Alpha-receptor Stimulation Research Articles

Abstract 18940: Can the Religious Observation of Fasting Cause Prinzmetal’s Angina?

CASE DESCRIPTION: A 73-year-old male with HTN, HLD, CAD/MI status post PCI to the RCA and LAD (2021), and former tobacco use presented with acute, severe, left-sided chest pain with nausea, diaphoresis and dizziness. He started fasting and adjusted his sleep schedule 3 days prior for Ramadan, but did not miss any of his medications including isosorbide and ranolazine. He was chest pain free on arrival, but subsequently developed severe chest pain becoming bradycardic, hypotensive and hypoxic. At that time the EKG (Figure 1) showed ST elevation (STEMI) in leads II, III and aVF with high degree atrioventricular block. He was started on intravenous fluids and a vasopressor but had spontaneous resolution of symptoms within 10 minutes. Emergent coronary angiography revealed stable 70% stenosis of an ostial left circumflex (LCx) artery and non-obstructive CAD of the RCA. Labs revealed normal blood glucose, negative urine toxicology and mild elevation of troponin (trended serially). Echocardiogram was normal with no regional wall motion abnormalities. He was treated as vasospastic angina with addition of a calcium channel blocker without recurrence of his symptoms. DISCUSSION: Vasospastic angina is an important cause of acute coronary syndrome. Our patient had severe vasospastic angina while being treated for CAD for over 10 years. No prior studies have linked fasting to vasospasm. We hypothesize that fasting and a diurnal sleep schedule may contribute to worsened episodes in susceptible individuals due to hormonal changes including glucose shifts and an increase in catecholamines and cortisol. Increased catecholamine levels may induce spasm by stimulation of alpha receptors in the coronary arteries, and cortisol can induce vascular inflammation, potentiating negative effects. We highlight the importance of keeping high clinical suspicion for a diagnosis of vasospasm, as well as the need to further understand the complex pathophysiology to counsel patients in the future.

836 Elucidating the cellular composition of lipomas to develop targeted treatment

Lipomas are benign tumors that consist of mature adipocytes. Most lipomas are sporadic, but some familial conditions predispose affected individuals to the development of up to thousands of lipomas. Currently, no targeted treatments exist. To develop such an agent, the cellular composition of lipomas must be elucidated. Using single-cell resolution techniques, we have successfully begun to characterize the transcriptomic landscape of lipomas. By determining the transcriptome of lipoma-derived adipocytes, we confirmed that lipomas consist of white adipocytes (WAT), not brown or beige types. We also compared lipomatous tissue to physiological WAT by single-cell RNA-sequencing and found that cellular composition was strictly conserved between the two. 4 major cell types were identified in lipomas: fibroblasts, immune, mural, and adipocyte progenitor cells. We conducted receptor expression profiling with 6 lipomas from different anatomic locations using a TaqMan array assay. The goal was to identify adrenergic and muscarinic receptors as potential therapeutic targets since modulators of these receptors are widely used in medical settings. 9 adrenergic and 3 muscarinic genes were selected, and the results were largely consistent between the samples. Alpha-1A, followed by beta-2, were the most highly expressed receptors. Stimulation of alpha-1 receptors in human adipose tissue has been shown to increase rates of lipolysis supporting its potential therapeutic capacity in lipomas. Surprisingly, the beta-3 receptor was minimally expressed or undetectable in all samples. In physiological WAT, the beta-3 receptor plays a vital role in the remodeling of WAT via lipolysis and fatty acid oxidation suggesting that these metabolic activities may be induced by different receptor-signaling pathways in lipomas than physiological WAT. To our knowledge, this is the first study to identify specific receptors types amongst several lipoma samples. These conclusions suggest that targeting alpha-1A and beta-2 receptors in lipomas may represent a novel medical treatment for their reduction.

Effects of vasoactive drugs on crystalloid fluid kinetics in septic sheep

PurposeCrystalloid fluid and vasoactive drugs are used in the early treatment of sepsis. The purpose of the present study was to examine how these drugs alter plasma volume expansion, peripheral edema, and urinary excretion.MethodsTwenty-five anesthetized sheep were made septic by cecal puncture and a short infusion of lipopolysaccharide. After 50 min, a slow infusion of isotonic saline was initiated: the saline either contained no drug, norepinephrine (1 μg/kg/min), phenylephrine (3 μg/kg/min), dopamine (50 μg/kg/min), or esmolol (50 μg/kg/min). Ten min later, 20 mL/kg Ringer´s lactate solution was given over 30 min. Central hemodynamics, acid-base balance, and the urinary excretion were monitored. Frequent measurements of the blood hemoglobin concentration were used as input in a kinetic analysis, using a mixed effects modeling software.ResultsThe fluid kinetic analysis showed slow distribution and elimination of Ringer´s lactate, although phenylephrine and dopamine accelerated the distribution. Once distributed, the fluid remained in the peripheral tissues and did not equilibrate adequately with the plasma. Overall, stimulation of adrenergic alpha1-receptors accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. A pharmacodynamic Emax model showed that Ringer´s lactate increased stroke volume by 13 ml/beat. Alpha1-receptors, but not beta1-receptors, further increased stroke volume, while both raised the mean arterial pressure. Modulation of the beta1-receptors limited the acidosis.ConclusionsStimulation of adrenergic alpha1-receptors with vasoactive drugs accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. The tendency for peripheral accumulation of fluid was pronounced, in particular when phenylephrine was given.

Pathophysiology of dilatation of pupils due to scorpion and snake envenomation and its therapeutic value: Clinical observations.

Dilated nonreacting pupils are routinely taken as a sign of irreversible brain damage. Alpha-receptor stimulation (scorpion sting) and presynaptic acetylcholine receptor blocker (krait bite) may result in dilation of pupils without involvement of the brain. This study was aimed to clinically evaluate the response of pupils in scorpion sting and krait bite. Victims of scorpion sting and krait bite were chosen from Raigad district. Scorpion sting and krait bite cases were admitted to hospital and were clinically evaluated in detail regarding neurological manifestations. Both cases had nonreacting dilation of pupils, complete neurological recovery accompanied with reverse of pupillary size and its response to light. In scorpion sting and krait bite poisoning, dilated nonreacting pupils are not the signs of irreversible brain damage.

Scorpion bite, a sting to the heart and to coronaries resulting in Kounis syndrome.

Sir, In the very interesting paper published in IJCCM,[1] the authors reported on a 14-year-old-boy who was bitten by scorpion and developed chest pain, vomiting, loose stools, cold sweating, raised jugular venous pressure, tachycardia and hypotension. Laboratory findings showed increased troponin T, proBNP and CPKMB, bilateral lung fluffy shadows, reduced ejection fraction, and ST segment elevation in II, III, aVF, V3, V4, V5, and V6, and T-wave inversion in I, aVL, V1 and V2 leads compatible with acute myocardial injury and pulmonary oedema. This case raises the following important questions on pathophysiology, treatment, and differential diagnosis of scorpion envenomation: Centruroides and parabuthus scorpions are associated primarily with neuromuscular toxicity, whereas androctonus, buthus, and mesobuthus scorpion envenomation is associated with cardiovascular involvement, resulting from hyperstimulation of autonomic centers release of catecholamines and vasoactive peptides. Since venom specific immunoglobulin E (IgEs) have been identified by using skin tests and IgE immunoblots and mast cell degranulation and histamine release are also involved in scorpion venom-induced-inflammatory pain, hypersensitivity cardiovascular involvement is also present[2] Myocardial infarction has been reported following scorpion envenomation on some occasions.[3,4] Scorpion envenomation may result in immediate late and delayed hypersensitivity reactions in susceptible individuals. Cardiovascular toxicity implies venom amount-dependent action with progressing effects, while hypersensitivity means inflammation causing either Kounis hypersenstivity-associated acute coronary syndrome or hypersensitivity myocarditis, which are not venom amount dependent and may arise at any time during or soon after envenomation. It seems likely that the described patient developed coronary vasospasm manifesting as Type I variant of Kounis syndrome progressing to myocardial injury.[5] Hypersensitivity or toxic myocarditis could not be confirmed because neither coronary angiography nor magnetic resonance imaging was available. Coronary angiography is normal in myocarditis while in Kounis syndrome may reveal the coronary spasm. Magnetic resonance imaging shows subendocardial concentration of gadolinium in Kounis syndrome while in myocarditis the gadoliniun is concentrated in subepicardial areas[5] Several studies have shown no significant difference in patients on steroids and in steroid-free patients in terms of mortality and intensive care unit length of stay. The hydrocortisone hemisuccinate regimen has limited effect in critically ill envenomated children and, therefore, it should not be recommended.[6] Antivenom combined with prazosin and dobutamine is indicated for cardiovascular effects and benzodiazepines for neuromuscular involvement. Adrenaline and fluid resuscitation – not glucocorticoids, antihistamines, or mast-cell stabilizers – are the mainstays of treatment for scorpion venom-induced anaphylaxis. However, administration of antihistamines and mast cell stabilizers, but not hydrocortisone, could be used as a supplementary treatment of life-threatening scorpion envenomation. The described patient developed a pulmonary edema and received corticosteroids but not prazosin. Alpha receptor stimulation plays an important role in the pathogenesis of pulmonary edema. The use of prazosin, a postsynaptic alpha blocker, is recommended for significant sympathetic symptoms. Cardiogenic pulmonary edema with arterial hypertension responds favorably to prazosin. Oral prazosin is fast acting, easily available, and highly effective. Corticosteroids are beneficial in interstitial noncardiogenic pulmonary edema. Scorpion envenomation is a complex condition, which requires rigorous action, meticulous treatment and careful follow-up.

Prazosin treatment in the management of scorpion envenomation

Scorpion stings represent an important and serious public health problem worldwide due to their high incidence and potentially severe and often fatal clinical manifestations. Children are at greater risk of developing severe cardiac, respiratory, and neurological complications due to lesser body surface area. Alpha receptor stimulation plays important role in the pathogenesis of pulmonary edema. Prazosin, a post synaptic alpha blocker, can be recommended as an effective drug in the treatment of serious scorpion envenomations with significant sympathetic symptoms. Oral prazosin is fast acting, easily available, relatively cheap, free from any anaphylaxis and highly effective.

Time for Reassessment: A Review of Beta-blockers in the Setting of Cocaine Associated Chest Pain and Acute Coronary Syndrome

Cocaine is the second most commonly used illicit drug in the United States, 1 and is the most frequent illicit substance to precipitate an emergency room visit, responsible for over 550,000 visits in 2007 alone. 2 The majority of patients present with a chief complaint of chest pain3, and approximately 6% are diagnosed with cocaine associated myocardial infarction.4For decades it has been thought that beta-blockade in the setting of cocaine use would precipitate coronary vasospasm and worsen cardiovascular outcomes due to unopposed alpha receptor stimulation. In 1999 this thinking was incorporated into the ACC/AHA guidelines, which currently recommend beta-blockers in all patients with an acute coronary syndrome except in the setting of prior cocaine use.4 Recently there have been several studies suggesting benefit from beta-blocker administration in patients with cocaine associated chest pain and myocardial ischemia.

Co–Analgetika – heute und morgen – Eine rezeptorbasierte Übersicht analgetischer Therapieoptionen

The sensation of pain arises through stimulation of peripheral nociceptors and is transmitted centrally involving several receptors and ion channels. In addition many endogenous physiologic pain-modulating mechanisms exist. Besides of classical analgesics, numerous other drugs showed analgesic properties based on diverse modes of actions along the pain pathway. These co-analgesics, administered in combination with classical drugs, are able to reduce painful states of different origin. We describe the peripheral action sites of co-analgesics, such as cannabinoids, capsaicin, bisphosphonates, steroids and somatostatin. We also summarise the effect of peripherally and centrally acting ion-channel blockers, e.g. local anaesthetics, carbamazepine and tolperisone working on sodium channels and gabapentin and pregabalin working on calcium channels. Finally, central analgesic mechanisms are discussed, for instance the inhibition of NMDA-receptors by ketamine or magnesium, the stimulation of alpha2-receptors by clonidine, tizanidine or antidepressants, the activation of GABA-receptors through baclofen and other analgesic mechanisms of i.e. ondansetron and neostigmine.

Phosphorylation of contractile proteins in response to α- and β-adrenergic stimulation in neonatal cardiomyocytes

alpha- and beta-Adrenergic receptor agonists induce an inotropic response in the adult heart by promoting the phosphorylation of several regulatory proteins, including myosin-binding protein C (MyBP-C), cardiac troponin I (cTnI), and phospholamban (PLB). However, the adrenergic-induced phosphorylation of these proteins has not been characterized in the developing heart. Accordingly, we evaluated MyBP-C, cTnI, and PLB phosphorylation in cultured neonatal rat cardiomyocytes (NRCMs) after alpha- and beta-receptor activation with phenylephrine and isoproterenol. alpha-Receptor stimulation increased, whereas beta-receptor activation reduced MyBP-C phosphorylation. Isoelectric-focusing experiments indicated that the amount of monophosphorylated MyBP-C was sensitive to alpha-adrenergic activation, but diphosphorylated and triphosphorylated MyBP-C levels were largely unaffected. The phosphorylation of cTnI and PLB was consistent with the mechanism observed in adult hearts: alpha- and beta-Receptor stimulation phosphorylated both proteins. For cTnI, the greatest difference associated with beta-receptor activation was observed in the diphosphorylated state, whereas alpha-receptor activation was associated with a marked increase in the tetraphosphorylated protein and absence of the unphosphorylated state. Despite these apparent changes in cTnI and PLB phosphorylation, beta-receptor activation failed to alter calcium transients in NRCMs. Collectively, these findings suggest that, unlike cTnI and PLB, MyBP-C and inotropy are not coupled to beta-adrenergic stimulation in NRCMs. Therefore, cTnI and PLB probably play a more central role in modulating contractile function in NRCMs in response to catecholamines than does MyBP-C, and MyBP-C may have a structural role in stabilizing thick filament assembly rather than influencing cross-bridge formation in developing hearts.

Effects of chronic infusion of norepinephrine on cardiac structure, function, and biochemistry: Physiologic versus pathologic hypertrophy

Ventricular hypertrophy should be divided into at least physiologic and patholgic states in order to clarify structural and functional clinical alterations. The elucidation of the structural, functional, and biochemical mechanisms of ventricular hypertrophy is vital to designing effective preventive and therapeutic measures for the hypertensive patient. Tissue markers may help differentiate pathologic from physiologic hypertrophy. Studies have established the concept that norepinephrine may be a myocardial cellular hypertrophying hormone. The studies ranged from the direct application of norepinephrine to isolated myocardial cells to the chronic subhypertensive infusion of norepinephrine into the conscious, free-roaming dog. Norepinephrine infusion can produce physiologic ventricular hypertrophy or a pathologic state of hypertrophic cardiomyopathy, the former by a three- to four-month infusion and the latter by an infusion of more than six months. The biochemical effect of subhypertensive infusion of norepinephrine was studied prior to the production of ventricular hypertrophy, thereby permitting the elucidation of the mechanism of the hypertrophic process. The biochemical stimulus for the production of myocardial cellular hypertrophy is postulated to be a diminution of cyclic AMP and a stimulation of alpha-1 receptors. Because the ventricular septum has the highest content of adenylate cyclase, which does not increase with cyclic AMP, these changes are postulated to be the biochemical basis for septal hypertrophy in the disease entity hypertrophic cardiomyopathy. A unique conscious-canine model for the production of a myocardial infarction capable of creating a controlled localized occlusion of the coronary artery is presented.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of Bioamine Metabolism by 5‐HT2B and α1D Autoreceptors through Reactive Oxygen Species and Tumor Necrosis Factor‐α Signaling in Neuronal Cells

Homeostasis of the central nervous system relies on the proper integration of cell-signaling pathways recruited by a variety of neuronal and non-neuronal factors, with the aim of tightly controlling neurotransmitter metabolism, storage, and transport. We took advantage of the 1C11 neuroectodermal cell line, endowed with the capacity to selectively differentiate into serotonergic (1C11(5-HT)) or noradrenergic (1C11(NE)) neurons, to identify functional targets of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) autoreceptors possibly involved in the control of neuronal functions. We demonstrate that 5-HT(2B) and adreno alpha(1D) receptors are coupled to reactive oxygen species (ROS) production through NADPH oxidase activation in 1C11(5-HT) and 1C11(NE) neuronal cells, respectively. In the signaling cascade linking 5-HT(2B) receptors to NADPH oxidase, phospholipase A2-mediated arachidonic acid production is required for ROS synthesis. ROS, in turn, act as second message signals and control the activation of TACE (TNF-alpha converting enzyme), a member of a disintegrin and metalloproteinase family. 5-HT(2B) and alpha(1D) receptor stimulation triggers TACE-dependent TNF-alpha shedding in the surrounding milieu of 1C11(5-HT) and 1C11(NE) cells. In these cells, shed TNF-alpha triggers degradation of 5-HT and NE into 5-HIAA and MHPG, respectively. Finally, we observe that 5-HT(2B) and alpha(1D) receptor couplings to the NADPH oxidase-TACE cascade are strictly restricted to 1C11-derived progenies that have implemented a complete neuronal phenotype. Altogether, our data indicate that couplings of 5-HT(2B) and alpha(1D) autoreceptors to ROS and TNF-alpha signaling control neurotransmitter metabolism in 1C11-derived neuronal cells. Eventually, we might explain the origin of oxidative stress and high level of TNF-alpha in neurodegenerative diseases as a consequence of deviation of normal signaling pathways coupled to neurotransmitters.

Endogenous Excitatory Drive Modulating Respiratory Muscle Activity across Sleep–Wake States

The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotransmitter substrate mediating respiratory muscle activation across sleep-wake states has not been identified. We determined if alpha1 receptor antagonism at the hypoglossal motor nucleus (HMN) decreases genioglossus (GG) activity consistent with a role for an endogenous noradrenergic drive contributing to GG activation across sleep-wake states. We also determined if alpha1 receptor stimulation could counteract reduced endogenous noradrenergic drive and increase sleeping GG activity. Thirty-five rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and GG and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN. Microdialysis perfusion of the alpha1 receptor antagonist terazosin into the HMN significantly decreased GG activity in wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. The alpha1 receptor agonist phenylephrine increased GG activity in wakefulness and sleep, but periods of motor inactivity persisted in REM sleep; there was no potentiating effect of combined alpha1 and 5-HT2 receptor stimulation. Identification of an endogenous noradrenergic drive contributing to GG activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and obstructive sleep apnea in humans and the potential for pharmacologic treatment.

Sedation Using Dexmedetomidine in Pediatric Burn Patients

Maintaining appropriate sedation and analgesia in pediatric burn patients can be quite challenging and often requires high doses of analgesics and anxiolytics because tolerance quickly develops. Escalating doses of opioids and benzodiazepines provide little additional benefit while increasing the incidence of side effects. Dexmedetomidine (DEX) is a novel alpha2-adrenergic agonist that provides sedation, anxiolysis, and analgesia with much less respiratory depression than other sedatives. In addition, DEX stimulation of alpha2 receptors on pancreatic beta cells may inhibit insulin secretion. Hyperglycemia has not been studied specifically in patients receiving DEX. Therefore, we hypothesized that DEX would improve sedation compared with our standard sedation regimen. In addition, we studied the effects of DEX on blood glucose levels. We performed a retrospective chart review of 65 pediatric burn patients (42 boys, 23 girls) in the intensive care unit admitted between 2001 and 2004 who received DEX infusion because of failure to achieve adequate sedation with our standard regimen of opioids and benzodiazepines. We recorded age, TBSA burn size, weight, dose and duration of infusion, adequacy of sedation before and after initiation of DEX, blood glucose levels before and after DEX, and the presence or absence of mechanical ventilation. The mean age was 5 years (range, 0.6-17), burn size was 36% TBSA (range, 3-94), and weight was 26 kg (range, 8-100). All patients were rated "inadequately sedate" before DEX infusion was initiated at 0.2 mug/kg/hr and titrated to effect. Twenty-six patients received a loading dose of 1 mug/kg. The average duration of DEX infusion was 11 days (range, 2-50), and no tachyphylaxis was noted. The mean dose was 0.5 mug/kg/hr (range, 0.1-2). Infusions were weaned over the course of 12 to 24 hours without evidence of rebound hypertension or withdrawal. With DEX titration, all patients were rated "adequately sedate," even though all were sedation failures with opioids and benzodiazepines. Eleven of 42 patients receiving ventilatory support were extubated while on DEX infusion, and no patient showed evidence of DEX induced respiratory depression. Patient's blood glucose levels averaged 121.2 +/- 8.9 mg/dl while on DEX infusion and 117.1 +/- 12.1 mg/dl while off, a nonsignificant difference.

Alternate Pathways of Thyroid Hormone Metabolism

The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and sulfated iodothyronines can be hydrolyzed to their precursors in gastrointestinal tract and various tissues. Thus, these conjugates can serve as a reservoir for biologically active iodothyronines (e.g., T(4), T(3), or T(2)). The acetic acid derivatives of T(4), tetrac and triac, are minor products in normal thyroid physiology. However, triac has a different pattern of receptor affinity than T(3), binding preferentially to the beta receptor. This makes it useful in the treatment of the syndrome of resistance to thyroid hormone action, where the typical mutation affects only the beta receptor. Thus, adequate binding to certain mutated beta receptors can be achieved without excessive stimulation of alpha receptors, which predominate in the heart. Ether link cleavage of TH is also a minor pathway in normal subjects. However, this pathway may become important during infections, when augmented TH breakdown by ether-link cleavage (ELC) may assist in bactericidal activity. There is a recent claim that decarboxylated derivates of thyronines, that is, monoiodothyronamine (T(1)am) and thyronamine (T(0)am), may be biologically important and have actions different from those of TH. Further information on these interesting derivatives is awaited.

Poster 184: β-Blockade exacerbates hypertension in autonomic dysreflexia: a case report.

Setting: Tertiary care Veterans Affairs medical center. Patient: A 52-year-old man with a C6 American Spinal Injury Association class B spinal cord injury (SCI). Case Description: The patient transferred from another hospital to our rehabilitation unit. He was well known to the rehabilitation team and had a history of autonomic dysreflexia usually secondary to bowel or bladder issues, but no hypertension. At admission, he was noted to be on 50mg of metoprolol twice a day with blood pressure significantly higher than his baseline. His indwelling urinary catheter was patent and his bowel program was effective. He had a stage III pressure ulcer. An extensive work-up revealed no causes for autonomic dysreflexia. His elevated blood pressure was treated with a calcium channel blocker, which was minimally effective with pressures as high as 190/93. Assessment/Results: The metoprolol was discontinued and the following day his blood pressure began to normalize. Within 3 days, blood pressure was within a desirable range without pharmacologic management. Discussion: This is the first reported case, to our knowledge, of a β-blocker exacerbating hypertension in an SCI patient prone to autonomic dysreflexia. It is stated in DeLisa’s Rehabilitation Medicine, 3rd edition, that β-blockers are to be avoided in autonomic dysreflexia because of the potential adverse effects of unopposed peripheral alpha stimulation. A physiologic possibility exists that, in a hyperadrenergic state, a β-blocker would cause unopposed alpha-receptor stimulation with subsequent peripheral vasoconstriction and elevated blood pressure. A study of rats with autonomic dysreflexia has demonstrated blood pressure elevations with the use of propanolol. Conclusion: β-blockade in autonomic dysreflexia may allow for unopposed alpha stimulation and subsequent exacerbation of hypertension.

Iodinated radiographic contrast media inhibit the capacitative calcium entry into smooth muscle cells of the swine renal artery.

To investigate whether nonionic, iodinated, radiographic contrast media (RCM) could modulate calcium release from or calcium entry into smooth muscle cells of the swine renal artery. Intracellular calcium concentrations of isolated myocytes loaded with the calcium-sensitive dye fluo-3 were analyzed using a fluorescence imaging system. Calcium signals were compared with isometric contractions of vascular segments in an organ bath. The effects of the triiodinated monomer iomeprol were compared with those of a mannitol solution. Stimulation of alpha-receptors by phenylephrine caused a biphasic calcium signal. Transient liberation of calcium from intracellular stores triggered the sustained entry of extracellular calcium (capacitative entry). Iomeprol and mannitol slightly inhibited the initial transient spike to the same extent. The calcium influx was reversibly inhibited by RCM by about 50%. Up to a concentration of 40 mmol/L, the inhibition induced by iomeprol was significantly higher than that induced by mannitol (P < 0.05-0.01). In isolated arterial segments, relaxation of the contraction phase depending on the calcium influx was significantly higher with the RCM than with mannitol (P < 0.01). Vasodilatation by CM is associated with a reduction in the capacitative entry of calcium. The mechanism of this effect is not clear, but it can be ruled out that it is mainly due to the high osmolarity of these compounds.

Pathogenesis of HIV-related pulmonary hypertension.

Human immunodeficiency virus (HIV)-related pulmonary hypertension (HRPR) is a cardiovascular complication of HIV infection that has been recognized in the last years with increasing frequency. The etiology of HRPH is unknown. All the attempts to isolate HIV on pulmonary vessels in HRPH patients failed, and an indirect role for HIV in this disease has been hypothesized. Current theories on the pathogenesis focus on abnormalities of endothelial and smooth muscle cells of pulmonary vasculature. Endothelial and smooth muscle cell injury could be due to a high production or to a reduced clearance of cytokines in these patients. In fact, in several studies high levels of ET-1, IL-1alpha, IL-6 and PDGF in primary pulmonary hypertension (PPH) and in HRPH have been found. HIV gp 120 could induce the production of these cytokines by a stimulation of monocytes/macrophages. A high alpha1-adrenoreceptors stimulation of pulmonary vessels could be also implicated in the pathogenesis of HRPH. Chronic hypoxia is observed with increased frequency in HIV patients, and this could induce a chronic stimulation of alpha1-receptors of pulmonary vasculature with typical pathological changes. However, only a small percentage of HIV- patients develop HRPH. This observation suggests the existence of an idiosyncratic susceptibility to the development of vascular disease. This susceptibility could have a genetic basis, and might be determined by particular major histocompatibility complex alleles.

Direct actions of adrenergic agents on rat anterior pituitary cells.

We studied the effects of adrenergic agents on the five main cell types of the rat anterior pituitary by monitoring the changes of the cytosolic free [Ca2+] ([Ca2+]i) in single cells that were identified by multiple sequential primary immunocytochemistry at the end of the Ca2+ measurements. Adrenaline (100 nM) increased [Ca2+]i in 30% of the cells. Responses were most prominent in somatotrophs and corticotrophs (40-65% of the cells responded) whereas the other three cell types, lactotrophs, thyrotrophs and gonadotrophs, gave poorer responses. Selective agonists and antagonists revealed the presence of both alpha1- and beta-adrenergic receptors. Alpha1-receptors dominated in corticotrophs, beta-receptors in somatotrophs. The alpha1-adrenergic responses increased with culture of the cells. The beta-adrenergic responses were mediated by cAMP and consisted of stimulation of Ca2+ entry through L-type voltage-gated channels. Stimulation of alpha1-receptors released Ca2+ from intracellular stores in corticotrophs and induced cAMP-independent Ca2+ entry in somatotrophs. The effects of alpha1-agonists were additive with those of the releasing factors growth hormone-releasing hormone (GHRH) and corticotropin releasing factor (CRF) whereas those of the beta-agonists were not. Our results suggest that direct effects of plasma catecholamines on AP cells may contribute to the hormonal response to stress.

Role of Ca2+-sensitive protein kinase C in phenylephrine enhancement of Ca2+ sensitivity in rat tail artery.

We investigated the role of protein kinase C (PKC) isoforms on changes in sensitivity of contractile mechanisms to intracellular Ca(2+) (force /[Ca(2+)]i) by phenylephrine (0.1-100 microM) in rat tail arterial helical strips using simultaneous measurements of force and [Ca(2+)]i. Force/[Ca(2+)]Ii induced by phenylephrine was greater than that induced by 80 mM K+. Force/[Ca(2+)]i induced by phenylephrine in physiologic saline solution or low Ca(2+) solution was dependent on the agonist concentration. Removal of Ca(2+) completely abolished the phenylephrine-induced contraction. The PKC inhibitors staurosporine and calphostin C inhibited the increase in force/[Ca(2+)]i induced by phenylephrine to a much greater extent than that induced by 80 mM K+. LY379196, a specific PKCbeta inhibitor, did not inhibit the increase of calcium sensitivity due to phenylephrine. The classic PKC isoforms, alpha, betaI, and II not gamma were demonstrated in the artery by immunohistochemistry. These results suggest that in rat tail arterial smooth muscle, PKCalpha, and not beta or gamma, mediates the increase of changes in sensitivity of contractile mechanisms to intracellular Ca(2+) to high dose of alpha1 receptor stimulation (phenylephrine 100 microM) on nonphysiologic conditions.

The pharmacology of the internal anal sphincter and new treatments of ano-rectal disorders.

Surgical options for faecal incontinence in the presence of intact sphincters are limited. Furthermore, in patients with fissures, lateral sphincterotomy reduces anal sphincter hypertonia but there has been concern about complications. A greater understanding of the basic pharmacology of the internal anal sphincter has led to the development of novel treatments for both these disorders. A Medline review was undertaken for internal anal sphincter pharmacology, anal fissures and faecal incontinence. This review is based on these articles and those found by further cross-referencing. Nitric oxide released from non-adrenergic non-cholinergic nerves is the main inhibitory agent in the internal anal sphincter. Relaxations are also mediated through beta-adrenoceptors and muscarinic receptors. Stimulation of alpha-receptors results in contraction. Calcium and its entry through L-type calcium channels is important for the maintenance of tone. Nitric oxide donors produce reductions in resting anal tone and heal fissures but are associated with side-effects. Muscarinic agents and calcium channel antagonists show promise as low side-effect alternatives. Botulinum toxin appears more efficacious than other agents in healing fissures. To date, alpha-receptor agonists have been disappointing at improving incontinence. Further understanding of the pharmacology of the internal anal sphincter may permit the development of new agents to selectively target the tissue with greater efficacy and fewer side-effects.