Drug-induced endocrine blood pressure elevation.

Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension with an identifiable cause. The patient's medications, its use of certain herbal supplements and over-the-counter agents represent potential causal factors for secondary hypertension that are often overlooked. The current review focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates and market withdrawals are reviewed. Finally, potential therapeutic strategies are discussed.

Drug screens of NGLY1 deficiency in worm and fly models reveal catecholamine, NRF2 and anti-inflammatory-pathway activation as potential clinical approaches.

N-glycanase 1 (NGLY1) deficiency is an ultra-rare and complex monogenic glycosylation disorder that affects fewer than 40 patients globally. NGLY1 deficiency has been studied in model organisms such as yeast, worms, flies and mice. Proteasomal and mitochondrial homeostasis gene networks are controlled by the evolutionarily conserved transcriptional regulator NRF1, whose activity requires deglycosylation by NGLY1. Hypersensitivity to the proteasome inhibitor bortezomib is a common phenotype observed in whole-animal and cellular models of NGLY1 deficiency. Here, we describe unbiased phenotypic drug screens to identify FDA-approved drugs that are generally recognized as safe natural products, and novel chemical entities, that rescue growth and development of NGLY1-deficient worm and fly larvae treated with a toxic dose of bortezomib. We used image-based larval size and number assays for use in screens of a 2560-member drug-repurposing library and a 20,240-member lead-discovery library. A total of 91 validated hit compounds from primary invertebrate screens were tested in a human cell line in an NRF2 activity assay. NRF2 is a transcriptional regulator that regulates cellular redox homeostasis, and it can compensate for loss of NRF1. Plant-based polyphenols make up the largest class of hit compounds and NRF2 inducers. Catecholamines and catecholamine receptor activators make up the second largest class of hits. Steroidal and non-steroidal anti-inflammatory drugs make up the third largest class. Only one compound was active in all assays and species: the atypical antipsychotic and dopamine receptor agonist aripiprazole. Worm and fly models of NGLY1 deficiency validate therapeutic rationales for activation of NRF2 and anti-inflammatory pathways based on results in mice and human cell models, and suggest a novel therapeutic rationale for boosting catecholamine levels and/or signaling in the brain.

Pharmacological prevention of combat-related PTSD: a literature review.

Preventing posttraumatic stress disorder (PTSD) could have a significant positive impact on military readiness and quality of life. Few studies have examined whether pharmacological agents may prevent PTSD, and there has not been a systematic and critical review of these studies in order to guide future research efforts. We performed a literature review of articles examining the use of pharmacological agents for the prevention of PTSD. A total of 27 articles met inclusion criteria for the review and their results are summarized. The review points to corticosteroids and propranolol as the most promising agents for future research. Gamma-Amino butyric acid mimetic drugs received the least support. Complementary approaches using psychotherapy and pharmacological agents could also yield good results. Research aimed at determining the potential efficacy of these agents could start being carried out in the field with smaller numbers of personnel that has not been personally injured but have witnessed traumatic events. In addition, psychological interventions immediately after postdeployment could be used in large numbers of soldiers. Preliminary studies regarding the use of pharmacologic agents for the secondary prevention of PTSD are promising. However, much larger studies are needed before implementation in generalized practice.

Neurocardiology: therapeutic implications for cardiovascular disease.

The term "neurocardiology" refers to physiologic and pathophysiological interplays of the nervous and cardiovascular systems. This selective review provides an update about cardiovascular therapeutic implications of neurocardiology, with emphasis on disorders involving primary or secondary abnormalities of catecholamine systems. Concepts of scientific integrative medicine help understand these disorders. Scientific integrative medicine is not a treatment method or discipline but a way of thinking that applies systems concepts to acute and chronic disorders of regulation. Some of these concepts include stability by negative feedback regulation, multiple effectors, effector sharing, instability by positive feedback loops, allostasis, and allostatic load. Scientific integrative medicine builds on systems biology but is also distinct in several ways. A large variety of drugs and non-drug treatments are now available or under study for neurocardiologic disorders in which catecholamine systems are hyperfunctional or hypofunctional. The future of therapeutics in neurocardiology is not so much in new curative drugs as in applying scientific integrative medical ideas that take into account concurrent chronic degenerative disorders and interactions of multiple drug and non-drug treatments with each other and with those disorders.

Indirect sympatholytic actions at ß-adrenoceptors account for the ocular hypotensive actions of cannabinoid receptor agonists.

Intraocular pressure (IOP) is the primary risk factor for glaucoma, a blinding eye disease. Cannabinoid agonists have long been known to decrease IOP, suggesting they may be useful in glaucoma treatment. However, the specific mechanism by which cannabinoids generate this ocular hypotensive effect remains unknown. The current evidence suggests the cannabinoids reduce IOP through actions at cannabinoid 1 (CB(1)) receptors within the eye, and adrenergic receptors (ARs) may also contribute to this action of cannabinoids. Considering this, the present study aimed to elucidate the mechanism behind the ocular hypotensive properties of cannabinoids through the use of mice genetically lacking either cannabinoid receptors or ßARs. Cannabinoid agonists, ßAR antagonists, and ßAR agonists decreased IOP in wild-type mice and CB(2)(-/-) mice. In contrast, none of these compounds were found to reduce IOP in ßAR(-/-) or CB(1)(-/-) mice. Desensitization of the ßARs and depletion of catecholamines in wild-type mice also eliminated the ability of the cannabinoid agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) to reduce IOP, strongly implicating a role for both ßARs and catecholamines in the ocular hypotensive properties of cannabinoids. Finally, CB(1) receptors were shown to colocalize with tyrosine hydroxylase, a marker for adrenergic neurons. Taken together, these findings suggest that ßARs are required for the ocular hypotensive properties of cannabinoids, and cannabinoids reduce IOP by acting as indirect sympatholytics and inhibiting norepinephrine release within the eye.

Catecholaminergic axonal varicosities appear to innervate growth hormone-releasing hormone-immunoreactive neurons in the human hypothalamus: the possible morphological substrate of the stress-suppressed growth.

CONTEXT: Stress is considered to be a major factor in the regulation of growth. Psychosocial dwarfism, characterized with short stature, delayed puberty, and depression, is typically preceded by psychological harassment or stressful environment. It has been observed that stress suppresses GH secretion, possibly via the attenuation of GHRH secretion. However, the exact mechanism of the impact of stress on growth has not been elucidated yet. OBJECTIVE: Our previous studies revealed intimate associations between neuropeptide Y (NPY)-immunoreactive (IR) axonal varicosities and GHRH-IR perikarya in the human hypothalamus. Because NPY is considered to be a stress molecule, NPY-GHRH juxtapositions may represent an important factor of stress-suppressed GHRH release. In addition to NPY, catecholamines are among the major markers of stress. Thus, in the present study, we examined the putative juxtapositions between the catecholaminergic tyrosine hydroxylase (TH)-/dopamine-ß-hydroxylase-/phenylethanolamine N-methyltransferase-IR and GHRH-IR neural elements in the human hypothalamus. To reveal these juxtapositions, double-label immunohistochemistry was used. RESULTS: Our findings revealed that the majority of the GHRH-IR perikarya formed intimate associations with TH-IR fiber varicosities. The majority of these juxtapositions were found in the infundibular nucleus/median eminence. CONCLUSIONS: The lack of phenylethanolamine N-methyltransferase-GHRH associations and the small number of dopamine-ß-hydroxylase-GHRH juxtapositions suggest that the vast majority of the observed TH-GHRH juxtapositions represent dopaminergic associations. The density of the abutting TH-IR fibers on the surface of the GHRH perikarya suggests that these juxtapositions may be functional synapses, and thus, in addition to NPY, catecholamines may regulate GHRH secretion via direct synaptic mechanisms.

Brown adipose tissue growth and development: significance and nutritional regulation.

The last decade has witnessed a profound resurgence in brown adipose tissue (BAT) research. The need for such a dramatic increase stems from the ever-growing trend toward global obesity. Indeed, it is currently estimated that rates of obesity in developed countries such as the United States exceed 35% of the population (1). The higher incidence of obesity is associated with increased prevalence of the metabolic syndrome including diabetes, hypertension, and coronary heart disease, among others (1, 2). BAT holds great promise in combating obesity given its unprecedented metabolic capacity. Leading the way has been recent studies, which conclusively demonstrate significant quantities of functional BAT in adult humans (3-7). These findings have been complimented by elegant studies elucidating the developmental origin of the brown adipocyte and the transcriptional regulation involved in its differentiation. This review will attempt to meld the wealth of new information regarding BAT development with established literature to provide an up to date synopsis of what is known and thus a framework for future research directions.

The role of catecholaminergic neurons in the hypothalamus and medullary visceral zone in response to restraint water-immersion stress in rats.

The activity of catecholaminergic neurons in the hypothalamus and the medullary visceral zone (MVZ) in rats in response to restraint water-immersion stress (RWIS) was measured by use of dual Fos and tyrosine hydroxylase (TH) immunohistochemistry. In RWIS rats Fos immunoreactive (Fos-IR) nuclei dramatically increased in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), the dorsal motor nucleus of the vagus (DMV), the nucleus of the solitary tract (NTS), the area postrema (AP), and the ventrolateral medulla (VLM). A small number of TH-immunoreactive (TH-IR) and Fos/TH double-labeling neurons in the PVN, and their absence from the SON, were observed in both RWIS and nonstressed rats. More TH-IR neurons were observed in the MVZ of RWIS rats than in nonstressed rats. In RWIS and nonstressed rats, the percentage of Fos-IR nuclei in TH-IR neurons was 38.0 and 14.3% in the DMV, 34.4 and 9.7% in the NTS, 18.6 and 4.5% in the AP, and 45.7 and 18.9% in the VLM, respectively. In conclusion, catecholaminergic neurons in the MVZ are involved in the response to RWIS; although the PVN and SON also participate in the response to RWIS, the mechanism is not via catecholaminergic neurons.

Mechanisms mediating the ability of caffeine to influence MDMA ('Ecstasy')-induced hyperthermia in rats.

BACKGROUND AND PURPOSE: Caffeine exacerbates the hyperthermia associated with an acute exposure to 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') in rats. The present study investigated the mechanisms mediating this interaction. EXPERIMENTAL APPROACH: Adult male Sprague-Dawley rats were treated with caffeine (10 mg x kg(-1); i.p.) and MDMA (15 mg x kg(-1); i.p.) alone and in combination. Core body temperatures were monitored before and after drug administration. KEY RESULTS: Central catecholamine depletion blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Caffeine provoked a hyperthermic response when the catecholamine releaser d-amphetamine (1 mg x kg(-1)) was combined with the 5-HT releaser D-fenfluramine (5 mg x kg(-1)) or the non-selective dopamine receptor agonist apomorphine (1 mg x kg(-1)) was combined with the 5-HT(2) receptor agonist DOI (2 mg x kg(-1)) but not following either agents alone. Pretreatment with the dopamine D(1) receptor antagonist Schering (SCH) 23390 (1 mg x kg(-1)), the 5-HT(2) receptor antagonist ketanserin (5 mg x kg(-1)) or alpha(1)-adreno- receptor antagonist prazosin (0.2 mg x kg(-1)) blocked MDMA-induced hyperthermia and its exacerbation by caffeine. Co-administration of a combination of MDMA with the PDE-4 inhibitor rolipram (0.025 mg x kg(-1)) and the adenosine A(1/2) receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-C]quinazolin-5-amine 15943 (10 mg x kg(-1)) or the A(2A) receptor antagonist SCH 58261 (2 mg x kg(-1)) but not the A(1) receptor antagonist DPCPX (10 mg x kg(-1)) exacerbated MDMA-induced hyperthermia. CONCLUSIONS AND IMPLICATIONS: A mechanism comprising 5-HT and catecholamines is proposed to mediate MDMA-induced hyperthermia. A combination of adenosine A(2A) receptor antagonism and PDE inhibition can account for the exacerbation of MDMA-induced hyperthermia by caffeine.

Anatomy of a songbird basal ganglia circuit essential for vocal learning and plasticity.

Vocal learning in songbirds requires an anatomically discrete and functionally dedicated circuit called the anterior forebrain pathway (AFP). The AFP is homologous to cortico-basal ganglia-thalamo-cortical loops in mammals. The basal ganglia portion of this pathway, Area X, shares many features characteristic of the mammalian striatum and pallidum, including cell types and connectivity. The AFP also deviates from mammalian basal ganglia circuits in fundamental ways. In addition, the microcircuitry, role of neuromodulators, and function of Area X are still unclear. Elucidating the mechanisms by which both mammalian-like and unique features of the AFP contribute to vocal learning may help lead to a broad understanding of the sensorimotor functions of basal ganglia circuits.

[Hormones and osteoporosis update. Regulation of bone remodeling by neuropeptides and neurotransmitters].

From the discovery of the regulation of bone remodelling by leptin, much attention has been focused on neurogenic control of bone remodelling. Various hypothalamic neuropeptides, which are involved in appetite regulation, are now revealed to be important regulators of bone remodelling. More recently, neurotransmitters, such as serotonin or catecholamines, are proven to be bone remodelling regulators.

Roles of central catecholamine and hypothalamic neuropeptide Y genome in the development of tolerance to phenylpropanolamine-mediated appetite suppression.

Phenylpropanolamine (PPA) is an appetite suppressant. Repeated treatment with PPA can decrease food intake on initial days, but on subsequent days, food intake gradually returns to normal (tolerant effect). In an attempt to investigate the underlying mechanisms of PPA tolerance, the authors examined the roles of catecholamine (CAT) and hypothalamic neuropeptide Y (NPY) genome. Results revealed that pretreatment with either bupropion, a CAT transporter inhibitor, or a-methylparatyrosine, a tyrosine hydroxylase inhibitor, modulated the effect of PPA tolerance. Moreover, results also revealed that the alteration in NPY messenger RNA level coincided with the change of feeding behavior during PPA treatment and that infusions of NPY antisense oligonucleotide into the cerebroventricle abolished the effect of PPA tolerance. These findings suggest that cerebral CAT and hypothalamic NPY genome are involved in the development of tolerance to PPA-induced appetite suppression.

Nicotine's attenuation of body weight involves the perifornical hypothalamus.

Previously we showed that intermittent administration of nicotine (NIC) in the dark phase decreased food intake and body weight and this could be blocked when the NIC receptor antagonist mecamylamine was infused into the fourth ventricle. Catecholaminergic neurons adjacent to the fourth ventricle contain NIC receptors and directly innervate the perifornical hypothalamus (PFH) which has been shown to be involved in regulation of feeding. This study explored whether NIC regulates feeding behavior by modulating catecholaminergic input to the PFH. Epinephrine and norepinephrine neuronal input was ablated within the PFH by infusion of 6-hydroxydopamine hydrobromide (6-OHDA), while bupropion was infused to protect dopaminergic neurons. After recovery of body weights to pre-surgery levels, food intake, meal size, meal number and body weight were measured after intermittent NIC injections. The results showed the PFH lesioned animals did not exhibit the typical prolonged drop in food intake, meal size and body weight normally associated with NIC administration. High performance liquid chromatography analyses demonstrated that compared to control rats, 6-OHDA administration significantly reduced PFH norepinephrine and epinephrine levels, but not dopamine levels. These results are consistent with NIC reducing food intake in part by acting through catecholaminergic neurons within or extending through the PFH.

Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by adrenergically mediated polymorphic ventricular tachyarrhythmias. Genetic investigations have identified two variants of the disease: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RyR2) and a recessive form associated with homozygous mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2). Functional characterization of mutations identified in the RyR2 and CASQ2 genes has demonstrated that CPVT are caused by derangements of the control of intracellular calcium. Investigations in a knock-in mouse model have shown that CPVT arrhythmias are initiated by delayed afterdepolarizations and triggered activity. In the present article, we review clinical and molecular understanding of CPVT and discuss the most recent approaches to develop novel therapeutic strategies for the disease.

Combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats: implications for obesity treatment.

Intense hyperleptinemia completely depletes adipocyte fat of normal rats within 14 days. To determine the mechanism, epididymal fat pads from normal wild-type (+/+) and obese (fa/fa) Zucker Diabetic Fatty (ZDF) donor rats were transplanted into normal +/+ and fa/fa ZDF recipients. Hyperleptinemia induced by adenovirus-leptin administration depleted all fat from native fat pads and from fat transplants from +/+ donors but not from transplants from ZDF(fa/fa) donors with defective leptin receptors. In both native and transplanted +/+ fat pads, large numbers of mitochondria were apparent, and genes involved in fatty acid oxidation were up-regulated. However, +/+ fat pads transplanted into fa/fa recipients did not respond to hyperleptinemia, suggesting lack of an essential leptin-stimulated cohormone(s). In +/+ but not in fa/fa rats, plasma catecholamine levels rose, and both P-STAT3 and P-CREB increased in adipose tissue, suggesting that both direct and indirect (hypothalamic) leptin receptor-mediated actions of hyperleptinemia are involved in depletion of adipocyte fat.

Pain and relaxation (review).

The modern notion of pain and its clinical management, along with its physiological origins, is of exceeding interest to both clinicians and basic science researchers. While much is known about the control of pain via non-steroidal anti-inflammatory medications or comparative exogenous analgesics, little is known about the interplay between pain perception and its relationship with catecholamine molecules. We believe that the perception of pain and the body's self-attempt to alleviate it utilizing conventional homeostatic mechanisms via endogenous opiate release is mediated by key catecholamines, and that this effect is further modulated by nitric oxide. We further propose a new paradigm which links pain, endogenous opiates, and the catecholamines in a unique robust fashion demonstrating a complex symbiotic signaling system.

[Individuality of emotional stress].

The author postulates a need of individual evaluation of experimental data characterizing emotional stress. In typical conflict situations inducing emotional stress, there are animals resistant or predisposed to disturbance of different physiological functions. Prognostic criteria of individual resistance of animals to stressors are presented. Stress resistance depends in large on neuromediators and neuropeptides content, in particular Substance P, a peptide responsible for delta-sleep, and beta-endorphin, in brain structures and peripheral tissues. It is emphasized that individual estimation of clinical indices of emotional stress is needed.

Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons.

Hypothalamic hypocretin enhances arousal, similar to the actions of norepinephrine (NE). The physiological actions of NE were examined in hypocretin neurons identified by selective green fluorescent protein expression in transgenic mouse hypothalamic slices using whole-cell recording. NE induced an outward current, inhibited spike frequency, and hyperpolarized hypocretin neurons dose dependently. Similar actions were evoked by the selective alpha2 adrenergic agonist clonidine. The alpha2 antagonist idazoxan increased spike frequency, suggesting tonic NE-mediated inhibition. The NE-induced current was inwardly rectified, and the reversal potential was dependent on external potassium concentration; it was blocked by barium in the bath and by GTP-gamma-S in the pipette, suggesting activation of a G-protein inward rectifying K+ (GIRK) current. NE and clonidine decreased calcium currents evoked by depolarizing voltage steps. The selective alpha1 adrenergic agonist phenylephrine had no effect on membrane potential but did increase IPSC frequency; miniature IPSC frequency was also increased, in some cells without any effect on amplitude, suggesting a facilitative presynaptic action at alpha1 receptors on GABAergic axons that innervate hypocretin neurons. NE therefore inhibits hypocretin neurons directly through two mechanisms: activation of a GIRK current, depression of calcium currents, and indirectly through increased inhibitory GABA input. Similar to NE, dopamine and epinephrine reduced or blocked spikes and, in the presence of TTX, showed direct hyperpolarizing actions. The action of dopamine was blocked by the D2 receptor antagonist eticlopride, whereas a D1/5 antagonist had no effect. These data suggest that catecholamines evoke strong inhibitory actions on hypocretin neurons and suggest negative feedback from catecholamine cells that may be excited by hypocretin.