Hypothalamic sites for cardiovascular and sympathetic modulation by prostaglandin E2

Prostaglandin E₂ (PGE₂, 0.5–5 nmol/kg) injected into the lateral cerebral ventricle of the rat increased the systemic blood pressure and heart rate in a dose dependent manner. These effects were accompanied by increases in plasma norepinephrine and epinephrine concentration. Injection of the low dose of prostaglandin E₂ into discrete hypothalamic nuclei induced a marked increase in heart rate, a moderate increase in the arterial blood pressure and a significant elevation of plasma norepinephrine level. This study suggests a possible central role for PGE₂ in modulation of cardiovascular dynamics and sympathetic nervous activity.     

Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project

OBJECTIVES: We sought to examine the independent predictive value of coronary artery calcium detection for coronary outcomes in a non-referred cohort of healthy men and women ages 40 to 50 years. BACKGROUND: Existing studies have suggested that coronary calcium might have incremental predictive value for coronary outcomes above standard coronary risk factors. However, additional data from non-referred and younger populations are needed. METHODS: Participants (n = 2,000; mean age 43 years) were evaluated with measured coronary risk variables and coronary calcium detected with electron beam tomography. Incident acute coronary syndromes and sudden cardiac death were ascertained via annual telephonic contacts, with follow-up (mean, 3.0 +/- 1.4 years; range, 1 to 6 years) in 99.2% of the cohort. RESULTS: Coronary calcium was found in 22.4% of men and 7.9% of women. A total of 9 acute events occurred in men at a mean age of 46 years, including 7 of 364 men with coronary calcium (1.95%) and 2 of 1,263 men without coronary calcium (0.16%; p < 0.0001 by log-rank). No events occurred in women. In these men, coronary calcium was associated with an 11.8-fold increased risk for incident coronary heart disease (CHD) (p = 0.002) in a Cox model controlling for the Framingham risk score. Among those with coronary artery calcification, the risk of coronary events increased incrementally across tertiles of coronary calcium severity (hazard ratio 4.3 per tertile). A family history of premature CHD was also predictive of incident events. The marginal cost effectiveness, assuming a 30% improvement in survival associated with primary prevention among at-risk men, was modeled to be 37,633 dollars per quality-adjusted life year saved. CONCLUSIONS: In young, asymptomatic men, the presence of coronary artery calcification provides substantial, cost-effective, independent prognostic value in predicting incident CHD that is incremental to measured coronary risk factors.     

Cannabinoid CB1 receptor-mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex

1. The present study investigated the binding characteristics of various ligands to cannabinoid CB(1) receptors in human neocortex and amygdala. In addition, the functionality of CB(1) receptors in the human neocortex was assessed by examining the effects of CB(1) receptor ligands on evoked [(3)H]-dopamine (DA) release in superfused brain slices and on synaptosomal cAMP accumulation. 2. Saturation-binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([(3)H]-CP55.940) revealed pK(d) values of 8.96 and 8.63, respectively. The numbers of binding sites (B(max)) were 3.99 and 2.67 pmol (mg protein)(-1), respectively. 3. Various cannabinoid receptor ligands inhibited [(3)H]-CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. 4. Electrically evoked [(3)H]-DA release from human neocortical slices was inhibited by CP55.940 (IC(50) 6.76 nm, I(max) 65%) and strongly enhanced by the cannabinoid receptor antagonist AM251. However, [(3)H]-DA release was not influenced in rat neocortex. In human tissue, the estimated endocannabinoid concentration in the biophase of the release-modulating CB(1) receptors was 1.07 nm, expressed in CP55.940 units. 5. K(+)-evoked [(3)H]-DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. 6. In human tissue, CP55.940 inhibited forskolin-stimulated cAMP accumulation (IC(50) 20.89 nm, I(max) 35%). AM251 blocked this effect and per se increased forskolin-stimulated cAMP accumulation by approximately 20%. 7. In conclusion, cannabinoids modulate [(3)H]-DA release and adenylyl cyclase activity in the human neocortex. CB(1) receptors are located on dopaminergic nerve terminals and seem to be tonically activated by endocannabinoids.     

Input resistance is voltage dependent due to activation of Ih channels in rat CA1 pyramidal cells

The contribution of the hyperpolarization-activated cation current (I(h)) to input resistance (R(N)) and resting potential (RP) was investigated during whole-cell patch-clamp recordings in CA1 pyramidal cells of rat hippocampal slices. In current-clamp mode, R(N) was determined at different membrane potentials. R(N) decreased with increasing hyperpolarization, from about 260 Momega to 140 Momega at potentials of about -60 mV and -110 mV, respectively. Both the potential of half-maximal reduction of R(N) and the potential of half-maximal I(h) activation (determined in voltage-clamp mode) were approximately -90 mV. The analysis of the voltage sag indicative of I(h) activation revealed a preferential activity of I(h) channels in a voltage range between -70 and -95 mV. ZD7288 (50 microM), a specific I(h) blocker, led to a hyperpolarization by about 4.8 mV, increased R(N) by approximately 45% within a potential range between -65 and -80 mV, and abolished the voltage dependence of R(N). Gabapentin (GBP, 100 microM), an I(h) channel agonist, led to a depolarization by about 2.4 mV and reduced R(N) by about 20% within a potential range between -65 and -80 mV. In conclusion, our data show that R(N) is voltage dependent due to I(h) channel activation and that I(h) channels are preferentially active at voltages between -70 and -95 mV. Furthermore, we demonstrated that R(N) can be modulated by antiepileptic drugs such as GBP, which may partly explain its antiepileptic effect as due to decreasing the sensitivity to excitatory input.     

Measurement properties of the calendar of premenstrual experience in patients with premenstrual syndrome

OBJECTIVE: To assess the reliability and factor structure of the Calendar of Premenstrual Experiences (COPE) in premenstrual syndrome (PMS) patients. STUDY DESIGN: Healthy women diagnosed with PMS (N = 215) completed daily diaries assessing 22 PMS behavioral and physical symptoms over two consecutive months. RESULTS: Internal consistency (alpha) was high (.93-.94) for the COPE total score and behavioral subscale score and moderately high (.79) for the physical subscale score. Test-retest correlations produced lower estimates of reliability (.55-.59). Four factors, accounting for 64% of the total variance, were extracted: mood symptoms, somatic/cognitive symptoms, appetitive symptoms and fluid retention symptoms. Symptom reports increased in consecutive luteal phases for three of the four factors; however, the factor structure remained consistent in consecutive months. CONCLUSION: The COPE diary is a reliable instrument for identifying fluctuations in behavioral and physical symptoms during the luteal phase, and PMS symptoms can be reliably conceptualized within four factors. Symptom expression may increase in response to daily self-monitoring.     

The prevalence and severity of coronary artery calcification on coronary artery computed tomography in black and white subjects

OBJECTIVES: We studied the relationship between coronary artery calcium (CAC) and race in asymptomatic, active-duty personnel in the Prospective Army Coronary Calcium (PACC) project. BACKGROUND: Valid cardiovascular risk assessments in black Americans using coronary artery computed tomography (coronary CT) require the generalizability of population-based CAC score distributions derived from primarily white patient populations. METHODS: Among 1,000 consecutive participants (mean age, 42 +/- 2 years; range, 40 to 45 years), 999 participants underwent coronary CT and indicated a specific racial affiliation. This included white, non-Hispanic in 699 (69.9%) participants and black, non-Hispanic in 194 (19.4%) participants. Univariate associations between race and cardiovascular risk variables were entered into a logistic regression model for CAC that also controlled for socioeconomic status and education. RESULTS: Coronary artery calcium was nearly twice as prevalent in white (19.2%) than in black participants (10.3%) (p = 0.004). Black individuals had a threefold greater prevalence of hypertension, left ventricular hypertrophy, ST-T-wave abnormalities, and current cigarette smoking. Black subjects also had significantly greater blood pressure, high-density lipoprotein cholesterol, glycosylated hemoglobin, lipoprotein(a) and fibrinogen levels, and lower triglyceride levels and waist girth than white subjects. After adjustment for these differences, and socioeconomic adjusters, black individuals were 39% as likely to have any CAC present (odds ratio, 0.39; 95% confidence interval, 0.20 to 0.78; p = 0.007). CONCLUSIONS: Despite a worse cardiovascular risk profile, black Americans have significantly less CAC than white Americans. The use of coronary CT as an accurate risk prediction tool in black Americans will require ethnic-specific data on the presence and severity of CAC.     

Repetitive short-term bile duct obstruction and relief causes reproducible and reversible bile acid regurgitation

BACKGROUND: Long-term bile duct obstruction causes sinusoidal regurgitation of bile acids, a shift in bile acid metabolism, and alterations of liver histology. In this study we investigated the regurgitation of bile acids during short-term bile duct obstruction and its reversibility and reproducibility. In addition, the biotransformation of taurodeoxycholate and its appearance in bile and perfusate effluent were studied as well as liver histology. METHODS: Rat livers (n = 5) were perfused in vitro with 32 nmol/min/g liver taurodeoxycholate over 85 min with the bile duct being intermittently closed for 30 and 20 min, respectively. RESULTS: Within the first 5 min after bile duct obstruction bile acids started to regurgitate to the perfusate effluent amounting to approximately 15% of hepatic uptake until the end of the perfusion period. After relief of obstruction, bile flow and biliary bile acid excretion showed an overshoot phenomenon and were almost doubled compared to preobstruction. In contrast, sinusoidal bile acid regurgitation declined. The same phenomenon was observed during the second closure/opening cycle of the bile duct. Regurgitated bile acids consisted of significantly more taurodeoxycholate metabolites (approximately 70%) than did biliary bile acids (approximately 30%). Histology of liver parenchyma was preserved. CONCLUSIONS: During repetitive short-term bile duct obstruction bile acid regurgitation is reversible and reproducible. The absence of altered mechanical barriers suggests that specific pathways are involved in the regurgitation process of bile acids.