied 12 patients with autonomic failure during and after 9 min of supine exercise, when fasted and after a liquid meal. Standing blood pressure was also measured before and after exercise. 2. When fasted, blood pressure fell during exercise from 162 ± 7/92 ± 4 to 129 ± 9/70 ± 5 mmHg (mean arterial pressure by 22 ± 5%), P < 0.0005. After the meal, blood pressure fell from 159 ± 8/88 ± 6 to 129 ± 6/70 ± 4 mmHg (mean arterial pressure by 22 ± 3%), P < 0.0001, and further during exercise to 123 ± 6/61 ± 3 mmHg (mean arterial pressure by 9 ± 3%), P < 0.01. The stroke distance—heart rate product, an index of cardiac output, did not change after the meal. During exercise, changes in the stroke distance—heart rate product were greater when fasted. 3. Resting forearm and calf vascular resistance were higher when fasted. Calf vascular resistance fell further after exercise when fasted. Resting superior mesenteric artery vascular resistance was lower when fed; 0.19 ± 0.02 compared with 032 ± 0.06, P < 0.05. After exercise, superior mesenteric artery vascular resistance had risen by 82%, to 0.53 ± 0.12, P < 0.05 (fasted) and by 47%, to 0.29 ± 0.05, P < 0.05 (fed). 4. On standing, absolute levels of blood pressure were higher when fasted [83 ± 7/52 ± 7 compared with 71 ± 2/41 ± 3 (fed), each P < 0.05]. Subjects were more symptomatic on standing post-exercise when fed. 5. In human sympathetic denervation, exercise in the fed state lowered blood pressure further than when fasted and worsened symptoms of postural hypotension.

scholarly journals Influence of long-term treatment with glyceryl trinitrate on remote ischemic conditioning

2018 ◽  
Vol 315 (1) ◽  
pp. H150-H158 ◽  
Author(s):  
Marie Hauerslev ◽  
Sivagowry Rasalingam Mørk ◽  
Kasper Pryds ◽  
Hussain Contractor ◽  
Jan Hansen ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Glyceryl Trinitrate ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rat Myocardium ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Human Endothelium

Remote ischemic conditioning (RIC) protects against sustained myocardial ischemia. Because of overlapping mechanisms, this protection may be altered by glyceryl trinitrate (GTN), which is commonly used in the treatment of patients with chronic ischemic heart disease. We investigated whether long-term GTN treatment modifies the protection by RIC in the rat myocardium and human endothelium. We studied infarct size (IS) in rat hearts subjected to global ischemia-reperfusion (I/R) in vitro and endothelial function in healthy volunteers subjected to I/R of the upper arm. In addition to allocated treatment, rats were coadministered with reactive oxygen species (ROS) or nitric oxide (NO) scavengers. Rats and humans were randomized to 1) control, 2) RIC, 3) GTN, and 4) GTN + RIC. In protocols 3 and 4, rats and humans underwent long-term GTN treatment for 7 consecutive days, applied subcutaneously or 2 h daily transdermally. In rats, RIC and long-term GTN treatment reduced mean IS (18 ± 12%, P = 0.007 and 15 ± 5%, P = 0.002) compared with control (35 ± 13%). RIC and long-term GTN treatment in combination did not reduce IS (29 ± 12%, P = 0.55 vs. control). ROS and NO scavengers both attenuated IS reduction by RIC and long-term GTN treatment. In humans, I/R reduced endothelial function ( P = 0.01 vs. baseline). Separately, RIC and long-term GTN prevented the reduction in endothelial function caused by I/R; given in combination, prevention was lost. RIC and long-term GTN treatment both protect against rat myocardial and human endothelial I/R injury through ROS and NO-dependent mechanisms. However, when given in combination, RIC and long-term GTN treatment fail to confer protection. NEW & NOTEWORTHY Remote ischemic conditioning (RIC) and long-term glyceryl trinitrate (GTN) treatment protect against ischemia-reperfusion injury in both human endothelium and rat myocardium. However, combined application of RIC and long-term GTN treatment abolishes the individual protective effects of RIC and GTN treatment on ischemia-reperfusion injury, suggesting an interaction of clinical importance.

Angiotensin II induces insulin resistance independent of changes in interstitial insulin

1999 ◽  
Vol 277 (5) ◽  
pp. E920-E926 ◽  
Author(s):  
Joyce M. Richey ◽  
Marilyn Ader ◽  
Donna Moore ◽  
Richard N. Bergman
Keyword(s):  
Insulin Resistance ◽  
Heart Rate ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Glucose Uptake ◽  
Peripheral Resistance ◽  
Glucose Turnover ◽  
Ang Ii

We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 ± 16 to 94 ± 14 mmHg, P < 0.001) with a compensatory decrease in heart rate (110 ± 7 vs. 86 ± 4 mmHg, P < 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg ⋅ ml−1⋅ min ( P < 0.05). ANG II infusion increased femoral artery blood flow (176 ± 4 to 187 ± 5 ml/min, P < 0.05) and resulted in additional increases in both plasma and lymph insulin (93 ± 20 to 122 ± 13 μU/ml and 30 ± 4 to 45 ± 8 μU/ml, P < 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 ± 1.2 vs. 5.4 ± 0.7 mg ⋅ kg−1⋅ min−1, P > 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin.

scholarly journals EFFECT OF ORAL MOXONIDINE IN THE ATTENUATION OF THE HAEMODYNAMIC RESPONSES SEEN DURING LAPAROSCOPIC SURGERIES

2017 ◽  
Vol 10 (3) ◽  
pp. 409
Author(s):  
Sidharth Sraban Routray ◽  
Ramakanta Mohanty
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Placebo Group ◽  
Stress Response ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Significant Rise ◽  
Hemodynamic Stability ◽  
Blinded Study ◽  
Double Blinded

ABSTRACTObjective: During laparoscopic surgeries, pneumoperitoneum can lead to various pathophysiologic changes in the cardiovascular system resulting inhypertension and tachycardia. Search for ideal drug to prevent this hemodynamic response goes on. The aim of our study was to evaluate the effect oforally administered moxonidine in attenuating the hemodynamic responses that occur during the laparoscopic surgeries.Methods: A total of 50 adult acetylsalicylic acid I and II patients scheduled for elective laparoscopic surgeries were selected for this prospectiverandomized double-blinded study. They were randomly allocated into two groups: moxonidine group (M) and placebo group (P). M group receivedoral moxonidine 0.3 mg at 8 pm on the day before surgery and at 8 am on the day of surgery. P group received a placebo at the same timing as that ofthe M group.Results: Following pneumoperitoneum rise in systolic blood pressure (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and heart rate (HR)was higher in P group in comparison to M group which was statistically significant.Conclusion: Significant rise in HR, SBP, DBP, and mean BP was noted in the P group in comparison to moxonidine group. Moxonidine provided betterperioperative hemodynamic stability in patients undergoing laparoscopic surgeries.Keywords: Moxonidine, Stress response, Laparoscopic.

scholarly journals Multifractal Analysis of Hemodynamic Behavior

2012 ◽  
Vol 117 (4) ◽  
pp. 810-821 ◽  
Author(s):  
Steven M. Bishop ◽  
Sarah I. Yarham ◽  
Vilas U. Navapurkar ◽  
David K. Menon ◽  
Ari Ercole
Keyword(s):  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
De Novo ◽  
Clinical Importance ◽  
Multifractal Spectrum ◽  
Clinical Problem ◽  
Abdominal Aortic Aneurysm Repair ◽  
Feedback Systems ◽  
Modulus Maxima

Background Physiologic instability is a common clinical problem in the critically ill. Many natural feedback systems are nonlinear, and seemingly random fluctuations may result from the amplification of external perturbations or even arise de novo as a consequence of their underlying dynamics. Characterization of the underlying nonlinear state may be of clinical importance, providing a technique to monitor complex physiology in real-time, guiding patient care and improving outcomes. Methods We employ the wavelet modulus maxima technique to characterize the multifractal properties of heart rate and mean arterial pressure physiology retrospectively for four patients during open abdominal aortic aneurysm repair. We calculated point-estimates for the dominant Hölder exponent (hm, hm) and multifractal spectrum width-at-half-height for both heart rate and mean arterial pressure signals. We investigated how these parameters changed with the administration of an intravenous vasoconstrictor and examined how this varied with atropine pretreatment. Results Hypotensive patients showed lower values of hm, consistent with a more highly fluctuating and complex behavior. Treatment with a vasoconstrictor led to a transient increase in hm, revealing the appearance of longer-range correlations, but did not impact hm. On the other hand, prior treatment with atropine had no effect on hm behavior but did tend to increase hm. Conclusions Hypotension leads to a reduction in dominant Hölder exponents for mean arterial pressure, demonstrating an increasing signal complexity consistent with the activation of important homeokinetic processes. Conversely, pharmacological interventions may also alter the underlying dynamics. Pharmacological restoration of homeostasis leads to system decomplexification, suggesting that homeokinetic mechanisms are derecruited as homeostasis is restored.

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