Outcomes of left main revascularization in patients with acute coronary syndromes and stable ischemic heart disease: Analysis from the EXCEL trial.

BACKGROUND: Prompt revascularization is often required in acute coronary syndromes (ACS), whereas stable ischemic heart disease (SIHD) may allow for more measured procedural planning. Whether the acuity of presentation preferentially affects outcomes after coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in patients with left main coronary artery disease (LMCAD) is unknown. We investigated whether the acuity of presentation discriminated patients who derived a differential benefit from PCI versus CABG in the randomized Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial. METHODS: We used multivariable Cox models to assess the interaction between the acuity of presentation, type of revascularization and outcomes in patients with low or intermediate SYNTAX scores enrolled in EXCEL. RESULTS: At baseline, 1151 patients (60.7%) presented with SIHD and 746 patients (39.3%) presented with an ACS. The acuity of presentation was not associated with the primary endpoint of all-cause death, MI, or stroke at 3 years (multivariable adjusted hazard ratio [HR] 0.94; 95% CI 0.70-1.26, P = .64). The primary endpoint rate was similar in patients assigned to PCI versus CABG whether they presented with SIHD (adjusted HR 1.04; 95% CI 0.73-1.48]) or with ACS (HR 0.82; 95% CI 0.54-1.26) (Pinteraction = .34). CONCLUSIONS: The acuity of presentation did not predict outcomes in patients with LMCAD undergoing revascularization, nor did it discriminate patients who derive greater event-free survival from PCI versus CABG.

Efficacy of a device to narrow the coronary sinus in refractory angina.

BACKGROUND: Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium. METHODS: We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months. RESULTS: A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction. CONCLUSIONS: In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).

The wise radialist's guide to optimal transfemoral access: Selection, performance, and troubleshooting.

Transradial access (TRA) has reduced vascular access-site complication (VASC) and bleeding rates in patients undergoing coronary angiography and intervention. A "radial-first" approach should be adopted and indications of TRA extended in order to maximize its beneficial effect. However, in certain clinical scenarios, transfemoral access (TFA) is a preferable or a mandatory route to successfully perform the procedure. Since the widespread adoption of TRA, a paradoxical increase in VASC rates has been observed in patients undergoing TFA, which might be attributed to a combination of increased risk profile of both the procedures and the patients, and a loss of skills in securing TFA by those who are now default radial operators. In the present article we provide recommendations on how to optimize patient selection for TRA and TFA, how to manage access site crossover, and how to perform state-of-the-art femoral artery puncture. © 2016 Wiley Periodicals, Inc.

Glucocorticoid-induced hyperglycemia is prevalent and unpredictable for patients undergoing cancer therapy: an observational cohort study.

BACKGROUND: Patients with cancer are often treated with glucocorticoids (gcs) as part of therapy, which may cause hyperglycemia. We sought to define the prevalence of, and risk factors for, hyperglycemia in this setting. METHODS: Adult patients taking gc as part of therapy protocols for primary brain tumour or metastasis, for lymphoma, or for bone marrow transplant (bmt) were screened with random glucometer measurements taken at least 3 hours after the last dose gcs. RESULTS: We screened 90 patients [44.4% women, 55.6% men; mean age: 59.6 years (range: 25-82 years); mean body mass index (bmi): 26.4 kg/m(2) (range: 15.8-45.3 kg/m(2))] receiving gc as part of cancer treatment. Mean total daily gc dose in the group was 238.5 mg (range: 30-1067 mg) hydrocortisone equivalents. Hyperglycemia (glucose ≥ 8.0 mmol/L) was found in 58.9% (53 of 90), and diabetes mellitus (dm)-range hyperglycemia (glucose ≥ 11.1 mmol/L) in 18.9% (17 of 90). The mean time from gc ingestion to glucometer testing was 5.5 hours (range: 3-20 hours). Presence of hyperglycemia did not correlate with traditional dm risk factors such as age, sex, bmi, and personal or family history of dm. A longer interval from gc dose to testing (p < 0.05), a higher gc dose (p = 0.04), and a shorter interval between the preceding meal and testing (p = 0.02) were risk factors for hyperglycemia in some patient groups. CONCLUSIONS: Glucocorticoid-induced hyperglycemia is common in patients undergoing cancer treatment and cannot be predicted by traditional risk factors for dm. We recommend that all cancer patients receiving gc be screened for hyperglycemia at least 4-6 hours after gc administration.

Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions.

OBJECTIVES: This study sought to assess the benefits of a coronary chronic total occlusion CTO recanalization after adjusting for the case-mix and the propensity to undergo the CTO intervention in a population of patients with stable coronary artery disease. BACKGROUND: The benefits of percutaneous recanalization of CTO are disputed. METHODS: In 1,602 patients with a least one CTO and treated by percutaneous coronary intervention (PCI), we derived a propensity score to undergo a CTO recanalization by comparing the characteristics of patients who did (n = 346) and did not (n = 1,256) undergo a CTO PCI attempt. Among the patients who underwent a CTO PCI attempt, we identified the angiographic predictors of failure. The primary analysis was ultimately performed by looking at the association between the outcome of the CTO recanalization and the survival free of death and cardiovascular rehospitalizations. Sensitivity analyses were performed by adjusting for the propensity to undergo a CTO recanalization, for the anatomical predictors of failure, and for the extent of coronary artery revascularization achieved. RESULTS: A successful CTO recanalization was not significantly associated with survival free of death and cardiovascular rehospitalization (HR = 0.90, 95% CI 0.64-1.25). Even more conservative hazards ratio point estimates were obtained with the sensitivity analyses. CONCLUSIONS: Successful percutaneous CTO recanalization is not associated with survival free of death and cardiovascular hospitalizations in a contemporary population of patients with symptomatic coronary artery disease.

Poor achievement of guidelines-recommended targets in type 2 diabetes: findings from a contemporary prospective cohort study.

AIMS: To prospectively evaluate diabetes management in the primary care setting and explore factors related to guideline-recommended triple target achievement [blood pressure (BP) ≤ 130/80 mmHg, A1C ≤ 7% and low-density lipoprotein (LDL)-cholesterol < 2.5 mmol/l]. METHODS: Baseline, 6 and 12 month data on clinical and laboratory parameters were measured in 3002 patients with type 2 diabetes enrolled as part of a prospective quality enhancement research initiative in Canada. A generalised estimating equation model was fitted to assess variables associated with triple target achievement. RESULTS: At baseline, 54%, 53% and 64% of patients, respectively, had BP, A1C and LDL-cholesterol at target; all three goals were met by 19% of patients. The percentage of individuals achieving these targets significantly increased during the study [60%, 57%, 76% and 26%, respectively, at the final visit, p < 0.0001 except for A1C, p = 0.27]. A much smaller proportion of patients had adequate control during the entire study period [30%, 39%, 53% and 7%, respectively]. In multivariable analysis, women, patients younger than 65 years and patients of Afro-Canadian origin were less likely to achieve the triple target. DISCUSSION: As part of a quality enhancement research initiative, we observed important improvements in the attainment of guidelines-recommended targets in patients with type 2 diabetes followed for a 12-month period in the primary care setting; however, many individuals still failed to achieve and especially maintain optimal goals for therapy, particularly the triple target. Results of the multivariable analysis reinforce the need to address barriers to improve diabetes care, particularly in more susceptible groups.

Rubidium-82 Positron Emission Tomography With Intravenous Ergonovine to Diagnose Vasospastic Angina.

The gold standard to diagnose vasospastic angina is intracoronary reactivity testing, which is performed selectively at dedicated centres. Noninvasive imaging with single-photon emission computerized tomography (SPECT) or echocardiography does not enable accurate localization of spasm or quantification of change in myocardial perfusion in response to an abnormal vasoreactivity. Rubidium-82 positron emission tomography myocardial perfusion imaging (82Rb PET-MPI) with intravenous ergonovine was used to diagnose refractory vasospastic angina in a patient with a complex ischemic syndrome, recent coronary stenting, and persistent atypical angina despite maximal tolerable doses of guideline-directed medical therapy.

Differential modulation of polyunsaturated fatty acids in patients with myocardial infarction treated with ticagrelor or clopidogrel.

Untargeted metabolomics is used to refine the development of biomarkers for the diagnosis of cardiovascular disease. Myocardial infarction (MI) has major individual and societal consequences for patients, who remain at high risk of secondary events, despite advances in pharmacological therapy. To monitor their differential response to treatment, we performed untargeted plasma metabolomics on 175 patients from the platelet inhibition and patient outcomes (PLATO) trial treated with ticagrelor and clopidogrel, two common P2Y12 inhibitors. We identified a signature that discriminates patients, which involves polyunsaturated fatty acids (PUFAs) and particularly the omega-3 fatty acids docosahexaenoate and eicosapentaenoate. The known cardiovascular benefits of PUFAs could contribute to the efficacy of ticagrelor. Our work, beyond pointing out the high relevance of untargeted metabolomics in evaluating response to treatment, establishes PUFA metabolism as a pathway of clinical interest in the recovery path from MI.

KiSS-1 mRNA in adipose tissue is regulated by sex hormones and food intake.

Hypothalamic KiSS-1 gene expression is critical for the maintenance of reproductive function, and levels are attenuated by sex hormones and by food restriction, providing a link between fat mass and fertility. We hypothesized that adipose tissue (FAT) would express KiSS-1. KiSS-1 mRNA was quantified in FAT, hypothalamus (HYP) and pituitary gland (PIT) using realtime RT-PCR. FAT KiSS-1 expression was sensitive to sex steroids and to nutritional status. Gonadectomized rats given estradiol (E; females) or testosterone (T; males) revealed striking increases in KiSS-1 mRNA in FAT (E: 8-fold, p<0.01; T: 5-fold, p<0.01). In contrast, HYP KiSS-1 expression was reduced by E/T, whereas PIT expression was reduced by gonadectomy only in females, reversed by E. Food restriction (18 h) increased FAT KiSS-1 mRNA in both sexes (2.5-4.0-fold, p<0.01), but decreased levels in male PIT and female HYP. Conversely, FAT expression was reduced in rats fed a high fat diet (HFD), as well as in obese Zucker rats, whereas PIT expression was increased in Zucker rats (p<0.05) but not by HFD. In contrast HYP KiSS-1 mRNA was elevated by HFD. Experiments in which the arcuate nucleus was damaged by an excitotoxic lesion revealed that hypothalamic KiSS-1 mRNA was significantly reduced, whereas FAT levels were unaffected, suggesting that regulation of KiSS-1 in FAT is independent of the hypothalamus. In conclusion, KiSS-1 expression is differentially regulated by sex hormones, food intake and obesity in FAT, HYP and PIT. Kisspeptins of adipose tissue origin may act as adipokines or as local regulators of adipocyte function.

Surgery Versus Transcatheter Interventions for Significant Paravalvular Prosthetic Leaks.

OBJECTIVES: This study sought to assess the relative merit of surgical correction (SC) versus transcatheter reduction on long-term outcomes in patients with significant paravalvular leak (PVL) refractory to medical therapy. BACKGROUND: PVL is the most frequent dysfunction following prosthetic valve replacement. Although repeat surgery is the gold standard, transcatheter reduction (TR) of PVL has been associated with reduced mortality. METHODS: From 1994 to 2014, 231 patients underwent SC (n = 151) or TR (n = 80) PVL correction. Propensity matching and Cox proportional hazards regression models were used to assess the effect of either intervention on long-term rates of all-cause death or hospitalization for heart failure. Survival after TR and SC were further compared with the survival in a matched general population and to matched patients undergoing their first surgical valve replacement. RESULTS: Over a median follow-up of 3.5 years, SC was associated with an important reduction in all-cause death or hospitalization for heart failure compared with TR (hazard ratio: 0.28; 95% confidence interval: 0.18 to 0.44; p < 0.001). There was a trend towards reduced all-cause death following SC versus TR (hazard ratio: 0.61; 95% confidence interval: 0.37 to 1.02; p = 0.06). Neither intervention normalized survival when compared with a general population or patients undergoing their first surgical valve replacement. CONCLUSIONS: In patients with significant prosthetic PVL, surgery is associated with better long-term outcomes compared with transcatheter intervention, but results in important perioperative mortality and morbidity. Future studies are needed in the face of increasing implementation of transcatheter PVL interventions across the world.

Narrowing of the Coronary Sinus: A Device-Based Therapy for Persistent Angina Pectoris.

Alongside the remarkable advances in medical and invasive therapies for the treatment of ischemic heart disease, an increasing number of patients with advanced coronary artery disease unsuitable for revascularization continue to suffer from angina pectoris despite optimal medical therapy. Patients with chronic angina have poor quality of life and increased levels of anxiety and depression. A considerable number of innovative therapeutic modalities for the treatment of chronic angina have been investigated over the years; however, none of these therapeutic options has become a standard of care, and none are widely utilized. Current treatment options for refractory angina focus on medical therapy and secondary risk factor modification. Interventions to create increased pressure in the coronary sinus may alleviate myocardial ischemia by forcing redistribution of coronary blood flow from the less ischemic subepicardium to the more ischemic subendocardium, thus relieving symptoms of ischemia. Percutaneous, transvenous implantation of a balloon expandable, hourglass-shaped, stainless steel mesh in the coronary sinus to create a fixed focal narrowing and to increase backwards pressure, may serve as a new device-based therapy destined for the treatment of refractory angina pectoris.

Transcatheter reduction of paravalvular leaks: a systematic review and meta-analysis.

BACKGROUND: Significant paravalvular leak (PVL) after surgical valve replacement can result in intractable congestive heart failure and hemolytic anemia. Because repeat surgery is performed in only few patients, transcatheter reduction of PVL is emerging as an alternative option, but its safety and efficacy remain uncertain. In this study we sought to assess whether a successful transcatheter PVL reduction is associated with an improvement in clinical outcomes. METHODS: We identified 12 clinical studies that compared successful and failed transcatheter PVL reductions in a total of 362 patients. A Bayesian hierarchical meta-analysis was performed using cardiac mortality as a primary end point. The combined occurrence of improvement in New York Heart Association functional class or hemolytic anemia and the need for repeat surgery, were used as secondary end points. RESULTS: A successful transcatheter PVL reduction was associated with a lower cardiac mortality rate (odds ratio [OR], 0.08; 95% credible interval [CrI], 0.01-0.90) and with a superior improvement in functional class or hemolytic anemia, compared with a failed intervention (OR, 9.95; 95% CrI, 2.10-66.73). Fewer repeat surgeries were also observed after successful procedures (OR, 0.08; 95% CrI, 0.01-0.40). CONCLUSIONS: A successful transcatheter PVL reduction is associated with reduced all-cause mortality and improved functional class in patients deemed unsuitable for surgical correction.

The Benefits Conferred by Radial Access for Cardiac Catheterization Are Offset by a Paradoxical Increase in the Rate of Vascular Access Site Complications With Femoral Access: The Campeau Radial Paradox.

OBJECTIVES: The purpose of this study was to assess whether the benefits conferred by radial access (RA) at an individual level are offset by a proportionally greater incidence of vascular access site complications (VASC) at a population level when femoral access (FA) is performed. BACKGROUND: The recent widespread adoption of RA for cardiac catheterization has been associated with increased rates of VASCs when FA is attempted. METHODS: Logistic regression was used to calculate the adjusted VASC rate in a contemporary cohort of consecutive patients (2006 to 2008) where both RA and FA were used, and compared it with the adjusted VASC rate observed in a historical control cohort (1996 to 1998) where only FA was used. We calculated the adjusted attributable risk to estimate the proportion of VASC attributable to the introduction of RA in FA patients of the contemporary cohort. RESULTS: A total of 17,059 patients were included. At a population level, the VASC rate was higher in the overall contemporary cohort compared with the historical cohort (adjusted rates: 2.91% vs. 1.98%; odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.17 to 1.89; p = 0.001). In the contemporary cohort, RA patients experienced fewer VASC than FA patients (adjusted rates: 1.44% vs. 4.19%; OR: 0.33, 95% CI: 0.23 to 0.48; p < 0.001). We observed a higher VASC rate in FA patients in the contemporary cohort compared with the historical cohort (adjusted rates: 4.19% vs. 1.98%; OR: 2.16, 95% CI: 1.67 to 2.81; p < 0.001). This finding was consistent for both diagnostic and therapeutic catheterizations separately. The proportion of VASCs attributable to RA in the contemporary FA patients was estimated at 52.7%. CONCLUSIONS: In a contemporary population where both RA and FA were used, the safety benefit associated with RA is offset by a paradoxical increase in VASCs among FA patients. The existence of this radial paradox should be taken into consideration, especially among trainees and default radial operators.

Importance of angina in patients with coronary disease, heart failure, and left ventricular systolic dysfunction: insights from STICH.

BACKGROUND: Patients with left ventricular (LV) systolic dysfunction, coronary artery disease (CAD), and angina are often thought to have a worse prognosis and a greater prognostic benefit from coronary artery bypass graft (CABG) surgery than those without angina. OBJECTIVES: This study investigated: 1) whether angina was associated with a worse prognosis; 2) whether angina identified patients who had a greater survival benefit from CABG; and 3) whether CABG improved angina in patients with LV systolic dysfunction and CAD. METHODS: We performed an analysis of the STICH (Surgical Treatment for Ischemic Heart Failure) trial, in which 1,212 patients with an ejection fraction ≤35% and CAD were randomized to CABG or medical therapy. Multivariable Cox and logistic models were used to assess long-term clinical outcomes. RESULTS: At baseline, 770 patients (64%) reported angina. Among patients assigned to medical therapy, all-cause mortality was similar in patients with and without angina (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 0.79 to 1.38). The effect of CABG was similar whether the patient had angina (HR: 0.89; 95% CI: 0.71 to 1.13) or not (HR: 0.68; 95% CI: 0.50 to 0.94; p interaction = 0.14). Patients assigned to CABG were more likely to report improvement in angina than those assigned to medical therapy alone (odds ratio: 0.70; 95% CI: 0.55 to 0.90; p < 0.01). CONCLUSIONS: Angina does not predict all-cause mortality in medically treated patients with LV systolic dysfunction and CAD, nor does it identify patients who have a greater survival benefit from CABG. However, CABG does improve angina to a greater extent than medical therapy alone. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595).

Leptin gene expression in the brain and pituitary gland.

The adipocyte-derived hormone, leptin, and its receptor, are now known to be integral components of a physiological signalling system that regulates fuel stores and energy balance. Constitutive leptin expression has been demonstrated only in adipose tissue, placenta and stomach. We have used RT-PCR to show that leptin mRNA is selectively transcribed in specific areas of rat brain and pituitary, and in a rat glioblastoma cell line. Using immunocytochemistry we have also shown leptin protein immunoreactivity in the corresponding tissues and cells, and confirmed this by Western blot using two epitope-specific antisera. Leptin mRNA expression in the hypothalamus is suppressed by fasting (48hr), suggesting a role for brain leptin in the central regulation of appetite. These data support the hypothesis that central nervous system derived leptin is a likely ligand for central leptin receptors.

Association of human corticotropin-releasing hormone to its binding protein in blood may trigger clearance of the complex.

Late in the last trimester of human pregnancy, as plasma CRH levels rise, the concentration of circulating CRH-binding protein (CRH-BP) falls. We have investigated, using nonpregnant subjects, the hypothesis that CRH has a negative effect on plasma levels of CRH-BP. A specific RIA developed with the aid of recombinant binding protein has been used to measure CRH-BP. Subjects given iv infusions of human CRH for 10 h showed a sustained fall in plasma CRH-BP for the duration of the infusion. Intravenous bolus injection of human CRH produced a rapid reduction in CRH-BP levels to 54% of the basal value, whereas ovine CRH was without effect, even though both peptides are cleared from the plasma at similar rates and have similar effects on the pituitary-adrenal axis. The rapid clearance was concluded to be related to ligand affinity, as ovine CRH has a 200-fold lower affinity than human CRH for CRH-BP. We suggest that the rising levels of CRH are responsible for the reduction in CRH-BP concentrations observed in late pregnancy, and that this reduction is triggered by the binding of CRH-BP to its ligand.

The effects of spiradoline (U-62066E), a kappa-opioid receptor agonist, on neuroendocrine function in man.

1. Opioid drugs act on specific receptors which are principally classified into mu, delta and kappa subtypes. Spiradoline (U-62066E) is a kappa-selective agent which has been shown to possess potent anti-nociceptive effects but does not show cross tolerance with morphine. 2. We have assessed the neuroendocrine effects of spiradoline in healthy volunteers with two doses (1.6 and 4.0 micrograms kg-1, i.m.) of the compound. Six male non-smokers aged 19-27 years were studied by use of a randomized, double-blind three-limb placebo-controlled cross-over design. Blood was taken from an in-dwelling venous cannula basally and at 15 min intervals for 2 h for determination of serum cortisol, prolactin, growth hormone (GH) and catecholamines. 3. Psychological function was assessed by the Stanford Sleepiness Scale (SSS) and the Addiction Research Centre Inventory (ARCI) administered before the medication and at 35 min, 1 h 25 min and 2 h afterwards. Cardiovascular variables were recorded at 10 min intervals. Results were analysed by analysis of variance. 4. Spiradoline showed a significant (P < 0.05) dose-dependent increase in free water clearance, as predicted for a kappa-opioid agonist. It also caused a dose-dependent stimulation of prolactin, (increment over baseline for higher dose 214%), GH (433%) and cortisol (215%) release (P < 0.05). There were no significant drug-related changes in plasma catecholamines, blood pressure, pulse or psychological variables. 5. We have therefore confirmed that kappa-opioids increase free-water clearance and may participate in the stimulation of prolactin and GH release. In contrast to mu and delta-opioid agonists, this novel kappa-agonist stimulates cortisol release in man.

Atrial natriuretic peptide in physiological doses does not inhibit the ACTH or cortisol response to corticotrophin-releasing hormone-41 in normal human subjects.

Whilst it has been postulated that atrial natriuretic peptide (ANP) may modulate pituitary hormone release, several investigations in non-human species have reported conflicting results when looking for an effect on the hypothalamo-pituitary-adrenal axis. However, in a recent study significant inhibition of corticotrophin-releasing hormone (CRH)-stimulated ACTH in cultured rat anterior pituitary cells occurred only with the complete peptide alpha-ANP(1-28). We have therefore investigated whether this form of ANP can inhibit CRH-stimulated ACTH and cortisol release in human subjects. Six healthy male volunteers received human alpha-ANP or placebo, and human CRH or placebo, on four separate occasions. ANP was infused at a rate of 0.01 micrograms/kg per min in order to achieve levels in the high physiological range. CRH was given as a bolus dose of 100 micrograms 30 min into the ANP infusion. Cortisol and ANP were measured by radioimmunoassay, the latter after extraction. ACTH was measured by immunoradiometric assay. The data were analysed by Student's paired t-test on basal, peak and incremental levels. Basal levels of ANP were within the normal range (2-5 pmol/l). With ANP infusion, mean +/- S.E.M. peak ANP levels were 29.6 +/- 3.1 pmol/l. There were no significant differences in mean basal cortisol and ACTH levels on each of the 4 study days. Mean peak cortisol and ACTH levels after CRH and ANP did not significantly differ from those achieved with CRH and placebo ANP. We thus conclude that at high physiological doses, circulating ANP does not inhibit CRH-stimulated ACTH or cortisol release.

Developmental regulation of leptin gene expression in rat brain and pituitary.

We have previously reported the expression of leptin mRNA and protein in adult rat brain and pituitary gland. We report here the presence of leptin and leptin receptor mRNA in neonatal female rat brain and pituitary using RT-PCR as well as leptin and leptin receptor immunoreactivity in neonatal rat brain. In addition, we describe age-related changes in leptin mRNA expression in female rat brain and pituitary from postnatal day 2 to 28, evaluated using semi-quantitative RT-PCR analysis. Age-related differences in leptin (ob) mRNA levels were tissue-dependent. The most striking developmental changes were noted in the pituitary and cerebral cortex. In the pituitary, ob mRNA levels were maximal during postnatal days 7-14 and fell sharply by postnatal day 22. In cortex, ob mRNA levels were low in neonatal pups (day 2-7) but increased significantly between postnatal days 14 and 28. Leptin mRNA was detectable at postnatal day 2 in hypothalamus and subcutaneous fat. No significant differences in the level of expression were observed between postnatal day 2 and 28. Serum leptin levels were highest at day 7-14 and decreased significantly by day 21-28, coincident with the fall in pituitary leptin expression. The high levels of leptin expression in the neonatal pituitary suggest that this gland may contribute to the circulating leptin levels during early postnatal development, when adipose deposits are minimal. These data indicate that regulation of leptin gene expression in the postnatal period is tissue-dependent, a finding, which suggests that local leptin expression may have important functional significance in the development of the brain-pituitary system.