Effect of α-blockers on Handgrip Test Response of Diastolic Blood Pressure in Hypertensive, Benign Hypertrophy of Prostate Patients in a Therapeutics Clinic, Kolkata: A Cross-sectional Study.

BACKGROUND: The isometric handgrip (IHG) test is commonly used to detect sympathetic autonomic dysfunction. Tamsulosin, approved for the management of symptomatic benign prostatic hyperplasia (BPH), acts as an antagonist for α1-adrenergic receptors (α1-AR), whereas prazosin, an α1 receptor blocker, being less selective than tamsulosin, is used as an antihypertensive agent clinically. Our objective was to investigate if there is a distinction in blood pressure (BP) increase during IHG exercise between individuals with essential hypertension taking tamsulosin compared to those taking prazosin. MATERIALS AND METHODS: A cross-sectional observational study was performed on 50 subjects receiving tablet prazosin and 47 subjects receiving tamsulosin, who were asked to undergo an IHG test. Pre- and posttest BP was recorded for both the groups, and the difference in diastolic BP (DBP) (delta DBP) was compared between the groups and to their respective baseline values. RESULTS: Post-IHG test, mean DBP was found to be 93.98 ± 9.13 mm Hg in the prazosin group and 101.00 ± 12.05 mm Hg in the tamsulosin group, respectively. The change of delta DBP in the tamsulosin group was significant, but the prazosin group showed an insignificant rise in DBP. CONCLUSION: Prazosin, being less selective than tamsulosin in terms of α1 receptor antagonism, showed suppression of BP during IHG. Tamsulosin demonstrates high selectivity for prostatic receptors while showing minimal affinity for vascular receptors. As a result, its impact on BP is expected to be minimal.

Prazosin Potentiates Mast Cell-Stabilizing Property of Adrenaline.

BACKGROUND/AIMS: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSION: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß2-adrenergic receptors.

The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells.

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC50 values for chlorpromazine and prazosin to have a molar range of 35-65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

Characteristics of α1-adrenoceptor antagonists-induced ejaculatory dysfunction on spontaneous seminal emission in rats.

Although α1-adrenoceptor (α1-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α1-AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin > terazosin > prazosin > naftopidil. The selective α1D-AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α1-AR antagonists against SSE was due to the involvement of α1A-AR subtypes. Our results further suggested that α1-AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved.

A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1.

The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.

Terazosin produces an antidepressant-like effect in mice exposed to chronic unpredictable mild stress behavioral alteration.

Terazosin is an α1-adrenergic receptor antagonist that can relax smooth muscle and is prescribed to treat benign prostatic hyperplasia and, rarely, hypertension. The present study investigated the antidepressant-like actions of terazosin (TZ) in mice. They were first subjected to chronic unpredictable mild stress (CUMS) and then the effects of TZ were assessed using the forced swimming test (FST) and tail suspension test (TST), sucrose preference test (SPT), actophotometer test (APT). The changes in the PGK1 levels, neurotransmitters, and proinflammatory cytokines levels after chronic stress and TZ treatment were examined. It was found that TZ exhibited an antidepressant-like effect in the FST, TST, SPT, and APT. It was effective in the CUMS model of depression. It was also found that TZ treatment reduced the levels of proinflammatory cytokines and elevated the neurotransmitter levels in mice. Results of this study suggest that TZ has antidepressant-like actions in mice models of CUMS induced depression.

Tonic noradrenergic input to neurons in the dorsal raphe nucleus mediates food intake in male mice.

The dorsal raphe nucleus (DRN) is essential for the control of food intake. Efferent projections from the DRN extend to several forebrain regions that are involved in the control of food intake. However, the neurotransmitters released in the DRN related to the control of food intake are not known. We have previously demonstrated that a tonic α1 action on DRN neurons contributes to satiety in the fed rats. In this study we investigated the participation of norepinephrine (NE) signaling in the DRN in the satiety response. Intra-DRN administration of NE causes an increase in the 2-hour food intake of sated mice, an effect that was blocked by previous administration of yohimbine, an α2 antagonist. Similarly, Intra-DRN administration of clonidine, an α2 agonist, increases food intake in sated mice. This result indicates that in the satiated mice exogenous NE acts on α2 receptors to increase food intake. Furthermore, administration of phenylephrine, an α1 agonist, decreases food intake in fasted mice and prazosin, an α1 antagonist, increases food intake in the sated mice. Taken together these results indicate that, in a satiated condition, a tonic α1 adrenergic action on the DRN neurons inhibits food intake and that exogenous NE administered to the DRN acts on α2 adrenergic receptors to increase food intake. These data reinforce the intricate neuronal functioning of the DRN and its effects on feeding.

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists.

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1-15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7-9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α1-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α1A and α1B, was conducted. Selected compounds were tested for their activity towards two α1-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC50 < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats.

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

Effects of RS17053 on α1 -adrenoceptors in rat vas deferens and aorta.

BACKGROUND: RS17053 is classed as an α1A -adrenoceptor selective antagonist. OBJECTIVES: We have examined its profile of action at all subtypes of α1 -adrenoceptor. METHODS: Noradrenaline (NA) evoked contractions of rat vas deferens involve α1D -adrenoceptors in phasic contractions and α1A -adrenoceptors in tonic contractions. Contractions of rat aorta to NA involve α1D - and α1B -adrenoceptors. RESULTS: RS17053 (10-5  M) shifted NA potency and virtually abolished tonic contractions to NA, with little or limited effect on phasic contractions. The α1D -adrenoceptor antagonist BMY7378 (3 × 10-7 M) significantly inhibited the remaining phasic component of the contractions, and the α1A -adrenoceptor antagonist RS100329 (10-7  M) inhibited further the residual tonic contraction. Hence, RS17053 shows high selectivity for α1A -adrenoceptors over α1D -adrenoceptors in rat vas deferens. However, RS17053 (10-5  M) produced a large shift in the potency of NA in rat aorta, with a pKB of 6.82. Large shifts of NA potency in rat aorta involve α1B -adrenoceptor blockade. CONCLUSION: Results in rat vas deferens demonstrate low potency of RS17053 at α1D -adrenoceptors, but results from rat aorta can only be explained as demonstrating α1B -adrenoceptor antagonism by RS17053. RS17053 may be a useful pharmacological tool when reclassified as a mainly α1A - and to a lesser extent α1B -adrenoceptor antagonist with little effect at α1D -adrenoceptors.

Effects of alpha-adrenergic receptor blockade on coronary circulation in postmenopausal women.

We sought to investigate the effect of the α1-adrenergic receptor blockade during handgrip exercise (Grip), isolated metaboreflex activation (Metabo), and cold pressor test (CPT) on coronary circulation in young (YW) and postmenopausal women (PMW). Ten YW and 9 PMW underwent two protocols: (1) 3 min of baseline followed by 3 min of CPT and (2) 3 min of rest, 3 min of Grip followed by 3 min of Metabo. Protocols were carried out under control conditions and α1-adrenergic receptor blockade (oral prazosin 0.03 mg·kg-1). Coronary blood velocity (CBV) and vascular conductance (CCI) were lower in PMW. Grip increased CBV only in YW (YW: Δ18.0 ± 21.1% vs. PMW: Δ4.2 ± 10.1%; p < 0.05), and the blockade did not change the CBV response to Grip in YW and PMW. During the Metabo, CBV returned to resting levels in YW and was unchanged from rest in PMW, before (YW:Δ1.7 ± 8.7% vs. PMW: Δ- 1.5 ± 8.6) and under the blockade (YW: Δ4.5 ± 14.8% vs. PMW: Δ9.1 ± 29.5%). CPT did not change CBV in both groups (YW: Δ3.9 ± 8.0 vs. PMW: Δ- 4.1 ± 6.2%), following the α1-blockade, CPT increased CBV only in YW (YW: Δ11.2 ± 12.8% vs. PMW: Δ2.2 ± 7.1%; p < 0.05 for group and condition). CCI decreased during Grip, Metabo, and CPT in YW and PMW, while the blockade prevented that decrease only in YW. The α1-adrenergic receptor plays a role in the control of coronary circulation in young women, evoking stronger vasoconstriction during CPT than Grip and Metabo in YW. PMW have impaired vasomotor control in the coronary circulation, which seems not to be caused by the α1-adrenergic receptor.

Psychosocial treatments for nightmares in adults and children: a systematic review.

BACKGROUND: As nightmares may be a risk factor for, or symptom of, multiple psychological disorders, some researchers suggest that nightmares should be screened, diagnosed, and treated. Treatments for nightmares include trauma-focused Cognitive Behavioural Therapy and Image Rehearsal Therapy, and pharmacological interventions such as prazosin and nitrazepam. As recent research has put into question our current understanding of treatment efficacy, there is a need to systematically review findings related to the effectiveness of nightmare treatments to inform best practice. The current review assessed the efficacy of psychosocial treatments of nightmare in all cohorts. METHODS: A systematic search of four databases for peer reviewed journal articles from 2000 onwards produced 69 (35 RCTs, 34 non-RCTs) eligible articles that underwent narrative synthesis. RESULTS: The results provide strong evidence for exposure and image rehearsal treatments for the reduction of nightmare frequency, severity, and distress, in civilian, military, idiopathic, and posttraumatic stress disorder (PTSD) cohorts. There is emerging evidence that self-guided and brief treatment modalities offer efficient and effective treatment options. There is an urgent need for clinical trials of treatment effectiveness in children. CONCLUSIONS: The results suggest that treatments for nightmares are most effective when they facilitate a sense of control or mastery by directly targeting the nightmare content and/or the client's emotional responses to the nightmare content. TRIAL REGISTRATION: A review protocol was registered with PROSPERO (CRD42020204861).

Prazosin Protects the Liver Against Renal Ischemia/Reperfusion Injury in Rats.

Acute kidney injury (AKI) is a common subsequent problem after many medical conditions. AKI is associated with distant organ dysfunction where systemic inflammation and oxidative stress play major roles. In this study, the effect of Prazosin, an α1-Adrenergic receptor antagonist, was investigated on the liver injury induced by kidney ischemia-reperfusion (I/R) in rats. Male adult Wistar rats (n=21) were divided into three groups: sham, kidney I/R, and kidney I/R pre-treated with Prazosin (1 mg/kg). Kidney I/R was induced by vascular clamping of the left kidney for 45 min to reduce the blood flow. Oxidative and antioxidant factors along with apoptotic (Bax, Bcl-2, caspase3), and inflammatory (NF-κß, IL-1ß, and IL-6) factors were measured in the liver at protein levels. Prazosin could reserve liver function (p<0.01) and increase glutathione level (p<0.05) after kidney I/R significantly. Malonil dialdehyde (MDA), a lipid peroxidation marker, was diminished more significantly in Prazosin-treated rats compared to the kidney I/R group (p<0.001). Inflammatory and apoptotic factors were diminished by Prazosin pre-treatment in the liver tissue (p<0.05). Pre-administration of Prazosin could preserve liver function and decrease its inflammatory and apoptotic factors under kidney I/R conditions.

Phenylephrine-Induced Contraction in Guinea Pig Thoracic Aorta Is Triggered by Stimulation of α1L-Adrenoceptors Functionally Coupled with Store-Operated Ca2+ Channels and Voltage-Dependent Ca2+ Channels.

We examined whether the α1L-adrenoceptor (AR), which shows low affinity (pA2 < 9) for prazosin (an α1-AR antagonist) and high affinity (pA2 ≈ 10) for tamsulosin/silodosin (α1A-AR antagonists), is involved in phenylephrine-induced contractions in the guinea pig (GP) thoracic aorta (TA). Intracellular signaling induced by α1L-AR activation was also examined by focusing on Ca2+ influx pathways. Tension changes of endothelium-denuded TAs were isometrically recorded and mRNA encoding α-ARs/Ca2+ channels and their related molecules were measured using RT-quantitative PCR. Phenylephrine-induced contractions were competitively inhibited by prazosin/tamsulosin, and their pA2 value were calculated to be 8.53/9.74, respectively. These contractions were also inhibited by silodosin concentration-dependently. However, the inhibition was not competitive fashion with the apparent pA2 value being 9.48. In contrast, phenylephrine-induced contractions were not substantially suppressed by L-765314 (an α1B-AR antagonist), BMY 7378 (an α1D-AR antagonist), yohimbine, and idazoxan (α2-AR antagonists). Phenylephrine-induced contractions were markedly inhibited by YM-254890 (a Gq protein inhibitor) or removal of extracellular Ca2+, and partially inhibited by verapamil (a voltage-dependent Ca2+ channel (VDCC) inhibitor). The residual contractions in the presence of verapamil were slightly inhibited by LOE 908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) and strongly inhibited by SKF-96365 (a store-operated Ca2+ channel (SOCC) and ROCC inhibitor). Among the mRNA encoding α-ARs/SOCC-related molecules, α1A-AR (Adra1a)/Orai3, Orai1, and Stim2 were abundant in this tissue. In conclusion, phenylephrine-induced contractions in the GP TA can be triggered by stimulation of Gq protein-coupled α1L-AR, followed by activation of SOCCs and VDCCs.

Effects of histamine on the contractility of the rat distal cauda epididymis.

The motor activity of the epididymis duct is an essential process for male fertility and it is regulated by hormonal, neuronal and epithelial mechanisms. However, although there is evidence for the presence of histamine in the epididymis, its effects on epididymal motor activity are unknown. This study sought to evaluate the contractile effects of histamine on the rat distal cauda epididymis duct. Segments of the distal cauda epididymis duct from male Wistar rats were isolated and used in isolated organ bath experiments to evaluate the contractile effects of histamine in the absence or presence of antagonists of histamine receptors, α1-adrenoceptors and muscarinic acetylcholine receptors. The effects of histamine on noradrenaline induced contractions were also investigated. Histamine was able to induce phasic contractions on rat distal cauda epididymis duct which were prevented by promethazine 10-1000 nM (H1 receptor antagonist), ranitidine 1-100 µM (H2 receptor antagonist), atropine 100 nM (muscarinic antagonist), and prazosin 100 nM (α1-adrenoceptor antagonist). In addition, histamine was also able to modify noradrenaline-induced contractions possibly via activation of H1 and H2 receptors. In conclusion, this study demonstrates that histamine can induce phasic contractions of rat distal cauda epididymis via H2 receptors and autonomic neurotransmitters. Histamine may also exert modulatory actions on contractions of rat distal cauda epididymis duct induced by adrenergic receptor agonists. Further studies are necessary to unveil the localization of histamine receptors within the epididymal duct and the consequences of manipulation of the histaminergic system on epididymal function and male fertility.

The sympathetic nervous system exacerbates carotid body sensitivity in hypertension.

AIMS: The carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We hypothesized that CB hyperexcitability is driven by its own sympathetic innervation. METHODS AND RESULTS: To test this, the chemoreflex was activated (NaCN 50-100 µL, 0.4 µg/µL) in SH and Wistar rats in situ before and after: (i) electrical stimulation (ES; 30 Hz, 2 ms, 10 V) of the superior cervical ganglion (SCG), which innervates the CB; (ii) unilateral resection of the SCG (SCGx); (iii) CB injections of an α1-adrenergic receptor agonist (phenylephrine, 50 µL, 1 mmol/L), and (iv) α1-adrenergic receptor antagonist prazosin (40 µL, 1 mmol/L) or tamsulosin (50 µL, 1 mmol/L). ES of the SCG enhanced CB-evoked sympathoexcitation by 40-50% (P < 0.05) with no difference between rat strains. Unilateral SCGx attenuated the CB-evoked sympathoexcitation in SH (62%; P < 0.01) but was without effect in Wistar rats; it also abolished the ongoing firing of chemoreceptive petrosal neurones of SH rats, which became hyperpolarized. In Wistar rats, CB injections of phenylephrine enhanced CB-evoked sympathoexcitation (33%; P < 0.05), which was prevented by prazosin (26%; P < 0.05) in SH rats. Tamsulosin alone reproduced the effects of prazosin in SH rats and prevented the sensitizing effect of the SCG following ES. Within the CB, α1A- and α1B-adrenoreceptors were co-localized on both glomus cells and blood vessels. In conscious SH rats instrumented for recording blood pressure (BP), the CB-evoked pressor response was attenuated after SCGx, and systolic BP fell by 16 ± 4.85 mmHg. CONCLUSIONS: The sympathetic innervation of the CB is tonically activated and sensitizes the CB of SH but not Wistar rats. Furthermore, sensitization of CB-evoked reflex sympathoexcitation appears to be mediated by α1-adrenoceptors located either on the vasculature and/or glomus cells. The SCG is novel target for controlling CB pathophysiology in hypertension.

Effect of Acute Caffeine Exposure on Blood Glucose and Hepatic Glycogen Content in Normal and Thyroidectomized Male Wistar Rats.

Acute caffeine exposure had been shown to induce hyperglycemia however; the influence of thyroid hormones on the caffeine-induced hyperglycemia is yet to be established. The present study was therefore designed to investigate the effect of caffeine exposure on blood glucose and hepatic glycogen content in thyroidectomized rats. Sixty adult male Wistar rats were randomly divided into 10 groups as I-X (n=6).  Rats in groups I, III, V, VII and IX were given normal saline, caffeine, prazosin + caffeine, propranolol +caffeine, combined prazosin+ propranolol+caffeine injections respectively while rats in groups  II, IV, VI, VIII and X were thyroidectomized  and treated in similar manner as the normal rats respectively. Surgical removal of the thyroid gland was done in the thyroidectomised groups while sham-operation was done in Normal group to serve as control. After healing and following an overnight fast, the rats were anaesthetized and the femoral vein and carotid artery were cannulated for drug administration and blood glucose measurement respectively. After stabilization, following basal measurements, rats from each group were injected normal saline or caffeine (6mg/kg) while another sets were pre-treated prazosin (0.2 mg/kg), propanolol (0.5 mg/kg) or their combination before caffeine administration. Blood glucose was then monitored for 60 minutes post-injection of caffeine at 5 minutes interval. Liver samples were collected at the end of the observation period for glycogen content determination. Caffeine caused significant increased blood glucose levels in both normal and thyroidectomized rats which were up to 210% and 180% respectively at the peak of their responses. Liver glycogen content of the thyroidectomized rats (3.11 ± 0.20 mg/100g tissue weight) was significantly higher than the normal rats (1.91 ± 0.43 mg/100g tissue weight). These glycogen contents were significantly reduced by caffeine in both normal (0.25 ± 0.04 mg/100g tissue weight) and thyroidectomized rats (1.65 ± 0.16 mg/100g tissue weight) when compared with their controls. The caffeine effects on blood glucose and hepatic glycogen content were abolished by pretreatment with propanolol or a combination of prazosin and propanolol in both normal and thyroidectomized rats but pretreatment with prazosin caused only significant reduction in hyperglycemic response to caffeine. The findings of this study suggest that caffeine-induced hyperglycemia in both normal and thyroidectomized rats are mediated through both alpha and beta adrenoceptors.

Cerebral endothelium-dependent function and reactivity to hypercapnia: the role of α1-adrenoreceptors.

We assessed hypercapnic cerebrovascular reactivity (CVR) and endothelium-dependent function [cerebral shear-mediated dilation (cSMD)] in the internal carotid artery (ICA) with and without systemic α1-adrenoreceptor blockade via Prazosin. We hypothesized that CVR would be reduced, whereas cSMD would remain unchanged, after Prazosin administration when compared with placebo. In 15 healthy adults (3 female, 26 ± 4 years), we conducted ICA duplex ultrasound during CVR [target +10 mmHg partial pressure of end-tidal carbon dioxide ([Formula: see text]) above baseline, 5 min] and cSMD (+9 mmHg [Formula: see text] above baseline, 30 s) using dynamic end-tidal forcing with and without α1-adrenergic blockade (Prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind, and randomized design. The CVR in the ICA was not different between placebo and Prazosin (P = 0.578). During CVR, the reactivities of mean arterial pressure and cerebrovascular conductance to hypercapnia were also not different between conditions (P = 0.921 and P = 0.664, respectively). During Prazosin, cSMD was lower (1.1 ± 2.0% vs 3.8 ± 3.0%; P = 0.032); however, these data should be interpreted with caution due to the elevated baseline diameter (+1.3 ± 3.6%; condition: P = 0.0498) and lower shear rate (-14.5 ± 23.0%; condition: P < 0.001). Therefore, lower cSMD post α1-adrenoreceptor blockade might not indicate a reduction in cerebral endothelial function per se, but rather, that α1-adrenoreceptors contribute to resting cerebral vascular restraint at the level of the ICA.NEW & NOTEWORTHY We assessed steady-state hypercapnic cerebrovascular reactivity and cerebral endothelium-dependent function, with and without α1-adrenergic blockade (Prazosin), in a placebo-controlled, double-blind, and randomized study, to assess the contribution of α1-adrenergic receptors to cerebrovascular CO2 regulation. After administration of Prazosin, cerebrovascular reactivity to CO2 was not different compared with placebo despite lower blood flow, whereas cerebral endothelium-dependent function was reduced, likely due to elevated baseline internal carotid arterial diameter. These findings suggest that α1-adrenoreceptor activity does not influence cerebral blood flow regulation to CO2 and cerebral endothelial function.

Vasoconstrictor and hemodynamic effects of a methanolic extract from Rhinella marina toad poison.

Rhinella marina toad is abundant in Brazil. Its poison contains cardiac glycosides called bufadienolides, which are extensively investigated for their bioactivity. Our aim was to characterize the vasoactivity of Rhinella marina poison (RmP) on the aorta of male Wistar rats. For this, the RmP was first collected and processed to obtain an alcoholic extract. To determine cardiovascular effects of RmP, we performed in vivo tests by administering RmP intravenously in doses of 0.1-0.8 mg/kg. Vascular reactivity was also performed through concentration-response curves to RmP (10 ng/mL to 200 µg/mL) in aortic segments with and without endothelium. RmP induced a concentration-dependent contraction in rat aorta which was partly endothelium-mediated. Nitric oxide contributes with this response in view that incubation with L-NAME increased the contractile response. Additionally, treatment with indomethacin [cyclooxygenase, (COX) inhibitor], nifedipine (L-type voltage-gated calcium channels blocker), and BQ-123 (ETA receptors antagonist) decreased maximum response, and ketanserin (5-HT2 receptors antagonist) decreased pEC50, suggesting active participation of these pathways in the contractile response. On the other hand, apocynin (NADPH oxidase inhibitor) did not alter contractility. Incubation with prazosin (α1-adrenergic receptor antagonist) abolished the contractile response, suggesting that the RmP-induced contraction is dependent on the adrenergic pathway. In the Na+/K+ ATPase protocol, a higher Emax was observed in the RmP experimental group, suggesting that RmP potentiated Na+/K+ATPase hyperpolarizing response. When this extract was injected (i.v.) in vivo, increase in blood pressure and decrease in heart rate were observed. The results were immediate and transitory, and occurred in a dose-dependent manner. Overall, these data suggest that the poison extract of R. marina toad has an important vasoconstrictor action and subsequent vasopressor effects, and its use can be investigated to some cardiovascular disorders.

An evidence-based approach to psychopharmacology for posttraumatic stress disorder (PTSD) - 2022 update.

Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from January 2011 to November 2021 were identified via PubMed and analyzed for evidence supporting changes. Following consideration of variations required by special patient populations, treatment of sleep impairments remains as the first recommended step. Nightmares and non-nightmare disturbed awakenings are best addressed with the anti-adrenergic agent prazosin, with doxazosin and clonidine as alternatives. First choices for difficulty initiating sleep include hydroxyzine and trazodone. If significant non-sleep PTSD symptoms remain, an SSRI should be tried, followed by a second SSRI or venlafaxine as a third step. Second generation antipsychotics can be considered, particularly for SSRI augmentation when PTSD-associated psychotic symptoms are present, with the caveat that positive evidence is limited and side effects are considerable. Anti-adrenergic agents can also be considered for general PTSD symptoms if not already tried, though evidence for daytime use lags that available for sleep. Regarding other pharmacological and procedural options, e.g., transcranial magnetic stimulation, cannabinoids, ketamine, psychedelics, and stellate ganglion block, evidence does not yet support firm inclusion in the algorithm. An interactive version of this work can be found at www.psychopharm.mobi.