Alpha-adrenergic Receptor Blockade Research Articles

Elucidation of the Molecular Signal Linking Psychological Trauma to T-lymphocyte Inflammation

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that not only exhibits significant behavioral pathology, but also increases the likelihood of comorbid inflammatory conditions such as autoimmune and cardiovascular diseases. While PTSD patients experience heightened systemic inflammation, the exact link between psychological trauma and immune dysregulation remains to be elucidated. Our group has recapitulated the psychological trauma-induced inflammatory phenotype in a pre-clinical murine model of PTSD known as repeated social defeat stress (RSDS). Importantly, a key site of this inflammation appears to originate from T-lymphocytes in the spleen, and targeted splenic nerve denervation was able to completely prevent splenic T-lymphocyte inflammation after RSDS (p<0.0001). This critical observation suggests the T-lymphocyte response to psychological trauma is neural derived as opposed to circulating, therefore, we began systematic investigation into possible neural-derived signals that may lead to enhanced T-lymphocyte inflammation. To investigate whether the signal involves the T-cell receptor (TCR), we utilized OT-I and OT-II mice that possess non-mouse antigen-restricted TCRs. RSDS induced T-lymphocyte inflammation in these mice similar to wild-type, therefore, suggesting the signal is not antigenic in nature (p>0.05). Next, we examined the role of norepinephrine and adrenergic signaling using both pharmacological blockade and genetic knockouts of both alpha and beta adrenergic receptors, but this too was insuffcient to reverse the RSDS-induced T-lymphocyte inflammation (p>0.05). Following this, we examined the role of damage associated molecular patterns (DAMPs) by pharmacological blockade of the toll-like receptor 4 (TLR4), yet again, this intervention did not attenuate T-lymphocyte inflammation after RSDS (p>0.05). Last, our data suggests interleukin 6 (IL-6) is upregulated early after psychological trauma; therefore, we examined the role for cytokine-induced T-lymphocyte inflammation. Using anti-IL-6 antibodies during RSDS, T-lymphocyte inflammation appeared blunted compared to wild-type animals (p<0.05). Moreover, T-lymphocytes treated with only IL-6 expressed similar inflammation gene profiles as those from RSDS animals (p<0.05). Taken together, our data suggest IL-6 may be the T-lymphocyte inflammation-inducing signal, but additional studies are warranted to understand the exact source of IL-6 and mechanisms underlying IL-6’s ability to drive T-lymphocyte inflammation. R01HL158521. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Designer Receptor Exclusively Activated by Designer Drug (DREADD)-Mediated Activation of the Periaqueductal Gray Restores Nociceptive Descending Inhibition After Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) patients frequently experience chronic pain that can enhance their suffering and significantly impair rehabilitative efforts. Clinical studies suggest that damage to the periaqueductal gray matter (PAG) following TBI, a principal center involved in endogenous pain control, may underlie the development of chronic pain. We hypothesized that TBI would diminish the usual pain control functions of the PAG, but that directly stimulating this center using a chemogenetic approach would restore descending pain modulation. We used a well-characterized lateral fluid percussion model (1.3 ± 0.1 atm) of TBI in male rats (n = 271) and measured hindpaw mechanical nociceptive withdrawal thresholds using von Frey filaments. To investigate the role of the PAG in pain both before and after TBI, we activated the neurons of the PAG using a Designer Receptor Exclusively Activated by Designer Drug (DREADD) viral construct. Immunohistochemical analysis of brain tissue was used to assess the location and confirm the appropriate expression of the viral constructs in the PAG. Activation of the PAG DREADD using clozapine N-oxide (CNO) caused hindpaw analgesia that could be blocked using opioid receptor antagonist, naloxone, in uninjured but not TBI rats. Due to the importance of descending serotonergic signaling in modulating nociception, we ablated spinal serotonin signaling using 5,7-DHT. This treatment strongly reduced CNO-mediated anti-nociceptive effects in TBI but not uninjured rats. To define the serotonergic receptor(s) required for the CNO-stimulated effects in TBI rats, we administered 5-HT7 (SB-269970) and 5-HT1A (WAY-100635) receptor antagonists but observed no effects. The selective 5-HT2A receptor antagonist ketanserin, however, blocked CNO's effects in the DREADD expressing TBI but not DREADD expressing sham TBI animals. Blockade of alpha-1 adrenergic receptors with prazosin also had no effect after TBI. Descending pain control originating in the PAG is mediated through opioid receptors in uninjured rats. TBI, however, fundamentally alters the descending nociceptive control circuitry such that serotonergic influences predominate, and those are mediated by the 5-HT2A receptor. These results provide further evidence that the PAG is a key target for anti-nociception after TBI.

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) 3min of baseline followed by 3min of CPT and (2) 3min of rest, 3min of Grip followed by 3min of Metabo. Protocols were carried out under control conditions and α1-adrenergic receptor blockade (oral prazosin 0.03mg·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.

Commentary: Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning.

Commentary: Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning.

Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning.

Activity of the alpha1-adrenergic receptor (α1-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral functions of the dopamine (DA) system. Indeed, intra-VTA α1-AR blockade attenuates conditioned stimulus dependent behaviors such as drug seeking responses signifying a role of the noradrenergic signaling in the VTA in conditioned behaviors. Importantly, the role of the VTA α1-AR activity in Pavlovian associative learning with positive outcomes remains unknown. Here, we aimed to examine how intra-VTA α1-AR blockade affects acquisition of cocaine-induced Pavlovian associative learning in the conditioned place preference (CPP) paradigm. The impact of α1-AR blockade on cocaine-reinforced operant responding and cocaine-evoked ultrasonic vocalizations (USVs) was also studied. In addition, both α1-AR immunoreactivity in the VTA and its role in phasic DA release in the nucleus accumbens (NAc) were assessed. We demonstrated cellular localization of α1-AR expression in the VTA, providing a neuroanatomical substrate for the α1-AR mechanism. We showed that prazosin (α1-AR selective antagonist; 1 μg/0.5 μl) microinfusion attenuated electrically evoked DA transients in the NAc and dose-dependently (0.1–1 μg/0.5 μl) prevented the acquisition of cocaine CPP but did not affect cocaine-reinforced operant responding nor cocaine-induced positive affective state (measured as USVs). We propose that the VTA α1-AR signaling is necessary for the acquisition of Pavlovian associative learning but does not encode hedonic value. Thus, α1-AR signaling in the VTA might underlie salience encoding of environmental stimuli and reflect an ability of alerting/orienting functions, originating from bottom-up information processing to guide behaviors.

Priapism secondary to antipsychotic treatments with favorable response to amisulpride

IntroductionPriapism is an abnormally prolonged erection, painful and irreducible, unrelated to sexual stimulation. Around 25-40% of cases are iatrogenic, especially associated with pharmacological treatments, of which antipsychotics (first and second generation) account for 50%.ObjectivesThe aim is to discuss a clinical case to provide further evidence.MethodsThe patient was a 37-year-old man with a diagnosis of schizophrenia who was admitted for clinical decompensation. He had stopped antipsychotic treatment three months earlier due to side effects. He reported previous episodes of priapism associated with Risperidone, Aripiprazole, Olanzapine, and Paliperidone. At admission, he was administered Asenapine 20mg with development of priapism. Treatment was stopped. The urologists performed a lavage of the corpora cavernosa and administered adrenaline. In the absence of effectiveness, surgical intervention was successfully performed. Given the psychopathological improvement, he was discharged without antipsychotic treatment and close follow-up.ResultsHe presented a new admission one month later. Amisulpride was prescribed up to 800mg/day with good evolution and no adverse effects.ConclusionsAntipsychotic-induced priapism appears to be related to the blockade of alpha-1 adrenergic receptors in the corpora cavernosa. There is a positive correlation between the affinity for the receptor and the propensity to cause priapism. The dose and duration of the medication do not appear to be correlated. Other risk factors are a history of previous episodes, restarting medication after noncompliance, use of concomitant substances or medications that cause priapism. Our choice of amisulpride was based on the fact that it has no affinity for alpha-1 adrenergic receptors.DisclosureNo significant relationships.

Alpha2-adrenergic receptor blockade in the ventral tegmental area interferes with acquisition but not retrieval of fear memories

Alpha2-adrenergic receptor blockade in the ventral tegmental area interferes with acquisition but not retrieval of fear memories

Catecholamine-induced cerebral vasospasm and multifocal infarctions in pheochromocytoma.

SummaryWe report the case of a 76-year-old male with a remote history of papillary thyroid cancer who developed severe paroxysmal headaches in the setting of episodic hypertension. Brain imaging revealed multiple lesions, initially of inconclusive etiology, but suspicious for metastatic foci. A search for the primary malignancy revealed an adrenal tumor, and biochemical testing confirmed the diagnosis of a norepinephrine-secreting pheochromocytoma. Serial imaging demonstrated multiple cerebral infarctions of varying ages, evidence of vessel narrowing and irregularities in the anterior and posterior circulations, and hypoperfusion in watershed areas. An exhaustive work-up for other etiologies of stroke including thromboembolic causes or vasculitis was unremarkable. There was resolution of symptoms, absence of new infarctions, and improvement in vessel caliber after adequate alpha-adrenergic receptor blockade for the management of pheochromocytoma. This clinicoradiologic constellation of findings suggested that the etiology of the multiple infarctions was reversible cerebral vasoconstriction syndrome (RCVS). Pheochromocytoma remains a poorly recognized cause of RCVS. Unexplained multifocal cerebral infarctions in the setting of severe hypertension should prompt the consideration of a vasoactive tumor as the driver of cerebrovascular dysfunction. A missed or delayed diagnosis has the potential for serious neurologic morbidity for an otherwise treatable condition.Learning points:The constellation of multifocal watershed cerebral infarctions of uncertain etiology in a patient with malignant hypertension should trigger the consideration of undiagnosed catecholamine secreting tumors, such as pheochromocytomas and paragangliomas.Reversible cerebral vasoconstriction syndrome is a serious but reversible cerebrovascular manifestation of pheochromocytomas that may lead to strokes (ischemic and hemorrhagic), seizures, and cerebral edema.Alpha-adrenergic receptor blockade can reverse cerebral vasoconstriction and prevent further cerebral ischemia and infarctions.Early diagnosis of catecholamine secreting tumors has the potential for reducing neurologic morbidity and mortality in patients presenting with cerebrovascular complications.

Alpha1-adrenergic receptor blockade in the ventral tegmental area modulates conditional stimulus-induced cocaine seeking

Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends particularly on phasic DA signaling downstream from the ventral tegmental area (VTA), a midbrain structure key for the regulation of cocaine seeking. In particular, the activity of the alpha1-adrenergic receptor (α1-AR), which has recently been hypothesized to modulate salience encoding, is capable of bidirectional regulation of VTA dopaminergic activity. Thus, the impact of the conditional stimuli (CSs) on drug-seeking behavior might involve α1-AR signaling in the VTA. To date, the role of VTA α1-ARs in regulating CS-induced cocaine seeking has not been studied. In male Sprague–Dawley rats, we found that intra-VTA terazosin, a selective α1-AR antagonist, attenuated CS-induced cocaine seeking in a novel context and under extinction conditions, as well as CS-induced reinstatement of cocaine seeking. In contrast, terazosin microinfusion in a dose that attenuated CS-induced cocaine seeking had no effects on CS-induced food seeking or stress (2 mg/kg yohimbine)-evoked reinstatement of cocaine seeking. The potential nonspecific effects (sedative, anxiogenic) of α1-AR blockade of the VTA were also measured in the open-field test. Finally, using immunostaining, we demonstrated dopamine β-hydroxylase (DBH)-positive afferents in the VTA of cocaine-abstinent rats, providing a neuroanatomical substrate for the α1-AR mechanism. These results demonstrated for the first time that NAergic signaling via VTA α1-ARs potently and selectively regulates CS-induced cocaine seeking. Our findings provide new neuronal mechanisms that regulate cocaine craving.

MON-381 A Missed Case of Pheochromocytoma in NF1 Patient Presenting as Pre-Eclampsia

Background Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder manifesting with skin lesions and neurofibromas. An increased risk of pheochromocytoma and paraganglioma (PPGL) is known with an estimated incidence of 0.1-5.7%1. While some data suggested screening for PPGL in NF1 patients2, this has not been emphasized on guidelines or in practice. Herein, we report a case of pheochromocytoma diagnosed in a patient with NF1 shortly after a pre-eclampsia complicated pregnancy. Clinical case A 25 year old woman with NF1 had poorly controlled hypertension, palpitations, and anxiety during her first pregnancy attributed to pre-eclampsia. She presented to the ED shortly post-partum with episodes of palpitations, tachycardia, hypotension, and GI symptoms. A CT scan of the abdomen and pelvis identified a heterogeneous, well-defined, 35 HU, left adrenal mass measuring 4.9 x 4.5 x 4.2 cm. Biochemical data noted elevated plasma metanephrines (2.42 nmol/L, n<0.49 nmol/L) and normetanephrines (15.85 nmol/L, n<0.89 nmol/L). 24 hour urinary metanephrines (1292 ug/g, n<300 ug/g), normetanephrines (4769 ug/g, n<44 ug/g), norepinephrine (731 ug/g, n<45 ug/g), and epinephrine (77 ug/g, n<20 ug/g) were elevated. She was started on an alpha-adrenergic receptor blockade (in addition to her beta and calcium channel blockers) 3 weeks, and metyrosine 3 days before she underwent a left laparoscopic adrenalectomy. A few weeks after surgery, she was able to stop all blood pressure and anxiety medications. She asked about PPGL screening in her daughter as she carries the NF1 mutation. Clinical Lesson PPGL occur in a small but meaningful number of patients with NF1, and can be associated with significant morbidity and mortality if not detected. The current guidelines suggests screening for PPGL need not be considered unless indicated by signs or symptoms. This case emphasize the significance of biochemical screening for PPGL in NF1 patients prior to elective surgical procedures and conception to avoid fatal complications.

Pheochromocytoma and paraganglioma-an update on diagnosis, evaluation, and management.

Pheochromocytomas and paragangliomas (PPGLs) generally grouped together are rare catecholamine-secreting endocrine tumors. Symptoms of catecholamine excess are non-specific and therefore a high index of suspicion in children with sustained hypertension, family history of endocrine tumors, or features of syndromes associated with PPGLs leads to a timely diagnosis and treatment. Freemetanephrines in theplasma or 24-h urine are the preferred tests to establish catecholamine excess. Considerations for false-positive conditions improve diagnostic yield and accuracy. Functional imaging, targeting either specific cell membrane transporters or vesicular catecholamine transport systems, is indicated for incidental lesions suspicious for PPGLs with inconclusive biochemical testing, assessment of regional extension or multifocality, and exclusion of metastases. Surgery is the mainstay of treatment for PPGLs. Preoperatively, sequential use of alpha adrenergic receptor blockade and volume expansion followed by beta blockade is mandatory to reduce intraoperative intravascular instability and blood pressure fluctuation due to tumor manipulation. Since genetic mutations have been reported in tumor susceptibility genes in nearly 50% of patients with PPGLs, genetic counselling and testing should be considered in all patients with a confirmed tumor.

Sex Differences in the Sympathetic Restraint of Skeletal Muscle Blood Flow in the Human Leg Vasculature

BackgroundThe sympathetic nervous system plays an important role in regulating skeletal muscle blood flow at rest and during exercise. Previous studies have identified sex differences in resting muscle sympathetic nerve activity1 and forearm alpha‐adrenergic receptor sensitivity.2 However, whether sympathetic restraint of limb blood flow differs between sexes, and the degree to which this restraint persists during dynamic exercise, is not well understood.MethodsIn four young men (28±2 yrs; 26±2 kg/m2) and six young women (24±2 yrs; 23±1 kg/m2), we evaluated changes in leg blood flow (LBF, Doppler ultrasound), mean arterial blood pressure (MAP, indwelling femoral artery catheter), and leg vascular conductance (LVC) before and after intra‐arterial infusion of phentolamine (PHEN, non‐selective alpha‐adrenergic antagonist, 5 μg/dL/min) at rest and during small muscle mass knee‐extensor (KE) exercise (15W). Influences from beta‐adrenergic receptors were blocked by intravenous administration of propranolol (0.07 mg/kg bolus).ResultsNo sex differences in LBF, MAP, or LVC were observed at rest. Following PHEN administration, sex differences were evident for both the drug‐induced increase in resting LBF (+337±79 vs. +172±43 mL/min, p&lt;0.05, men vs. women) and LVC (+3.69±1.04 vs. +1.97±0.45 mL/min/mmHg, men vs. women, p=0.06). During KE exercise, no sex differences were evident for LBF, MAP, or LVC prior to PHEN infusion, and drug administration provoked similar increases in LBF (+630±128 vs. +560±85 mL/min, men vs. women) and LVC (+7.2±1.5 vs. +6.9±1.6 mL/min/mmHg, men vs. women) between groups.ConclusionAt rest, men demonstrate a larger increase in LBF and LVC in response to local alpha adrenergic receptor blockade via PHEN infusion, suggesting a greater degree of basal sympathetic vasoconstriction than their female counterparts. However, during exercise, similar increases in leg hemodynamics were observed between men and women following PHEN administration. Together, these data support the presence of a sex difference in the sympathetic restraint of resting limb blood flow that does not persist during moderate intensity exercise.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha1-adrenergic receptor (α1-AR) signaling in the VTA affects conditioned fear. The role of α1-AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1–1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α1-AR blockade in the mammillary bodies (MB) – a brain region with α1-AR expression adjacent to the VTA. Intra-VTA but not intra-MB α1-AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α1-AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α1-AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α1-AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α1-AR signaling in the regulation of stress responsiveness and fear memory.

Alpha adrenergic receptor blockade increases capillarization and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle.

To assess the effect of elevated basal shear stress on angiogenesis in humans and the role of enhanced skeletal muscle capillarization on blood flow and O2 extraction. Limb haemodynamics and O2 extraction were measured at rest and during one-leg knee-extensor exercise (12 and 24 W) in 10 healthy untrained young men before and after 4-week treatment with an α1 receptor-antagonist (Terazosin, 1-2 mg day-1 ). Corresponding biopsies were taken from the m. vastus lateralis. Resting leg blood flow was increased by 57% 6 h following Terazosin treatment (P < 0.05), while basal capillary-to-fibre ratio was 1.69 ± 0.08 and increased to 1.90 ± 0.08 after treatment (P < 0.05). Leg O2 extraction during knee-extensor exercise was higher (4-5%; P < 0.05), leg blood flow and venous lactate levels lower (6-7%; P < 0.05), while leg VO2 was not different after Terazosin treatment. These results demonstrate that daily treatment with an α-adrenergic receptor blocker induces capillary growth in human skeletal muscle, likely due to increased shear stress. The increase in capillarization resulted in an increased fractional O2 extraction, a lower blood flow and venous lactate levels in the exercising leg. The increase in capillarization, and concomitant functional readouts in the exercising leg, may provide a basis for novel angiotherapy.

Pharmacological Effects of Gemfibrozil on Some Isolated Smooth Muscle Preparations of Experimental Animals

Background: Gemfibrozil is a member of fibrates (gemfibrozil, fenofibrate, ceprofibrate, and benzafibrate) which is employed for treatment of dyslipidemia particularly hypertriglyceridemiae through its action on peroxisome proliflator activated receptors (PPAR-α). Objective: The aim of this work was to study the site of action and pharmacololgical effects of different doses of gemfibrozil on some isolated smooth muscles preparations of experimental animals. Materials and Methods: The experiments were conducted on isolated jejunum of rabbits, isolated spiral tracheal and urinary bladder strips of guinea pigs. Results: I- On isolated rabbit jejunum, gemfibrozil produced a dose-dependent reduction on the amplitude of jejunal contractions. The inhibitory effect of gemfibrozil was not abolished after complete blockade of alpha and beta adrenergic receptors, while it was completely abolished after inhibition of nitric oxide synthase by N-methyl L-arginine. On the other hand the stimulatory effects of nicotine small dose, acetylcholine, calcium gluconate, histamine and serotonin were not abolished after administration of gemfibrozil. II- On isolated tracheal spiral strips of ginea pigs, gemfibrozil produced a dose- dependent relaxation on the basal tone and a dose-dependent reduction on the amplitude of acetylcholine-induced tracheal contractions of the tracheal strips. The inhibitory effect of gemfibrozil was completely abolished after inhibition of nitric oxide synthase by N-methyl L-arginine. Gemfibrozil completely abolished also serotonin-induced contraction, while it has no effect on histamine or calcium-induced tracheal contractions. III- On isolated urinary bladder strips of guinea pigs, gemfibrozil produced a dose-dependent reduction on the amplitude of urinary bladder contractions. The inhibitory effect of gemfibrozil was not abolished after complete blockade of beta adrenergic receptors, while it was completely abolished after inhibition of nitric oxide synthase by N-methyl L-arginine. On the other hand the stimulatory effects of acetylcholine and serotonin were not abolished after administration of gemfibrozil. Conclusion: Gemfibrozil (antidyslipidemic, PPAR-α agonist) reduced jejunal and urinary bladder contractions and has a relaxant effect on tracheal basal tone. So it has a beneficial effect in obstructive airway diseases and cases of urgency and frequency of micturation and urinary incontinence. However, it may be used cauciously in cases of ,GIT disturbances as constipation and prostatic hypertrophy.

Pharmacological evidence of α-adrenergic receptors in the hypotensive effect of Chamaemulum nobile L.

This study aims to evaluate the underlying mechanism of action involved in the hypotensive effect of Chamaemulum nobile L. (Cn) aqueous extract and in anesthetized Wistar rats. Lyophilized aqueous extract was administered in the jugular vein, arterial blood pressure and heart rate were measured in the carotide artery over 120 min of injection throughout an invasive direct blood pressure measuring procedure. Intravenous bolus injection of aqueous Cn extract at the doses of 50, 100 and 200 mg/kg produced a dose dependent reduction in arterial blood pressure and heart rate (p<0.001). Specific receptor antagonists (Phentolamine, Terazosin and Atropine) and pharmacological agents (N(omega)-Nitro-L-Arginine Methyl Ester and Captopril) were used for determining the underlying mechanism involved in the hypotensive effect of Cn. Only Phentolamine treatment (2 mg/kg) reduced significantly the hypotensive effect of aqueous Cn extract at a dose of 200 mg/kg. Intravenous perfusion of aqueous Cn extract caused a significant reduction of arterial blood pressure (p<0.01) and reduced the hypertensive effect of intravenous injection of norepinephrine at a dose of 1 &#181;g/kg. We conclude that aqueous Cn extract exhibits a hypotensive effect which may be probably due to an alpha adrenergic receptor blockade mechanism.

Pheochromocytoma in pregnancy

Pheochromocytoma occurs with a frequency estimated at 2-7 per 100,000 pregnant women. Unrecognized, and thus untreated pheochromocytoma is associated with very high (40-50%) maternal and fetal mortality. Pheochromocytoma occurs sporadically or as a family trait. Its presence should be suspected in women with paroxysmal or established hypertension, especially before the 20th week of pregnancy, accompanied by headaches and palpitations, and excessive sweating, muscle tremors, vomiting, anxiety, vasomotor disturbances and blurred vision. The variety of clinical presentations and rarity are the cause of not including the disease in differential diagnosis of hypertension in pregnancy. Biochemical tests are essential in the diagnosis of pheochromocytoma, and involving the assessment of methoxycatecholamine urinary excretion. The second step in the diagnostics is magnetic resonance imaging of adrenal glands. Adrenalectomy is the treatment of choice for pheochromocytoma with adrenal location, which depends on the timing of the tumor diagnosis. Conservative treatment for 10-14 days with pharmacological blockade of alpha-adrenergic receptors should precede the surgery. Early diagnosis and properly planned treatment of pheochromocytoma significantly reduces the risk to the mother and fetus.

Evaluation of the antihypertensive activity and alpha adrenergic receptor interaction of cleistanthins A and B.

Hypertension was induced in male Sprague Dawley rats with twice weekly administration of deoxycorticosterone acetate (DOCA) salt (20 mg/kg s.c) for 4 weeks. They were divided into eight groups of six animals each viz., hypertensive control, standard (prazosin 1 mg/kg), cleistanthin A 12.5, 25, 50 mg/kg and cleistanthin B 12.5, 25 mg/kg, and 50 mg/kg. One more group served as normal control. The hypertension was induced in 4 weeks, and the animals were given assigned treatment in 5th week. The alteration in blood pressure (BP) was recorded weekly using a rodent noninvasive blood pressure system. At the end of the experiment alpha-adrenergic receptor response of drugs like adrenaline, nor adrenaline, dopamine (doses 1 μg and 2 μg) was recorded invasively. Two-way repeated measures ANOVA followed by Bonferroni post-hoc test was used to analyze the data. The systolic BP and diastolic BP of test groups rose to a higher level after DOCA administration and fell to the normal range (P < 0.05) following the administration of cleistanthins A and B. There were no differences in the weekly heart rate among the groups. In the test group animals pretreated with prazosin and cleistanthins, adrenaline, noradrenaline and dopamine failed to raise the mean arterial pressure and the end-diastolic pressure from baseline (P > 0.05) cleistanthins A and B exert a significant antihypertensive effect through alpha-adrenergic receptor blockade similar to prazosin.

Effects of selective versus nonselective alpha adrenergic receptor blockade on cardiovascular parameters, body temperature and sympathetic tone in rats

Effects of selective versus nonselective alpha adrenergic receptor blockade on cardiovascular parameters, body temperature and sympathetic tone in rats

Vasorelaxant effect of ranolazine on isolated normal and diabetic rat aorta: A study of possible mechanisms

Ranolazine, an antianginal drug, acts through blocking the cardiac late sodium channels and/or inhibition of fatty acids beta-oxidation. While its cardiac action has been studied extensively, few studies have focused on its vascular effects. In the present study, the vasodilatory effect of ranolazine on isolated rat aorta in normal and diabetic rats has been studied. The effect of cumulative concentrations of ranolazine on aortic rings precontracted with phenylephrine, calcium and KCl (40 and 100 mM; in the absence and presence of glibenclamide) were studied and its potency and maximum relaxant effects were calculated. Ranolazine relaxed the phenylephrine and calcium induced contractions in both the normal and diabetic aortas. It also relaxed the contractions induced by both low and high concentrations of KCl. Preincubation of the tissues with glibenclamide had no effect. The potency and maximum effect of ranolazine did not differ significantly between the normal and diabetic rings except when the tissues were contracted by calcium in which ranolazine showed greater potency toward normal tissues. It is concluded that ranolazine could relax the aortic contractions in both normal and diabetic states. It seems that both blockade of alpha-adrenergic receptors and voltage-operated calcium channels contribute to this effect.