神经降压素和新福林对大鼠下丘脑减压区神经元放电的影响

观察了升压以及离子微电泳神经降压素(NT),微量注射抗NT 血清对大鼠下丘脑减压区(HDA)神经元放电的影响。结果表明,多数HDA 神经元对升压呈兴奋性反应;HDA 区微量注入抗NT 血清后,这一反应受到抑制;微电泳NT 可兴奋部分HDA 神经元,主要是对升压呈兴奋性反应的神经元。提示HDA 区可能是减压反射中枢通路的组成部分,NT 可能作为调制物起作用。     

Altered in vivo catecholamine release in the hypothalamic paraventricular nucleus of the aged rat

The effect of age on basal and stimulated noradrenaline release in the hypothalamic paraventricular nucleus (PVN) of the rat was examined by in vivo microdialysis. Microdialysis probes were inserted into the PVN of 3 and 18 month old anaesthetised Sprague Dawley rats and perfused with a modified Ringer solution. Following four basal 30-min collections, transmitter release was stimulated by perfusion with 100 mM potassium for one collection. After re-equilibration, blood pressure was raised 60 mmHg for 30 min by phenylephrine infusion (1–1.3 mg/kg) then a 2-h recovery period followed. Dialysate collections were injected directly onto a reverse phase HPLC-ECD (HPLC with electrochemical detection).Basal extracellular noradrenaline concentrations were found to be similar in adult and old animals. Basal dihydroxyphenylacetic acid (DOPAC) concentrations were significantly greater in old compared to adult rats (P < 0.05). Potassium depolarisation induced a significant increase in noradrenaline concentrations in both age groups (P < 0.001), however the noradrenaline response to potassium stimulation was significantly reduced in the aged rats (P < 0.05). Potassium-induced decreases in DOPAC and homovanillic acid (HVA) concentrations were seen in both age groups. Following phenylephrine infusion, a modest delayed reduction in noradrenaline levels, which failed to reach statistical significance, was seen. Phenylephrine-induced hypertension was associated with decreased DOPAC and HVA concentrations in adult (P < 0.05) and old (P < 0.05) rats, respectively.These results indicate that ageing is associated with changes in dopaminergic and noradrenergic activity in the PVN of the rat. A reduction in noradrenaline response to maximal stimulation induced by potassium depolarisation was observed with ageing. The alteration in the activity of the catecholaminergic pathways to the PVN induced by phenylephrine infusion appears to be age dependent.     

Prior vasorelaxation enhances diadenosine polyphosphate-induced contractility of rat mesenteric resistance arteries

Low-threshold concentrations of diadenosine polyphosphates (ApnA: Ap3A, Ap4A, Ap5A, Ap6A) or ATP, which at basal vessel tone induce just measurable vasoconstrictions, induce up to ten times enhanced vasoconstrictions of previously relaxed (by acetylcholine or sodium nitroprusside or 8Br₂ cGMP or isoproterenol or levcromakalim) pre-contracted rat mesenteric resistance arteries (MrA) in a microvessel–myograph. These enhanced vasoconstrictions were of similar magnitude for threshold concentrations of all ApnA.Possibly, the low concentrations of ApnA reverse the prior vasorelaxation by inhibiting a common vasorelaxation pathway, but obviously this is not due to inhibition of guanylate cyclase, which has been previously described to be inhibited by ApnA, because the enhanced vasoconstrictions can be observed with guanylate cyclase-independent vasorelaxants (8Br₂ cGMP, isoproterenol or levcromakalim), too. The enhanced vasoconstrictions are endothelium-independent because after mechanical vascular de-endothelialization the results were identical. De-endothelialized vessels, which fail to relax by acetylcholine, showed no enhanced ApnA-induced vasoconstrictions, demonstrating that the mere prior vasorelaxation of the vessel is required to provide the enhanced vasoconstriction by ApnA. Furthermore, the enhanced contractility is not based on a potentiation of the phenylephrine contraction because it equally occurs with other agents used for arterial pre-contraction. Systemically applied ApnA considerably decrease arteriovascular resistance, resulting in hypotension. But here it is demonstrated that a preceding vasorelaxation enables the resistance arteries to generate a strong and persistent ApnA-induced vasoconstriction. Thus, in vivo at very low concentrations ApnA may serve to counteract severe conditions of hypotension (e.g., shock syndrome or anaphylaxis) by the constriction of resistance arteries.     

Analysis of the adrenergic receptors of pacemaker and myocardial cells

Chronotropic and inotropic dose-response curves for epinephrine and phenylephrine were determined in rabbit atria spontaneously beating and electrically-driven. The curves were obtained in the absence and in the presence of propranolol, 10⁻⁷ M, or phentolamine, 2 × 10⁻⁶ M. Propranolol antagonized the chronotropic effects of epinephrine and phenylephrine, and the inotropic effects of epinephrine. This antagonist reduced the inotropic responses to high doses of phenylephrine, but left unaltered the effects of low doses. Phentolamine antagonized the inotropic effects of low doses of phenylephrine which were unaffected by propranolol. The inotropic curve for epinephrine was shifted 2.5-fold to the right by phentolamine. In contrast, phentolamine did not modify the chronotropic responses to these amines.     

Peripheral α-adrenoreceptor and central dopamine receptor activity in depressive patients

Depressive patients before and after clinical recovery were investigated by the tyramine-dose/pressor-response test, the noradrenaline-dose/pressor-response test, and the phenylephrine-dose/pressor-response test, and were compared with normal subjects. Depressive patients were more sensitive on all three tests than control subjects and tended to revert back to normal after clinical recovery. Amitriptyline decreased the sensitivity to tyramine, and this decrease was highly (r=0.80) and significantly correlated with the plasma concentration of nortriptyline, but drug-induced changes in the tyramine-dose/pressor-response test did not correlate with clinical recovery. The patients became more sensitive to NA while on amitriptyline, and the increase was not related to clinical improvement. The patients became less sensitive to phenylephrine while on amitriptyline, and this change was highly (r=0.80) and significantly positively correlated with poor clinical outcome. The changes showed a positive correlation with plasma levels of nortriptyline. Central dopamine receptor activity was investigated using the bromocryptine/prolactin response test. No significant difference between patients and controls was found in the prolactin plasma level before the administration of bromocryptine (although concentration of prolactin tended to be lower in patients), nor in the decrease induced by bromocryptine. After 4 weeks' administration of amitriptyline, the patients had significantly decreased prolactin concentration compared to controls. Ciclazindol, a drug that predominantly inhibits the reuptake of noradrenaline, tended to increase the basal level of prolactin. Amitriptyline decreased to response to bromocryptine, and ciclazindol increased the response to bromocryptine.     

Effects of cardiotoxic doses of adrenergic amines on myocardial cyclic AMP.

The role of beta-adrenergic activation in the cardiotoxicity of adrenergic amines was assessed by measuring rat myocardial cyclic AMP at various times after subcutaneous injection of necrosis-inducing amounts of isoproterenol, phenylephrine or epinephrine in the presence and in the absence of the phosphodiesterase inhibitor aminophylline. The β-adrenergic agonist isoproterenol (5.25 mg/kg) increased myocardial cyclic AMP at 1 h to 147% of control and in the presence of aminophylline (75 mg/kg) to 261% of control as compared to 146% for aminophylline alone. Propranolol (6.25 mg/kg) blocked isoproterenol-induced increases in cyclic AMP. Neither the α-adrenergic agonist phenylephrine (15 mg/kg) nor epinephrine (4 mg/kg), which has both α- and β-adrenergic properties, increased myocardial cyclic AMP above control levels even in the presence of aminophylline. With α-adrenergic blockade by tolazoline (15 mg/kg) or phenoxybenzamine (2 mg/kg), combined administration of epinephrine and aminophylline caused an increase of the myocardial cyclic AMP content to 163% and 173%, respectively, of that of control rats. These results suggest that in the intact rat, cyclic AMP-mediated myocardial stimulation is an important factor in the cardiotoxicity of isoproterenol but not of phenylephrine, while the beta-adrenergic component of epinephrine cardiotoxicity is unmasked only in the presence of α-adrenergic blockade.     

Prophylactic infusion of phenylephrine is effective in attenuating the decrease in regional cerebral blood volume and oxygenation during spinal anesthesia for cesarean section

BackgroundHypotension induced by spinal anesthesia for cesarean section causes a decrease in maternal regional cerebral blood volume and oxygenation. We used near-infrared spectroscopy to determine whether prophylactic infusion of phenylephrine attenuates these decreases.MethodsSixty patients undergoing bupivacaine spinal anesthesia for cesarean section were randomly divided into one of three intravenous infusion groups: saline (P0), phenylephrine 25 (P25) or 50 µg/min (P50). Mean arterial pressure, heart rate and near-infrared spectroscopy measurements were made at one-minute intervals for 20 minutes, and oxyhemoglobin, deoxy-hemoglobin and total-hemoglobin concentrations and tissue oxygenation index were determined. Mean changes in the values between baseline and each measurement time after intrathecal injection were compared.ResultsSignificant decreases in mean arterial pressure were seen in group P0 compared to P25 and P50 (P <0.01). Heart rate decreased in a dose-dependent manner during phenylephrine infusion (P0 vs. P25 and P50, P25 vs. P50; P <0.05). Significantly higher total-hemoglobin levels were observed in the phenylephrine groups versus the P0 group (P <0.01). The largest decrease in tissue oxygenation index was found in the P50, followed by P0 and P25 groups (P0 vs. P25 and P50, P25 vs. P50; P <0.05).ConclusionProphylactic infusion of phenylephrine, especially at 25 µg/min, can effectively suppress decreases in regional cerebral blood volume and regional cerebral blood oxygenation after induction of spinal anesthesia for cesarean section.     

Alpha adrenoceptor agonist-induced microcirculatory oscillations are reduced in diabetic neuropathy

In diabetic patients small fiber neuropathy has been associated with impairment of 0.1 Hz microvascular vasomotion. The aim of this study was (1) to investigate whether vasoconstriction-induced microvascular oscillations in the skin are reduced in diabetic patients with peripheral and/or autonomic neuropathy, and (2) whether this method could be used as a non-invasive surrogate marker to assess diabetic small fiber neuropathy.Four matched groups were studied: diabetic patients without neuropathy (D), with peripheral neuropathy (DPN), with peripheral and autonomic neuropathy (DAN), and non-diabetic controls (Ctrl). All participants were evaluated for peripheral and autonomic neuropathy, microvascular endothelial function, and metabolic syndrome indicators. Laser Doppler flowmetry was used to measure oscillations after iontophoresis of the alpha one selective agonist phenylephrine.~ 0.1-Hz oscillations recorded at the foot were significantly attenuated in diabetic patients with peripheral and/or autonomic neuropathy (DPN and DAN groups) compared to diabetic patients without neuropathy or non-diabetic controls. In the forearm, microvascular oscillations were significantly reduced only in patients with autonomic neuropathy (DAN).Oscillation measures correlated significantly (P < 0.001) with all markers of peripheral neuropathy but not with markers of measurements of microvascular endothelial function, or metabolic syndrome markers. In a logistic regression model, reduced microvascular oscillations at the foot were a strong predictor for the presence of peripheral neuropathy.The measurement of phenylephrine-induced ~ 0.1-Hz microvascular oscillation may represent a useful non-invasive tool with which to study the effects of treatment strategies on the diabetic small fiber neuropathy.     

The efficacy and adverse effects of topical phenylephrine for anal incontinence after low anterior resection in patients with rectal cancer

Background Anal incontinence is experienced by some patients with rectal cancer who received low anterior resection. This study was to examine the efficacy and adverse effects of the alpha-1 adrenergic agonist phenylephrine, which causes contraction of the internal anal sphincter and raises the resting pressure in these patients. Patients and methods Thirty-five patients with anal incontinence were treated with 30% phenylephrine or a placebo randomly allocated in a double-blind study. The efficacy of the drug was assessed by changes in the following standardized questionnaire scores: the fecal incontinence severity index (FISI), fecal incontinence quality of life (FIQL) scales, and a global efficacy question. Anal sphincter function was evaluated using anorectal manometry. Results Phenylephrine did not improve either the FISI score or any of the four FIQL scores. Five of 17 (29%) patients reported subjective improvement after phenylephrine compared with 4 of 12 (33%) using the placebo. The maximum resting anal pressure did not differ between baseline and after 4 weeks application of phenylephrine (30.0 to 27.3 mmHg). In the phenylephrine group, allergic dermatitis was developed in five patients and headache in two. Conclusion In the patients with anal incontinence after low anterior resection for rectal cancer, phenylephrine gel did not seem to be helpful in relieving symptoms with some adverse effects.