Significant Decrease In Mean Arterial Pressure Research Articles

Insulin-like growth factor-I decreases mean blood pressure and selectively increases regional blood flow in normal rats.

The insulin-like growth factor-I (IGF-I) and its receptors are widely distributed in peripheral vascular tissue, yet their role in the regulation of blood pressure and blood flow remains unknown. This study investigated the effect of IGF-I on blood pressure and selected regional blood flow in normal Wistar rats anesthetized with chloralose/urethane. The femoral artery was cannulated and used to monitor arterial blood pressure. Electromagnetic flow probes were placed around the left common iliac artery, left renal artery, and the superior mesenteric artery, and used to measure blood flow. IGF-I (2.6 micrograms, 5.1 or 10.3 nmol/animal Iv) was injected as a bolus into the femoral vein. Following the injection of IGF-I (10.3 nmol), we observed a significant decrease of plasma glucose (57%) and a significant decrease of mean arterial pressure (MAP) that continued to decline throughout the 60-min experimental period. IGF-I (5.1 nmol) significantly decreased blood glucose by 44% and decreased the MAP by 14% with a nadir at 15 min and recovery after 60 min. A smaller dose of IGF-I (2.6 nmol) did not significantly decrease the blood glucose but resulted in a slight but significant decrease in MAP. The heart rate was increased by 10.3 and 5.1 but not 2.5 nmol of IGF-I. IGF-I (10.3 nmol) was associated with regional vascular responses with a preferential increase in flow of the iliac and superior mesenteric vessels, measured as vascular conductance. IGF-I (5.1 and 2.6 nmol) increased preferentially renal vascular conductance. Preinfusion with L-NAME, a nitric oxide inhibitor, inhibited the effects of IGF-I on flow. We conclude that IGF-I can selectively dilate vascular beds leading to a decrease in blood pressure and that the response to IGF-I is mediated by nitric oxide.

Pressor and sympathoexcitatory effects of nitric oxide in the rostral ventrolateral medulla.

It has been shown that nitric oxide (NO) plays an important role in the central control of arterial pressure and sympathetic nerve activity. The aim of this study was to determine whether NO can regulate sympathetic nerve activity by an action on pressor neurons within the rostral part of the ventrolateral medulla (VLM). Experiments were performed on anaesthetized rabbits with denervated arterial and cardiopulmonary baroreceptors. The mean arterial pressure (MAP), heart rate and renal sympathetic nerve activity were measured. Microinjections of the NO donors sodium nitroprusside (SNP, 4-50 nmol) and S-nitroso-glutathione (10 nmol), the NO precursor L-arginine (50 nmol) and the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 50 nmol), were made into the functionally identified pressor region in the rostral VLM. The effects of SNP were also determined before and after injection of 5 nmol methylene blue into the same area. In control experiments, injections of D-arginine (50 nmol) and D-NAME (50 nmol), which are the inactive isomers of L-arginine and L-NAME, respectively, were also made into the functionally identified pressor region in the rostral VLM. Microinjections of SNP into the rostral VLM pressor region produced a dose-dependent increase in mean arterial pressure and renal sympathetic nerve activity. At the highest dose of 50 nmol, the increase in MAP was 26 +/- 5 mmHg (P < 0.001) and the sympathetic nerve activity was 53 +/- 5% (P < 0.001). These effects were abolished following methylene blue injection into the same region. Injection of 10 nmol S-nitroso-glutathione also produced increases in MAP (15 +/- 2 mmHg, P < 0.001) and in renal sympathetic nerve activity (28 +/- 2%, P < 0.001). Microinjections of L- or D-arginine resulted in very small depressor responses, but had no significant effect on renal sympathetic nerve activity. Microinjections of L-NAME, but not of D-NAME, caused significant decreases in MAP (19 +/- 1 mmHg, P < 0.001) and in sympathetic nerve activity (30 +/- 3%, P < 0.001). The results indicate that, in the anaesthetized rabbit with denervated baroreceptors, NO has a pressor and sympathoexcitatory action in the rostral VLM, which is mediated by a cyclic GMP-dependent mechanism. Second, endogenous NO may modulate sympathetic activity tonically, by a direct or indirect action on sympathoexcitatory neurons within the rostral VLM.

Normovolaemic haemodilution attenuates cardiac depression induced by sodium bicarbonate in canine metabolic acidosis

This study was designed to determine if coexisting metabolic acidosis or normovolaemic haemodilution, or both, modifies the acute cardiodepressant effect of i.v. sodium bicarbonate. Thirty-one mongrel dogs were anaesthetized with halothane, and the lungs ventilated mechanically; dogs were allocated randomly to one of four groups: control group (pHa 7.39 (SD 0.03), base excess -1.0 (1.6) mmol litre-1, haemoglobin 13.9 (2.5) g dl-1 (n = 8)), metabolic acidosis group (pHa 7.21 (0.05), base excess -11.2 (2.1) mmol litre1, haemoglobin 13.4 (2.6) g dl-1 (n = 8)), anaemia group (pHa 7.40 (0.04), base excess 0.1 (2.0) mmol litre-1, haemoglobin 7.2 (1.1) g dl-1 (n = 8)) or anaemia acidosis group (pHa 7.22 (0.04), base excess -11.0 (2.2) mmol litre-1, haemoglobin 7.4 (0.3) g dl-1 (n = 7)). Metabolic acidosis was induced by continuous i.v. infusion of hydrochloric acid 2 mol litre-1. Normovolaemic haemodilution was undertaken by phlebotomy and simultaneous exchange with lactated Ringer's solution at 37 degrees C. Mean arterial pressure (MAP), pulmonary artery pressure, right atrial pressure (RAP), maximum rate of change of pressure in the right ventricle (RV dP/dtmax) and pulmonary blood flow (PBF) were measured at 30 s, 1 and 3 min after administration of 7% sodium bicarbonate solution 1 mmol kg-1 given into the right atrium over 5 s. Sodium bicarbonate produced significant decreases in MAP and RV dP/dtmax at 30 s in all groups except for the anaemia acidosis group (P < 0.05). There was a significant decrease in right ventricular stroke volume in the metabolic acidosis group from baseline values (P < 0.05), and compared with the three other groups (P < 0.05). These results indicate that the cardiodepressant effect of sodium bicarbonate 1 mmol kg-1 i.v. during metabolic acidosis was more pronounced than without acidosis, but was attenuated in the presence of normovolaemic haemodilution.

Central IGF-1 decreases systemic blood pressure and increases blood flow in selective vascular beds.

IGF-1 and its receptors have been identified in many tissues including the central nervous system (CNS). We have previously demonstrated that injection of insulin directly into the cerebral ventricles (ICV) is followed by a drop in mean arterial pressure (MAP) associated with an increase in skeletal muscle blood flow. Given the similarities between the IGF-1 and insulin molecules and their respective receptors, we have investigated the effect of ICV administration of IGF-1 on systemic blood pressure and blood flow in selected vascular beds. ICV cannulas were implanted into normal rats and the animals were allowed to recover for 3 to 4 days. The femoral artery and vein were cannulated for blood pressure monitoring and blood sampling and blood flow probes placed around the iliac, the renal and the superior mesenteric artery were used to assess regional blood flow. ICV injection of IGF-1 resulted in a significant decrease in MAP with a nadir at 15 minutes and a gradual return to baseline by 60 minutes; heart rate increased 40 minutes after the injection. IGF-1 significantly enhanced vascular flow and conductance in the iliac, but not in the renal and superior mesenteric arteries. The effects of IGF-1 were much smaller than those observed previously with equimolar amounts of insulin. We conclude that IGF-1 can decrease MAP by selectively increasing blood flow to skeletal muscle through a direct action on the central nervous system.

Role of area postrema in transgene hypertension.

Transgenic [Tg(+)] rats carrying the mouse Ren-2d gene [(mRen-2d)27] are a newly established monogenetic form of experimental hypertension. To determine whether the area postrema contributes to the development of hypertension in mRen-2 Tg(+) rats, this circumventricular organ in the fourth ventricle was removed from 5-week-old Tg(+) rats. From weeks 4 through 9, systolic blood pressure was measured weekly by tail-cuff plethysmography in area postrema-lesioned and sham-lesioned Tg(+) rats. Although systolic blood pressure rose markedly in sham-lesioned Tg(+) rats, the increase in systolic blood pressure was significantly attenuated in area postrema-lesioned Tg(+) rats. At 9 weeks of age, a femoral artery was cannulated for the measurement of arterial pressure in awake rats. Mean arterial pressure (MAP) in area postrema-lesioned Tg(+) rats was significantly (P < .01) lower than that in sham-lesioned rats: 171 +/- 7 and 132.+/- 5 mm Hg, respectively. Baroreceptor reflex was evaluated by intravenous infusion of sodium nitroprusside. There was no significant difference in baroreceptor reflex sensitivity between the two groups. Intravenous pentolinium (5 mg/kg), used to produce sympathetic ganglionic block, caused significant decreases in MAP in both groups. However, the reduction of MAP in the sham-lesioned group was significantly (P < .05) greater than that in the area postrema-lesioned group: -73 +/- 4 and -48 +/- 6 mm Hg, respectively. The ratio of left ventricular weight to body weight in sham-lesioned Tg(+) rats was significantly larger than that of area postrema-lesioned rats. These results suggest that ablation of the area postrema markedly attenuates the development of hypertension in mRen-2d Tg(+) rats, and this attenuation may be attributed to decrease in sympathetic outflow.

The Effects of Bolus Administration of Opioids on Cerebrospinal Fluid Pressure in Patients with Supratentorial Lesions

In many studies reporting an increase in cerebrospinal fluid pressure (CSFP) after opioid administration, concomitant decreases in mean arterial pressure (MAP) have been observed.Autoregulatory cerebral vasodilation may therefore have been a factor in the CSFP increases. We tested the hypothesis that increases in CSFP after bolus injection of opioids could be minimized by modifying concomitant decreases in MAP with phenylephrine. Thirty-three patients with supratentorial mass lesions were studied in a randomized, prospective, double-blind, saline-controlled comparative trial. The principal outcome measures were lumbar CSFP, MAP, and heart rate (HR). Study drugs, sufentanil 0.8 micro gram/kg (n = 12), fentanyl 4.5 micro gram/kg (n = 11), or normal saline (n = 10), were injected intravenously (IV) during stable general anesthesia with 0.3-0.7 minimum alveolar anesthetic concentration (MAC) of isoflurane in oxygen and controlled ventilation (end-tidal carbon dioxide 32-35 mm Hg). Phenylephrine 50-100 micro gram was injected IV when MAP decreased by more than 15% of initial values, and atropine 0.5 mg IV when HR decreased to less than 45 bpm. Opioid administration was associated with significant decreases in MAP, 21 +/- 9 mm Hg (mean +/- SD) in the sufentanil group and 16 +/- 7 mm Hg in the fentanyl group; P < 0.001. These decreases in MAP were of short duration (i.e., corrected with 1-2 min). Patients in the sufentanil group needed more phenylephrine than patients in the fentanyl group (170 +/- 89 micro gram vs 100 +/- 47 micro gram; P < 0.05). No significant change in the CSFP was seen in either the sufentanil-(1 +/- 6 mm Hg) or fentanyl-treated patients (0 +/- 2 mm Hg). No significant changes in MAP or CSFP were observed in the saline-treated patients. HR decreased after injection of either study drug (P < 0.01) but remained unchanged in the saline group. In summary, during stable anesthesia with isoflurane in oxygen, bolus injections of fentanyl or sufentanil, despite producing rapidly corrected mean decreases in MAP of 18% and 25%, respectively, were not associated with any change in CSFP. (Anesth Analg 1996;82:600-6)

The Effects of Bolus Administration of Opioids on Cerebrospinal Fluid Pressure in Patients with Supratentorial Lesions

In many studies reporting an increase in cerebrospinal fluid pressure (CSFP) after opioid administration, concomitant decreases in mean arterial pressure (MAP) have been observed. Autoregulatory cerebral vasodilation may therefore have been a factor in the CSFP increases. We tested the hypothesis that increases in CSFP after bolus injection of opioids could be minimized by modifying concomitant decreases in MAP with phenylephrine. Thirty-three patients with supratentorial mass lesions were studied in a randomized, prospective, double-blind, saline-controlled comparative trial. The principal outcome measures were lumbar CSFP, MAP, and heart rate (HR). Study drugs, sufentanil 0.8 micrograms/kg (n = 12), fentanyl 4.5 micrograms/kg (n = 11), or normal saline (n = 10), were injected intravenously (IV) during stable general anesthesia with 0.3-0.7 minimum alveolar anesthetic concentration (MAC) of isoflurane in oxygen and controlled ventilation (end-tidal carbon dioxide 32-35 mm Hg). Phenylephrine 50-100 micrograms was injected IV when MAP decreased by more than 15% of initial values, and atropine 0.5 mg IV when HR decreased to less than 45 bpm. Opioid administration was associated with significant decreases in MAP, 21 +/- 9 mm Hg (mean +/- SD) in the sufentanil group and 16 +/- 7 mm Hg in the fentanyl group; P < 0.001. These decreases in MAP were of short duration (i.e., corrected with 1-2 min). Patients in the sufentanil group needed more phenylephrine than patients in the fentanyl group (170 +/- 89 micrograms vs 100 +/- 47 micrograms; P < 0.05). No significant change in the CSFP was seen in either the sufentanil (1 +/- 6 mm Hg) or fentanyl-treated patients (O +/- 2 mm Hg). No significant changes in MAP or CSFP were observed in the saline-treated patients. HR decreased after injection of either study drug (P < 0.01) but remained unchanged in the saline group. In summary, during stable anesthesia with isoflurane in oxygen, bolus injections of fentanyl or sufentanil, despite producing rapidly corrected mean decreases in MAP of 18% and 25%, respectively, were not associated with any change in CSFP.

Cardiovascular effects of NMDA and MK-801 infusion at area postrema and mNTS in rat

In urethane-anesthetized male Sprague-Dawley rats, microinfusion of N- methyl- D -aspartate (NMDA) into the area postrema (AP) at the dose of 10 ng produced significant decreases in mean arterial pressure (MAP) (−26 ± 5 mmHg), heart rate (HR) (−34 ± 6 bpm), renal blood flow, mesenteric blood flow, and iliac vascular resistance. In addition, microinfusion of the same dosage of NMDA into the medial nucleus tractus solitarius (mNTS) produced significant decreases in MAP (−33 ± 4 mmHg), HR (−33 ± 6 bpm), renal blood flow, mesenteric blood flow and vascular resistance, and iliac blood flow and resistance. MK-801 (dizocilpine) microinfusion alone produced no significant changes in MAP or HR when microinfused either into the AP or unilaterally into the mNTS; however, bilateral microinfusion of MK-801 into mNTS produced sustained hypertension and tachycardia, lasting about 30 min. MK-801 pretreatment at both AP and mNTS effectively blocked NMDA-induced cardiovascular responses. MK-801 microinfusion at AP significantly attenuated baroreceptor reflex-mediated bradycardia elicited by intravenous injection of phenylephrine, but did not alter reflex tachycardia elicited by intravenous nitroprusside. In conclusion, NMDA receptor-mediated neurotransmission is involved in the cardiovascular functions of both AP and mNTS. Both loci appear to be sites of action for mK-801.

TRANSESOPHAGEAL ECHOCARDIOGRAPHIC ASSESSMENT OF LEFT VENTRICULAR FUNCTION DURING APNEA TESTING FOR BRAIN DEATH

The effects of apnea testing-induced respiratory acidosis on left ventricular function (LVF) are still controversial. The aim of the study was to assess LVF during apnea testing using transesophageal echocardiography (TEE). Twenty consecutive patients suspected of brain death, hemodynamically stable, and considered as potential organ donors were prospectively studied. A 20-min apnea test was performed after obtaining a PaCO2 > 35 mmHg and 20 min of FIO2 1 ventilation. LVF was assessed using TEE with a CFM 750 (Diasonic) connected to a 5 MHz probe. Heart rate (HR), mean arterial pressure (MAP), left ventricle end-diastolic and systolic area (LVEDA, LVESA), and LVF assessed by fractional area changes (FAC), systolic wall motion (SWM) scores, and blood gases were recorded at baseline, and after 5, 10, 15, and 20 min of apnea testing. In 19 patients, no spontaneous respiratory movement occurred during the standard 20-min period. In one patient (No. 15), the apnea test had to be stopped after 10 min because of hypoxia. HR, LVEDA, LVESA, and SWM were not significantly modified during the study. There was a progressive statistically significant decrease in MAP during apnea (from 77 +/- 10 to 63 +/- 11 mmHg), associated with a statistically significant increase in FAC at 20 min (from 48 +/- 13 to 56 +/- 8%). PaCO2 progressively rose (from 40 +/- 3 to 95 +/- 11 mmHg), associated with a decrease in pH (from 7.42 +/- 0.06 to 7.09 +/- 0.08). At the same time, PaO2 decreased slightly in all patients, but values remained well above hypoxic levels, except for one patient. Despite severe respiratory acidosis the increase in FAC suggests that apnea testing is well tolerated for brain death assessment.

Sufentanil Increases Intracranial Pressure in Patients with Head Trauma

Sufentanil is an intravenous opioid often used as a component of anesthesia during neurosurgical procedures. However, the effects of sufentanil on intracranial pressure in patients with diminished intracranial compliance are not well established, and remain controversial. Ten patients with head trauma, in each of whom the trachea was intubated, were studied for the effects of sufentanil on intracranial pressure (ICP) and on cerebral perfusion pressure (CPP). In all patients, ICP monitoring was instituted before the study. Sedation was obtained using a propofol infusion, and paralysis was achieved with vecuronium. After obtaining control of ICP (between 15 and 25 mmHg) hemodynamic values and blood gas tensions (PaCO2 between 30 and 35 mmHg), the level of sedation was deepened with an intravenous injection of sufentanil (1 microgram/kg over 6 min), followed by an infusion of 0.005 microgram.kg-1min-1. Mean arterial pressure (MAP), ICP (fiberoptic intracranial pressure monitor), and end-tidal CO2 were continuously measured and recorded at 1-min intervals throughout the 30-min study period. Sufentanil injection was associated with a statistically significant increase in ICP of 9 +/- 7 mmHg (+ 53%), which peaked at 5 min. Then ICP gradually decreased and returned to baseline after 15 min. This was accompanied by a significant decrease in MAP (24% decrease) and, thus, CPP (38% decrease). After 5 min, MAP and CPP gradually increased, but remained significantly decreased throughout the study. The results of the current study indicate that caution should be exercised in the administration of sufentanil bolus to patients with abnormal intracranial elastance, particularly if ICP is significantly increased.

HAEMODYNAMIC CHANGES PRODUCED BY INHALATION ANAESTHETICS IN THE PHOSPHODIESTERASE INHIBITION

We have investigated the circulatory effects of halothane and isoflurane in the presence of the phosphodiesterase inhibitor, enoximone, in 20 patients, ASA class III, aged 40-70 yr, undergoing coronary artery bypass grafting. After induction of anaesthesia (midazolam, fentanyl, etomidate and pancuronium) all patients received enoximone 0.5 mg kg-1, followed, 10 min later, by either halothane 1 MAC (group I; n = 10) or isoflurane 1 MAC (group II; n = 10). Haemodynamic variables were measured and blood samples (arterial and mixed venous) were obtained before (control, t0), 5 (t1) and 10 (t2) min after the injection of enoximone and immediately (t3) and 5 (t4) min after steady state conditions with halothane or isoflurane, as verified by the end-expiratory concentration. Heart rate, mean arterial pressure (MAP), mean pulmonary artery pressure, pulmonary capillary wedge pressure and right atrial pressure were recorded. Cardiac (CI) and stroke volume indices, systemic (SVR) and pulmonary vascular resistance, oxygen availability (QO2), oxygen consumption and oxygen extraction rate were calculated using standard formulae. MAP decreased significantly in both groups after bolus injection of enoximone (group I: 11%; group II: 7%). Under steady state conditions with the volatile anaesthetics, a further significant decrease in MAP was observed (group I: 12%; group II: 12%). Enoximone produced a significant increase in CI (group I: 25%; group II: 27% compared with control). After administration of isoflurane, CI remained essentially unchanged, while halothane decreased CI significantly by 20%. In both groups, SVR decreased significantly after administration of enoximone (group I: 26%; group II: 24%).(ABSTRACT TRUNCATED AT 250 WORDS)

Enkephalins, substance P and acetylcholine microinjected into the nucleus ambiguus elicit vagal bradycardia in rats

Little is known about putative transmitters in the nucleus ambiguus (NA) mediating parasympathetic control of the heart, although Metenkephalin (m-ENK), Leu-enkephalin (l-ENK), substance P (SP) and acetylcholine (Ach) have been detected in the cell bodies and fibers of this nucleus. The effects of these substances on arterial pressure (AP) and heart rate (HR) were studied by microinjecting them (4–20 nl) into the NA. Experiments were done in 26 spinal (high cervical) rats that were anesthetized with urethane and artificially ventilated. l-Glutamate (GLU) was microinjected into the right NA to identify the location of cell bodies from which decreases in HR and AP could be elicited. m-ENK, l-ENK, SP or Ach was then microinjected into these sites. Microinjection of 1 nmol of GLU elicited significant decreases in HR (−72.2 ± 9.7 bpm, n = 15) which were not accompanied by significant decreases in mean AP. Microinjection of m-ENK (15–200 pmol; n = 7), l-ENK (15–200 pmol; n = 6), SP (0.9–15 pmol; n = 7) and Ach (2.0–20 pmol; n = 7) into the NA decreased HR in a dose-dependent manner but did not affect AP. The magnitudes of HR responses to m-ENK, l-ENK, SP and Ach were smaller but of longer duration than the changes in HR to microinjection of GLU. These results suggest a physiological role for GLU, enkephalins, SP and Ach in the vagal control of HR mediated by the NA.

Functional evidence for sympathetic nerve activity in conscious cervical spinal rats

Experiments in anesthetized animals have demonstrated sympathetic nerve activity after cervical spinal cord transection (CST), yet little evidence exists for sympathetic nerve activity in conscious spinal animals. We determined the effect of CST on mean arterial pressure (MAP), heart rate (HR), and plasma renin activity (PRA) in conscious rats. Next, we tested for the presence of functionally significant sympathetic nerve activity 24 h after CST by measuring MAP, HR, urine flow, urinary sodium excretion (UNaV), urinary potassium excretion (UKV), and PRA before and for 2 h during administration of adrenergic antagonists (propranolol + phentolamine) or vehicle. CST resulted in significant decreases in MAP (100.0 +/- 1.6 to 75.0 +/- 1.4 mmHg), HR (353 +/- 7.5 to 315 +/- 6.6 beats/min), and PRA (2.2 +/- 0.3 to 1.2 +/- 0.2 ng angiotensin I.ml-1.h-1). Subsequent adrenergic blockade resulted in a further drop in HR (-52 +/- 21 beats/min), as well as two- to threefold increases in UNaV and UKV. We conclude that CST causes an overall decrease in sympathetic drive. However, sympathetic nerve activity to the heart and kidney remains after CST and is responsible for support of HR and retention of sodium and potassium.

Effects of renin inhibition in the conscious primate Macaca fascicularis.

Pro-His-Pro-Phe-His-Statine-Ile-Phe-NH2 (R-Pep-27), a potent renin inhibitory peptide, was infused into the conscious, sodium-depleted Macaca fascicularis at doses of 0, 0.1, 1, 4, 16, and 32 micrograms/kg/min for 10 minutes. At all doses greater than 0.1 microgram/kg/min, there was a parallel decrease in mean arterial pressure (MAP), plasma renin activity, and plasma angiotensin II (Ang II) concentration. On the other hand, assays with monoclonal antibodies specific for total renin and active renin demonstrated that the peptide's inhibition of circulating active renin stimulated the release of both. The maximal effective R-Pep-27 dose was approximately 16 micrograms/kg/min, which reduced MAP by an average of 15.8 +/- 1.4 mm Hg (n = 14) and plasma renin activity and plasma Ang II concentration to 3% (n = 9) and 15% (n = 5), respectively, of the pretreatment values. At 0.1 microgram/kg/min, there was no significant decrease in MAP; however, measurement of plasma renin activity showed an average decrease in activity of 42% (n = 3). No significant change in the heart rate was observed at all the doses studied. For comparison, intravenous captopril (400 micrograms/kg bolus) was administered after the MAP of the monkeys had recovered from the peptide experiments, and it reduced MAP by 25.1 +/- 2.4 mm Hg (n = 10) without significantly changing plasma renin activity. As anticipated, injection of angiotensin I (80-160 ng/kg bolus) into sodium-depleted monkeys during peptide infusion caused a transient rise in MAP of 14.8 +/- 5.4 mm Hg (n = 4) above the mean pretreatment value.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Aminophylline and Pentoxifylline on Multiple Organ Damage afterEscherichia coliSepsis

We studied the effects of the methylxanthines, aminophylline (AMPH) and pentoxifylline (PTXF), on multiple organ damage following Escherichia coli sepsis in guinea pigs. To assess multiple organ damage, 125I-labeled albumin accumulation was measured in bronchoalveolar lavage (BAL) fluid, lung, kidneys, liver, heart, adrenal glands, and spleen and expressed as a ratio of BAL fluid or tissue to 125I-labeled albumin plasma (albumin index: Al). Wet-to-dry lung weight (W/D) ratios were also measured. The methylxanthines were administered by a bolus injection followed by a continuous infusion. The seven experimental groups included: saline-control, AMPH-control, PTXF-control, E. coli septic-control, E. coli septic-AMPH high dose, E coli septic-AMPH low dose, and E. coli septic-PTXF. The AI of the BAL fluid and all examined organs significantly increased in the septic-control group compared to those in the saline-, AMPH-, and PTXF-control groups, In all septic-methylxanthine groups, the AI of the BAL fluid and all organs, except for the spleen, were significantly lower than those of the septic-control group. Compared to the saline-, AMPH-, and PTXF-control groups, the septic-control group revealed a significant increase in lung W/D ratios, whereas the septic-AMPH high and low dose groups and the septic-PTXF group did not. Of importance, the septic-PTXF group did not cause a significant decrease in mean arterial pressure (MAP) as compared to the control groups, whereas the septic-AMPH groups did cause a significant decrease in MAP compared to the septic-control group. Therefore, the data from this experiment demonstrate that both AMPH and PTXF attenuate the multiple organ albumin leak seen in septic guinea pigs. However, PTXF exerted this protective effect with no discernible effect on the MAP whereas the MAP of AMPH-treated guinea pigs was significantly decreased.

Propranolol antagonizes hypotension induced by α-blockers but not by sodium nitroprusside or methacholine

A pressor response has been observed with propranolol, a nonselective beta-adrenoceptor antagonist, in animals given a nonselective alpha-adrenoceptor antagonist. This study investigates whether a pressor response to propranolol occurs in conscious unrestrained rats following a hypotensive response induced by phentolamine (nonselective alpha-antagonist), prazosin (selective alpha 1-antagonist) and (or) rauwolscine (selective alpha 2-antagonist), sodium nitroprusside (smooth muscle relaxant), or methacholine (muscarinic agonist). The rats were subjected to a continuous infusion of a hypotensive agent or normal saline followed by i.v. injection of propranolol. The infusion of phentolamine significantly decreased mean arterial pressure (MAP). Subsequent injection of propranolol restored MAP to the control level. Prazosin and rauwolscine each caused a small but not significant decrease in MAP which was reversed by propranolol. Concurrent infusions of prazosin and rauwolscine caused a significant decrease in MAP. Subsequent injection of propranolol caused a large pressor response which increased MAP to 20% above control MAP prior to the administration of drugs. Nitroprusside or methacholine each caused a significant decrease in MAP, but the hypotension was not antagonized by propranolol. The concurrent infusions of a low dose of nitroprusside and prazosin caused a significant decrease in MAP which was reversed by propranolol. The infusion of saline did not alter MAP, and propranolol did not cause a pressor response. It is concluded that propranolol antagonizes the hypotensive effect of an alpha-blocker but not that of sodium nitroprusside or methacholine. Our results suggest the presence of a specific interaction between alpha- and beta-antagonists.

Toxic Shock Syndrome is Mediated by Interleukin 1 and Tumor Necrosis Factor

Toxic shock syndrome toxin 1 (TSST-1) induction of interleukin 1 (IL-1) secretion in the human and the rabbit has previously been demonstrated. Stimulation of the secretion of tumor necrosis factor (TNF) by TSST-1 in the human and the rabbit in vitro and in vivo is now reported. TNF (2-jg/kg bolus) and IL-1 (2to 5-jig/kg bolus) induce a sharp fall of mean arterial pressure (MAP) in the rabbit within 10-15 minutes. Associated with the fall in MAP, decreases in the systemic vascular resistance (SVR) and central venous pressure (CVP) were observed, while cardiac output and heart rate increased. Intravenous injection of 2 jg of TSST-1/kg into the rabbit induced significant decreases in MAP and SVR and an increase in CVP. The dose of 5 jg/kg caused a shock-like state followed by death. High serum TNF levels in the TSST-l-injected rabbits were detected by use of a cytotoxicity test with L929 cells. The bioassay also demonstrated the secretion of TNF from culture supernatants of rabbit mononuclear cells (MNCs) that were stimulated with TSST-1. Both the radioimmunoassay and the bioassay showed a significant TNF secretion from human MNCs; 1 ng of TSST-1/mL induced 800 pg of TNF/mL. Combined administration of IL-1 and TNF (each with a 1-jg/kg bolus and a 5 ng/[kg-min] infusion for 2 hours) in the rabbit caused a shock-like state with a more profound and sustained fall into MAP than did single administration of IL-1 or TNF These results demonstrate that TSST-1 induces the secretion of IL-1 and TNF by human and rabbit MNCs and that IL-1 and TNF act synergistically to induce a profound shock-like state.

Combined H1 and H2 Receptor Blockade Attenuates the Cardiovascular Effects of High-Dose Atracurium for Rapid Sequence Endotracheal Intubation

HOSKING MP, LENNON RL, GRONERT GA. Combined H1 and H2 receptor blockade attenuates the cardiovascular effects of high-dose atracurium for rapid sequence endotracheal intubation. Anesth Analg 1988;67:1089-92. Large doses of atracurium (1.5 mg/kg) (six times the ED95) can result in significant histamine release, resulting in systemic hypotension. The efficacy of histamine receptor blockade in attenuating atracurium induced hypotension was therefore studied. Four groups of seven patients each were studied: group I, control; group II, H1 blockade (1 mg/kg diphenhydramine); group III, H2 blockade (cimetidine 4 mg/kg); and group IV, H1 and H2 blockade (diphenhydramine 1 mg/kg and cimetidine 4 mg/kg). All patients were anesthetized with an intravenous narcotic-nitrous oxide technique and then given 1.5 mg/kg atracurium. In group I, mean arterial pressure (MAP) decreased 30 mm Hg after 2 minutes and remained 25 mm Hg below baseline at 3 minutes, a change significantly greater than that in group IV, in which MAP decreased 8 and 7 mm Hg, respectively. H1 receptor blockade was associated with no significant attenuation of changes in MAP. H2 receptor blockade alone was associated with significant decreases in MAP, possibly secondary to enhanced release of histamine via an antagonist effect on recently described H3 receptors. Plasma histamine levels increased significantly 2 minutes after atracurium administration and correlated with hemodynamic changes. It is concluded that combined H1 and H2 receptor blockade attenuates cardiovascular effects associated with large doses of atracurium in humans. Histamine-releasing agents may be contraindicated in patients subject to chronic H2 receptor blockade.

Combined H1 and H2 Receptor Blockade Attenuates the Cardiovascular Effects of High-Dose Atracurium for Rapid Sequence Endotracheal Intubation

Large doses of atracurium (1.5 mg/kg) (six times the ED95) can result in significant histamine release, resulting in systemic hypotension. The efficacy of histamine receptor blockade in attenuating atracurium induced hypotension was therefore studied. Four groups of seven patients each were studied: group I, control; group II, H1 blockade (1 mg/kg diphenhydramine); group III, H2 blockade (cimetidine 4 mg/kg); and group IV, H1 and H2 blockade (diphenhydramine 1 mg/kg and cimetidine 4 mg/kg). All patients were anesthetized with an intravenous narcotic-nitrous oxide technique and then given 1.5 mg/kg atracurium. In group I, mean arterial pressure (MAP) decreased 30 mm Hg after 2 minutes and remained 25 mm Hg below baseline at 3 minutes, a change significantly greater than that in group IV, in which MAP decreased 8 and 7 mm Hg, respectively. H1 receptor blockade was associated with no significant attenuation of changes in MAP. H2 receptor blockade alone was associated with significant decreases in MAP, possibly secondary to enhanced release of histamine via an antagonist effect on recently described H3 receptors. Plasma histamine levels increased significantly 2 minutes after atracurium administration and correlated with hemodynamic changes. It is concluded that combined H1 and H2 receptor blockade attenuates cardiovascular effects associated with large doses of atracurium in humans. Histamine-releasing agents may be contraindicated in patients subject to chronic H2 receptor blockade.

COMBINED H1 AND H2 RECEPTOR BLOCKADE ATTENUATES THE CARDIOVASCULAR EFFECTS OF HIGH DOSE ATRACURIUM FOR RAPID SEQUENCE ENDOTRACHEAL INTUBATION

Large doses of atracurium (1.5 mg/kg) (six times the ED95) can result in significant histamine release, resulting in systemic hypotension. The efficacy of histamine receptor blockade in attenuating atracurium induced hypotension was therefore studied. Four groups of seven patients each were studied: group I, control; group II, H1 blockade (1 mg/kg diphenhydramine); group III, H2 blockade (cimetidine 4 mg/kg); and group IV, H1 and H2 blockade (diphenhydramine 1 mg/kg and cimetidine 4 mg/kg). All patients were anesthetized with an intravenous narcotic-nitrous oxide technique and then given 1.5 mg/kg atracurium. In group I, mean arterial pressure (MAP) decreased 30 mm Hg after 2 minutes and remained 25 mm Hg below baseline at 3 minutes, a change significantly greater than that in group IV, in which MAP decreased 8 and 7 mm Hg, respectively. H1 receptor blockade was associated with no significant attenuation of changes in MAP. H2 receptor blockade alone was associated with significant decreases in MAP, possibly secondary to enhanced release of histamine via an antagonist effect on recently described H3 receptors. Plasma histamine levels increased significantly 2 minutes after atracurium administration and correlated with hemodynamic changes. It is concluded that combined H1 and H2 receptor blockade attenuates cardiovascular effects associated with large doses of atracurium in humans. Histamine-releasing agents may be contraindicated in patients subject to chronic H2 receptor blockade.