Adrenergic Mechanisms Research Articles

Adrenergic mechanisms do not contribute to age-related decreases in calf venous compliance

Limb venous compliance decreases with advancing age, even in healthy humans. To test the hypothesis that adrenergic mechanisms contribute to age-associated reductions in limb venous compliance, we measured calf venous compliance before and during acute systemic α- and β-adrenergic blockade in eight young (27 ± 1 yr old, mean ± SE) and eight older healthy men (67 ± 2 yr old). Calf venous compliance was determined in supine subjects by inflating a thigh-collecting cuff to 60 mmHg for 8 min and then decreasing it (1 mmHg/s) to 0 mmHg while calf volume was indexed with a strain gauge. The slope (·10⁻³) of the pressure-compliance relation (compliance= β₁ + 2·β₂·cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Δlimb volume) = β₀+ β₁·(cuff pressure) + β₂·(cuff pressure)²] during reductions in cuff pressure, was used to quantify calf venous compliance. Calf venous compliance was ∼30% lower (P < 0.01) in older compared with young men before adrenergic blockade. In response to adrenergic blockade calf venous compliance did not increase in young (-2.62 ± 0.14 and -2.29 ± 0.18 ml·dl⁻¹·mmHg⁻¹, before and during blockade, respectively) or older men (-1.78 ± 0.27 and -1.68 ± 0.21 ml·dl⁻¹ ·mmHg⁻¹). Moreover, during adrenergic blockade differences in calf venous compliance between young and older men observed before adrenergic blockade persisted. Collectively, these data strongly suggest that adrenergic mechanisms neither directly restrain calf venous compliance in young or older men nor do they contribute to age-associated reductions in calf venous compliance in healthy men.

A Preliminary Candidate Genotype–Intermediate Phenotype Study of Satiation and Gastric Motor Function in Obesity

Stomach motility contributes significantly to fullness sensation while eating and cessation of food intake in humans. Genes controlling adrenergic and serotonergic mechanisms (ADRA2A, GNB3, and SLC6A4) affect gastric emptying (GE), volume (GV), and satiation. Fat mass and obesity-associated gene (FTO) is linked with satiety. Our aim was to examine the association of these candidate genes with stomach functions that signal postprandial fullness: GE, GV, and maximum tolerated volume (MTV). These biomarkers constitute a component of the intermediate phenotype of satiation. A total of 62 overweight or obese participants underwent genotyping of the candidate genes, and validated measurements of GE of solids and liquids by scintigraphy, fasting and postprandial change in GV by SPECT (single photon emission computed tomography), and MTV by nutrient drink test. These markers of satiation were compared for 38 genetic variants in ADRA2A, ADR2C, ADRB3, uncoupling protein (UCP)-2 and -3, GNB3, FTO, and SLC6A4 using a recessive model of inheritance. ADRA2A, ADR2C, UCP-3, GNB3, and FTO loci were significantly associated with the intermediate phenotype markers of satiation: ADR2C (Ins-Del322_325) with accelerated GE; GNB3 (rs1047776) with delayed GE; ADRA2A (rs491589 and rs553668) and GNB3 (rs2269355, rs10849527, and rs3759348) with decreased postprandial GV; ADRA2A (rs3750625) and GNB3 (rs4963517 and rs1129649) with increased postprandial GV; UCP-3 (rs1685356) with increased MTV, and FTO (rs9939609) decreased MTV. Genetic susceptibility to postprandial satiation can be identified through intermediate phenotype markers. With independent validation, these markers may guide patient selection of weight-loss therapies directed at gastric motor functions.

Neural control of acetylcholine release by T cells attenuates TNF production in endotoxemia (138.24)

Abstract The cholinergic anti-inflammatory pathway regulates pro-inflammatory cytokine production through vagus nerve signaling via the α7 subunit of the nicotinic acetylcholine receptor expressed on macrophages. Vagus nerve stimulation requires an intact splenic nerve to attenuate TNF production by spleen macrophages. Despite exhaustive search, cholinergic fibers have not been observed in spleen. Here, we used transgenic mice that express enhanced green fluorescent protein (eGFP) under control of transcriptional regulatory elements of choline acetyltransferase, the enzyme that synthesizes acetylcholine. eGFP was detected in spleen B and T cells, some of which were located in close proximity to catecholaminergic nerve endings in the parenchyma of the white pulp. Vagus nerve stimulation significantly increased acetylcholine levels in spleen. In vitro, adrenergic stimulation induced the release of acetylcholine by spleen lymphocytes through a β2 adrenergic receptor dependent mechanism. Vagus nerve stimulation failed to suppress TNF in endotoxemic nude mice, and transfer of CD3+ T cells into nude mice restored vagus nerve control of cytokine production. Together, these data identify T cells as an essential component of the cholinergic anti-inflammatory pathway, and suggest that neural signals increase acetylcholine release from spleen T cells, which in turn attenuates TNF production in spleen via α7 expressed on innate immune cells.

Mechanisms underlying the hypertensive response induced by capsaicin

Acute ingestion of large quantity of chili peppers (rich source of capsaicin) produced hypertensive crisis in a patient. The hypertensive response was explained on the basis of decreased vasodilator substance calcitonin gene-related peptide (CGRP) from sensory nerve terminals by capsaicin. Here we present our experimental observations in anaesthetized rats regarding the mechanisms underlying hypertensive response induced by capsaicin. Our results demonstrate non-involvement of adrenergic and angiotensinergic mechanisms and also the cardiac changes in producing the response. Thus, the direct action of capsaicin on vascular smooth muscle or the activation of endothelin is proposed.

Nervous and humoral catecholaminergic control of blood pressure and cardiac performance in the Antarctic fish Pagothenia borchgrevinki

The role of circulating and neural catecholamines for cardiovascular control in the Antarctic fish Pagothenia borchgrevinki was studied in vivo using pharmacological tools and with immunohistochemistry on isolated tissues. Adrenergic nerve blockade with bretylium decreased dorsal aortic pressure (P(da)) and systemic vascular resistance (R(sys)), while cardiac output (Q) did not change. The blockade of alpha-adrenoceptors with phentolamine reduced P(da) and R(sys) further, revealing that vasomotor tone was influenced by circulating catecholamines in bretylium treated fish. The physiological evidence for an adrenergic nervous control of the vasculature was corroborated by the presence of tyrosine hydroxylase (TH)-immunoreactive fibres associated with blood vessels in spleen, gonads and gastrointestinal tract. TH-immunoreactive fibres were not observed in the atrium and ventricle, but a dense population of TH-immunoreactive fibres was apparent in the bulbus arteriosus. The present study suggests that an adrenergic nervous mechanism is responsible for maintaining vasomotor tone in P. borchgrevinki. While experiments failed to demonstrate a tonic adrenergic nervous influence affecting cardiac performance, an adrenergic nervous control of bulbar compliance may be essential for optimizing gill blood flow dynamics in this species, which has a high relative stroke volume and displays profound changes in stroke volume in vivo.

Post-retrieval disruption of a cocaine conditioned place preference by systemic and intrabasolateral amygdala β2- and α1-adrenergic antagonists

Previous work has demonstrated post-retrieval impairment in associative learning paradigms, including those mediated by drugs of abuse, using nonspecific beta-adrenergic receptor (beta-AR) antagonists. Remarkably little is known about the role of the specific beta-AR subtypes, or other adrenergic receptors, in these effects. The current study examined the effects of beta(1) and beta(2), as well as alpha(1)-adrenergic receptor antagonism following retrieval of a cocaine conditioned place preference (CPP). We found that rats administered the beta(2) antagonist ICI 118,551 (8 mg/kg intraperitoneal [IP]) or the alpha(1) antagonist prazosin (1 mg/kg IP) following a drug-free test for CPP showed attenuated preference during a subsequent test, while the beta(1) antagonist betaxolol (5 or 10 mg/kg IP) and a lower dose of prazosin (0.3 mg/kg IP) had no effect. Furthermore, post-test microinfusion of ICI 118,551 (6 nmol/side) or prazosin (0.5 nmol/side) into the basolateral amygdala (BLA) also impaired a subsequent preference. Systemic or intra-BLA ICI 118,551 or prazosin administered to rats in their home cages, in the absence of a preference test, had no effect on CPP 24 h later. ICI 118,551 also attenuated the FOS response in the BLA induced by the CPP test. These results are the first to demonstrate a role for alpha(1)- and beta(2)-specific adrenergic mechanisms in post-retrieval memory processes. These systemic and site-specific injections, as well as the FOS immunohistochemical analyses, implicate the importance of specific noradrenergic signaling mechanisms within the BLA in post-retrieval plasticity.

Not so free associations

According to PubMed, there have been 62 872 genetic association studies published, about 2 for every gene in the human genome. That assessment is of course incorrect. Both the notorious insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and polymorphisms in the angiotensinogen gene have representative papers numbering in the thousands. However, the adrenergic receptors have not been sleeping in this regard; their polymorphism paper number currently stands at 1334 reports. In this issue of Nephrol Dial Transplant appears the next such paper. Fung et al. [1] reported that adrenergic beta1 receptor (ADB1R) genetic variation predicts the rate of estimated glomerular filtration rate (eGFR) decline in participants of the African American Study of Kidney Disease and Hypertension (AASK) study cohort. The authors obtained a similar result in a second cohort from San Diego, CA, USA, termed the ‘replication’ cohort. Do we now have the genetic basis for the decline in eGFR over time in patients with hypertension-induced kidney damage? AASK was a (US National Institutes of Health sponsored) drug study in black Americans [2]. The study was heroic in that participants underwent a renal biopsy to verify that they indeed had hypertension-associated nephrosclerosis. The study compared two levels of blood pressure reduction and three antihypertensive drug classes and tested the effect on eGFR. Briefly, AASK detected no additional benefit of slowing progression of hypertensive nephrosclerosis with the lower blood pressure goal. The authors stated that ACE inhibitors appeared to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline. However, they also admitted that none of the drug group comparisons showed consistent significant differences in the eGFR slope. Disappointing surely for the participants was the fact that in many AASK patients, eGFR declined relentlessly although they controlled their blood pressure to contemporary guideline goals. eGFR declined relentlessly even though they did everything their doctors asked. With such a result, we could conclude either that blood pressure control and drug classes are not as important as we all believe or that something else (genes for instance) is at fault. Large drug trials, irrespective of the sponsors, are favourite for polymorphism studies and most, if not all, feature one or more genetic ‘spin-off’ studies. For instance, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) featured an entire polymorphism consortium disingenuously entitled GENHAT. This group published the presence of an absence of an interaction between the ACE gene insertion–deletion polymorphism and pravastatin in cardiovascular disease in ALLHAT patients [3]. The AASK study has already been milked for polymorphisms. A paper on G-protein-coupled receptor kinase 4 polymorphisms and response to metoprolol in the AASK cohort has recently been published. Several authors on the current report also appear on that paper [4]. Why did the authors pick ADB1R? The hypothesis is not directly stated. However, the senior author is specifically interested in adrenergic mechanisms in hypertension and perhaps that is the reason. Did the authors make a good choice in selecting polymorphisms? Yes, they did. First, adrenergic tone is decidedly increased with diminished renal function. The issue has been studied with direct measurement of muscle sympathetic nerve activity. Converse et al. recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with haemodialysis, 5 patients receiving haemodialysis who had undergone bilateral nephrectomy and 11 normal subjects [5]. They showed unequivocally that chronic renal failure is accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys. The literature on the issue is extensive. A recent review outlines all the findings in detail [6]. Too bad that the sympatholytic drugs are not renoprotective. Metoprolol, a predominantly ADB1R blocker, did not seem to help the AASK participants very much. The authors got their best mileage out of the Ser49Gly polymorphism in ADB1R, with minimal decline in persons homozygous for Gly49Gly. This finding is a bit surprising, because the most highly touted polymorphism, at least for a risk of heart failure in ADB1R has been Arg389Gly [7], which was only in partial linkage disequilibrium with Ser49Gly according to the authors [1]. The authors’ polymorphism is located towards the aminoterminus of the receptor, at the other end compared to the Arg389Gly

Novelty-induced arousal enhances memory for cued classical fear conditioning: Interactions between peripheral adrenergic and brainstem glutamatergic systems

Exposure to novel contexts produce heightened states of arousal and biochemical changes in the brain to consolidate memory. However, processes permitting simple exposure to unfamiliar contexts to elevate sympathetic output and to improve memory are poorly understood. This shortcoming was addressed by examining how novelty-induced changes in peripheral and/or central arousal modulates memory for Pavlovian fear conditioning. Male rats were either exposed to the conditioning chamber for 5-min or given no exposure 24 h before conditioning with five tone-shock (0.35 mA) pairings. Retention was assessed 48 h later in a different context. Non-pre-exposed animals exhibited significantly greater freezing during conditioned stimulus (CS) presentations than did pre-exposed animals (P < 0.05). The improvement in retention produced by novelty was attenuated by pretraining a blockade of peripheral beta-adrenergic receptors with sotalol (6 mg/kg, i.p.). Study 2 revealed that novelty-induced increases in peripheral autonomic output are conveyed to the brain by visceral afferents that synapse upon brainstem neurons in the nucleus tractus solitarius (NTS). Blocking AMPA receptor activity in the NTS with CNQX (1.0 microg) significantly reduced freezing to the CS in non-pre-exposed animals (P < 0.01). Study 3 showed that elevating epinephrine levels in habituated animals influences learning through mechanisms similar to those produced by novelty-induced arousal. Pre-exposed animals given epinephrine (0.1 mg/kg) froze significantly more than saline controls (P < 0.01), and this effect was attenuated by intra-NTS infusion of CNQX. The findings demonstrate that novelty-induced arousal or increasing sympathetic activity with epinephrine in pre-exposed animals enhances memory through adrenergic mechanisms initiated in the periphery and transmitted centrally via the vagus/NTS complex.

Adrenergic mechanisms of the Kölliker-Fuse/A7 area on the control of water and sodium intake

The blockade of serotoninergic receptors with methysergide or the activation of α 2-adrenoceptors with moxonidine into the lateral parabrachial nucleus (LPBN) increases water and 0.3 M NaCl intake in rats treated with furosemide (FURO) combined with captopril (CAP). In the present study we investigated the effects of bilateral injections of noradrenaline (the endogenous neurotransmitter for α-adrenoceptors) alone or combined with the α 2-adrenoceptor antagonist RX 821002 into the LPBN or into the rostral portion of the Kölliker-Fuse nucleus that includes also the A7 area (KF/A7 area) on FURO+CAP-induced water and 0.3 M NaCl intake. Male Holtzman rats with bilateral stainless steel guide-cannulas implanted into KF/A7 area or LPBN were used. FURO+CAP-induced 0.3 M NaCl intake strongly increased after bilateral injections of noradrenaline (80 or 160 nmol/0.2 μl) into LPBN (26.5±5.9 and 20.7±2.0 ml/2 h versus saline: 4.4±0.9 ml/2 h) or into the KF/A7 area (31.5±6.1 and 25.9±4.7 ml/2 h versus saline: 7.2±1.6 ml/2 h). Water intake increased with noradrenaline injected in KF/A7 area, however, this treatment reduced 0.06 M sucrose intake, suggesting that the increase of water and NaCl intake is not related to non-specific effect. Bilateral injections of RX 821002 (160 nmol/0.2 μl) into LPBN or KF/A7 area abolished the effects of noradrenaline (160 nmol/0.2 μl) in the same areas on 0.3 M NaCl intake (7.5±2.5 and 9.8±4.4 ml/2 h, respectively). Moxonidine (0.5 nmol/0.2 μl) injected bilaterally into the KF/A7 area increased 0.3 M NaCl intake (39.5±6.3 ml/3 h) and water intake, while methysergide (4 μg/0.2 μl) into the KF/A7 area did not alter 0.3 M NaCl or water intake. The results suggest that α 2-adrenoceptor activation is a common mechanism in the KF/A7 area and LPBN to facilitate sodium intake. However, the serotonergic mechanism is present in LPBN, not in the KF/A7 area.

Exercise-induced reduction in systemic vascular resistance: A covert killer and an unrecognised resuscitation challenge?

Systemic vascular resistance falls in exercise as a consequence of metabolically-linked vasodilatation in active skeletal muscles. This exercise-induced vasodilatation is closely linked with reduced muscle tissue oxygen tension in and is characterised by reduced response to adrenergic vasoconstrictor mechanisms which is often referred to as functional sympatholysis. Systemic arterial blood pressure in exercise is maintained at normal or, more commonly, at elevated levels by increase in cardiac output and increased sympathetic vasomotor tone. Recovery of normal resting skeletal muscle tissue oxygen tension and skeletal muscle vascular tone after exercise depends on the post-exercise recovery process. This process requires ongoing elevated skeletal muscle perfusion and can therefore be predicted to be impaired in shock and cardiopulmonary resuscitation scenarios. Comprehensive consideration of this exercise physiology and its extrapolation into shock, cardiac arrest and resuscitation scenarios supports the proposal that exercise-induced sympatholytic vasodilatation in skeletal muscle may be of considerable unrecognised significance for resuscitation medicine. MAIN HYPOTHESIS: Reduced systemic vascular resistance due to pre-existing exercise-induced sympatholytic vasodilatation in skeletal muscle can significantly exacerbate systemic arterial hypotension in acute shock states and resuscitation scenarios. SUB-HYPOTHESES: 1. Onset of syncope, clinical shock states and pulseless electrical activity can occur at significantly higher cardiac output levels in subjects who were engaged in immediate pre-morbid exercise as compared to resting subjects. 2. The efficacy of external chest compression in generating coronary and cerebral perfusion in cardiopulmonary resuscitation can be significantly impaired when cardiac arrest has occurred during exercise. 3. The efficacy of adrenergic vasopressor agents in resuscitation scenarios can be significantly impaired in subjects who were engaged in immediate pre-morbid exercise. The limited available evidence is compatible with the hypothesis being true but does not provide direct confirmation. There is no evidence available directly supporting or refuting the hypothesis. Significant potential clinical implications are outlined relating to the management of cardiopulmonary and trauma resuscitation for patients who were involved in immediate pre-morbid exercise, particularly, but not exclusively, at higher exercise intensities. There are also significant potential prognostic implications. Reduction in systemic vascular resistance due to exercise-induced sympatholytic vasodilatation in skeletal muscle may largely explain the reported poor success rate for cardiopulmonary resuscitation with prompt defibrillation for sudden cardiac arrest in young previously healthy athletes. Investigation of this unexplored area of pathophysiology poses major difficulties but could lead to significant improvements in the outcomes of resuscitation for patients who were involved in immediate pre-morbid exercise.

Adrenergic mechanism in hyperketonemia in thyrotoxic and starved rats.

To evaluate the possible role of the adrenergic mechanism in hyperketonemia in hyperthyroidism and starvation, the plasma concentrations of FFA, acetoacetate (AcAc), and beta-hydroxybutyrate (BOHB) were measured in thyrotoxic and starved rats for 96 hours. Thyrotoxemia was induced in rats by a daily subcutaneous thyroxine (100 micrograms/kg/day) injection carried out for 7 days. Some of the thyrotoxic and starved rats were administered subcutaneous phentolamine (2 mg/kg, twice daily) or propranolol (0.1 mg/kg, twice daily). Plasma levels of FFA, AcAc, and BOHB were significantly increased in thyrotoxic and starved rats compared with the control rats. Phentolamine and propranolol administration did not alter plasma levels of FFA, AcAc, and BOHB in thyrotoxic rats. In starved rats, propranolol did not alter plasma levels of FFA, AcAc, and BOHB, however, phentolamine did increase plasma levels of FFA, AcAc, and BOHB. These results indicate that the adrenergic mechanism may not contribute to the hyperketonemia in thyrotoxic rats, but may have a slight inhibitory effect on ketogenesis in starvation probably due to alpha-antilipolytic action.

Effects of metyrapone and a combined alpha- and beta-adrenergic blockade on plasma glucose recovery from insulin-induced hypoglycaemia in pigs.

The recovery of plasma glucose from insulin-induced hypoglycaemia was investigated in growing pigs during an inhibition of corticosteroid secretion (metyrapone infusion), an alpha- and beta-adrenergic blockade (phentolamine and propranolol infusion) or a combination of both treatments. In pigs which received an infusion of metyrapone for 4 h before and 3 h after a bolus injection of insulin (0.1 IU/kg body-weight), the plasma glucose response did not differ significantly from control animals. The infusion of phentolamine and propranolol (in each case 120 micrograms/kg/h for 3 h after a priming dose of 100 micrograms/kg) starting at the time of insulin injection significantly attenuated the restoration of normoglycaemia. An additional infusion of metyrapone increased this effect significantly only at the end of the experiment. The results indicate that adrenergic mechanisms are involved in the glucose counterregulation after an insulin-induced hypoglycaemia in pigs and the glucocorticoid secretion may become critical when the catecholamine response is impaired.

Evidence for a noradrenergic mechanism causing hypertension and abnormal glucose metabolism in rats with relative deficiency of γ‐melanocyte‐stimulating hormone

A close association between salt-sensitive hypertension and insulin resistance has been recognized for more than two decades, although the mechanism(s) underlying this relationship have not been elucidated. Recent data in mice with genetic disruption of the gamma-melanocyte-stimulating hormone (gamma-MSH) system suggest that this system plays a role in the pathophysiological relationship between hypertension and altered glucose metabolism during ingestion of a high-sodium diet (8% NaCl, HSD). We tested the hypothesis that these two consequences of interrupted gamma-MSH signalling were the result of sympathetic activation by studying rats treated with the dopaminergic agonist bromocriptine (5 mg kg(-1) i.p., daily for 1 week; Bromo) to cause relative gamma-MSH deficiency. Bromo-treated rats fed the HSD developed hypertension and also exhibited fasting hyperglycaemia (P < 0.005) and hyperinsulinaemia (P < 0.025). Furthermore, Bromo-treated rats on the HSD had impaired glucose tolerance and blunted insulin-mediated glucose disposal. Intravenous infusion of gamma(2)-MSH, or of the alpha-adrenergic receptor antagonist phentolamine, to Bromo-HSD rats lowered both mean arterial pressure (MAP) and blood glucose to normal after 15 min (P < 0.001 versus control), but had no effect in rats receiving vehicle and fed the HSD; gamma(2)-MSH infusion also reduced the elevated plasma noradrenaline to control levels in parallel with the reductions in MAP and blood glucose concentration. Infusion of hydralazine to Bromo-HSD rats lowered MAP but had only a trivial effect on blood glucose. We conclude that rats with relative gamma-MSH deficiency develop abnormal glucose metabolism, with features of insulin resistance, in association with hypertension when ingesting the HSD. Elevated plasma noradrenaline concentration in Bromo-HSD rats is normalized by gamma(2)-MSH infusion, suggesting that an adrenergic mechanism may link the salt-sensitive hypertension and the impaired glucose metabolism of relative gamma-MSH deficiency.

The antinociceptive properties of reboxetine in acute pain

The antinociceptive effects of the selective noradrenaline reuptake inhibitor antidepressant reboxetine and its interaction with various opioid and noradrenaline receptor subtypes were evaluated. Reboxetine (i.p.) induced a weak dose-dependent antinociceptive effect in acute pain, using the hotplate model. The reboxetine-induced antinociception was significantly inhibited by the opioid receptor antagonists naloxone, nor-BNI, naltrindole and b-FNA, implying a non-selective role for the opioid receptors in the reboxetine's antinociceptive effect. The adrenergic antagonists yohimbine and phentolamine attenuated to some extent the reboxetine-induced antinociception, implying a minor adrenergic mechanism of antinociception. The addition of opioid or alpha2 agonists, did not potentiate the antinociception effect of reboxetine. Thus, it seems that reboxetine possesses a weak antinociceptive effect, mediated by non-selective opioid receptors and influenced somewhat by noradrenaline alpha2 receptors. These results suggest that reboxetine as monotherapy does not have sufficient efficacy in the management of acute pain. However, further research is needed in order to establish its possible use alone or in combination with other antidepressants or analgesics in the amelioration of chronic pain disorders.

Control of eating by hepatic oxidation of fatty acids. A note of caution

Langhans [Langhans, W. (2008). Fatty acid oxidation in the energostatic control of eating—a new idea. Appetite, 51, 446–451] suggested that the liver might not be involved in the control of eating by fatty acid oxidation (FAO). However, the evidence presented against the role of the liver is weak at best, and may be incorrect. Inhibition of FAO by metabolic inhibitors generally stimulates eating, but in recent experiments from the author's laboratory, inhibition of β-oxidation failed to stimulate eating when FAO was elevated by fasting or adrenoceptor agonists. The author used these experiments as evidence that the liver is not involved in the control of eating by FAO, but this conclusion is open to question because mercaptoacetate, the agent used to inhibit FAO, stimulates anorexia through adrenergic mechanisms. The evidence supporting a role for hepatic FAO in metabolic regulation of food intake remains strong.

Diminution of ejaculatory capacity induced by frequent ejaculation in dogs: prevention and reversal by yohimbine.

The effect of yohimbine, an alpha-2 adrenoceptor antagonist, on diminished ejaculatory capacity induced by frequent ejaculation was investigated in dogs. Ejaculation was elicited by manual penile stimulation (for 5 min) 5-8 times every 30 min. The amount of ejaculate produced by the stimulation was drastically reduced during a period of frequent ejaculation in a frequency-dependent manner. When administered immediately after the first ejaculation, yohimbine (0.1 mg kg-1, i.p.) completely prevented the decrease in the amount of ejaculate produced in the succeeding ejaculation. Moreover, similar treatment with yohimbine immediately after the fifth ejaculation when the dogs displayed a greatly reduced ejaculatory capacity restored the capacity to the initial level. In addition, yohimbine increased the total number of sperm produced during a period of frequent ejaculation. These data corroborate our previous finding that yohimbine at a low dose has a stimulatory effect on ejaculatory function in dogs. The present study also indicates that an alpha-2 adrenergic mechanism may be involved in the diminution of ejaculatory capacity induced by frequent ejaculation.

Pharmacogenetics of low dose clonidine in irritable bowel syndrome

Adrenergic and serotonergic (ADR-SER) mechanisms alter gut (gastrointestinal, GI) sensorimotor functions. We aimed to determine whether candidate ADR-SER genes affect GI responses to low dose clonidine (CLO) in humans. Forty healthy and 120 irritable bowel syndrome (IBS) participants received CLO, 0.1 mg or 0.15 mg b.i.d., for 6 days. At baseline and post-CLO, we measured: gastric volume (GV); satiation volume; rectal compliance, sensation thresholds and ratings with distensions. Genetic variations tested were: alpha2A (C-1291G), alpha2C (Del 322-325), GNbeta3 (C825T) and solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) (serotonin transporter linked polymorphic region). CLO reduced volume to satiation (P = 0.002), postprandial GV (P < 0.001), sensation threshold for pain (<0.001); CLO increased rectal compliance (P = 0.024). There were significant associations between post-CLO responses and gene variations for DeltaGV (alpha2A and SLC6A4), rectal sensation of gas (alpha2A, GNbeta3), urgency (alpha2A); and pain (GNbeta3 and SLC6A4); and rectal compliance (SLC6A4). alpha2A, GNbeta3 and SLC6A4 genotypes significantly modify responses to CLO on sensory and motor GI functions in health and IBS.

Involvement of central α 1-adrenoceptors on renal responses to central moxonidine and α-methylnoradrenaline

Moxonidine (α 2-adrenoceptor/imidazoline receptor agonist) injected into the lateral ventricle induces diuresis, natriuresis and renal vasodilation. Moxonidine-induced diuresis and natriuresis depend on central imidazoline receptors, while central α 1-adrenoceptors are involved in renal vasodilation. However, the involvement of central α 1-adrenoceptors on diuresis and natriuresis to central moxonidine was not investigated yet. In the present study, the effects of moxonidine, α-methylnoradrenaline (α 2-adrenoceptor agonist) or phenylephrine (α 1-adrenoceptor agonist) alone or combined with previous injections of prazosin (α 1-adrenoceptor antagonist), yohimbine or RX 821002 (α 2-adrenoceptor antagonists) intracerebroventricularly (i.c.v.) on urinary sodium, potassium and volume were investigated. Male Holtzman rats ( n = 5–18/group) with stainless steel cannula implanted into the lateral ventricle and submitted to gastric water load (10% of body weight) were used. Injections of moxonidine (20 nmol) or α-methylnoradrenaline (80 nmol) i.c.v. induced natriuresis (196 ± 25 and 171 ± 30, respectively, vs. vehicle: 101 ± 9 µEq/2 h) and diuresis (9.0 ± 0.4 and 12.3 ± 1.6, respectively, vs. vehicle: 5.2 ± 0.5 ml/2 h). Pre-treatment with prazosin (320 nmol) i.c.v. abolished the natriuresis (23 ± 4 and 76 ± 11 µEq/2 h, respectively) and diuresis (5 ± 1 and 7.6 ± 0.8 ml/2 h, respectively) produced by i.c.v. moxonidine or α-methylnoradrenaline. RX 821002 (320 nmol) i.c.v. abolished the natriuretic effect of α-methylnoradrenaline, however, yohimbine (320 nmol) did not change renal responses to moxonidine. Phenylephrine (80 nmol) i.c.v. induced natriuresis and kaliuresis that were blocked by prazosin. Therefore, the present data suggest that moxonidine and α-methylnoradrenaline acting on central imidazoline receptors and α 2-adrenoceptors, respectively, activate central α 1-adrenergic mechanisms to increase renal excretion.

Complex adrenergic and inflammatory mechanisms contribute to phase 2 ventricular arrhythmias in anaesthetized rats

The mechanisms responsible for phase 2 (infarct-related) ventricular arrhythmias remain unclear. We have investigated the role of alpha(1) and beta(1) adrenoceptor activation and the interaction of this with infarct neutrophil accumulation, in anaesthetized rats. Neutrophil-replete Sprague-Dawley rats (n = 8-9 per group) were anaesthetized and randomized to receive vehicle, prazosin (0.5 mg.kg(-1) i.v.), atenolol (4 mg.kg(-1) i.v.) or their combination prior to left main coronary artery occlusion. A further group was depleted of neutrophils and received both atenolol and prazosin. Coronary ligation in all groups was maintained for 240 min. Atenolol and prazosin treatment lowered heart rates and blood pressures respectively, but neither agent given alone affected the incidence of phase 2 ventricular tachycardia or fibrillation. However, co-administration of atenolol with prazosin reduced phase 2 ventricular premature beats (log(10)-transformed totals were 1.25 +/- 0.26 vs. 2.43 +/- 0.18 in controls; P < 0.05). Neutrophil depletion attenuated this antiarrhythmic effect (log(10)-transformed total ventricular premature beats were 1.66 +/- 0.35; P > 0.05 vs. controls). Phase 2 arrhythmias appear to depend in part on a complex interaction between catecholamines and neutrophils. A model of this interaction is proposed.

Muscarinic and α 1-adrenergic mechanisms contribute to the spinal mediation of stimulation-induced antinociception from the pedunculopontine tegmental nucleus in the rat

The effects of intraperitoneal (i.p.) or intrathecal (i.t.) injection of antagonists of acetylcholine, noradrenaline, serotonin, dopamine, opioids and GABA on stimulation-produced antinociception (SPA) from the pedunculopontine tegmental nucleus (PPTg) of rats were studied using the tail-flick test. The electrical stimulation of the PPTg produced a strong and long-lasting increase in tail-flick latency. The intensity and duration of the effect were significantly reduced in rats pretreated with i.p. or i.t. atropine (a non-selective muscarinic cholinergic antagonist), or i.t. phenoxybenzamine or WB 4101 (non-selective and selective α 1-adrenergic antagonists, respectively). Intraperitoneal phenoxybenzamine, i.p. or i.t. methysergide or naloxone (non-selective serotonin and opioid antagonists, respectively), or i.t. idazoxan (a selective α 2-adrenergic antagonist) only reduced the duration of the effect. The duration of SPA from the PPTg was increased by i.t. phaclofen (a GABA B antagonist). The effect from the nucleus was not altered following i.t. bicuculline (a GABA A antagonist), or i.p. or i.t. mecamylamine, propranolol or haloperidol (non-selective nicotinic cholinergic, β-adrenergic and dopaminergic antagonists, respectively). Thus, SPA from the PPTg involves the spinal activation of muscarinic and α 1-adrenergic but not nicotinic cholinergic, β-adrenergic and dopaminergic mechanisms. Serotonergic, endogenous opioid and α 2-adrenergic mechanisms are involved in the duration but not in the intensity of the effect.