Heparinase: in vivo activity and immunogenicity in rabbits

Anticoagulation with heparin is required during extracorporeal circulation for hemodialysis and cardiopulmonary bypass as well as during vascular surgery. Reversal of anticoagulation with protamine may be associated with hypotension and rebound anticoagulation and requires stoichiometric doses. Heparinase from Flavobacterium heparinum catalytically degrades heparin and reverses its anticoagulant effect. Heparin was administered to New Zealand White rabbits and plasma levels were assayed with the APTT anticoagulant assay and the azure A chemical assay. Heparinase actively degraded heparin both in vitro in rabbit plasma and in vivo in rabbit blood as determined by both the anticoagulant and chemical assays when compared to control heparin disappearance curves. Antibodies to heparinase were demonstrated by the ELISA technique in rabbits receiving i.v. heparinase. These antibodies, however, did not effect the activity of the enzyme in vitro or in vivo. No toxic effects of heparinase were noted in observations of the animals or in blood and histologic studies. Heparinase, either free or immobilized, may be a useful heparin-reversing agent without the drawbacks of protamine.     

Acetylstrophanthidin does not enhance the reflex pressor response to static muscular contraction

Summary. Cardiac glycosides have been shown to enhance the sensitivity of the reflex cardiovascular responses to stimulation of mechanoreceptors in the heart, carotid sinus and aorta. Little is known, however, about the effect of glycosides on the reflex cardiovascular responses to the contraction-induced stimulation of afferent endings in hindlimb skeletal muscle. We therefore examined the reflex heart rate and arterial pressure responses to static contraction of the hindlimb muscles before and after femoral arterial injection of two doses of acetylstrophanthidin (20 and 80 μ/kg). Neither of the two doses enhanced the reflex cardiovascular responses to contraction, although the larger of the two significantly increased femoral venous potassium concentrations from 3·4±0·2 to 3·8±0·1 mM. Although injection of the two doses as well as injection of a very large dose of acetylstrophanthidin (400 μg/kg) increased baseline mean arterial pressure, these effects were probably caused by the vasoconstrictor action of this agent and not by a chemoreflex, because the increase was not attenuated by denervation of the hindlimb.     

Pharmacological analysis of the actions of SKF 82526 on cardiovascular dopamine receptors

We have performed experiments with SKF 82526, a selective dopamine (DA1) receptor agonist to determine whether this compound would activate either ganglionic and/or central DA receptors. Bilateral hindlimb perfusion was carried out at controlled flow rates and changes in hindlimb perfusion pressure were recorded to evaluate the action of SKF 82526 on vascular resistance in anesthetized dogs. Intracisternal administration of SKF 82526 (10 and 40 micrograms/kg) did not produce any changes in blood pressure, heart rate or hindlimb vascular resistance. When the same doses were administered i.v., SKF 82526 produced hypotension and a decrease in perfusion pressure in the innervated limb, whereas perfusion pressure in the denervated limb was not altered. Intravenous SKF 82526 did not produce any changes in heart rate. When given into the lower abdominal aorta, SKF 82526 caused a dose-dependent decrease in perfusion pressure only in the innervated hindlimb, no significant changes in perfusion pressure occurred in the denervated limb. The hypotensive and the hindlimb vasodilatory actions of SKF 82526 could be antagonized by RS-sulpiride. It was discovered that SCH 23390, a selective DA1 receptor antagonist was most potent in blocking the hypotensive action of i.v. SKF 82526; however, it did not influence the neurogenic hindlimb vasodilation produced by intra-aortic SKF 82526. On the other hand, R-sulpiride, another selective DA1 receptor antagonist significantly antagonized the hypotensive as well as hindlimb vasodilatory actions of SKF 82526. S-sulpiride, a selective DA2 receptor antagonist, was least effective in blocking hypotension and did not influence the hindlimb vasodilatory action.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Effect of Cromakalim on the Hindlimb Vascular Bed of the Male Rat: Do Glybenclamide and/or Nitric Oxide Modulate the Vasodilation?

Cromakalim, a benzopyran derivative, is a member of a novel class of antihypertensive agents that increase membrane K(+) conductance through ATP-sensitive K(+) channels. The effects of glybenclamide and N(omega)-L-arginine methyl ester (L-NAME), a specific inhibitor of nitric oxide synthesis from L-arginine were investigated on the vasodilator response to cromakalim in the hindlimb vascular bed in the male rat, as well as the combination glybenclamide and L-NAME. Thirty male Sprague--Dawley rats (350--450 g) were studied. Cromakalim in three doses (10, 30, 100 &mgr;g) injected into the hindlimb through a catheter induced a significant dose-dependent decrease in both mean arterial pressure (MAP) and hindlimb perfusion pressure (HPP). These responses were significantly modified by either glybenclamide or L-NAME. The role of a combination of glybenclamide and L-NAME on the vasodilator responses to cromakalim, acetylcholine, and nitroglycerin were also investigated. Three doses of either acetylcholine, nitroglycerin, or cromakalim caused dose-dependent reduction in HPP of the rats. The responses to acetylcholine were significantly blocked by L-NAME, but the responses to nitroglycerin were not. The vasodilation induced by cromakalim was not only partly blocked by glybenclamide but also by L-NAME. This blockade was significantly augmented when both glybenclamide and L-NAME were infused. These results suggest that nitric oxide may play an important role in regulating hindlimb vascular tone under physiologic conditions. The data also suggest that nitric oxide may be an additional mediator for cromakalim vasodilation as well as K(APT)(+) channel activation in the hindlimb vascular bed of the male rat.     

人脐静脉血管内皮细胞缺氧复氧损伤时黏结合蛋白多糖1及细胞外信号调节酶表达与肝素酶Ⅰ的调节

背景:研究发现肝素酶可以促使肿瘤细胞的syndecan-1脱落,而且低氧增加的巨噬细胞运动也可能与硫酸已酰肝素蛋白多糖的生物合成调节相关.目的:观察肝素酶Ⅰ对缺氧复氧损伤人脐静脉血管内皮细胞黏结合蛋白多糖1及细胞外信号调节酶的调节作用.方法:采用缺氧复氧处理肝素酶Ⅰ预培养的人脐静脉血管内皮细胞,用免疫组织化学、RT-PCR及western blot枪测人脐静脉血管内皮细胞细胞黏结合蛋白多糖1、ERK2的表达.结果与结论:单纯缺氧复氧后人脐静脉血管内皮细胞的黏结合蛋白多糖1和ERK2表达轻度上调.缺氧复氧处理肝素酶预培养人脐静脉血管内皮细胞的黏结合蛋白多糖1和ERK2明显上调,与单纯缺氰复氧处理人脐静脉血管内皮细胞相比差异有显著性意义.黏结合蛋白多糖1与ERK2上调表达成正相关.结果表明,黏结合蛋白多糖1和细胞外信号调节酶参与了人脐静脉血管内皮细胞缺氧复氧损伤的病理生理过程,肝素酶Ⅰ可能通过调节黏结合蛋白多糖1来影响细胞外信号调节酶的表达.     

Effects of vasopressin, norepinephrine, and L-arginine on intestinal microcirculation in endotoxemia

OBJECTIVE: The effects of vasopressin, norepinephrine, and L-arginine alone or combined on intestinal microcirculation were evaluated in the septic mouse by intravital microscopy, with which we measured the erythrocyte flux and velocity in villus tip arterioles and the density of perfused villi. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Female BALB/c mice weighing between 18 and 21 g. INTERVENTIONS: Anesthetized and ventilated mice received at t0 an intravenous injection of Escherichia coli endotoxin (2 mg/kg bolus intravenously), inducing after 1 hr (t60) a decrease in mean arterial blood pressure to 40-50 mm Hg associated with a significant decrease in erythrocyte flux and velocity in villus tip arterioles and in the density of perfused villi. The mice then received a randomly different treatment for endotoxin-induced shock. Treatments consisted in continuous intravenous infusion for 1 hr with either saline (control group), norepinephrine, vasopressin, L-arginine, vasopressin+L-arginine, or norepinephrine+L-arginine. The doses of vasopressors (used alone or combined with L-arginine) were titrated to restore mean arterial pressure to the baseline level. MEASUREMENTS AND MAIN RESULTS: At the end of the treatment (t120), we observed in the control group further decreases in arteriolar flux and velocity and in the density of perfused villi. In the groups treated by a vasopressor alone, mean arterial pressure returned to baseline and there were no additional decreases in arteriolar flux and velocity or in the density of perfused villi. However, these latter three variables did not return to their preshock baseline values. Even though L-arginine did not restore mean arterial pressure, the infusion of L-arginine alone prevented the decrease in flux or erythrocyte velocity occurring between t60 and t120 and conserved to some extent the density of perfused villi compared with that in the control groups. In addition, we found that simultaneous administration of norepinephrine or vasopressin with L-arginine improved all microcirculation variables more efficiently than either vasopressor alone. CONCLUSIONS: From these data, we conclude that a) restoring mean arterial pressure after 1 hr of endotoxemia was not sufficient to restore ad integrum intestinal mucosa microvascular perfusion; b) L-arginine could have a beneficial effect at the microcirculatory level, which was independent of mean arterial pressure; and c) administration of L-arginine combined with the maintenance of perfusion pressure by vasopressive drugs allowed a better preservation of intestinal microcirculation at an early stage of endotoxemia.     

Evaluation of the role of alpha-1 and alpha-2 adrenoceptors in the maintenance of neurogenic tone to the hindlimb vasculature

The location of two distinct subtypes of alpha adrenoceptors on blood vessels is now well established. The present study was designed to assess the relative contribution of alpha-1 and alpha-2 adrenoceptors to the maintenance of sympathetic vasoconstrictor tone to the canine hindlimb. Bilateral hindlimb perfusion was carried out at controlled flow rates where one of the hindlimbs was neurally intact and the other limb was denervated surgically. Vascular resistances in the hindlimbs were evaluated by pressure-flow curves which were constructed by recording perfusion pressures at various flow levels. Administration of alpha-1 adrenoceptor antagonist, prazosin (50 micrograms/kg), which selectively inhibited the hindlimb vasoconstrictor effect of phenylephrine but not of B-HT 933, produced a significant decrease in the hindlimb vascular resistance in the innervated limb. This was reflected in a decrease in perfusion pressure and a downward shift of the pressure-flow curve of 30% from control. No changes in resistance occurred in the denervated limb. The alpha-2 adrenoceptor antagonist, yohimbine (100 micrograms/kg), which selectively antagonized vasoconstriction to B-HT 933 but not to phenylephrine, further decreased by 27% hindlimb vascular resistance in the innervated limb when given to the same group of prazosin-treated animals. The magnitude of the decrease in vascular resistance produced by yohimbine (27%) was similar to that caused by prazosin (30%). The vascular resistance in the innervated limb was now similar to that in the denervated limb after prazosin and yohimbine. Phentolamine, when administered after prazosin and yohimbine, did not produce any changes in the hindlimb vascular resistance in these dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phorbol-12,13-dibutyrate-induced vasoconstriction in vivo: characterization of response in genetic hypertension

To assess the role of protein kinase C (PKC) in the control of vessel tone in vivo in genetic hypertension, the vascular effects of phorbol-12,13-dibutyrate (PDBu), a PKC activator, was measured in the autoperfused hindlimb of reserpinized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). PDBu infusion (1-3000 ng/kg/min) into the hindlimb elevated perfusion pressure in a dose-related manner. Vasoconstriction response characteristics (latency, T1/2 to peak effect, decay of effect) of PDBu were significantly longer (2- to 10-fold) than that produced by membrane receptor agonists; phenylephrine, SKF 89748, a lipophilic alpha-1 agonist, angiotensin II and 5-hydroxytryptamine. The tonic vasoconstriction induced by PDBu was not antagonized by prazosin, rauwolscine, cyproheptadine, [Sar1lle8]-angiotensin II but was inhibited reversibly by microbial PKC-inhibitors, K252a and staurosporine at concentrations (1.56-2.8 micrograms/kg/min) which did not block vasoconstriction by phenylephrine or 5-hydroxytryptamine. The EC50 for PDBu was identical in SHR and WKY. However, the maximal response to PDBu was significantly greater in SHR compared to WKY. Staurosporine lowered mean arterial pressure equally in SHR (20%) and WKY (17%) but reduced perfusion pressure in SHR (13%) to a slightly greater extent than in WKY (5%). Unlike the in vivo response, aortic rings removed from SHR were more sensitive to cumulative doses of PDBu than rings from WKY. It is concluded that PDBu-vasoconstriction in vivo is mediated largely through activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the neurogenic vasodilatation elicited by central dopamine receptor stimulation with pergolide

In the present study, we have employed the procedure of bilateral hindlimb perfusion at controlled flow rates to investigate centrally mediated actions of the dopamine receptor agonist pergolide on hindlimb vascular resistance in anesthetized dogs. Intracisternal administration of pergolide caused sustained hypotension, bradycardia and a decrease in perfusion pressure in the innervated hindlimb, whereas perfusion pressure in the denervated limb was not altered by pergolide. In addition, the pressure-flow curves were shifted to the right in the innervated hindlimb but not in the denervated limb, suggesting that pergolide caused neurogenic dilatation in the hindlimb vasculature. Intravenous administration of the same dose of pergolide elicited transient hypertension and marked vasoconstriction in the denervated limb. Hypotension and neurogenic hindlimb vasodilatation of lesser magnitude than that produced by intracisternal pergolide were seen only 40 to 50 min after administration of i.v. pergolide. The hindlimb vasodilator action of intracisternal pergolide could be antagonized by sulpiride, which suggests that activation of central dopamine receptors was responsible for the action of pergolide. Because the neural innervation to the hindlimb is comprised of sympathetic vasoconstrictor as well as cholinergic and dopaminergic vasodilator fibers, additional experiments were performed to determine the mechanisms involved in the neurogenic vasodilatation caused by pergolide. Treatment with atropine did not alter the neurogenic decrease in the hindlimb vascular resistance produced by pergolide, indicating that activation of cholinergic vasodilator fibers was not responsible for this phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats

Alkalinization of the blood by administration of sodium bicarbonate or hyperventilation is widely recommended for treatment of cardiac toxicity due to tricyclic antidepressant overdose, yet its efficacy and mechanism of action are poorly defined. We studied the effects and possible mechanism of action of 1 M NaHCO3 on desipramine (DMI) toxicity in anesthetized, paralyzed rats. Administration of DMI (45 mg/kg i.p.) produced a mean increase in QRS duration of 142% and a mean decrease in mean arterial pressure of 46%. Treatments were administered i.v. 35 min after DMI and their effects were assessed 10 min later. NaHCO3 (1 M) at doses of 3 and 6 mEq/kg decreased mean QRS duration 15 +/- 5 and 24 +/- 6%, respectively (mean +/- S.D.) and was superior to no treatment (P less than .01). NaCl (1 M) was as effective as NaHCO3 in decreasing QRS duration, as was 1 M NaHCO3 supplemented with 48 mM KCl. Respiratory alkalosis and 10% mannitol did not decrease QRS duration. NaHCO3, NaCl and NaHCO3/KCl all produced comparable increases in mean arterial blood pressure. Respiratory alkalosis and mannitol did not increase mean arterial pressure, but did prevent the decline seen in control animals. Acidosis produced by ventilation with 10% CO2 exacerbated QRS prolongation due to DMI. In acidotic animals, NaHCO3 and NaCl were equally effective in reversing QRS prolongation and hypotension. Correction of respiratory acidosis by discontinuation of inhaled CO2 did not improve QRS duration or mean arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of cerebral blood flow by radionuclide cerebral angiography and by microspheres in cats.

BACKGROUND: Radionuclide cerebral angiography is commonly used as an adjunct to the diagnosis of brain death. Despite its acceptance as a diagnostic tool, it is not clear whether the absence of cerebral blood flow by radionuclide cerebral angiography denotes a complete lack of cerebral blood flow. METHODS: To compare cerebral blood flow estimated by radionuclide cerebral angiography with cerebral blood flow measured by the radiolabeled microsphere technique, we systematically varied cerebral perfusion pressure (mean arterial BP minus intracranial pressure) in anesthetized cats by infusing artificial cerebral spinal fluid into the lateral ventricle to increase intracranial pressure. We measured cerebral blood flow with both techniques as cerebral perfusion pressure was decreased from its baseline of 111 +/- 10 mm Hg to 20, 10, 5, 0, and less than 0 mm Hg, causing a stepwise decrease in cerebral blood flow. RESULTS: We found a correlation by regression analysis (r2 = .47, p less than .05) between radionuclide cerebral angiography and microsphere measurements of cerebral blood flow, when both blood flow measurements were expressed as a percentage of baseline values. However, if 20% of baseline flow was assigned as a cut-off point for critically low cerebral blood flow (based on human studies), radionuclide cerebral angiography was only 33% sensitive to detect critically reduced cerebral blood flow and had a positive predictive accuracy (of low-flow interpretation) of only 60%. Radionuclide cerebral angiography was unable to demonstrate a complete lack of cerebral blood flow, even in two instances when cerebral blood flow by microspheres was less than 0.1% of baseline. CONCLUSIONS: We conclude that the ability of radionuclide cerebral angiography to quantify low cerebral blood flow is poor, and that this technique may not identify severely reduced cerebral blood flow.     

Detection of a systolic pressure threshold for reliable readings in pulse oximetry

OBJECTIVE: To determine the error of measurement in pulse oximetry with a decreased arterial perfusion and to identify a systolic pressure threshold for (1) initial detection and (2) a reliable reading of oxygen saturation. DESIGN: An experimental clinical prospective study. The study was approved by the local ethics committee. SETTING: Eighteen bed intensive care unit at a University hospital. PATIENTS AND PARTICIPANTS: Twenty-five adult mechanically ventilated and critically ill patients in the ICU during a 3-month period. INTERVENTIONS: A blood pressure cuff at the upper arm (same side as an arterial catheter already in place) was inflated to decrease the arterial pulsatile flow. The cuff was deflated stepwise and the resulting oxygen saturation was measured simultaneously. The error of measurement [delta S = SpO2 (baseline)-SpO2 (indicated)] was calculated for each 5 mmHg of blood pressure (BP). MEASUREMENTS AND RESULTS: Twenty-five patients (9 female, 16 male, 48 +/- 15.9 years old) with a mean SpO2 of 98.3 +/- 1.5% and a BP of 129 +/- 18.4 mmHg participated. The mean systolic BP to obtain initial readings with pulse oximetry was 45.8 +/- 17.7 (range, 25-101) mmHg (35% of the baseline pressure) resulting in lower readings of pulse oximetry (mean -11.5 +/- 13.6%, range -45 to +4%). With a systolic BP > 80 mmHg the mean bias was within the manufacturers limits of +/-2%. CONCLUSIONS: Pulse oximetry is reliable with a systolic blood pressure > 80 mmHg. The lower the BP, the lower the pulse oximetry readings leading to a bias of up to -45%.     

Hemodynamic effects of verapamil in the beta-blocked dog

The use of the calcium channel-blocking agent, verapamil, in beta-blocked patients has been the subject of intense investigation, particularly because both verapamil and the beta-blockers can produce negative inotropic effects. We studied the hemodynamic effects of verapamil in beta-blocked dogs to establish specific measurements that could be used clinically for early identification of combined negative inotropism. Seven anesthetized, mongrel dogs were beta-blocked with propranolol, and then given 2.5-, 5.0-, and 10.0-mg iv boluses of verapamil. The 2.5- and 5.0-mg boluses represent clinical doses, whereas the 10.0-mg bolus is a large pharmacologic dose. Hemodynamic measurements showed that verapamil was well tolerated at clinical doses; increases in stroke volume compensated for decreases in mean arterial pressure. At high doses of verapamil this response was not observed and left ventricular stroke work decreased. Cardiac and stroke indices were not useful indicators of combined drug toxicity in this dog model.     

Pharmacology and toxicology of a new aqueous formulation of intravenous amiodarone (Amio-Aqueous) compared with Cordarone IV

Hypotension is the most frequent adverse event reported with intravenous amiodarone (Cordarone IV). The hypotension has been attributed to the vasoactive solvents of the formulation, polysorbate 80 and benzyl alcohol, both known to exhibit negative inotropy and hypotensive effect. A new aqueous formulation of intravenous amiodarone (Amio-Aqueous) does not contain vasoactive excipients and may be less toxic and cause less hypotension than Cordarone IV. This hypothesis was tested in a series of animal studies with direct comparison of Amio-Aqueous and Cordarone IV. All studies were performed on Sprague-Dawley rats. The acute toxicology study showed that both LD50 and LD100 were 30% greater for Amio-Aqueous than for Cordarone. At the dose at which all animals expired on Cordarone, 50% of animals were still alive on Amio-Aqueous. The study on myocardial contractility showed that Amio-Aqueous was a far less negative inotropic than Cordarone IV (P < 0.001). Amio Aqueous did not have an effect on contractility at 5- and 10-mg/kg dose levels while Cordarone resulted in a 25% (P < 0.01) and 29% (P < 0.002) decrease, respectively. The study on arterial blood pressure showed that Cordarone caused a significant decrease in blood pressure at each of the 3, 5, 10, and 20 mg/kg doses (P < 0.05 to P < 0.001) while Amio-Aqueous did not. The study on the antiarrhythmic effects showed comparable efficacy for both formulations. In conclusion, Cordarone IV was more toxic and caused significant hypotension and negative inotropy while Amio-Aqueous lacked the hypotensive and cardiotoxic properties of Cordarone. Therefore, Amio-Aqueous is a safer alternative than the standard formulation.     

Hemodynamic effects of the converting enzyme inhibitor teprotide in normal- and high-renin hypertension

The hemodynamic effects of the converting enzyme inhibitor teprotide (SQ 20881) were investigated in five patients with normal plasma renin activity who were normotensive during the study (group I), in five patients with hypertension and normal plasma renin activity (group II), and in five patients with hypertension and high plasma renin activity (group III). No significant hemodynamic changes were observed during teprotide administration in group I. In group II there was a decrease in mean arterial pressure by 10 +/- 2% (p < 0.005) that was associated with a decrease by 16 +/- 7% (p < 0.05) in stroke volume and cardiac output, possibly due to venodilatation and without a concurrent change in total peripheral resistance. In group III the larger decrease of 19 +/- 4% (p < 0.005) in mean arterial pressure was due to a decrease by 30 +/- 3% (p < 0.005) in peripheral resistance. In this group stroke volume and cardiac output increased by 13 +/- 2% (p < 0.025). There were no compensatory changes in heart rate despite the decrease in mean arterial pressure and vasodilatation. These results indicate that teprotide decreases arterial pressure by a dual hemodynamic mechanism. Cardiac output is increased by teprotide in patients with high-renin hypertension who exhibit the greatest decrements in peripheral resistance.     

Effects of positive end-expiratory pressure on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation

OBJECTIVE: Acute respiratory dysfunction frequently occurs following severe aneurysmal subarachnoid hemorrhage requiring positive end-expiratory pressure (PEEP) ventilation to maintain adequate oxygenation. High PEEP levels, however, may negatively affect cerebral perfusion. The goal of this study was, to examine the influence of various PEEP levels on intracranial pressure, brain tissue oxygen tension, regional cerebral blood flow, and systemic hemodynamic variables. DESIGN: Animal research and clinical intervention study. SETTING: Surgical intensive care unit of a university hospital. SUBJECTS AND PATIENTS: Experiments were carried out in five healthy pigs, followed by a clinical investigation of ten patients suffering subarachnoid hemorrhage. INTERVENTIONS: Under continuous monitoring of intracranial pressure, brain tissue oxygen tension, regional cerebral blood flow, mean arterial pressure, and cardiac output, PEEP was applied in increments of 5 cm H2O from 5 to 25 cm H2O in the experimental part and from baseline to 20 cm H2O in the clinical part. MEASUREMENTS AND MAIN RESULTS: In animals, high PEEP levels had no adverse effect on intracranial pressure, brain tissue oxygen tension, or regional cerebral blood flow. In patients with severe subarachnoid hemorrhage, stepwise elevation of PEEP resulted in a significant decrease of mean arterial pressure and regional cerebral blood flow. Analyses of covariance revealed that these changes of regional cerebral blood flow depended on mean arterial pressure changes as a result of a disturbed cerebrovascular autoregulation. Consequently, normalization of mean arterial pressure restored regional cerebral blood flow to baseline values. CONCLUSIONS: Application of high PEEP does not impair intracranial pressure or regional cerebral blood flow per se but may indirectly affect cerebral perfusion via its negative effect on macrohemodynamic variables in case of a disturbed cerebrovascular autoregulation. Therefore, following severe subarachnoid hemorrhage, a PEEP-induced decrease of mean arterial pressure should be reversed to maintain cerebral perfusion.     

Arginine8-vasopressin reduces spinal cord blood flow after spinal subarachnoid injection in rats

Arginine8-vasopressin (AVP) causes hindlimb paralysis, loss of nociceptive responsiveness and increased arterial pressure after spinal subarachnoid injection in rats. In these experiments, the effects of paralytic intrathecal doses of AVP on rat brain and spinal cord blood flow, vascular resistance and cardiac output were measured using radiolabeled microspheres. Ten minutes after injection, AVP (10-100 pmol) elevated mean arterial pressures significantly, increased vascular resistances in thoracic and lumbosacral spinal cord and reduced blood flow to the lumbosacral spinal cord without altering cardiac output, total peripheral resistance and blood flow to brain and other spinal cord regions. Lumbosacral blood flows remained significantly reduced 30 min after injection of 100 pmol of AVP, and recovered to pretreatment base-line levels by 60 min postinjection. Lactic acid concentrations were elevated significantly in spinal cerebrospinal fluid samples removed 5 to 15 min after AVP injection (100 pmol). The selective AVP V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] arg8-vasopressin, which previously blocked the effects of AVP on hindlimb motor and nociceptive function, in these experiments also blocked the AVP-induced increases in arterial pressure and reductions in lumbosacral perfusion. Intravenous infusion of the vasodilators papaverine and nifedipine failed to block AVP-induced hindlimb paralysis. Nifedipine, however, did accelerate subsequent recovery of hindlimb motor function, although it did not alter the lumbosacral blood flow reductions measured at 10 and 30 min after AVP injection. These findings indicate that AVP has significant vascular effects in the rat spinal cord that are associated with ischemia and neurological dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrathoracic pressure regulation improves vital organ perfusion pressures in normovolemic and hypovolemic pigs

BACKGROUND: The intrathoracic pressure regulator (ITPR) was created to improve hemodynamics by generating continuous negative airway pressure between positive pressure ventilations to enhance cardiac preload in apnoeic animals. In normovolemic and hypovolemic pigs, we tested the hypothesis that continuous negative intrathoracic pressure set at -5 or -10mmHg, interrupted only for intermittent positive pressure ventilations, would decrease intracranial (ICP) and right atrial (RAP) pressure, and increase mean arterial pressure (MAP). METHODS: Twelve pigs were anesthetized with propofol and ventilated with a bag. The ITPR was used to vary baseline endotracheal pressures (ETPs) for 5min periods in the following sequence: 0, -5, 0, -10, 0mmHg under normovolemic conditions. Six pigs were bled 50% (32.5+/-mL/kg) of their estimated blood volume and the airway pressure sequence was repeated. Six other pigs were bled 35% (22.75+/-mL/kg) of their estimated blood volume and the same airway pressure sequence was repeated. Intracranial, aortic, right atrial pressures, arterial blood gases, end tidal CO(2) (ETCO(2)), were measured. ANOVA was used for statistical analysis. Linear regression analysis was performed for ETP and ICP. RESULTS: Mean arterial and vital organ perfusion pressures were significantly improved and RA pressure significantly decreased with the use of the ITPR; the effect was greater with the more negative ETPs and lower circulating blood volume. The change of ICP was linearly related to the ETP and blood loss: DeltaICP=[1.22-0.84(1-%blood loss/100)]xETP, r(2)=0.88 (in mmHg), p<0.001. There were no adverse device effects and there was a significant increase of ETCO(2) with the use of ITPR. CONCLUSION: The ITPR decreased RAP and ICP significantly and improved mean arterial and cerebral and coronary perfusion pressures without affecting acid base balance severely. The decrease in ICP was directly proportional to the reduction in intrathoracic pressure. The effects were more pronounced in severe hypovolemic and hypotensive states with more negative ETP pressure.     

高血压性灌注对心肺复苏成功后肺的影响

目的 猪心肺复苏成功后,用去甲肾上腺素诱导高血压性灌注,研究其埘血清TNF-α和IL-6、肺组织Na~+-K~+-ATP酶以及肺组织形态学的影响.方法 10只家猪窒颤4 min,给予标准心肺复苏,复苏成功后分两绀:(1)高血压组(n=5)立即给予去甲肾上腺素,使平均动脉压维持在室颤前血压的130%4 h;(2)正常血压组(n=5)给予适量的去甲肾上腺素,维持平均动脉压为室颤前水平4h.监测血流动力学指标;分别在室颤前、复苏成功后10 min,2 h,4 h取血,检测血清TNF-α和IL-6;复苏成功后24 h取肺组织,检测Na~+-K~+-ATP酶,并行普通病理和超微结构检测.用配对t检验对数据进行统计学分析.结果 高血压组除影响血压和心率外,对其他血流动力学指标影响较小,能够减少TNF-α和IL-6的释放(P<0.01),增强肺泡细胞膜Na~+-K~+-ATP酶的活性,减少肺泡表面活性物质的消耗.结论 去甲肾上腺素诱导的高血压性灌注能够减少炎症因子的释放,增强肺泡细胞ATP酶的活性,对肺脏具有重要的保护作用.     

Addition of enoximone to adrenergic agents in the management of severe heart failure.

OBJECTIVE: To assess the hemodynamic effects of the addition of small bolus doses of the phosphodiesterase inhibitor enoximone to adrenergic therapy in patients with severe heart failure. DESIGN: Open label, prospective study. SETTING: Multidisciplinary department of intensive care in a university academic hospital. PATIENTS: Twelve surgical patients after cardiac surgery and ten medical patients with ischemic or dilated cardiomyopathy who had signs of altered tissue perfusion associated with a low cardiac index (less than 2.25 L/min/m2), despite adrenergic therapy. INTERVENTIONS: Small iv bolus doses of 0.25 mg/kg of enoximone. MEASUREMENTS AND MAIN RESULTS: This treatment resulted in significant increases in cardiac index and left ventricular stroke work index without significant changes in heart rate or mean arterial pressure. Furthermore, the effects of half this dose (i.e., 0.125 mg/kg), studied in 11 patients, demonstrated a significant drug-induced increase in mean (+/- SD) cardiac index (from 1.58 +/- 0.29 to 1.84 +/- 0.27 L/min/m2, p less than .01) without change in mean arterial pressure (from 74.5 +/- 12.1 to 76.5 +/- 12.6 mm Hg, nonsignificant). CONCLUSIONS: Direct iv injections of enoximone can significantly increase the cardiac index in critically ill patients treated by adrenergic agents for severe heart failure. The administration of small doses of enoximone is effective and has minimal effect on arterial pressure.