Search

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments. [ABSTRACT FROM AUTHOR]

Objectives: Sexualized Drug Use (SDU) consists of using any drug purposely before or during sex with the intent of modifying sex experiences. SDU is especially practiced among Gay and Bisexual Men who have Sex with Men (GBMSM). This study aims to review the relevant literature to identify and summarize the reasons reported by GBMSM to engage in SDU. Methods: A systematic review of the literature using PubMed/Medline, Scopus, Google Scholar, and PsycINFO, comprising qualitative and quantitative papers published between 2010 and 2022, was conducted with a narrative synthesis of the findings. PRISMA guidelines were followed. Results: Our search identified 1400 publications, of which 23 were included. Reasons to engage in SDU were aggregated as follows: (1) Enhancing sexual sensations and performance, (2) Achieving hedonic mental and emotional states, (3) Tackling negative thoughts and feelings, and (4) Social motivations. Different sample methods and ways of asking for motivations may limit the internal validity of these conclusions. Conclusion: Both individual and social factors are involved in the decision to engage in SDU. SDU practices should not be medicalized, however therapeutic support if needed should provide multidisciplinary, pleasure-centered, harm-reducing care interventions, specifically designed for these minorities of GBMSM. [ABSTRACT FROM AUTHOR]

Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual's lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc ([Pdc.sup.[-/-]] mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from [Pdc.sup.[-/-]] mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, [Pdc.sup.[-/-]] mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene-based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12-15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension., Introduction Hypertension and its cardiovascular consequences contribute to the leading causes of morbidity and mortality worldwide (1). In over 90% of hypertensive patients, the causes of increased blood pressure are [...]

(1) Institute of Experimental and Clinical Pharmacology and Toxicology and Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany. (2) Human and Molecular Genetics Center and (3) Department of Physiology, [...]

Targeted deletion or selective pharmacological inhibition of α2C-adrenoceptors in mice results in increased brain tissue levels of dopamine and its precursor L-3,4-dihydroxyphenylalanine (L-DOPA), without significant changes in L-DOPA synthesis. L-DOPA uptake is considered the rate-limiting step in dopamine synthesis in the kidney. Since α2C-adrenoceptors may influence the transport of L-DOPA, we investigated the effect of α2C-adrenoceptor activation on L-DOPA uptake in a kidney cell line (opossum kidney cells). L-DOPA and dopamine kidney tissue levels in α2C-adrenoceptor knockout (α2CKO) mice and in mice treated with the selective α2C-adrenoceptor antagonist JP-1302 were also evaluated. The α2-adrenoceptor agonist medetomidine (0.1-1,000 nM) produced a concentration-dependent decrease in L-DOPA uptake in opossum kidney cells (IC50: 2.5 ± 0.5 nM and maximal effect: 28 ± 5% of inhibition). This effect was abolished by a preincubation with JP-1302 (300 nM). Furthermore, the effect of medetomidine (100 nM) was abolished by a preincubation with U-0126 (10 ±M), a MEK1/2 inhibitor. Kidney tissue levels of L-DOPA were significantly higher in α2CKO mice compared with wild-type mice (wild-type mice: 58 ± 2 pmol/g tissue and α2CKO mice: 81 ± 15 pmol/g tissue, P < 0.05) and in mice treated with JP-1302 (3 μmol/kg body wt) compared with control mice (control mice: 62 ± 2 pmol/g tissue and JP-1302-treated mice: 75 ± 1 pmol/g tissue, P < 0.05), both without significant changes in dopamine kidney tissue levels. However, mice treated with JP-1302 on a high-salt diet presented significantly higher dopamine levels in the kidney and urine compared with control animals on a high-salt diet. In conclusion, in a kidney cell line, α2C-adrenoceptor activation inhibits L-DOPA uptake, and in mice, deletion or blockade of α2C-adrenoceptors increases L-DOPA kidney tissue levels. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that α2C-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human α2C-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of α2C-gene copy number for feedback control of epinephrine release in gene-targeted mice. Methods: Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/−) or no functional α2C-adrenoceptor gene (α2C−/−). Results: Heterozygous α2C-receptor deletion (α2C+/−) resulted in a 43% reduction of adrenal α2C mRNA copy number and in a similar decrease in α2-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74±15% in α2C+/− and by 142±23% in α2C−/− mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in α2C-adrenoceptor-deficient mice. α2C+/− mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than α2C+/+ mice. Conclusion: Adrenal α2-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, α2C, operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of α2C-adrenoceptor dysfunction in humans. [Copyright &y& Elsevier]

The contribution of neuropeptide Y (NPY), deriving from adrenal medulla, to the adrenosympathetic tone is unknown. We found that in response to NPY, primary cultures of mouse adrenal chromaffin cells secreted catecholamine, and that this effect was abolished in cultures from NPY Y1 receptor knockout mice (Y1-/-). Compared with wild-type mice (Y1+/+), the adrenal content and constitutive release of catecholamine were increased in chromaffin cells from Y1-/- mice. In resting animals, catecholamine plasma concentrations were higher in Y1-/- mice. Comparing the adrenal glands of both genotypes, no differences were observed in the area of the medulla, cortex, and X zone. The high turnover of adrenal catecholamine in Y1-/- mice was explained by the enhancement of tyrosine hydroxylase (TH) activity, although no change in the affinity of the enzyme was observed. The molecular interaction between the Y1 receptor and TH was demonstrated by the fact that NPY markedly inhibited the forskolin-induced luciferin activity in Y1 receptor-expressing SK-N-MC cells transfected with a TH promoter sequence. We propose that NPY controls the release and synthesis of catecholamine from the adrenal medulla and consequently contributes to the sympathoadrenal tone. [ABSTRACT FROM AUTHOR]

D[sub 1]-like dopamine receptor activation and natriuresis by nitrocatechol COMT inhibitors.. Background.: In recent years, several nitrocatechol derivatives (tolcapone, entacapone, and nitecapone) have been developed and found to be highly selective and potent inhibitors of catechol-O-methyltransferase (COMT). More recently, natriuretic properties were described for two of these compounds (entacapone and nitecapone), although this was not accompanied by enhanced urinary excretion of dopamine. We hypothesized that nitrocatechol derivatives stimulate D[sub 1]-like dopamine receptors. Methods.: Adult male Wistar rats were treated with a nitrocatechol COMT inhibitor (entacapone, tolcapone, or nitecapone, 30 mg/kg, orally), and the urinary excretion of dopamine and sodium was quantitated. The interaction of nitrocatechol derivatives with D[sub 1]-like receptors was evaluated by their ability to displace [[sup 3]H]-Sch23390 binding from membranes of rat renal cortex and cAMP production in opossum kidney (OK) cells. Results.: Urinary excretion of sodium (μmol/h) was markedly increased by all three nitrocatechol derivatives: vehicle, 55.0 ± 5.6; entacapone, 98.4 ± 9.3; tolcapone, 97.5 ± 9.3; and nitecapone, 120.5 ± 12.6. Pretreatment with the selective D[sub 1] antagonist Sch 23390 (60 μg/kg) completely prevented their natriuretic effects. Nitecapone and tolcapone were equipotent (IC[sub 50s] of 48 and 42 μmol/L) and more potent than entacapone and dopamine (IC[sub 50s] of 107 and 279 μmol/L) in displacing [[sup 3]H]-Sch23390 binding. In OK cells, all three nitrocatechol derivatives significantly increased cAMP accumulation and reduced Na[sup +]/H[sup +] exchange and Na[sup +],K[sup +]-ATPase activities, this being prevented by a blockade of D[sub 1]-like receptors. Conclusion.: Stimulation of D[sub 1]-like dopamine receptors and inhibition of Na[sup +]/H[sup +] exchange and Na[sup +],K[sup +]-ATPase activities by nitrocate... [ABSTRACT FROM AUTHOR]

Aim: Evaluate the activity of L-aminoacid decarboxylase (AADC), an enzyme involved in monoamine synthesis, and Catechol-O-methyltranferase (COMT), an enzyme involved in monoamine metabolism, in the brain of α2C-adrenoceptor (α2CADR) homozygous knockout (KO) and α2CADR heterozygous knockout (HET) mice. Methods: Brains from α2CKO, α2CHET and wild type (WT) mice (C57BL/6) aged 15 weeks were used. AADC activity was measured using different concentrations of L-DOPA and measuring the production of dopamine (DA). COMT activity was measured using different concentrations of adrenaline and measuring the production of metanepinephrine (MN). The assay of DA and MN was carried out by HPLC-ED. Results are given as arithmetic mean±sem. Statistical analysis was done by ANOVA. Results: AADC activity was significantly higher in the brain of α2CKO and α2CHET compared to WT (Vmax: 40±1, 50±1*, 51±1* in nmol/mgprot/h; Km: 1.6±0.1, 1.9±0.1, 1.8±0.1 in mM; WT, α2CKO and α2CHET respectively, n=4). COMT activity was significantly higher in the brain of α2CKO mice compared to WT and α2CHET (Vmax: 2.0±0.0, 2.2±0.1*, 2.0±0.1 in nmol/mgprot/h; Km: 2.0±0.1, 2.2±0.2, 2.0±0.1 in µM; WT, α2CKO and α2CHET respectively, n=4). (*P<0.05 compared to WT). Conclusion: In mice brain, lack of one copy significantly increases AADC enzyme activity, whereas lack of both copies of the α2CADR gene significantly increases COMT and AADC enzyme activity. [ABSTRACT FROM AUTHOR]