Effects of spantide ([D-Arg1,D-Trp7,9,Leu11]substance P) on coronary resistance vessels were studied in isolated guinea pig hearts perfused at constant rate with isotonic buffer containing 20 or 40 mM KCl. Spantide (1 μM) caused a 20-fold rightward shift of the substance P (SP) dose-response curve for vasodilation with no change in maximum (KB=5.3×10-8 M). Bolus injections of 0.25 to 250 pmol spantide had no effect, but higher doses caused a brief vasodilation followed by a larger, more prolonged vasoconstriction. Histamine produced similar changes in perfusion pressure. Antihistamines (H1 and H2) reduced or blocked responses to spantide and histamine. These findings indicate spantide is a competitive antagonist to SP in guinea pig coronary resistance vessels. In addition, high doses of spantide can cause prominent vascular effects which are mediated by histamine.

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson's disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 μg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites l-3,4- dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H 1 ; cimetidine, H 2 ; thioperamide, H 3 agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H 3 antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.

To determine whether noradrenergic nerves might have a modulatory role on the sensitivity or reactivity of histaminergic receptor systems in brain, behavioral effects of the respective histamine H1, H2 and H3 antagonists S(+)chlorpheniramine, cimetidine and thioperimide in control adult rats were compared to the effects in adult rats that had been lesioned as neonates with the noradrenergic neurotoxin DSP-4. On the 1st and 3rd days after birth rat pups were treated with either saline or DSP-4 (50 mg/kg sc), then returned to their home cages with the dam. At 8 weeks when rats were tested, S(+)chlorpheniramine (10 mg/kg ip) was found to increase locomotor activity in intact and DSP-4 lesioned rats, while cimetidine (5 mg/kg, ip) and thioperimide (5 mg/kg, ip) increased activity severalfold solely in the DSP-4 group. Exploratory activity, nociceptive activity, and irritability were little altered by the histamine antagonists, although oral activity was increased by thioperimide in intact and lesioned rats, and by cimetidine or S(+)chlorpheniramine in DSP-4 rats. High performance liquid chromatography with electrochemical detection was used to determine that DSP-4 produced a 90% reduction in frontal cortex, hippocampus and hypothalamus, with a 90% elevation of NE in cerebellum - reflecting reactive sprouting of noradrenergic fibers consequent to lesion of noradrenergic tracts projecting to proximal brain regions. These findings indicate that perinatal noradrenergic fiber lesioning in rat brain is associated with an altered behavioral spectrum by histamine H1, H2 and H3 receptor antagonists, thereby implicating histaminergic systems as modulators of noradrenergic systems in brain.

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The start of the menopausal transition involves the introduction of various somatic, urogenital, and psychological symptoms; of the symptoms, irritability is one of the main complaints reported by women. The use of bioidentical hormone replacement therapy has become more prevalent in society, specifically treating the somatic and urogenital symptoms of the menopausal transition. This study aims to determine the effects of bioidentical hormone replacement therapy (BHRT) on irritability in menopausal women. To test the hypotheses, an online survey was distributed to women via social media and word-of-mouth. Participants were asked to respond to various questions, which were then analyzed based on BHRT use. An independent samples t-test was used to analyze the data. The results exemplified no significant relationship between BHRT and irritability; using BHRT does not significantly reduce irritability scores.

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Objective: The aim was to determine if isolated rat cardiomycytes could be protected from ischaemic cell death by preincubation with adenosine or adenosine agonists. Methods: Cardiomyocytes isolated from rat hearts were preincubated in the presence of adenosine, CCPA (2-chloro-N6-cyclopentyladenosine), or carbachol prior to concentration into an ischaemic slurry. Effects of glycolysis and of isoprenaline were determined by addition of iodoacetic acid or isoprenaline to the ischaemic incubates and by exclusion of glucose from all media. Rates of ischaemic contracture were determined and survival of the myocytes versus paired control preparations was determined after various times of ischaemia, following resuspension of the cells in isotonic or hypotonic media. Results: Adenosine and CCPA produced only a small reduction of the rates of contracture and death of isolated myocytes. Carbachol gave no significant protection. Neither the degree of injury of control cells nor the amount of protection by CCPA was altered in the presence of added isoprenaline. Protection was abolished by the A1 receptor blocker sulphophenyl theophylline, iodoacetic acid, and exclusion of glucose. Conclusions: Adenosine and adenosine agonists afford a minimal degree of protection to ischaemic isolated myocytes by a glucose dependent mechanism. This protection does not appear to account for the larger degree of protection seen in intact hearts, following similar preconditioning protocols. The failure of adenosine to protect may be related to the quiescent state of isolated cardiomyocytes, or be species specific in that adenosine may not be the trigger for preconditioning in rats.Cardiovascular Research 1993;27:1670-1676.

Resveratrol and catechin have behavioral and neuroprotective effects that may be due to their interaction with neuronal ion channels. It was hypothesized that the grape compounds, resveratrol and catechin modulate GABAAA receptors. To address this hypothesis, the effects of resveratrol and catechin were investigated on human recombinant GABAA receptors expressed in HEK-293 cells using electrophysiological techniques.<.p> HEK-293 cells were cultured and transfected using eDNA encoding human GABAA receptors. GABA-evoked currents were recorded from HEK cells 24-48 hours following transfection. Cells were voltage clamped in the whole cell configuration at -60mV using the patch-clamp technique. Ligand-activated currents were recorded and stored, using Win WCP software, on a desktop computer. Resveratrol (1- 100μM) dose-dependently potentiated GABA-evoked currents recorded from α1β2< /sup>γ2 and α1β2 GABAA receptors. Resveratrol did not modulate a α1β2< /sup>γ2 and α1β2 GABAA receptors. Furthermore, resveratrol did not act through the benzodiazepine binding site. The low efficacy and subunit selectivity of resveratrol is a promising discovery for the development of a highly specific GABAergic modulator. Conversely, catechin (1-100αM) dose-dependently inhibited GABA-evoked currents recorded from α1β2 and α1β1 GABAA receptors. The degree of inhibition was the same for both receptor subtypes. Catechin did not modulate α1β2γ2 or α1β1γ2 GABAA receptors. The selectivity of catechin for receptors lacking the γ subunit is similar to the effects of zinc and did not involve the benzodiazephine site on GABAA receptors. This study has shown that catechin and resveratrol are subunit-selective modulators of human GABAA receptors. These compounds could lead to the development of novel agents to be used in treating neurological disorders. These data support the use and study of natural products for the development of agents that act selectively on the nervous system.