On the mechanism of action of phenylephrine in rat atrial heart muscle

Both in rat left atrial heart and in aortic smooth muscle preparations, phenylephrine (PE) caused a concentration-dependent increase in force of contraction (F_c) in the presence of atenolol (10 mol/l), which was antagonized by phentolamine, prazosin and WB 4101 in a competitive manner. The pA₂ values of the antagonists in the cardiac tissue were 10–20fold lower than those in the rat thoracic aorta. In the spontaneously beating right atrium, PE exerted a positive chronotropic action, which was not significantly antagonized by phentolamine or prazosin. It is therefore assumed that the effects of phenylephrine in the left atrium and in the aorta are mediated by different subtypes of ₁-adrenoceptors, whereas the effects in the sino-atrial node are probably unrelated to ₁-adrenoceptors. To further elucidate the mechanisms of the positive inotropic effect of PE, action potential configuration and ⁴⁵Ca²⁺ fluxes were monitored in the rat left atrium. The increase in F_c by PE was associated with an increase in action potential duration (APD) and a reduction in resting membrane potential (RP). In the presence of (–)-devapamil (13888), the effects of PE on APD and RP persisted, whereas the increase in F_c was antagonized in a non-competitive manner. Forskolin (300 nmol/l) enhanced the positive inotropic effect of PE. PE exerted a significant increase in ⁴⁵CA²⁺ uptake in beating preparations, which was abolished in the presence of (–)13888 (1 mol/l). In addition to the PE-induced increase in ⁴⁵Ca²⁺ uptake, a decrease in ⁴⁵Ca²⁺ efflux was observed. Similarly, depolarization of the membrane by raising [K⁺]_o to 85 mmol/l revealed an increase in ⁴⁵Ca²⁺ uptake and a decrease in ⁴⁵Ca²⁺ efflux. The latter observations support the view that the membrane potential strongly determines the movement of ⁴⁵Ca²⁺ across the membrane. It is assumed that the ₁-adrenoceptor-mediated changes in APD and RP may enhance F_c, first, by increasing net Ca²⁺ entry from the extracellular space through voltage-dependent Ca²⁺ channels and, second, by decreasing Ca²⁺ efflux possibly via the Na ⁺/Ca²⁺ exchange mechanism.     

Structure and mechanics of growing arterial microvessels from hypertrophied urinary bladder in the rat

Rat bladder hypertrophy, induced by a partial ligation of the urethra, was used to study the accompanying changes of microvascular smooth muscle mechanics, pharmacology and morphology. A segment of a microarterial vessel to the bladder was taken from a defined anatomical location and studied in a wire myograph in vitro at the length for maximal isometric force development (L _max). After 10 days of ligation, bladder hypertrophy resulted in a microvascular growth response compared to non-operated controls which was characterized by (i) an increase of the calculated diameter at L _max from 134±5 m to 222±19 m; (ii) an increase of the media thickness from 22.4±1.9 m to 32.2±3.0 m; (iii) an increase of the active tension from 1.42±0.28 mN/mm to 3.06±0.33 mN/mm; (iv) no change of the wall/lumen ratio (from 0.83±0.10 to 0.79±0.15). Normalized length/force relations (active, passive and total) did not differ significantly between microarteries from control and hypertrophic bladders. Microvascular smooth muscle growth was also associated with a decreased sensitivity to K⁺-induced depolarization and an increased sensitivity to ₁-adrenergic stimulation. No differences were noted regarding the Ca²⁺ sensitivity of force during K⁺-induced depolarization. The results suggest that microvascular growth (1) is immediately and positively influenced by the organ growth; (2) results in a functional resetting of the microvascular segments towards larger diameters without gross morphological or mechanical alterations; and (3) is accompanied by pharmacological alterations of the smooth muscle reactivity.     

大鼠胸主动脉舒缩反应节段性差异的等效转换

目的: 通过相关分析消除离体动脉不同节段反应差异对实验结果的影响.方法: 以生理多道记录仪记录离体大鼠胸主动脉环从下到上4节段舒缩张力反应,用回归方程对舒缩反应节段性差异作等效转换.结果: 大鼠胸主动脉下段对苯肾上腺素收缩反应高于次下段、次上段和上段,次下段高于次上段、上段 (P<0.05);下段对乙酰胆碱舒张反应高于次下段、次上段和上段,次下段高于次上段和上段(P<0.05).相关分析显示节段间收缩反应呈直线相关;舒张反应上段对下段呈曲线相关,余呈直线相关.按相关方程等效转换各动脉节段的舒缩反应,可消除反应的节段差异(P>0.05).结论: 通过回归方程作等效转换可消除动脉舒缩反应的节段性差异.     

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.     

Allergic contact eczema to phenylephrine

A female patient developed periorbital eczema and conjunctivitis prior to cataract surgery. Investigations revealed an allergic contact eczema to phenylephrine hydrochloride 10% eyedrops being used pre-operatively for mydriasis.     

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.     

脊椎麻醉后低血压高危产妇预防性使用去氧肾上腺素的效果和安全性探讨

目的探索脊椎麻醉后低血压高危产妇预防性使用去氧肾上腺素的效果和安全性,为临床治疗产后低血压疾病提供依据。方法选择本院2016年1月至2017年12月ASA分级为Ⅱ~Ⅲ级且MAP差值>8mmHg的剖宫术产妇98例作为观察对象,按数字表法分为49例去氧肾上腺素预防组(观察组)和49例生理盐水对照组(对照组),并对两组产妇麻醉之后仰卧位的MAP值变化、胎儿Apgar评分、脐带静脉血气分析及产妇不良反应等情况进行分析。结果麻醉之后观察组的MAP值明显高于对照组(t=6.562,P=0.002)。胎儿1min、5minApgar评分、血气分析及乳酸分析均无统计学意义。观察组的不良反应总发生率明显低于对照组的发生率,并两组比较差异具有统计学意义(χ2=5.848,P=0.003)。结论预防性使用去氧肾上腺对于高危产妇脊椎麻醉后低血压高具有良好的疗效,对于产妇和胎儿没有显著的不良影响,具有较高的临床价值。