The importance of optimal medical therapy in patients undergoing lower extremity bypass.

PURPOSE OF REVIEW: The prevalence of peripheral artery disease is growing, with millions of people globally suffering its end-stage manifestation, chronic limb-threatening ischemia (CLTI). Revascularization procedures like lower extremity bypass play a vital role in limb salvage but optimal medical therapy is essential for maximizing the benefit of these procedures and reducing long-term risks of cardiovascular and limb-related events. RECENT FINDINGS: Patients with PAD who undergo lower extremity bypass warrant a comprehensive approach to risk factor modification for both primary and secondary prevention of cardiovascular and limb-related complications. This includes appropriate use of high-intensity statins, smoking cessation, and management of hypertension and diabetes. Additionally, antiplatelet therapy is indicated for all patients with CLTI and additional treatment with low-dose anticoagulation may also be beneficial. SUMMARY: Optimal medical therapy is essential for optimizing outcomes in patients with PAD undergoing lower extremity bypass.

Vascular Anastomoses and Dissection: A Six-Part Simulation Curriculum for Surgical Residents.

Introduction: As surgical technologies grow, so too do demands on surgical trainees to master increasing numbers of skill sets. With the rise of endovascular surgery, trainees have fewer opportunities to practice open vascular techniques in the operating room. Simulation can bridge this gap. However, existing published open vascular simulation curricula are basic or based on expensive models. Methods: We iteratively developed an open vascular skills curriculum for second-year surgery residents comprising six 2-hour sessions. We refined the curriculum based on feedback from learners and faculty. The curriculum required skilled facilitators, vascular instruments, and tissue models. We evaluated the latest iteration with a survey and by assessing participants' technical skills using the Objective Structured Assessment of Technical Skills (OSATS) form. Results: Over the past 10 years, 101 residents have participated in the curriculum. Nine of 13 residents who participated in the latest curricular iteration completed the survey. All respondents rated the sessions as excellent and strongly agreed that they had improved their abilities to perform anastomoses with tissue and prosthetic. Facilitators completed 18 OSATS forms for residents in the fifth and sixth sessions of the latest iteration. Residents scored well overall, with a median 26.5 (interquartile range: 24-29) out of a possible score of 35, with highest scores on knowledge of instruments. Discussion: This simulation-based curriculum facilitates open vascular surgical skill acquisition among surgery residents. The curriculum allows residents to acquire critical vascular skills that are challenging to learn in an increasingly demanding operative setting.

The Utility of Prevena Negative Pressure Wound Therapy on Groin Incisions for Critical Limb-Threatening Ischemia: A Single Institution Experience.

BACKGROUND: Incisional negative pressure wound therapy (iNPWT) is an adjunctive treatment that uses constant negative pressure suction to facilitate healing. The utility of this treatment modality on vascular operations for critical limb-threatening ischemia (CLTI) has yet to be elucidated. This study compares the incidence of postoperative wound complications between the Prevena Incision Management System, a type of iNPWT, and standard wound dressings for vascular patients who also underwent plastic surgery closure of groin incisions for CLTI. METHOD: We performed a retrospective cohort study of 40 patients with CLTI who underwent 53 open vascular surgeries with subsequent sartorius muscle flap closure. Patient demographics, intraoperative details, and wound complications were measured from 2015 to 2018 at the University of California San Francisco. Two cohorts were generated based on the modality of postoperative wound management and compared on wound healing outcomes. RESULTS: Of the 53 groin incisions, 29 were managed with standard dressings, and 24 received iNPWT. Patient demographics, comorbidities, and operative characteristics were similar between the 2 groups. Patients who received iNPWT had a significantly lower rate of infection (8.33% vs 31.0%, P = 0.04) and dehiscence (0% vs 41.3%, P < 0.01). Furthermore, the iNPWT group had a significantly lower rate of reoperation (0% vs 17.2%, P = 0.03) for wound complications within 30 days compared with the control group and a moderately reduced rate of readmission (4.17% vs 20.7%, P = 0.08). CONCLUSIONS: Rates of infection, reoperation, and dehiscence were significantly reduced in patients whose groin incisions were managed with iNPWT compared with standard wound care. Readmission rates were also decreased, but this difference was not statistically significant. Our results suggest that implementing iNPWT for the management of groin incisions, particularly in patients undergoing vascular operations for CLTI, may significantly improve clinical outcomes.

Case planning and execution of inframalleolar bypass for chronic limb-threatening ischemia.

Chronic limb-threatening ischemia is challenging to treat because of the complex patient population, heterogeneity of limb presentations, and complicated arterial pathology. To meet this challenge, vascular surgeons need a broad range of skills to appropriately tailor interventions to each patient's specific needs. One tool in the armamentarium for patients with extensive arterial occlusive disease below the knee is an inframalleolar bypass. However, these procedures require a systematic approach to surgical planning and a high degree of technical competence. We describe our approach to inframalleolar bypass for limb preservation in suitable patients with advanced tibial artery disease.

Defining sources and ramifications of mistreatment among female vascular surgery trainees.

OBJECTIVE: Mistreatment among vascular surgery trainees is a known risk factor for physician burnout. This study aims to characterize forms of and identify sources of mistreatment. METHODS: This is a cross-sectional study of United States vascular surgery trainees who voluntarily participated in an anonymous survey administered after the 2021 Vascular Surgery In-Training Examination. The primary outcome measures were self-reported mistreatment and sources of mistreatment between genders. Logistic regression was used for multivariable analysis. RESULTS: Representing all 125 vascular surgery training programs, 510 trainees (66.9% male) participated in the survey (83.6% response rate). Mistreatment was reported by 54.8% of trainees, with twice as many women reporting as men (82.3% vs 41.0%; P < .001). Women reported higher rates of being shouted at (44.1% vs 21.1%; P < .001); repeatedly reminded of errors (24.3% vs 16.1%; P = .04); ignored/treated hostilely (28.9% vs 10.5%; P < .001); subjected to crude/sexually demeaning remarks, stories, jokes (19.2% vs 2.1%; P < .001); evaluated by different standards (29.3% vs 2.1%; P < .001); and mistaken for a non-physician (75.2% vs 3.5%; P < .001). Among trainees reporting bullying, attendings were the most common source (68.5%). Patients and their families were the most common source of sexual harassment (66.7%), gender discrimination (90.4%), and racial discrimination (74.4%). Compared with men, women identified more patients and families as the source of bullying (50.0% vs 29.7%; P = .005), gender discrimination (97.2% vs 50.0%; P < .001), and sexual harassment (78.4% vs 27.3%; P = .003). Compared with men, women more frequently felt unprepared to respond to the behavior in the moment (10.4% vs 4.6%; P = .002), did not know how to report mistreatment at their institution (7.6% vs 3.2%; P = .04), and did not believe that their institution would take their mistreatment report seriously (9.0% vs 3.9%; P = .002). On multivariable analysis, female gender was an independent risk factor for both gender discrimination (odds ratio, 56.62; 95% confidence interval, 27.89-115) and sexual harassment (odds ratio, 26.2; 95% confidence interval, 3.34-14.8) when adjusting for children, training year, relationship status, and training program location. CONCLUSIONS: A majority of vascular surgery trainees experience mistreatment during training. Sources and forms of abuse are varied. Understanding the sources of mistreatment is critical to guide intervention strategies such as faculty remediation and/or sanctions; allyship training for staff, residents, and faculty; and institutional procedures for patient-initiated abuse.

Persistent racial discrimination among vascular surgery trainees threatens wellness.

OBJECTIVE: Racial/ethnic discrimination is one form of mistreatment and a known risk factor for physician burnout. In the present study, we aimed to characterize the forms and identify the sources of racial/ethnic discrimination among vascular surgery trainees. METHODS: We performed a cross-sectional study of U.S. vascular surgery trainees who had voluntarily participated in an anonymous survey administered after the 2021 Vascular Surgery In-Training Examination. The primary outcome measures were self-reported mistreatment and sources of mistreatment between race and ethnicity groups. We used χ2 tests and logistic regression for bivariate and multivariable analyses, respectively. RESULTS: Representing all 123 vascular surgery training programs, 510 trainees (66.9% men) participated in the survey (83.6% response rate). Most of the trainees had self-identified as White (53.1%), followed by Asian (24.4%), Hispanic/Latinx (7.6%), Black (4.2%), and other/prefer not to say (10.8%). No significant differences were found in the self-reported duty hour violations among the groups. Black (56.3%) and Asian (36.3%) trainees reported higher rates of racial/ethnic discrimination compared with the White, Hispanic/Latinx, and other/prefer not to say groups (P < .001). Patients and their families were reported as the most common source (74.7%). Other reported sources of discrimination included nurses or staff (60%), attendings (37.4%), co-residents (31.3%), and administration (16.9%). Regarding specific forms of racial discrimination, Black and Asian trainees reported the highest rates of different standards of evaluation (20% and 5.9%, respectively), being mistaken for a nonphysician (50.0% and 5.9%, respectively), slurs and/or hurtful comments (13.3% and 5.9%, respectively), social isolation (13.0% and 1.0%, respectively), and being mistaken for another trainee of the same race/ethnicity (60.0% and 33.7%, respectively). Only 62.5% of Black trainees reported their program/institution would take their mistreatment report seriously compared with the White (88.9%), Hispanic/Latinx (88.2%), Asian (83.2%), and other/prefer not to say (71.4%) trainees (P = .01). On multivariable analysis, female gender (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.44-4.33), Asian race (OR, 6.9; 95% CI, 3.53-13.3), Black race (OR, 13.6; 95% CI, 4.25-43.4), and training in the Southeastern United States (OR, 3.8; 95% CI, 1.17-12.80) were risk factors for racial/ethnic discrimination. CONCLUSIONS: The results from the survey revealed that racial/ethnic discrimination persists in surgical training programs, with Asian and Black trainees reporting higher rates than other racial and ethnic groups. Overall, patients and family members were the most common source of racial/ethnic discrimination. However, faculty, staff, and co-trainees also contributed to racial/ethnic discrimination. Further interventions that optimize diversity, equity, and inclusion strategies and policies to address all forms of racial/ethnic discrimination with faculty, staff, and patients within the hospital are critically needed.

Open revascularization approach is associated with healing and ambulation after transmetatarsal amputation in patients with chronic limb threatening ischemia.

BACKGROUND: Transmetatarsal amputation (TMA) allows for maintenance of ambulatory function for patients with significant forefoot tissue loss. Effective revascularization is key to optimizing limb salvage for patients with chronic limb threatening ischemia (CLTI). We hypothesized that CLTI patients requiring TMA will have better healing and functional outcomes with open bypass than with endovascular revascularization. METHODS: Consecutive TMAs performed at three affiliated centers between 2008 and 2020 were retrospectively reviewed. The baseline characteristics, including WIfI (wound, ischemia, foot infection) stage, noninvasive vascular studies, healing, and ambulatory outcomes, were collected. Catheter-based angiographic images were evaluated using the GLASS (global limb anatomic staging system). The primary outcomes were TMA healing and community ambulation. The secondary outcomes were TMA that had healed at study end, any ambulatory function postoperatively, major amputation, and mortality. Descriptive statistics and univariate, multivariable, and Kaplan-Meier analyses were performed. RESULTS: A total of 346 TMAs had been performed in 318 patients, 209 of whom had had peripheral artery disease (PAD). The median follow-up was 2.5 years. Patients with PAD had had significantly lower rates of healing compared with those without PAD (64% vs 77%; P = .007). Revascularization was performed in 185 limbs, with 102 treated endovascularly and 83 with open surgery. The patients who had undergone endovascular surgery were significantly less likely to have had the TMA healed at any point (55% vs 76%; P = .003) and less likely to have remained healed at study end (49% vs 66%; P = .02). Patients with GLASS stage 3 anatomy were significantly more likely to have healed after open surgery (75% vs 45%; P = .003). Long-term ambulation data were available for 72% of the revascularized patients. Endovascular surgery was associated with a lower likelihood of community ambulation after TMA (34% vs 57%; P = .002). On multivariable analysis, open surgery was significantly associated with TMA healing (odds ratio, 2.8; P = .007) and ambulation (odds ratio, 2.9; P = .001). CONCLUSIONS: For patients with CLTI and significant tissue loss requiring TMA, an initial open approach to revascularization was associated with improved healing and higher rates of ambulation compared with endovascular interventions. The metabolic requirement for healing of a TMA in patients with CLTI might be better met by open revascularization.

Euglycemic diabetic ketoacidosis following major vascular surgery is a new item on the differential for postoperative acidosis.

New pharmacologic advances in the treatment of diabetes include SGLT-2 inhibitors, which have been demonstrated in randomized-controlled clinical trials to reduce overall and cardiac-specific mortality and slow progression of chronic kidney disease. Euglycemic diabetic ketoacidosis is a rare but life-threatening complication associated with the use of SGLT-2 inhibitors. Here we describe a case of severe euglycemic diabetic ketoacidosis after lower extremity bypass in a patient taking an SGLT-2 inhibitor. Awareness of this potential complication is essential as these novel agents are increasingly used in patients with cardiovascular disease.

11ßHSD2 Efficacy in Preventing Transcriptional Activation of the Mineralocorticoid Receptor by Corticosterone.

Affinity of the mineralocorticoid receptor (MR) is similar for aldosterone and the glucocorticoids (GC) cortisol and corticosterone, which circulate at concentrations far exceeding those of aldosterone. 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) inactivation of GC within the immediate vicinity of the MR is credited with prereceptor specificity for aldosterone in cells coexpressing MR and 11ßHSD2. 11ßHSD2 efficacy is also critical to other recently described 11ßHSD2 substrates. The aim of this work was to address doubts that low levels of expression of 11ßHSD2 in aldosterone target tissues suffice to prevent the initiation of gene transcription by the MR activated by physiological concentrations of corticosterone. Cell models stably expressing an MR/Gaussia luciferase reporter and various levels of constitutive or induced 11ßHSD2 at concentrations lower than those in rat kidney homogenates and microsomes were produced. Aldosterone and corticosterone were equipotent transactivators of the MR reporter gene in cells without 11ßHSD2. Rate of conversion of tritiated corticosterone to 11-dehydrocorticosterone increased and corticosterone-induced nuclear translocation of MR decreased, as 11ßHSD2 expression increased. The 50% maximal MR activation for the reporter gene stimulation by corticosterone rose with increasing 11ßHSD2 expression, shifting the steroid dose-response curve for corticosterone-induced MR transactivation to the right. Several stable cell lines expressing an easily and reproducibly measured MR reporter system and consistent incremental amounts of 11ßHSD2 protein were produced and used to document that 11ßHSD2 within low physiological levels inactivates relevant concentrations of GC and decreases MR transactivation by GC in a dose-dependent fashion, laying to rest doubts of the efficacy of this enzyme.

A Critical Analysis of Prosthetic Augmentation of Autologous Microvascular Breast Reconstruction.

INTRODUCTION: The combined approach using both an implant and autologous tissue for breast reconstruction has become more common over the last 10 years. We sought to provide a systematic review and outcomes analysis of this technique. METHODS: We searched PubMed and the Cochrane Library database to identify studies that described implant augmentation of autologous flaps for breast reconstruction. The references of selected articles were also reviewed to identify any additional pertinent articles. RESULTS: We identified 11 articles, which included 230 patients and 378 flaps. Implants used ranged in size from 90 to 510 cc, with an average size of 198 cc. Implants were more frequently placed at the time of autologous reconstruction and in the subpectoral plane. There were no total flap losses, and partial flap loss occurred in 3 patients (1%). There were no cases of venous or arterial thrombosis and no early return to the operating room for flap compromise. Eight implants (2%) were lost because of infection or extrusion, and capsular contracture occurred in 9 breasts (3%). When stratified by the timing of implant placement (immediate vs delayed), there were no significant differences in any postoperative outcomes except the immediate group had a higher infection rate. CONCLUSIONS: The criteria for women to be candidates for autologous tissue breast reconstruction can be expanded by adding an implant underneath the flap. We found the overall flap loss rate is comparable with standard autologous flap reconstruction, and the implant loss rate is lower than that in patients who undergo prosthetic reconstruction alone.

Prepectoral Breast Reconstruction in the Setting of Postmastectomy Radiation Therapy: An Assessment of Clinical Outcomes and Benefits.

BACKGROUND: Prepectoral breast reconstruction following mastectomy has become a more widely performed technique in recent years because of its numerous benefits for women. These include full pectoralis muscle preservation, reduced loss of strength, reduced pain, and elimination of animation deformity. As with any breast reconstruction technique, widespread adoption is dependent on a low morbidity profile in the setting of postmastectomy radiation therapy, as this adjuvant therapy is routine in breast cancer treatment. The authors assess the clinical outcomes of patients undergoing postmastectomy radiation therapy following prepectoral breast reconstruction, and compare these to outcomes of patients undergoing postmastectomy radiation therapy with submuscular reconstruction. METHODS: A single surgeon's experience with immediate prepectoral breast reconstruction, followed by postmastectomy radiation therapy, from 2015 to 2017 was reviewed. Patient demographics and incidence of complications during the tissue expander stage were assessed. In addition, the morbidity profile of these patients was compared to that of patients undergoing submuscular/dual-plane reconstruction and postmastectomy radiation therapy over the same period. RESULTS: Over 3 years, 175 breasts underwent immediate prepectoral reconstruction, and 236 breasts underwent immediate submuscular/dual-plane reconstruction. Overall rates of adjuvant radiation therapy (postmastectomy radiation therapy) were similar between prepectoral [26 breasts (14.9 percent)] and submuscular [31 breasts (13.1 percent)] (p = 0.6180) reconstruction. There were no significant differences in complication rates between the two reconstructive cohorts, in the setting of postmastectomy radiation therapy, including rates of explantation (15.4 percent versus 19.3 percent; p = 0.695). CONCLUSIONS: Prepectoral breast reconstruction is a safe and effective option in the setting of postmastectomy radiation therapy. The morbidity profile is similar to that encountered with submuscular reconstruction in this setting. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers.

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC0-t , Cmax and t1/2 of aripiprazole were higher and clearance of aripiprazole, AUC0-t of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC0-t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC0-t of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC0-t (p = 0.039) and Cmax of dehydro-aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC0-t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which a significant proportion of patients do not respond to treatment. The objective of this study was to examine the role of genetic risk variants in the response to treatment with methylphenidate (MPH). The effectiveness of MPH was evaluated based on variations in the CGI-S and CGAS scales over a 12-month treatment period using linear mixed effects models. A total of 208 ADHD patients and 34 polymorphisms were included in the analysis. For both scales, the response was associated with time, extended-release MPH/both formulations, and previous MPH treatment. For the CGI-S scale, response was associated with SLC6A3 rs2550948, DRD4 promoter duplication, SNAP25 rs3746544, and ADGRL3 rs1868790. Interactions between the response over time and SLC6A3 and DRD2 were found in the CGI-S and CGAS scales, respectively. The proportion of the variance explained by the models was 18% for the CGI-S and 22% for the CGAS. In this long-term study, the effects of SLC6A3, DRD4, SNAP25, and ADGRL3 on response to treatment reflect those observed in previous studies. In addition, 2 previously unreported interactions with response to treatment over a 12-month period were found (SLC6A3 and DRD2).

Attention deficit hyperactivity disorder: genetic association study in a cohort of Spanish children.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) has a strong genetic component. The study is aimed to test the association of 34 polymorphisms with ADHD symptomatology considering the role of clinical subtypes and sex in a Spanish population. METHODS: A cohort of ADHD 290 patients and 340 controls aged 6-18 years were included in a case-control study, stratified by sex and ADHD subtype. Multivariate logistic regression was used to detect the combined effects of multiple variants. RESULTS: After correcting for multiple testing, we found several significant associations between the polymorphisms and ADHD (p value corrected ≤0.05): (1) SLC6A4 and LPHN3 were associated in the total population; (2) SLC6A2, SLC6A3, SLC6A4 and LPHN3 were associated in the combined subtype; and (3) LPHN3 was associated in the male sample. Multivariable logistic regression was used to estimate the influence of these variables for the total sample, combined and inattentive subtype, female and male sample, revealing that these factors contributed to 8.5, 14.6, 2.6, 16.5 and 8.5 % of the variance respectively. CONCLUSIONS: We report evidence of the genetic contribution of common variants to the ADHD phenotype in four genes, with the LPHN3 gene playing a particularly important role. Future studies should investigate the contribution of genetic variants to the risk of ADHD considering their role in specific sex or subtype, as doing so may produce more predictable and robust models.

The ubiquitous mineralocorticoid receptor: clinical implications.

Mineralocorticoid receptors (MR) exist in many tissues, in which they mediate diverse functions crucial to normal physiology, including tissue repair and electrolyte and fluid homeostasis. However, inappropriate activation of MR within these tissues, and especially in the brain, causes hypertension and pathological vascular, cardiac, and renal remodeling. MR binds aldosterone, cortisol and corticosterone with equal affinity. In aldosterone-target cells, co-expression with the 11ß-hydroxysteroid dehydrogenase 2 (HSD2) allows aldosterone specifically to activate MR. Aldosterone levels are excessive in primary aldosteronism, but in conditions with increased oxidative stress, like CHF, obesity and diabetes, MR may also be inappropriately activated by glucocorticoids. Unlike thiazide diuretics, MR antagonists are diuretics that do not cause insulin resistance. Addition of MR antagonists to standard treatment for hypertension and cardiac or renal disease decreases end-organ pathology and sympathetic nerve activation (SNA), and increases quality of life indices.

Aldosterone synthesis in the brain contributes to Dahl salt-sensitive rat hypertension.

The enzymes required for aldosterone synthesis from cholesterol are expressed in rat and human brains. The hypertension of Dahl salt-sensitive (SS) rats is mitigated by the intracerebroventricular (i.c.v.) infusion of antagonists of the mineralocorticoid receptor (MR) and downstream effectors of mineralocorticoid action, as well as ablations of brain areas that also abrogate mineralocorticoid-salt excess hypertension in normotensive rats. We used real time RT-PCR to measure mRNA of aldosterone synthase and 11beta-hydroxylase, the requisite enzymes for the last step in the synthesis of aldosterone and corticosterone, respectively, MR and the determinants of MR ligand specificity, 11beta-hydroxysteroid dehydrogenase types 1 and 2 (11beta-HSD1&2) and hexose-6-phosphate dehydrogenase (H6PDH). A combination of extraction and ELISA was used to measure aldosterone concentrations in tissue and urine of SS and Sprague-Dawley (SD) rats. Aldosterone synthase mRNA expression was higher in the brains and lower in the adrenal glands of SS compared with SD rats. The amounts of mRNA for MR, 11beta-hydroxylase, 11beta-HSD1&2 and H6PD were similar. Aldosterone concentrations were greater in brains of SS than SD rats, yet, in keeping with the literature, the circulating and total aldosterone production of aldosterone in SS rats were not. The selective inhibitor of aldosterone synthase, FAD286, was infused i.c.v. or subcutaneously in a cross-over blood pressure study in hypertensive SS rats further challenged by a high-salt diet. The i.c.v. infusion of FAD286, at a dose that had no effect systemically, significantly and reversibly lowered blood pressure in SS rats. Aldosterone synthesis in brains of SS rats is greater than in SD rats and is important in the genesis of their salt-sensitive hypertension.