The adrenergic system is known for its ability to influence various physiological and metabolic processes; however, its involvement in thyroid function in non-mammalian vertebrates remains poorly explored. Adult male lizards were treated with β-adrenergic agonists (isoproterenol, terbutaline, and L-isopropylamino-3-(2-thiazoloxy)-2-propanol) and the α-adrenergic antagonist (phentolamine). The effects of β-adrenergic agonists and the α-adrenergic antagonist administered as single and repeated injections were evaluated on plasma TSH, thyroid hormones, hepatic 5'-T4 ORD (type II monodeiodinase) activity, hepatic thyroid hormone contents, blood glucose levels, and thyroid gland histology. β-adrenergic stimulation produced a dose-dependent decrease in plasma TSH, accompanied by significant increases in circulating T3 and T4 levels. These changes were associated with enhanced hepatic monodeiodinase activity, increased hepatic T3 content, reduced hepatic T4 levels, and histological features indicative of thyroid activation. Repeated administrations amplified these effects. In contrast, phentolamine treatment increased plasma TSH levels but reduced circulating and hepatic T3, increased hepatic T4, and tended to decrease deiodinase activity, indicating impaired peripheral thyroid hormone activation. Histological analysis showed reduced follicular synthetic activity, although colloid resorption vacuoles were still present. IPT treatment produced no significant effects. All treatments induced hyperglycaemia, with stronger responses after repeated administrations, suggesting coordinated regulation of thyroid function and energy metabolism by adrenergic pathways. The results demonstrate that β-adrenergic signaling promotes thyroid activation and peripheral hormone conversion, whereas α-adrenergic blockade disrupts thyroid hormone homeostasis. These findings highlight a key role of adrenergic mechanisms in the neuroendocrine and metabolic regulation of reptiles, supporting their importance in physiological adaptation to environmental variability.

The application of epinephrine in digit procedures has historically been a subject of debate in medical education. Trainees are often advised to avoid its use in fingers, toes, and other terminal areas due to concerns about tissue ischemia and necrosis. However, numerous studies demonstrate that, when used at appropriate concentrations, epinephrine can be safely administered in these regions, challenging long standing misconceptions. The belief that epinephrine causes digital necrosis stems from outdated reports from the early to mid-20th century, many of which involved procaine or cocaine-anesthetics with inherent vasoconstrictive properties that may have compounded the effects of epinephrine. Additionally, procaine alone has been shown to impair tissue viability, likely contributing to observed necrosis. Some case reports of digital necrosis did not involve epinephrine at all, suggesting alternative causes. Despite this, cautious use of epinephrine in digital anesthesia has been incorporated into contemporary medical education. Many reputable textbooks, journals, and online learning resources continue to advise caution against the use of epinephrine in digits, even in light of extensive research suggesting otherwise. When used at an appropriate concentration (1:100,000) alongside an appropriate reversal agent such as phentolamine, epinephrine in the digits has been demonstrated to be safe, with very few reports of necrosis. The use of epinephrine in hand procedures aligns with current best practices and should not be viewed as controversial. Bridging the gap between evidence and education is essential for training clinicians who are confident, competent, and guided by up-to-date, evidence-based practices.

Tyramine signaling orchestrates essential physiological processes in insects, yet the functional diversification of tyramine receptors (TARs) and the evolutionary significance of receptor gene duplication remain poorly understood. While most lepidopterans harbor a single TAR1, the diamondback moth Plutella xylostella uniquely possesses two TAR1 paralogs (PxTAR1 and PxTAR1A) alongside PxTAR2, providing an exceptional model to investigate sub-functionalization. However, functional characterization of PxTARs has been limited to TAR1. Here, we uncover striking functional differentiation of TARs through integrated pharmacological and genetical analyses. Despite high structural conservation with lepidopteran orthologs (∼80% identity), PxTAR2 exhibited no obvious plasma membrane localization and complete pharmacological silence in HEK293 cells-showing no measurable cAMP or Ca[2+] responses to tyramine, suggesting obligate dependence on unavailable cellular cofactors. In sharp contrast, PxTAR1A was predominantly localized to the plasma membrane in HEK293 cells. It displayed canonical TAR1-like properties (tyramine EC50 = 51.36 nM; octopamine EC50 = 8.9 μM) yet distinct pharmacological fingerprinting, including unique antagonist susceptibility to phentolamine. CRISPR/Cas9-mediated gene knockout revealed drastic functional partitioning: while PxTAR2 deficiency caused only modest late-stage oviposition decline, PxTAR1A knockout severely compromised reproductive fitness, reducing fecundity by 24% (194 to 148 eggs/female) and, critically, collapsing embryonic hatchability from 81% to 47% due to late developmental arrest. qRT-PCR analyses further elucidated this divergence: PxTAR1A is predominantly expressed in embryos (14.6-fold and 9-fold higher than PxTAR2 and PxTAR1, respectively), while PxTAR2 displays the lowest expression among PxTARs throughout the entire life cycle. These findings advance our understanding of tyramine receptor diversification, establish PxTAR1A as a master regulator of insect embryogenesis, and identify a high-value target for next-generation pest management targeting reproduction.

Catecholamine-secreting tumors (CSTs) are an uncommon tumor in pediatrics that can result in hypertensive crisis secondary to catecholamine release from the tumor cells. Pheochromocytoma is the tumor type most associated with excessive catecholamine release, but paragangliomas and neuroblastoma tumors can also generate and release excessive amounts of catecholamines. Surgical resection is typically the treatment of choice for these tumor types; however, manipulation during surgical resection can lead to further catecholamine release. If the patient's adrenergic receptors are not fully inhibited before undergoing surgery, the patient is at risk for experiencing additional hypertensive crises and arrhythmias due to the catecholamine release secondary to the surgery. Although studies have identified sequential α- and β-adrenergic blockade as a prerequisite for surgery to minimize the effects of further catecholamine release during resection, there is little guidance regarding medication timing, dosing, and testing to ensure the pediatric patient has adequately suppressed adrenergic receptors before surgery. Further, with recent shortages of the first-line medication treatment options for this indication, it is vital to establish a treatment plan with alternative treatments for use during drug shortages. This case series describes the successful use of enteral phenoxybenzamine and parenteral phentolamine for α-adrenergic blockade, coupled with enteral atenolol and parenteral esmolol or labetalol for β-adrenergic blockade, in 9 pediatric patients with CST before surgical resection of the tumors. Eight patients underwent a phenylephrine challenge, and all demonstrated appropriate α-blockade preceding tumor removal.

Elevated muscle sympathetic nerve activity (MSNA) at high altitude is associated with blunted transduction of sympathetic signals to blood pressure in lowlanders and indigenous Andean highlanders. However, it is unclear whether this is due to reduced adrenergic communication or other factors (e.g., augmented dilatory signaling). Therefore, we quantified the contribution of α-adrenoreceptor activity to 1) resting systemic sympathetic transduction and 2) pressor responses to sympathoexcitation in acclimatizing lowlanders (9 M and 4 F) and Andean highlanders (15 M) at 4,300 m. MSNA (microneurography) and mean arterial pressure (MAP; finger photoplethysmography) were measured at rest, during maximal voluntary apnea, and with an α1-adrenergic agonist (phenylephrine) before and following partial α-adrenergic blockade (phentolamine). Sympathetic transduction was quantified as the slope of the relationship between MAP and total MSNA associated with sequences of sympathetic bursts. Transduction was attenuated in both lowlanders (0.0041 ± 0.0037 to 0.0017 ± 0.0017 mmHg·%[-1], P = 0.026) and highlanders (0.0033 ± 0.0024 to 0.0008 ± 0.0007 mmHg·%[-1], P = 0.005) under α-adrenergic blockade (main effect P < 0.001) and was not different between groups (main effect P = 0.276). However, pressor responses to apnea (lowlanders, +25 ± 5 mmHg and highlanders, +22 ± 7 mmHg) were unchanged following phentolamine (lowlanders, +25 ± 8 mmHg and highlanders, +20 ± 8 mmHg; main effect P = 0.174) despite unchanged MSNA responses between conditions (main effect P = 0.162). Highlanders exhibited reduced MSNA responses compared with lowlanders regardless of condition (main effect P = 0.014). Partial α-adrenergic blockade reduced sympathetic transduction similarly in both groups. Yet, apnea responsiveness was maintained, achieved through lesser sympathoexcitation in highlanders. This suggests that resting blood pressure control is modulated primarily through α-adrenergic receptors in both populations, but pressor responses to stress may result from alternative mechanisms.NEW & NOTEWORTHY This study provides insight into the mechanisms involved in the sympathetic control of blood pressure at rest and in response to autonomic stress in different populations at high altitude. We demonstrate that resting blood pressure regulation is mediated primarily through α-adrenergic mechanisms in both lowlanders and Indigenous Andean highlanders at high altitude. However, pressor responses to apneic stress appear to be regulated by an alternative mechanism, particularly in highlanders who require less sympathetic activation.

Vasopressors are the cornerstone of the management of shock, a life-threatening condition characterized by inadequate tissue perfusion, with risks of organ failure and death. Prompt initiation of vasopressors restores hemodynamic stability and prevents shock sequelae. Vasopressors have long been administered via central venous catheters (CVCs) due to concerns about extravasation and tissue injury with peripheral venous administration. However, CVC placement is an invasive, time-consuming procedure requiring specialized personnel and resources, potentially delaying the initiation of life-saving medications. With the 'time to management' being a detrimental factor in shock, there has been a renewed interest in peripheral vasopressor therapy, particularly in emergent or resource-limited settings where complications and delays exceed expectations. Over the last decade, multiple observational studies have demonstrated the safety and efficacy of peripheral vasopressor administration, especially when using large-bore catheters placed in proximal upper extremity veins and under vigilant monitoring. Early initiation of vasopressors via peripheral venous access has been associated with faster attainment of target mean arterial pressure and shorter time to hemodynamic stabilization, without increased mortality or severe complications. Prompt recognition and management of extravasation, including the use of phentolamine, further mitigates risks. Guidelines suggest starting vasopressors peripherally to avoid delays, with a transition to central access if prolonged infusion is anticipated. Institutional protocols, including site selection, catheter type, infusion duration, and escalation criteria, are essential to optimize safety. Further research is needed to refine protocols and address remaining knowledge gaps regarding prolonged use and optimal catheter selection.

This study aimed to assess the cutaneous analgesic effect of the lidocaine-synephrine combination and its underlying α-adrenergic receptor-mediated mechanism in comparison with phenylephrine. Cutaneous analgesia after subcutaneous drug injection was assessed by inhibition of the cutaneous trunci muscle reflex in response to needle pinpricks on the shaved dorsal skin of Sprague-Dawley rats. Synephrine, like the local anesthetic lidocaine, is capable of inducing cutaneous analgesia but is less potent. On an equipotent basis (ED25, ED50 [50% effective dose], and ED75), the block duration induced by synephrine or phenylephrine was longer than that induced by lidocaine (p < 0.01). When combined with lidocaine, the ED50 for synephrine decreased from 326 (183-579) μmol/kg to 141 (128-156) μmol/kg (p < 0.01), and for phenylephrine, it decreased from 15.8 (9.0-27.9) μmol/kg to 6.2 (5.9-6.6) μmol/kg (p < 0.01). Lidocaine (ED95) in combination with either synephrine (52 μmol/kg) or phenylephrine (1.6 μmol/kg) prolonged the duration of action (p < 0.001), while phentolamine (0.3 μmol/kg) reversed these effects. We concluded that synephrine produces dose-dependent cutaneous analgesia that is less potent but longer-lasting than lidocaine. The enhanced analgesic effects of the lidocaine-synephrine and lidocaine-phenylephrine combinations are mediated through α-adrenergic receptor activation.

Brain injury in preterm infants is common but often difficult to detect in the early stages. The present study investigated whether evolving preterm brain injury after exposure to hypoxia-ischaemia (HI) is associated with dynamic changes in arterial blood pressure variability (BPV) and tested the hypothesis that it was mediated by alpha-adrenoreceptor activity. Chronically instrumented 0.7 gestation fetal sheep received sham-HI (n = 8) or HI induced by 25 min of umbilical cord occlusion, followed by i.v. infusion of either the alpha-adrenergic blocker phentolamine (n = 6) or saline (n = 8) from 15 min to 8 h post-HI. HI was associated with acutely reduced beat-to-beat dispersion, sequential and spectral BPV measures, which normalised by 3 h post-HI, followed by increased low-frequency BPV from 3 h to 4 h. From 8 h to 13 h post-HI, there was sustained reduction in all BPV measures throughout the secondary phase of injury. Alpha-adrenoreceptor blockade abolished the increase in low-frequency power during the latent phase and partly influenced secondary phase BPV. The HI group also showed greater 3 hourly reading-to-reading BPV during the first 24 h post-HI, which was completely suppressed with alpha-adrenoreceptor inhibition. Based on these initial findings, in a subsequent validation cohort [sham-HI (n = 10) and HI-saline (n = 10)] a short-term BPV threshold had 90% sensitivity and 80% specificity for HI. This study highlights the evolving, phase-dependent changes in BPV after HI, that they are partly mediated by alpha-adrenoreceptor activation, and suggests that BPV could be a potential early biomarker for brain injury. KEY POINTS: Brain injury in preterm infants is common but often difficult to detect clinically, partly because of their normal low muscle tone and that seizures are typically electrographic. Blood pressure variation (BPV) is mediated mainly by autonomic activity, and so may be a marker for neural injury. In preterm fetal sheep, hypoxia-ischaemia was associated with evolving, phase-dependent changes in BPV. Changes in BPV were partly mediated by alpha-adrenoreceptor activation. These findings support the concept that BPV could be a useful, pragmatic tool to help screen for brain injury.

Local anesthetics are fundamental to dermatologic practice, yet their safety profile requires nuanced understanding in high-risk contexts including end-arterial sites, barrier-compromised skin, and scenarios predisposing to systemic toxicity. This narrative review synthesizes contemporary evidence across these three interacting domains to provide an integrated, risk-stratified framework for clinical decision-making. Regarding end-arterial territories, over two decades of clinical evidence encompassing more than 200,000 digital and acral injections has effectively dismantled the historical dogma against epinephrine use in digits, nose, ear, and penis, demonstrating an excellent safety profile when dilute concentrations are used in patients with adequate perfusion, with phentolamine providing reliable rescue for rare, prolonged vasoconstriction. In barrier-compromised skin (e.g. burns, ulcers, and inflammatory dermatoses) topical anesthetics function as absorption amplifiers, with dramatically accelerated systemic uptake that can precipitate local anesthetic systemic toxicity or prilocaine- and benzocaine-induced methemoglobinemia, particularly in infants and frail elderly patients. For large, denuded areas, dilute tumescent infiltration offers a pharmacokinetically safer alternative to high-dose topical therapy. The review details systemic toxicity risk factors, recognition, and management, emphasizing that intravenous lipid emulsion therapy has transformed severe toxicity from an often-fatal event to a manageable emergency. Special considerations for pediatric and geriatric populations, drug interactions, and cumulative dosing across modalities are addressed. The overarching conclusion is that context-sensitive risk stratification which includes integrating vascular status, barrier integrity, and host pharmacokinetics combined with office preparedness including phentolamine and lipid emulsion, enables safe local anesthesia even in traditionally high-risk dermatologic scenarios.