Radiofrequency Renal Denervation Protects the Ischemic Heart via Inhibition of GRK2 and Increased Nitric Oxide Signaling.

RATIONALE: Catheter-based renal denervation (RDN) is currently under development for the treatment of resistant hypertension and is thought to reduce blood pressure via interruption of sympathetic pathways that modulate cardiovascular function. The sympathetic nervous system also plays a critical role in the pathogenesis of acute myocardial infarction and heart failure. OBJECTIVE: We examined whether treatment with radiofrequency (RF)-RDN would protect the heart against subsequent myocardial ischemia/reperfusion injury via direct effects on the myocardium. METHODS AND RESULTS: Spontaneously hypertensive rats received either bilateral RF-RDN or sham-RDN. At 4 weeks after RF-RDN (n=14) or sham-RDN (n=14) treatment, spontaneously hypertensive rats were subjected to 30 minutes of transient coronary artery occlusion and 24 hours -7 days reperfusion. Four weeks after RF-RDN, myocardial oxidative stress was markedly attenuated, and transcription and translation of antioxidants, superoxide dismutase 1 and glutathione peroxidase-1, were significantly upregulated compared with sham-RDN spontaneously hypertensive rats. RF-RDN also inhibited myocardial G protein-coupled receptor kinase 2 pathological signaling and enhanced myocardial endothelial nitric oxide synthase function and nitric oxide signaling. RF-RDN therapy resulted in a significant reduction in myocardial infarct size per area at risk compared with sham-RDN (26.8 versus 43.9%; P<0.01) at 24 hours postreperfusion and significantly improved left ventricular function at 7 days after myocardial ischemia/reperfusion. CONCLUSIONS: RF-RDN reduced oxidative stress, inhibited G protein-coupled receptor kinase 2 signaling, increased nitric oxide bioavailability, and ameliorated myocardial reperfusion injury in the setting of severe hypertension. These findings provide new insights into the remote cardioprotective effects of RF-RDN acting directly on cardiac myocytes to attenuate cell death and protect against ischemic injury.

The potential of interprofessional education to translate physiology curricula effectively into future team-based healthcare.

Incorporating active interprofessional education (IPE) opportunities into the classroom setting is a potentially effective mechanism to enhance student learning both in the basic sciences and for future interprofessional collaboration. We integrated an IPE exercise into a graduate-level human physiology course at our health sciences center that enrolled physician assistant (PA), physical therapy (PT), and graduate studies students. Our activity adopted and targeted the four Interprofessional Education Collaborative (IPEC) competency domains of values/ethics (VE), roles/responsibilities, interprofessional communication, and teams and teamwork (TT). Effectiveness of the training exercise was determined via pre- and postsurveys, which assessed student self-perceptions of IPEC competency domains, as well as student reflections and evaluations of the exercise itself. We noted a significant improvement in each of the targeted IPEC subcompetencies among all of the students, and within both PT and PA groups when analyzed separately. Moreover, a positive correlation was found between the number of previous IPE experiences and presurvey IPEC VE and TT subcompetency ratings. Our discoveries provide an example of broad acquisition of IPE learning within the context of a physiology curriculum. Perhaps more importantly, our findings indicate that a history of IPE training sets the stage for future IPE learning, reflecting a potential for IPE to transform basic physiological principles into team-based practice and improvement in patient outcomes.

Mode of ethanol administration influences the severity of hemorrhage-induced lactic acidemia in conscious guinea pigs.

Mechanisms that limit metabolic acidemia during shock are limited by ethanol (EtOH). This may be due to (1) loss of respiratory compensation, (2) a greater fall in cardiac output, (3) altered removal of plasma lactate by the liver, and (4) alterations in central nervous system orchestration of compensatory responses. We have previously shown that loss of metabolic compensation during hemorrhage is correlated with plasma EtOH concentrations. The present study determines if the mode of ethanol administration influences compensation during hemorrhage. Male guinea pigs were administered EtOH (1 g/kg, 30% wt/vol) via intraperitoneal (IP) or intragastric (IG) routes. After 30 minutes, 60% of the estimated blood volume was removed. Animals remained in shock for 30 minutes were resuscitated with lactated Ringer solution and monitored for 3 hours. Plasma EtOH levels were similar in the 2 groups at the initiation of, and during, hemorrhage and resuscitation. Animals given EtOH IP exhibited more severe acidemia. The mode of EtOH administration may affect hepatic ethanol and lactate metabolism, thus exacerbating acidemia. An altered central nervous system response may impact compensatory responses during shock. Our results indicate that the "history" of the EtOH episode may be an important determinant in the compensation for hemorrhage and resuscitation.

Integrating an Interprofessional Education Experience Into a Human Physiology Course.

PURPOSE: To obtain physician assistant (PA) student perceptions about an interprofessional education (IPE) training experience embedded in a multidisciplinary science course. METHODS: An IPE training experience was integrated into a graduate human physiology course offered to PA, physical therapy, and graduate studies students. The focus of the activity related to the Interprofessional Education Collaborative (IPEC) competency domains of (1) roles and responsibilities and (2) teams and teamwork. Effectiveness was assessed in pretraining and posttraining surveys, which included questions addressing student self-perceptions of IPEC competency domains, student assessment of the learning activity, and student reflection. RESULTS: We observed a statistically significant positive change in PA student perceptions of IPEC competency domains. Students also provided a positive evaluation of the IPE activity and communicated personal improvements in IPE perspectives. CONCLUSIONS: Incorporating planned IPE experiences into multidisciplinary health science courses represents an appropriate venue for PA students to learn and apply interprofessional competencies, which may benefit future interprofessional practice.

Sepsis-induced myocardial dysfunction and myocardial protection from ischemia/reperfusion injury.

Sepsis, bacteremia and inflammation cause myocardial depression. The mechanism of the dysfunction is not clearly established partly because dysfunction can be elicited by many different mechanisms which can all manifest in disruption of myocardial mechanical function. In addition the models of sepsis and bacteremia and inflammation may vary drastically in the sequence of the coordinated immune response to the inflammatory or septic stimulus. Patterns of cytokine expression can vary as can other responses of the immune system. Patterns of neurohumoral activation in response to the stress of sepsis or bacteremia or inflammation can also vary in both magnitude of response and temporal sequence of response. Stress induced activation of the sympathetic nervous system and humoral responses to stress have a wide range of intensity that can be elicited. The fairly uniform response of the myocardium indicating cardiac dysfunction is surprisingly constant. Systolic performance, as measured by stroke volume or cardiac output and pressure work as estimated by ventricular pressure, are impaired when myocardial contraction is compromised. At times, diastolic function, assessed by ventricular relaxation and filling, is impaired. In addition to the dysfunction that occurs, there is a longer term response of the myocardium to sepsis, and this response is similar to that which is elicited in the heart by multiple brief ischemia/reperfusion episodes and by numerous pharmacological agents as well as heat stress and modified forms of lipopolysaccharide. The myocardium develops protection after an initial stress such that during a second stress, the myocardium does not exhibit as much damage as does a non-protected heart. Many agents can induce this protection which has been termed preconditioning. Both early preconditioning (protection that is measurable min to hours after the initial stimulus) and late preconditioning (protection that is measurable hours to days after the initial trigger or stimulus) are effective in protecting the heart from prolonged ischemia and reperfusion injury. Understanding the mechanisms of sepsis/bacteremia induced dysfunction and protection and if the dysfunction and protection are the products of the same intracellular pathways is important in protecting the heart from failing to perform adequately during severe sepsis and/or septic shock and for understanding the multitude of mechanism by which the myocardium maintains reserve capacity.

Ethanol intoxication and lactated Ringer's resuscitation prolong hemorrhage-induced lactic acidosis.

Ethanol (EtOH) blunts the respiratory and metabolic compensation during hemorrhage, resulting in a more severe lactic acidemia. We hypothesized that lactated Ringer's (LR) resuscitation may exacerbate this lactic acidemia. Male guinea pigs were implanted with arterial and venous catheters. Two days after catheter placement, conscious animals were injected intraperitoneally with 1 g/kg EtOH, 0.3 g/kg EtOH, or an equal volume of water 30 min before hemorrhage (60% of estimated blood volume). After 30 min of hemorrhagic shock, animals were resuscitated with isotonic saline (S) or LR at 1 mL/min (three times shed blood volume). Mean arterial blood pressure (MABP) was not affected by pretreatment with either dose of EtOH, but was significantly decreased by hemorrhage in all groups. Both S and LR resuscitation slightly increased MABP, but neither restored it to prehemorrhage values. Blood lactate levels increased in all groups during hemorrhage and remained elevated for 3 h in animals pretreated with 1 g/kg EtOH. In the group pretreated with 0.3 g/kg EtOH, pH decreased during shock but returned to prehemorrhage levels during the resuscitation period. Resuscitation with S returned pH to prehemorrhage values in animals pretreated with 1.0 g/kg EtOH. Resuscitation with LR did not exacerbate, but did prolong, the lactic acidemia after shock in animals pretreated with 1.0 g/kg EtOH. Administration of additional lactate during intoxication and hypovolemia for hemodynamic stabilization before blood transfusion may exacerbate a metabolic stress.

Antioxidant nutrients and alcohol.

Alcohol is a constituent of the diet that is generally taken in on a voluntary basis. The amount and type of alcohol consumed along with the frequency of alcohol consumption can vary tremendously and can have divergent effects on an organism. Animal models have been developed to investigate the mechanisms by which both acute alcohol administration and chronic alcohol consumption affect the various organ systems of the body. The deleterious effects of alcohol, at least partly involve alcohol induced oxidative injury that has been documented by measurement of oxidant radicals, alterations in oxidant/antioxidant balance and oxidant induced changes in cellular proteins and lipids. In addition, evidence for alcohol-induced oxidant injury comes from studies in which pretreatment with antioxidants such as vitamin E, vitamin C, and agents that enhance antioxidant capacity attenuate alcohol induced effects. The susceptibility of tissues to alcohol-induced injury is related to their function and the method by which they are exposed to alcohol. For example, the stomach and liver are exposed to the highest concentrations upon ingestion and absorption of alcohol. The liver is also the major organ for metabolism, and with chronic alcohol use, P450 2E1 is induced. This enzyme activity however, adds additional oxidative stress to the liver. Although antioxidants can attenuate alcohol-induced injury, there is no one antioxidant that protects all organs during all modes of exposure. In addition, more studies are needed to determine if administration of antioxidants after alcohol exposure can reverse alcohol induce tissue damage. This review will summarize results from experiments in which alcohol has been delivered for a short time (acute) or prolonged period (chronic); in vivo or in vitro; at physiologic doses or at supraphysiologic doses. The effects of alcohol on various tissues will be presented and finally, the contribution of oxidant injury to alcohol induced tissue damage will be discussed.

Effects of the HIV-1 protein Tat on myocardial function and response to endotoxin.

HIV-1 infection has been associated with cardiomyopathy in a subset of patients. In order to determine whether HIV-1 alters myocardial function or the myocardial response to stress, transgenic mice that express the HIV-1 protein Tat were used. Heart function was assessed using the isolated working heart preparation. Response to infection was assessed by measuring heart function at various times after endotoxin administration. Since cytokines are implicated in myocardial dysfunction, plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) and myocardial mRNA and protein levels of TNF-alpha and IL-6 were determined. Tat by itself did not cause myocardial dysfunction; however, 4 h after endotoxin, myocardial function was more severely compromised in the Tat mice than in control mice. Plasma TNF-alpha levels were elevated at 2 h and higher in the control group but myocardial levels were similar in the two groups. Plasma IL-6 was increased but myocardial levels were different only at 24 h at which time myocardial function was no longer depressed. Tat expression, by itself, did not impair intrinsic myocardial function but did increase myocardial injury induced by endotoxin. Although cytokines are associated with dysfunction, TNF-alpha and IL-6 were probably not responsible for the exaggerated dysfunction in Tat mice receiving endotoxin.

Alcohol does not modulate the augmented acetylcholine-induced vasodilatory response in hemorrhaged rodents.

Our previous studies have shown that acute alcohol intoxication (AAI) decreases blood pressure, exacerbates hypotension after hemorrhagic shock, impairs the pressor response to fluid resuscitation, and blunts neuroendocrine activation. We hypothesized that impaired hemodynamic compensation during and after hemorrhagic shock in the acute alcohol-intoxicated host is the result of blunted neuroendocrine activation or, alternatively, of an impaired vascular responsiveness to vasoactive agents. The aim of this study was to examine the effects of AAI, AAI and hemorrhagic shock, and AAI and hemorrhagic shock and resuscitation on reactivity of isolated blood vessel rings to phenylephrine and acetylcholine. Chronically instrumented, conscious male Sprague-Dawley rats (300-350 g) received a primed continuous 15-h intragastric alcohol infusion (2.5 g x kg(-1) + 300 mg x kg(-1) x h(-1)), and time-matched controls received an isocaloric-isovolumic dextrose infusion. At completion of infusions, animals were randomized to sham, 60-min fixed-pressure hemorrhage, or hemorrhagic shock followed by resuscitation with lactated Ringer's solution. At the completion of the experimental protocols, animals were killed, and thoracic aorta and mesenteric artery ring segments (1-2 mm) were prepared and studied in myograph baths. Acute alcohol intoxication did not produce significant alterations in either pressor or dilator responses in aortic or mesenteric rings. These findings suggest that impaired hemodynamic counterregulation during hemorrhagic shock in AAI is not due to decreased vasopressor responsiveness. However, our results suggest a role for accentuated vasodilatory responses that may be central in progression to decompensatory shock.

Low-dose ethanol alters the cardiovascular, metabolic, and respiratory compensation for severe blood loss.

BACKGROUND: Compensation for hemorrhage and shock requires coordination of responses and sufficient physiologic reserve capacity of the cardiovascular, respiratory, renal, and neuroendocrine systems. Intake of ethanol (EtOH) is known to degrade physiologic response to stress. The purpose of this study was to investigate how acute EtOH exposure changes responses to severe blood loss, shock, and resuscitation. METHODS: Conscious male Duncan Hartley guinea pigs were given an intraperitoneal injection of either EtOH (1 g/kg) or an equal volume of water 30 minutes before controlled hemorrhage (60% blood volume), resuscitated after 30 minutes of hypovolemia with a lactated Ringer's solution volume equal to that of the shed blood volume, and observed for 24 hours. Hemodynamic (heart rate, arterial blood pressure), clinical laboratory (arterial blood gases, glucose, lactate, hematocrit), and metabolic gas exchange (oxygen consumption, carbon dioxide production) indicators of shock were monitored. RESULTS: Of the animals that survived 24 hours, changes in arterial pH and lactate were significantly greater in the experiment group than in the control group. Mortality at 24 hours was 77% in the experiment group (EtOH-treated) and 42% (p = 0.39) in the control group (water-treated). CONCLUSION: Acute EtOH exposure, with blood EtOH concentration similar to legal intoxication levels, limits physiologic reserve during hemorrhagic shock and resuscitation. In survivors of shock and resuscitation, compensation is compromised and physiologic reserve is adversely affected by acute EtOH intake.