Michael W. Manning

Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E–deficient mice

Increased plasma concentrations of angiotension II (Ang II) have been implicated in atherogenesis. To examine this relationship directly, we infused Ang II or vehicle for 1 month via osmotic minipumps into mature apoE(-/-) mice. These doses of Ang II did not alter arterial blood pressure, body weight, serum cholesterol concentrations, or distribution of lipoprotein cholesterol. However, Ang II infusions promoted an increased severity of aortic atherosclerotic lesions. These Ang II-induced lesions were predominantly lipid-laden macrophages and lymphocytes; moreover, Ang II promoted a marked increase in the number of macrophages present in the adventitial tissue underlying lesions. Unexpectedly, pronounced abdominal aortic aneurysms were present in apoE(-/-) mice infused with Ang II. Sequential sectioning of aneurysmal abdominal aorta revealed two major characteristics: an intact artery that is surrounded by a large remodeled adventitia, and a medial break with pronounced dilation and more modestly remodeled adventitial tissue. Although no atherosclerotic lesions were visible at the medial break point, the presence of hyperlipidemia was required because infusions of Ang II into apoE(+/+) mice failed to generate aneurysms. These results demonstrate that increased plasma concentrations of Ang II have profound and rapid effects on vascular pathology when combined with hyperlipidemia, in the absence of hemodynamic influences.

Differential Effects of Doxycycline, a Broad-Spectrum Matrix Metalloproteinase Inhibitor, on Angiotensin II–Induced Atherosclerosis and Abdominal Aortic Aneurysms

Objective—Angiotensin II (AngII) infusion into hyperlipidemic mice leads to the rapid formation of atherosclerotic lesions and abdominal aortic aneurysms (AAAs). To define the role of matrix metalloproteinases (MMPs) in the development of these vascular pathologies, we administered the broad-spectrum MMP inhibitor doxycycline to saline- and AngII-infused LDL receptor−/− mice. Methods and Results—Mice were placed on a high-fat diet for 1 week before infusion with either saline or AngII (1000 ng · kg−1 · min−1) via osmotic pumps for 28 days. Doxycycline (30 mg · kg−1 · d−1) was administered in the drinking water to both saline- and AngII-infused mice. Administration of doxycycline did not significantly influence systolic blood pressure, serum cholesterol concentrations, or lipoprotein-cholesterol distribution. Doxycycline had no effect on the extent of atherosclerosis in saline- or AngII-infused mice. In contrast, doxycycline markedly reduced the incidence of AAA formation (86% vs 35%, AngII vs AngII+doxycycline, respectively;P <0.05), in addition to reducing aneurysm severity. Conclusions—These data do not imply a role for MMPs in AngII-induced atherosclerosis but provide evidence consistent with a role in AngII-induced AAA formation.

Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis.

We have recently demonstrated that chronic infusion of Angiotensin II into apoE−/− mice promotes the development of abdominal aortic aneurysms. To determine the involvement of specific Angiotensin II receptors in this response, we co‐infused Angiotensin II (1000 ng kg−1 min−1 for 28 days) with losartan (30 mg kg−1 day−1) or PD123319 (3 mg kg−1 day−1) to antagonize AT1 and AT2 receptors, respectively. Infusion of Angiotensin II promoted the development of abdominal aortic aneurysms in 70% of mature female apoE−/− mice. The formation of aortic aneurysms was totally inhibited by co‐infusion of Angiotensin II with losartan (30 mg kg−1 day−1; P=0.003). In contrast, the co‐infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. To determine whether AT2 antagonism also promoted Angiotensin II‐induced atherosclerosis, Angiotensin II was infused into young female apoE−/− mice that had little spontaneous atherosclerosis. In these mice, co‐infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co‐infusion with PD123319. While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II‐induced vascular pathology.

Abdominal aortic aneurysms: fresh insights from a novel animal model of the disease

Abdominal aortic aneurysms (AAA) have a high prevalence in aged populations and are responsible for a large number of deaths. Despite the widespread nature of the disease, relatively little is known regarding mechanisms for formation and progression of aortic aneurysms. In part, this lack of knowledge is attributable to a paucity of animal models for this disease. This review summarizes the available animal models of AAA and focuses on a novel model of reproducible AAA generated by infusion of angiotensin II (AngII) into mice rendered hyperlipidemic by the absence of either apolipoprotein E or low-density lipoprotein receptors. AAA generated by AngII infusion have many characteristics of the human disease including marked luminal expansions, perimedial remodeling, inflammation, thrombosis and a link to hyperlipidemia. As in the human disease, male mice are more susceptible to the development of AAA than females. The vascular pathology occurs from the effects of AngII at AT1 receptors present on bone marrow-derived cells. Studies are ongoing to define the mediators responsible for AngII-induced inflammation and degradation of the medial layer of the vascular wall. The AngII-induced model of AAA has the potential to provide novel insights into the underlying mechanisms of this disease and assist with the development of pharmacological therapies.

Restorative Effects of GDNF on Striatal Dopamine Release in Rats Treated with Neurotoxic Doses of Methamphetamine

Repeated methamphetamine (METH) administration to animals can result in long‐lasting decreases in striatal dopamine (DA) release and content. Glial cell line‐derived neurotrophic factor (GDNF) has pronounced effects on dopaminergic systems in vivo, including neuroprotective effects against METH. The present experiments were designed to examine the ability of GDNF to reverse, or accelerate recovery from, METH‐induced alterations in striatal DA release. Male Fischer‐344 rats were administered METH (5 mg/kg, s.c.) or saline 4 times in one day at 2‐hour intervals. Seven days later the animals were anesthetized and given a single injection of 10 μg GDNF, or vehicle, into the right striatum. Three weeks later microdialysis experiments were carried out in both the right and left striata to examine basal and evoked levels of DA and its metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In animals treated with METH followed by vehicle 7 days later, there were significant reductions in potassium‐ and amphetamine‐evoked overflow of DA, and in basal levels of DOPAC and HVA, compared to control animals. In rats treated with METH followed 7 days later with GDNF, there were significant increases in potassium‐ and amphetamine‐evoked overflow of DA on the right, GDNF‐treated, side of the brain compared to the left side. Basal levels of DOPAC and HVA were also elevated on the GDNF‐treated side of the brain. These results suggest that GDNF can accelerate recovery of dopaminergic release processes in the striatum of rats treated with neurotoxic doses of METH.

Effects of neurotoxic doses of methamphetamine on potassium and amphetamine evoked overflow of dopamine in the striatum of awake rats

The effects of neurotoxic doses of methamphetamine on basal and evoked overflow of dopamine in the striatum were examined in awake rats using microdialysis. Male Fischer-344 rats were administered methamphetamine (5 mg/kg s.c.) or saline four times in 1 day at 2-h intervals. Microdialysis experiments were carried out 1 week later. Basal levels of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were reduced in the striatum of the methamphetamine-treated animals. Local application of excess potassium (100 mM) and amphetamine (100 microM), and intraperitoneal injection of amphetamine (1.5 mg/ kg), led to increased levels of extracellular dopamine in the striatum of both methamphetamine- and saline-treated rats. However, the increase was significantly less in the methamphetamine-treated animals. Tissue levels of dopamine and metabolites were reduced in the striata of rats treated with methamphetamine. These results indicate that treatment with neurotoxic doses of methamphetamine can lead to functional changes in dopamine release in the striatum of Fischer-344 rats.

Augmented methamphetamine-induced overflow of striatal dopamine 1 day after GDNF administration

Glial cell line-derived neurotrophic factor (GDNF) can attenuate the dopamine (DA)-depleting effects of neurotoxic doses of methamphetamine (METH) when given 1 day prior to the METH. The neurotoxic effects of METH may be due, in part, to sustained increases in extracellular levels of DA. It is therefore possible that GDNF may be altering the effects of METH by influencing extracellular levels of DA during the METH treatment. The purpose of the present study was to determine if GDNF has effects on extracellular levels of DA in the striatum by 24-h post-administration. GDNF (10 microgram in 2 microliter vehicle) or vehicle was injected into the right striatum or substantia nigra of anesthetized male rats. The next day the animals were anesthetized again and dialysis probes were positioned in both the right and left striata and perfused with artificial cerebrospinal fluid. Following the collection of baseline samples the rats were administered METH (5 mg/kg, s.c.). The METH injections dramatically increased extracellular DA levels on both sides of the brain. However, levels on the GDNF injected side were significantly greater than levels on the contralateral side. Basal levels of DA were not significantly different between the two sides, but levels of DA metabolites were elevated on the GDNF side. Post-mortem tissue levels of DA metabolites, but not DA, were also elevated in the striatum and substantia nigra. These results indicate that GDNF has significant effects on DA neuron functioning within 24 h of administration and that GDNF can augment DA overflow while inhibiting the neurotoxic effects of METH.

Effect of A1C and Glucose on Postoperative Mortality in Noncardiac and Cardiac Surgeries

OBJECTIVE Hemoglobin A1c (A1C) is used in assessment of patients for elective surgeries because hyperglycemia increases risk of adverse events. However, the interplay of A1C, glucose, and surgical outcomes remains unclarified, with often only two of these three factors considered simultaneously. We assessed the association of preoperative A1C with perioperative glucose control and their relationship with 30-day mortality. RESEARCH DESIGN AND METHODS Retrospective analysis on 431,480 surgeries within the Duke University Health System determined the association of preoperative A1C with perioperative glucose (averaged over the first 3 postoperative days) and 30-day mortality among 6,684 noncardiac and 6,393 cardiac surgeries with A1C and glucose measurements. A generalized additive model was used, enabling nonlinear relationships. RESULTS A1C and glucose were strongly associated. Glucose and mortality were positively associated for noncardiac cases: 1.0% mortality at mean glucose of 100 mg/dL and 1.6% at mean glucose of 200 mg/dL. For cardiac procedures, there was a striking U-shaped relationship between glucose and mortality, ranging from 4.5% at 100 mg/dL to a nadir of 1.5% at 140 mg/dL and rising again to 6.9% at 200 mg/dL. A1C and 30-day mortality were not associated when controlling for glucose in noncardiac or cardiac procedures. CONCLUSIONS Although A1C is positively associated with perioperative glucose, it is not associated with increased 30-day mortality after controlling for glucose. Perioperative glucose predicts 30-day mortality, linearly in noncardiac and nonlinearly in cardiac procedures. This confirms that perioperative glucose control is related to surgical outcomes but that A1C, reflecting antecedent glycemia, is a less useful predictor.

Angiotensin Receptor Blockade Improves Cardiac Surgical Outcomes in Patients With Metabolic Syndrome

BACKGROUND Perioperative use of angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEis) in patients undergoing cardiac operations remains controversial. The current practice of discontinuing renin-angiotensin-system inhibitors preoperatively may negate their beneficial effects in vulnerable populations, including patients with metabolic syndrome, who exhibit elevated renin-angiotensin system activity. We hypothesized that preoperative ARB use is associated with reduced incidence of postoperative complications, compared with ACEi or no drug, in patients with metabolic syndrome undergoing coronary artery bypass grafting. METHODS We used propensity matching to derive a cohort of 1,351 patients from 2,998 who underwent coronary artery bypass grafting based on preoperative use of ARBs, ACEis, or no renin-angiotensin-system inhibitors. Our primary end point was a composite of adverse events occurring within 30 days after the operation: new-onset atrial fibrillation/flutter, arrhythmia requiring cardioversion, perioperative myocardial infarction, acute renal failure, need for dialysis, cerebrovascular accidents, acute respiratory failure, or perioperative death. RESULTS At least one adverse event occurred in 524 (38.8%) of matched cohort patients (1,184 [39.6% of all patients]). Adjusting for European System for Cardiac Operative Risk Evaluation and metabolic syndrome in the matched cohort, preoperative use of ARBs was associated with a lower incidence of adverse events in patients with metabolic syndrome compared with preoperative use of no renin-angiotensin-system inhibitors (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.99) or ACEis (odds ratio, 0.38; 95% confidence interval, 0.16 to 0.88). CONCLUSIONS Preoperative use of ARBs, but not ACEis, confers a benefit within 30 days after cardiac operations in patients with metabolic syndrome, suggesting potential efficacy differences of these drug classes in reducing cardiovascular morbidity and death in ambulatory vs surgical patients.

Enhanced Recovery After Surgery and Multimodal Strategies for Analgesia

Enhanced recovery after surgery is an evidence-based, multimodal approach to the perioperative care of a patient undergoing surgery. These pathways seek to attenuate the stress response to surgery facilitating postoperative recovery. Analgesia is a critical component of these pathways, because optimal pain relief is critical for patients to mobilize quickly after surgery, preventing such complications as infection and thromboembolism. Traditional analgesic regimens for major surgery rely heavily on opioids to provide analgesia but can cause a wide range of serious side effects, delaying recovery. Enhanced recovery protocols should incorporate multimodal analgesic strategies that minimize opioid use and optimize analgesia.