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British Journal of Pharmacology Jul 19891. The effects of cromakalim, a novel vasodilator agent believed to open K+ channels, were studied in a range of large and small arteries in vitro. In dog isolated...
1. The effects of cromakalim, a novel vasodilator agent believed to open K+ channels, were studied in a range of large and small arteries in vitro. In dog isolated coronary artery, precontracted with U46619 (a thromboxane A2-mimetic), cromakalim caused concentration-dependent relaxation which could be inhibited by phentolamine (10-100 microM). 2. The ability of phentolamine to antagonize cromakalim was selective since it did not affect responses to a number of other vasodilators including isoprenaline, nitroprusside or nicorandil. 3. The effect of phentolamine was not related to its alpha-adrenoceptor blocking actions since other alpha-adrenoceptor antagonists (prazosin 10 microM, rauwolscine 10 microM and phenoxybenzamine 1 microM) failed to influence the action of cromakalim. 4. A number of compounds structurally related to phentolamine were also able to block the vaso-relaxant response to cromakalim in the dog isolated coronary artery. The rank order of potency was alinidine = phentolamine = ST91 greater than tramazoline = naphazoline. Clonidine and tolazoline were inactive. The most potent compounds (alinidine and phentolamine) were effective only at concentrations above 1 microM. 5. Electrophysiological studies, in which resting membrane potential and tension were measured simultaneously, were carried out on rat isolated femoral artery. Phentolamine (30 microM) antagonized both the vasorelaxation and hyperpolarization caused by cromakalim. 6. These results suggest that phentolamine and some structurally related compounds, may inhibit K+ channel opening, an action which would account for their ability to antagonize the actions of cromakalim. Such compounds may prove useful in determining the role of K+ channels in regulating vascular smooth muscle tone in vivo and in vitro.
Topics: Animals; Benzopyrans; Coronary Vessels; Cromakalim; Dogs; Drug Interactions; Guinea Pigs; In Vitro Techniques; Isometric Contraction; Membrane Potentials; Muscle Relaxation; Muscle, Smooth, Vascular; Phentolamine; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pyrroles; Rats; Rats, Inbred WKY
PubMed: 2758244
DOI: 10.1111/j.1476-5381.1989.tb12035.x -
The Journal of Physiology Sep 19681. Exposure to cold increased the plasma levels of glucose and lactate in young lambs (< 1-63 days old). Free fatty acid concentrations also increased, the increase...
1. Exposure to cold increased the plasma levels of glucose and lactate in young lambs (< 1-63 days old). Free fatty acid concentrations also increased, the increase being much greater in lambs older than 20 days.2. Intravenous infusions of adrenaline and noradrenaline into lambs under a neutral thermal environment caused large increases in plasma glucose, lactate and free fatty acids.3. Adrenaline and noradrenaline infusions increased the concentration of palmitic, stearic and oleic acids in the plasma of young lambs.4. Treatment of lambs in summit metabolism with either alpha- or beta-adrenergic blocking agents (phentolamine or propranolol, respectively) caused the plasma levels of free fatty acids to fall. Phentolamine hydrochloride decreased the concentration of plasma glucose, but did not change the lactate level. In contrast, propranolol decreased the concentration of both of these metabolites in a significant proportion of the experiments.5. Induction of muscular paralysis by suxamethonium chloride, in lambs exposed to cold, resulted in a rise in plasma free fatty acids, and a fall in glucose and lactate levels.6. These observations suggest that the circulating level of plasma metabolites in young lambs is not the limiting factor in the metabolic response to cold exposure.
Topics: Animals; Animals, Newborn; Basal Metabolism; Blood Glucose; Cold Temperature; Epinephrine; Fatty Acids, Nonesterified; Lactates; Metabolism; Norepinephrine; Phentolamine; Propranolol; Sheep; Succinylcholine
PubMed: 5698274
DOI: 10.1113/jphysiol.1968.sp008606 -
American Journal of Physiology. Heart... Jan 2023Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular...
Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance () was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (, phentolamine; 10 adults), cholinergic blockade (, glycopyrrolate; 9 adults), and myogenic blockade (, nicardipine; 14 adults). In e, phentolamine increased similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; = 0.45). In , glycopyrrolate increased cerebrovascular (72 ± 61%) and forearm vascular (74 ± 64%) to a similar extent ( = 0.88). In , nicardipine increased but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm. Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.
Topics: Adult; Humans; Forearm; Phentolamine; Nicardipine; Glycopyrrolate; Retrospective Studies; Blood Pressure; Cerebrovascular Circulation; Adrenergic Agents; Cholinergic Agents; Regional Blood Flow
PubMed: 36459447
DOI: 10.1152/ajpheart.00377.2022 -
Anesthesiology Apr 1978The effects of 3H-epinephrine on the duration of block and on the time course of uptake and efflux of local anesthetic (14C-lidocaine hydrochloride) were determined in...
The effects of 3H-epinephrine on the duration of block and on the time course of uptake and efflux of local anesthetic (14C-lidocaine hydrochloride) were determined in the infraorbital nerve of the pentobarbital-obtunded rat. Epinephrine, 1:50,000, doubled the duration of behavioral block produced by 37 mM (1 per cent) lidocaine; 1:100,000, 1:200,000 and 1:400,000 prolonged the block correspondingly less, the relation being inversely proportional to the log of the epinephrine concentration. The nerural level of 3H-epinephrine reached a peak within 10 minutes and then declined linearly with time, as did the associated neural level of 14C-lidocaine. Linearity apparently results from the summation of the time-linked decreasing diffusion gradient of drug and the consequently increasing rate of perfusion with blood. Phentolamine antagonizes the epinephrine-caused prolongation of behavioral block. The results suggest that in spinal anesthesia the extent of dilution of an epinephrine additive by cerebrospinal fluid will significantly affect the duration of the block.
Topics: Anesthesia, Local; Animals; Epinephrine; Lidocaine; Nerve Block; Peripheral Nerves; Phentolamine; Rats
PubMed: 637334
DOI: 10.1097/00000542-197804000-00008 -
Anesthesia Progress 2008Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have received local anesthetic injections containing a vasoconstrictor. The... (Randomized Controlled Trial)
Randomized Controlled Trial
Phentolamine mesylate accelerates recovery from oral soft tissue anesthesia in patients who have received local anesthetic injections containing a vasoconstrictor. The proposed mechanism is that phentolamine, an alpha-adrenergic antagonist, blocks the vasoconstriction associated with the epinephrine used in dental anesthetic formulations, thus enhancing the systemic absorption of the local anesthetic from the injection site. Assessments of the pharmacokinetics of lidocaine and phentolamine, and the impact of phentolamine on the pharmacokinetics of lidocaine with epinephrine were performed to characterize this potentially valuable strategy. The blood levels of phentolamine were determined following its administration intraorally and intravenously. Additionally, the effects of phentolamine mesylate on the pharmacokinetics of intraoral injections of lidocaine with epinephrine were evaluated. Sixteen subjects were enrolled in this phase 1 trial, each receiving 4 drug treatments: 1 cartridge lidocaine/epinephrine followed after 30 minutes by 1 cartridge phentolamine (1L1P), 1 cartridge phentolamine administered intravenously (1Piv), 4 cartridges lidocaine/epinephrine followed after 30 minutes by 2 cartridges phentolamine (4L2P), and 4 cartridges lidocaine/epinephrine followed by no phentolamine (4L). Pharmacokinetic parameters estimated for phentolamine, lidocaine, and epinephrine included peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve from 0 to the last time point (AUClast) or from time 0 to infinity (AUCinf), elimination half-life (t1/2), clearance (CL), and volume of distribution (Vd). The phentolamine Tmax occurred earlier following the intravenous administration of 1Piv (7 minutes than following its submucosal administration in treatment 1L1P (15 minutes) or 4L2P (11 minutes). The phentolamine t1/2, CL, and Vd values were similar for 1L1P, 1Piv, and 4L2P. The Tmax for lidocaine occurred later and the Cmax for lidocaine was slightly higher when comparing the 4L2P treatment and the 4L treatment. The phentolamine-induced delay of the lidocaine Tmax likely represents phentolamine's ability to accelerate the systemic absorption of lidocaine from oral tissues into the systemic circulation.
Topics: Administration, Oral; Adolescent; Adrenergic alpha-Antagonists; Adult; Anesthesia Recovery Period; Anesthetics, Local; Area Under Curve; Biological Availability; Cross-Over Studies; Drug-Related Side Effects and Adverse Reactions; Epinephrine; Female; Humans; Injections, Intravenous; Lidocaine; Male; Metabolic Clearance Rate; Middle Aged; Phentolamine; Vasoconstriction; Vasoconstrictor Agents
PubMed: 18547152
DOI: 10.2344/0003-3006(2008)55[40:POLWEF]2.0.CO;2 -
International Journal of Molecular... Jun 2023This study aimed to elucidate the vasodilatory effects and cytotoxicity of various vasodilators used as antispasmodic agents during microsurgical anastomosis. Rat smooth...
This study aimed to elucidate the vasodilatory effects and cytotoxicity of various vasodilators used as antispasmodic agents during microsurgical anastomosis. Rat smooth muscle cells (RSMCs) and human coronary artery endothelial cells (HCAECs) were used to investigate the physiological concentrations and cytotoxicity of various vasodilators (lidocaine, papaverine, nitroglycerin, phentolamine, and orciprenaline). Using a wire myograph system, we determined the vasodilatory effects of each drug in rat abdominal aortic sections at the concentration resulting in maximal vasodilation as well as at the surrounding concentrations 10 min after administration. Maximal vasodilation effect 10 min after administration was achieved at the following concentrations: lidocaine, 35 mM; papaverine, 0.18 mM; nitroglycerin, 0.022 mM; phentolamine, 0.11 mM; olprinone, 0.004 mM. The IC for lidocaine, papaverine, and nitroglycerin was measured in rat abdominal aortic sections, as well as in RSMCs after 30 min and in HCAECs after 10 min. Phentolamine and olprinone showed no cytotoxicity towards RSMCs or HCAECs. The concentrations of the various drugs required to achieve vasodilation were lower than the reported clinical concentrations. Lidocaine, papaverine, and nitroglycerin showed cytotoxicity, even at lower concentrations than those reported clinically. Phentolamine and olprinone show antispasmodic effects without cytotoxicity, making them useful candidates for local administration as antispasmodics.
Topics: Humans; Rats; Animals; Parasympatholytics; Papaverine; Nitroglycerin; Phentolamine; Endothelial Cells; Microsurgery; Muscle, Smooth, Vascular; Vasodilator Agents; Vasodilation; Myocytes, Smooth Muscle; Lidocaine
PubMed: 37446027
DOI: 10.3390/ijms241310850 -
Acta Medica Okayama Jun 2022Mirror image pain (MIP) is a type of extraterritorial pain that results in contralateral pain or allodynia. Glutamate transporter-1 (GLT-1) is expressed in astrocytes...
Mirror image pain (MIP) is a type of extraterritorial pain that results in contralateral pain or allodynia. Glutamate transporter-1 (GLT-1) is expressed in astrocytes and plays a role in maintaining low glutamate levels in the synaptic cleft. Previous studies have shown that GLT-1 dysfunction induces neuropathic pain. Our previous study revealed bilateral GLT-1 downregulation in the spinal cord of a spared nerve injury (SNI) rat. We hypothesized that spinal GLT-1 is involved in the mechanism of MIP. We also previously demonstrated noradrenergic GLT-1 regulation. Therefore, this study aimed to investigate the effect of an α1 adrenergic antagonist on the development of MIP. Rats were subjected to SNI. Changes in pain behavior and GLT-1 protein levels in the SNI rat spinal cords were then examined by intrathecal administration of the α1 adrenergic antagonist phentolamine, followed by von Frey test and western blotting. SNI resulted in the development of MIP and bilateral downregulation of GLT-1 protein in the rat spinal cord. Intrathecal phentolamine increased contralateral GLT-1 protein levels and partially ameliorated the 50% paw withdrawal threshold in the contralateral hind paw. Spinal GLT-1 upregulation by intrathecal phentolamine ameliorates MIP. GLT-1 plays a role in the development of MIPs.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Disease Models, Animal; Neuralgia; Phentolamine; Rats; Rats, Sprague-Dawley
PubMed: 35790355
DOI: 10.18926/AMO/63719 -
Anesthesia Progress 2009OraVerse, an injectable formulation of phentolamine mesylate (PM), was recently approved by the U.S. Food and Drug Administration (FDA) for reversal of anesthesia of the... (Comparative Study)
Comparative Study
OraVerse, an injectable formulation of phentolamine mesylate (PM), was recently approved by the U.S. Food and Drug Administration (FDA) for reversal of anesthesia of the lip and tongue and associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. Because PM had not been approved previously for submucosal administration, 2 Good Laboratory Practices (GLP) studies in dogs designed to investigate systemic toxicity and the local effects of single and repeated dosing of OraVerse on the inferior alveolar nerve and branches of the superior alveolar nerve and adjacent soft tissues after local administration were conducted. Systemic toxicity was measured by preinjection and postinjection clinical examinations, clinical chemistry, and gross and microscopic examinations of major organs after necropsy. No evidence of systemic toxicity was detected. Local nerve and adjacent tissue damage was assessed by conventional histopathology. Nerve degeneration was evident in 1 animal. Mild perineural inflammation adjacent to the inferior alveolar nerve and inflammatory exudates were observed in submucosal tissues in several animals. No changes were observed in the nerves at injection sites of dogs from any dose group that were considered directly related to the test articles. These data reveal that single and repeated intraoral administrations of OraVerse are well tolerated in beagle dogs.
Topics: Adrenergic alpha-Antagonists; Anesthetics, Local; Animals; Cranial Nerve Diseases; Dogs; Hematocrit; Hemoglobins; Injections; Mandibular Nerve; Maxillary Nerve; Mouth Mucosa; Nerve Degeneration; Nerve Fibers; Neuritis; Organ Size; Phentolamine; Random Allocation; Tissue Distribution; Vasodilator Agents
PubMed: 20020792
DOI: 10.2344/0003-3006-56.4.123 -
FEBS Letters Mar 1986In the reactions with dye free radicals, catecholamines exhibited reversible electron donor and acceptor properties with the effectiveness increasing from tyrosine to...
In the reactions with dye free radicals, catecholamines exhibited reversible electron donor and acceptor properties with the effectiveness increasing from tyrosine to norepinephrine. The physiological antagonists haloperidol and phentolamine showed opposite patterns of behaviour in the same reactions, changing their properties as acceptors to electron donors. The regularity observed is similar to that demonstrated earlier by a variety of Na+ and Ca2+ channel modulators.
Topics: Coloring Agents; Free Radicals; Haloperidol; Hemin; Kinetics; NAD; Norepinephrine; Oxidation-Reduction; Phentolamine; Photochemistry
PubMed: 3956723
DOI: 10.1016/0014-5793(86)81198-x -
British Journal of Pharmacology Aug 19911. The patch clamp technique has been used to characterize the effects of phentolamine, an unselective blocker of alpha 1- and alpha 2-adrenoceptors, on the electrical...
1. The patch clamp technique has been used to characterize the effects of phentolamine, an unselective blocker of alpha 1- and alpha 2-adrenoceptors, on the electrical activity of isolated RINm5F insulin-secreting cells and the gating of ATP-regulated potassium (K+ATP) channels. 2. Current-clamp experiments carried out by use of both conventional whole-cell recordings and nystatin-perforated cells, have demonstrated that phentolamine (5-20 microM) in the complete absence of alpha-adrenoceptor agonists, caused a sharp depolarization of the cell membrane from approximately -66 mV to -42 mV. This depolarization was associated with the generation of calcium action potential-like spikes. In the continued presence of phentolamine, diazoxide (100 microM) reversed these effects by causing a hyperpolarization of the cell, thereby preventing Ca2+ spikes. 3. Unitary current events from K+ATP channels were recorded from both outside-out membrane patches and saponin permeabilized or open-cells. When added to either the inside or the outside of the plasma membrane, phentolamine (0.1-100 microM) blocked openings from these channels. The effects of phentolamine were rapid, sustained and fully reversible. Phentolamine was apparently a more effective blocker of channels from the inside than the outside of the membrane. 4. The KI value, corresponding to 50% inhibition of channels was estimated to be approximately 0.7 microM when phentolamine was added to the inside of the membrane and the Hill coefficient approximately 1. 5. Yohimbine (1-10 microM) and the chemically 2-substituted imidazoline alpha-adrenoceptor antagonists, antazoline (25 microM) and tolazoline (25 microM) were also found to block K+ATP channels in isolated patches of membrane. 6. In conclusion the present study demonstrates that phentolamine and other imidazoline adrenoceptor antagonists have effects upon ATP-sensitive K+ channels that are not associated with stimulation of the adrenoceptor.
Topics: Adenosine Triphosphate; Adrenergic alpha-Antagonists; Clone Cells; Phentolamine; Potassium Channels
PubMed: 1680516
DOI: 10.1111/j.1476-5381.1991.tb12340.x