Systemic Hemodynamic Effects Research Articles

Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

Oral sildenafil citrate lacks genotoxicity and cytotoxicity in a primate model: Callithrix jacchus

To determine sildenafil citrate (SC) genotoxicity and cytotoxicity in the Callithrix jacchus. Fifteen organisms were assigned to one of three groups as follows: experimental (25 mg/kg of SC); negative control (glucose solution 5%); and positive control (3 mg/kg of cytocine arabinoside). Systemic hemodynamic changes were monitored in each animal before and after each treatment. A drop of blood was obtained before and after the treatment at 24-120 h. Smears were made and the frequency of micronucleated erythrocytes (MNE), micronucleated polychromatic erythrocytes (MNPCE) and polychromatic erythrocytes (PCE) was counted. No significant differences in MNE, MNPCE and PCE were found in the group that received sildenafil and negative control. A significant increase in genotoxicity and cytotoxicity was observed in the positive control group. No changes were observed in systemic hemodynamic changes. The macro-dose of SC lacks genotoxic, cytotoxic or systemic hemodynamic changes effects in this species.

Automated Peritoneal Dialysis Has Significant Effects on Systemic Hemodynamics

Maintenance of residual renal function (RRF) is an important determinant of outcome in peritoneal dialysis patients. It remains contentious as to whether automated peritoneal dialysis (APD) leads to an increased rate of decline of RRF compared with continuous ambulatory peritoneal dialysis (CAPD). We studied whether APD was associated with significant systemic hemodynamic changes that may play a role in the accelerated loss of RRF. As a follow-on from a previous study, 8 well-established CAPD patients underwent a 4-hour APD treatment consisting of 3 drain/fill cycles using 2 x 2.5 L 1.36% glucose and 1 x 3.86% glucose dialysate. Each dwell phase lasted 76 minutes. Blood pressure (BP) and a full range of hemodynamic variables, including pulse (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR), were measured noninvasively using continuous arterial pulse wave analysis. BP fell during 2 of the 3 drain/fill periods when dialysate was drained from the peritoneal cavity, but then rose upon instillation of dialysate fluid. The fall in BP was associated with a fall in TPR, matched by an inadequate rise in SV and CO. Over the entire study period, TPR progressively rose to +53.4% above baseline (p = 0.032). Both SV and CO fell over the same period, to -21.1% (p = 0.060) and -22.4% from baseline (p = 0.037) respectively. This did not result in any significant difference between start and end BP. This study demonstrates that APD is associated with significant systemic hemodynamic effects. The increased number of drain/fill cycles compared to CAPD, or the progressive rise in TPR and reduction in CO (possibly due to a cooling effect), may potentially be factors that adversely affect RRF in APD patients.

Systemic and renal haemodynamic effects of the specific kappa opioid receptor agonist, U50488H, during postnatal maturation in conscious lambs

The present experiments were carried out to investigate the role of κ-opioids in modulating systemic and renal haemodynamics in conscious, chronically instrumented lambs aged ~one week (n = 10) and six weeks (n = 15). Mean arterial pressure (MAP), mean venous pressure (MVP) and renal blood flow (RBF) were measured for 30 min before (Control) and for 90 min after I.V. administration of U50488H (EC100 dose, experiment one) or vehicle (experiment two). Heart rate (HR) was calculated from the systolic peaks of the arterial pressure waveforms; renal vascular resistance (RVR) was calculated as (MAP - MVP)/RBF. Responses to U50488H were also tested at 1, 24, 48, 72, and 96 h after administration of the selective κ-opioid receptor antagonist, GNTI. In one week old lambs, 20 min after administration of U50488H, MAP decreased from 79±4 to 74±3 mmHg, remaining at the same level for the next 30 min. In contrast, at six weeks, MAP increased by 10 min after U50488H from 80±6 to 86±9 mmHg, returning to control by 20 min. There was a marked increase in HR after U50488H from 206±26 to 243±15 and from 126±15 to 169±32 bpm, at one and six weeks, respectively; HR remained elevated for the duration of the experiment in both age groups. These responses to U50488H were abolished by GNTI at 24 – 96 h but not 1 h. There were no significant effects on RVR or RBF after U50488H, before or after GNTI, and no effects of vehicle on any of the measured or calculated variables. These data demonstrate that κ-opioids modulate resting systemic but not renal haemodynamics early in life, in an age-dependent manner. Funded by the Canadian Institutes for Health Research.

Inhaled aerosolized iloprost in the evaluation of heart transplant candidates—experiences with 45 cases

Purpose Pulmonary hypertension represents a significant predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. As the use of intravenous vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost in heart transplant candidates with elevated pulmonary vascular resistance. Methods Forty-five male heart transplant candidates with dilated or ischemic cardiomyopathy were included in the study. After assessing baseline hemodynamics, 20 μg of aerosolized iloprost was administered by ultrasonic inhalation. All patients were breathing spontaneously. Results Inhalation of iloprost reduced pulmonary vascular resistance index (395 ± 205 vs 327 ± 222 dyne · s · cm −5 · m −2; P < 0.05) and mean pulmonary arterial pressure (28.7 ± 10 vs 24.3 ± 10 mm Hg; P < 0.05). An additional improvement of ventricular performance with an increase of cardiac index (2.7 ± 0.7 vs 3.0 ± 0.8 L · min −1 · m −2; P < 0.05) and a decrease of pulmonary capillary wedge pressure (16.6 ± 7.7 vs 13.4 ± 7.3 mm Hg; P < 0.05) was accompanied by a slight decrease of systemic vascular resistance (1280 ± 396 vs 1172 ± 380 dyne · s · cm −5; P < 0.05). However, the mean arterial pressure remained uninfluenced. Conclusions Inhaled aerosolized iloprost effectively reduces mean pulmonary arterial pressure and also induces an increase in cardiac index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost represents a useful drug to screen for vascular reactivity in cardiac transplantation patients.

Hemodynamic and antifibrotic effects of a selective liver nitric oxide donor V-PYRRO/NO in bile duct ligated rats

To assess whether a liver specific nitric oxide (NO) donor (V-PYRRO/NO) would prevent the development of portal hypertension and liver fibrosis in rats with bile duct ligation (BDL). Treatment (placebo or V-PYRRO/NO 0.53 micromol/kg per hour) was administered i.v. to rats 2 d before BDL (D-2) and maintained until the day of hemodynamic measurement (D26). Intra-hepatic NO level was estimated by measuring liver cGMP level. Effects of V-PYRRO/NO on liver fibrosis and lipid peroxidation were also assessed. Compared to placebo treatment, V-PYRRO/NO improved splanchnic hemodynamics in BDL rats: portal pressure was significantly reduced by 27% (P<0.0001) and collateral circulation development was almost completely blocked (splenorenal shunt blood flow by 74%, P=0.007). Moreover, V-PYRRO/NO significantly prevented liver fibrosis development in BDL rats (by 30% in hepatic hydroxyproline content and 31% in the area of fibrosis, P<0.0001 respectively), this effect being probably due to a decrease in lipid peroxidation by 44% in the hepatic malondialdehyde level (P=0.007). Interestingly, we observed a significant and expected increase in liver cGMP, without any systemic hemodynamic effects (mean arterial pressure, vascular systemic resistance and cardiac output) in both sham-operated and BDL rats treated with V-PYRRO/NO. This result is in accordance with studies on V-PYRRO/NO metabolism showing a specific release of NO in the liver. Continuous administrations of V-PYRRO/NO in BDL rats improved liver fibrosis and splanchnic hemodynamics without any noxious systemic hemo-dynamic effects.

Early systemic effects of hind limb ischemia-reperfusion on hemodynamics and acid–base balance in the rat

We investigated the systemic hemodynamic effects and the early arteriovenous acid-base changes after 2-h tourniquet ischemia on left hind limb in rats during the first hour of reperfusion. The right femoral artery and vein were prepared and catheterized for direct blood pressure monitoring and blood sampling. In ischemia-reperfusion group, 5 min before releasing the tourniquet and during the first hour of the reperfusion (5', 10', 15', 30', 45', and 60'), arterial and venous blood samples were taken in parallel with a sham operated control group. In the ischemia-reperfusion group venous pH continuously decreased during reperfusion and was significantly lower compared to control and base in the 60th min, while arterial pH remained almost unchanged. PCO2 and pO2 showed moderate signs of a parallel respiratory compensation. Mean arterial pressure decreased almost by 20%, heart rate slightly increased during reperfusion. Our data indicates that besides the general effects anesthesia, limb ischemia-reperfusion results in hemodynamic and acid-base changes during the first hour of reperfusion.

Dose‐dependent systemic and renal haemodynamic effects of angiotensin II in conscious lambs: role of angiotensin AT1 and AT2 receptors

The present experiments were designed to measure the effects of acute administration of angiotensin (ANG) II on mean arterial pressure (MAP) and renal blood flow (RBF) in conscious, chronically instrumented lambs at two different stages of postnatal maturation, and to determine the receptors through which these effects of ANG II are elicited. Experiments consisted of haemodynamic measurements for 10 s before (Control) and for 60 s after intravenous (i.v.) administration of one of 11 doses of ANG II (0-200 ng kg(-1)). Administration of ANG II was associated with a dose-dependent increase in MAP to a maximal effective concentration (EC100) of 100 ng kg(-1) in lambs aged 1 and 6 weeks. Administration of ANG II has caused a dose-dependent decrease in RBF, with EC100 values of 50 ng kg(-1) in 1-week-old lambs, and 25 ng kg(-1) in 6-week-old lambs. Responses to ANG II at the EC(50) were also measured in the presence of the specific ANG II AT(1) receptor antagonist, ZD 7155, the specific AT2 receptor antagonist, PD 123319, and vehicle. Administration of ZD 7155, but not PD 123319 or vehicle, abolished the MAP and RBF responses to ANG II in both age groups. In addition, MAP decreased and RBF increased in both age groups after administration of ZD 7155, but not PD 123319; the effects were similar in both age groups. These data provide new information that pressor and renal vasoconstrictor effects of ANG II during the first 6 weeks of postnatal life in lambs are elicited by activation of AT1 but not AT2 receptors.

Ethyl pyruvate improves systemic and hepatosplanchnic hemodynamics and prevents lipid peroxidation in a porcine model of resuscitated hyperdynamic endotoxemia*

To investigate the systemic, pulmonary, and hepatosplanchnic hemodynamic and metabolic effects of delayed treatment with ethyl pyruvate in a long-term porcine model of hyperdynamic endotoxemia. Prospective, randomized, controlled experimental study with repeated measures. Investigational animal laboratory. Anesthetized, mechanically ventilated, and instrumented pigs. After 12 hrs of continuous infusion of lipopolysaccharide and hydroxyethyl starch to keep mean arterial pressure >60 mm Hg, swine randomly received placebo (Ringer's solution; control group, n = 11) or ethyl pyruvate in lactated Ringer's solution (n = 8; 0.03 g.kg(-1) loading dose over 10 mins, thereafter 0.03 g.kg(-1)hr(-1) for 12 hrs). Whereas mean arterial pressure significantly decreased in control animals, mean arterial pressure was maintained at the baseline level in pigs treated with ethyl pyruvate. Global oxygen uptake was comparable, so that the trend toward a higher oxygen transport and the significantly higher mixed venous hemoglobin oxygen saturation resulted in a significantly lower oxygen extraction in the ethyl pyruvate group. Ethyl pyruvate reduced intrapulmonary venous admixture and resulted in significantly greater Pa(O2)/F(IO2) ratios. Despite comparable urine production in the two groups during the first 18 hrs of endotoxemia, ethyl pyruvate significantly increased diuresis during the last 6 hrs of the study. Lipopolysaccharide-induced systemic and regional venous metabolic acidosis was significantly ameliorated by ethyl pyruvate. Endotoxemia increased both blood nitrate + nitrite and isoprostane concentrations, and ethyl pyruvate attenuated the response of these markers of nitric oxide production and lipid peroxidation. Ethyl pyruvate infusion resulted in improved hemodynamic stability and ameliorated acid-base derangements induced by chronic endotoxemia in pigs. Reduced oxidative stress and an decreased nitric oxide release probably contributed to these effects.

C-terminal amide to alcohol conversion changes the cardiovascular effects of endomorphins in anesthetized rats

Endomorphin1-ol (Tyr-Pro-Trp-Phe-ol, EM1-ol) and endomorphin2-ol (Tyr-Pro-Phe-Phe-ol, EM2-ol), with C-terminal alcohol (-ol) containing, have been shown to exhibit higher affinity and lower intrinsic efficacy in vitro than endomorphins. In the present study, in order to investigate the alterations of systemic hemodynamic effects induced by C-terminal amide to alcohol conversion, responses to intravenous (i.v.) or intracerebroventricular (i.c.v.) injection of EM1-ol, EM2-ol and their parents were compared in the system arterial pressure (SAP) and heart rate (HR) of anesthetized rats. Both EM1-ol and EM2-ol induced dose-related decrease in SAP and HR when injected in doses of 3–100 nmol/kg, i.v. In terms of relative vasodepressor activity, it is interesting to note that EM2-ol was more potent than endomorphin2 [the dose of 25% decrease in SAP (DD 25) = 6.01 ± 3.19 and 13.99 ± 1.56 nmol/kg, i.v., respectively] at a time when responses to EM1-ol were less potent than endomorphin1. Moreover, decreases in SAP in response to EM1-ol and EM2-ol were reduced by naloxone, atropine sulfate, l-NAME and bilateral vagotomy. It indicated that the vasodepressor responses were possibly mediated by a naloxone-sensitive, nitric oxide release, vagus-activated mechanism. It is noteworthy that i.c.v. injections of -ol derivatives produced dose-related decreases in SAP and HR, which were significantly less potent than endomorphins and were attenuated by naloxone and atropine sulfate. In summary, the results of the present study indicated that the C-terminal amide to alcohol conversion produced different effects on the vasodepressor activity of endomorphin1 and endomorphin2 and endowed EM2-ol distinctive hypotension characters in peripheral (i.v.) and central (i.c.v.) tissues. Moreover, these results provided indirect evidence that amidated C-terminus might play an important role in the regulation of the cardiovascular system.

Functional and Morphologic Imaging of Coronary Atherosclerosis in Living Mice Using High-Resolution Color Doppler Echocardiography and Ultrasound Biomicroscopy

This study aimed to establish non-invasive methods of assessing coronary artery morphology in normal and atherosclerotic mice in vivo. Coronary flow velocity reserve (CFVR) has been shown to correlate with coronary minimal lumen diameter (MLD) in patients with coronary artery stenosis. In mice, there are no existing non-invasive imaging techniques allowing quantitative measurement of the coronary artery morphology and function. Systemic hemodynamic effects of adenosine were studied in seven C57BL/6 mice. In 17 C57BL/6 mice, CFVR was measured in the mid left coronary artery (LCA) using either hypoxia- or adenosine-induced coronary hyperemia. Further, in another 10 atherosclerotic low-density lipoprotein receptor (LDLR)-/- mice, the hypoxia-induced CFVR was performed and proximal LCA MLD was measured using ultrasound biomicroscopy (UBM). Histologic sections of the LCA were collected. The adenosine dose of 160 microg/kg/min induced maximal coronary hyperemia without any systemic hemodynamic effects. Adenosine and hypoxia-induced CFVR values averaged at 2.0 +/- 0.1 and 1.9 +/- 0.3, respectively, in C57BL/6 mice (p = NS). In LDLR-/- mice, CFVR and MLD ranged between 1.4 to 2.9 microm and 190 to 370 microm, respectively. Histology revealed proximal lumen-narrowing plaques in the LCA. Significant correlation was found between hypoxia-induced CFVR and the MLD (p < 0.005, R2 = 0.8707). The CDE and UBM technique can be used to measure atherosclerosis-related lumen narrowing of the LCA in living mice. These non-invasive techniques may provide us with novel tools for following up disease status in mouse coronary arteries in a quantitative manner.

Short-lasting systemic and regional benefits of early crystalloid infusion after intravenous inoculation of dogs with live Escherichia coli

We investigated the systemic and regional hemodynamic effects of early crystalloid infusion in an experimental model of septic shock induced by intravenous inoculation with live Escherichia coli. Anesthetized dogs received an intravenous infusion of 1.2 x 10(10) cfu/kg live E. coli in 30 min. After 30 min of observation, they were randomized to controls (no fluids; N = 7), or fluid resuscitation with lactated Ringer's solution, 16 ml/kg (N = 7) or 32 ml/kg (N = 7) over 30 min and followed for 120 min. Cardiac index, portal blood flow, mean arterial pressure, systemic and regional oxygen-derived variables, blood lactate, and gastric PCO2 were assessed. Rapid and progressive cardiovascular deterioration with reduction in cardiac output, mean arterial pressure and portal blood flow (approximately 50, approximately 25 and approximately 70%, respectively) was induced by the live bacteria challenge. Systemic and regional territories showed significant increases in oxygen extraction and in lactate levels. Significant increases in venous-arterial (approximately 9.6 mmHg), portal-arterial (approximately 12.1 mmHg) and gastric mucosal-arterial (approximately 18.4 mmHg) PCO2 gradients were also observed. Early fluid replacement, especially with 32 ml/kg volumes of crystalloids, promoted only partial and transient benefits such as increases of approximately 76% in cardiac index, of approximately 50% in portal vein blood flow and decreases in venous-arterial, portal-arterial, gastric mucosal-arterial PCO2 gradients (7.2 +/- 1.0, 7.2 +/- 1.3 and 9.7 +/- 2.5 mmHg, respectively). The fluid infusion promoted only modest and transient benefits, unable to restore the systemic and regional perfusional and metabolic changes in this hypodynamic septic shock model.

Systemic and regional hemodynamic effects of a high intravenous dose of cocaine under halothane or sevoflurane anesthesia

Systemic and regional hemodynamic effects of a high intravenous dose of cocaine under halothane or sevoflurane anesthesia

The Effects of Dexmedetomidine on Left Ventricular Function During Hypoxia and Reoxygenation in Isolated Rat Hearts

Hypoxia resulting from apnea in patients with sleep apnea is an important factor in heart disease. We designed the present study to determine whether dexmedetomidine (DEX) has a direct protective effect against hypoxia-reoxygenation-induced left ventricular dysfunction without systemic hemodynamic and humoral effects. Isolated rat hearts were exposed to 60-min hypoxia followed by 30-min reoxygenation with 0, 10, or 100 nM DEX prehypoxia administration (n = 7 each group). In a second experiment (n = 7), 100 nM DEX was administered posthypoxia. In a third experiment (n = 7 each group), an alpha 2 antagonist, yohimbine was given with and without 100 nM DEX prehypoxia administration. DEX prehypoxia, but not posthypoxia, administration significantly improved the recovery of left ventricular developed pressure after reoxygenation (0, 10, 100 nM DEX prehypoxia or 100 nM DEX posthypoxia values were 53 +/- 6, 64 +/- 9, 78 +/- 13, or 62 +/- 12 mm Hg [mean +/- sd]) and reversed by yohimbine, 58 +/- 8 mm Hg, respectively. We conclude that DEX exerts the direct protective effect on the left ventricular dysfunction caused by hypoxia-reoxygenation through mainly alpha 2-adrenergic stimulation before and during the hypoxic period.

Repeated daily injections and osmotic pump infusion of isoproterenol cause similar increases in cardiac mass but have different effects on blood pressure

We found in mice that repeated single daily subcutaneous (s.c.) isoproterenol (ISO) injections, like constant infusions using osmotic minipumps, caused increased biventricular mass or weight relative to body weight (VW/BW). We found that 5 (1/d) s.c. injections of 2, 10, or 20 microg/g body weight caused equivalent VW/BW increases as compared with 5-d infusions at 20 microg/(g.d)). While it is often presumed that ISO elicits hypertrophy by a direct effect on the myocytes, growth may also be secondary to systemic hemodynamic effects. The 2 modes of ISO administration had different effects on mean arterial blood pressure (MABP) and heart rate. Using telemetry we observed that single injections of ISO (0, 0.5, 2, and 10 microg/g) were associated with hypotension and tachycardia with a duration but not a magnitude that was dose dependent. MABP dropped rapidly to 60 mm Hg for more than 2 h at the highest dose. Constant s.c. infusion of ISO at 20 microg/(g.d) initially lowered MABP to about 70 mm Hg for 24 h. At 48 h MABP was normal, but rose 10 mm Hg higher than baseline by day 5. Thus, different routes of administration of ISO that cause comparable increases in VW/BW had different effects on MABP. Thus when evaluating mouse models of ISO-induced cardiac hypertrophy, both repeated daily injections or infusions can cause similar increases in VW/BW, but the daily doses that are required are not the same. Furthermore, these different routes of administration have different hemodynamic sequelae and could potentially evoke different cardiac phenotypes.

Intraperitoneal administration of adenosine inhibits formation of abdominal adhesions.

Previously we demonstrated that peritoneal lavage with high concentrations of adenosine (1 mM) provides pharmacologic levels of adenosine in the intestines without elevating adenosine levels in the systemic circulation and without causing systemic hemodynamic effects (Alimentary Pharmacology & Therapeutics 2000; 14:1371-80). Because adenosine can be safely administered into the peritoneal cavity, and because it inhibits fibroblast proliferation and collagen production and inflammation and enhances angiogenesis, we tested the hypothesis that adenosine applied into the abdominal cavity safely and effectively reduces formation of abdominal adhesions. To test this hypothesis, in Sprague-Dawley rats, a window of right parietal peritoneum was removed and the cecum was brushed and placed next to the damaged peritoneum. After injury, rats received in the abdominal cavity either 20 ml of saline (n = 12, Saline Group) or 20 ml of 1 mM adenosine (n = 12, Adenosine 1X Group; and n = 12, Adenosine 4X Group). At 24, 48, and 72 hours after surgery, rats received by intraperitoneal injection either 10 ml of saline (Saline Group and Adenosine 1X Group) or 10 ml of 1 mM adenosine (Adenosine 4X Group). After 14 days, the degree of adhesion formation was scored (0 to 4) by a blinded observer. Animals tolerated the adenosine treatments without signs of discomfort or distress. The adhesion scores were 2.6 +/- 0.34, 1.7 +/- 0.40, and 0.74 +/- 0.29 in the Saline, Adenosine 1X, and Adenosine 4X groups, respectively (P = 0.0035, Kruskal-Wallis analysis of variance). Peritoneal administration of 1 mM adenosine safely and effectively reduces adhesion formation.

Effects of anesthetics on systemic hemodynamics in mice.

The aim of this study was to compare the systemic hemodynamic effects of four commonly used anesthetic regimens in mice that were chronically instrumented for direct and continuous measurements of cardiac output (CO). Mice (CD-1, Swiss, and C57BL6 strains) were instrumented with a transit-time flow probe placed around the ascending aorta for CO measurement. An arterial catheter was inserted into the aorta 4 or 5 days later for blood pressure measurements. After full recovery, hemodynamic parameters including stroke volume, heart rate, CO, mean arterial pressure (MAP), and total peripheral resistance were measured with animals in the conscious state. General anesthesia was then induced in these mice using isoflurane (Iso), urethane, pentobarbital sodium, or ketamine-xylazine (K-X). The doses and routes of administration of these agents were given as required for general surgical procedures in these animals. Compared with the values obtained for animals in the conscious resting state, MAP and CO decreased during all anesthetic interventions, and hemodynamic effects were smallest for Iso (MAP, -24 +/- 3%; CO, -5 +/- 7%; n = 15 mice) and greatest for K-X (MAP, -51 +/- 6%; CO, -37 +/- 9%; n = 8 mice), respectively. The hemodynamic effects of K-X were fully antagonized by administration of the alpha(2)-receptor antagonist atipamezole (n = 8 mice). These results indicate that the anesthetic Iso has fewer systemic hemodynamic effects in mice than the nonvolatile anesthetics.

Magnesium-induced vasodilation in the dorsal hand vein.

Magnesium affects blood pressure by modulating vascular tone and reactivity. In obstetric patients, magnesium is administered to prevent eclamptic seizures and as a tocolytic to treat preterm labour. Prior to studying vascular sensitivity in women with pre-eclampsia, we sought to determine the effect of magnesium on venous tone in healthy women of childbearing age. Dose-response study. Columbia-Presbyterian Medical Center, New York. Ten healthy non-pregnant women (age range 21-47 years). Vascular response to magnesium sulphate (MgSO4) was measured in a dorsal hand vein using the linear variable differential transformer (LVDT) technique. Complete dose-response curves to MgSO4 (0.0000275-0.088 mmol/min) were determined after 50% preconstriction of the vein with phenylephrine. The ED50 of MgSO4 (dose resulting in 50% of maximal effect, Emax) was determined. Blood samples from the contralateral upper extremity were obtained to assess total plasma magnesium levels at baseline and at the highest infused dose of magnesium. ED50 results are expressed as geometric mean (95% confidence interval, CI). Emax results and magnesium plasma concentrations are expressed as mean [SD]. The ED50 of MgSO4 was 0.000307 mmol/min (95% CI 0.138, 0.666) and Emax was 102% [20%]. Magnesium induces dose-dependent venodilation in healthy women in the absence of systemic haemodynamic effects. The dose resulting in vasodilation using the LVDT/hand vein model is two to three orders of magnitude less than the therapeutic doses of magnesium used for tocolysis or seizure prophylaxis. Studies of the effect of systemically administered therapeutic doses of magnesium on vascular reactivity in pre-eclampsia will be of interest.

Bradykinin Contributes to the Systemic Hemodynamic Effects of Chronic Angiotensin-Converting Enzyme Inhibition in Patients With Heart Failure

Bradykinin is an endogenous vasodilator that may contribute to the systemic effects of angiotensin-converting enzyme (ACE) inhibitor therapy. Using B9340, a bradykinin receptor antagonist, we determined the contribution of bradykinin to the systemic hemodynamic effects of long-term ACE inhibition in patients with chronic heart failure. Fourteen patients with heart failure received enalapril (10 mg twice daily) or losartan (50 mg twice daily) in a randomized double-blind crossover trial. After 6 weeks treatment, patients underwent right heart catheterization and were randomized to an intravenous infusion of B9340 (2 to 20 microg/kg per minute) or saline placebo. After B9340 infusion in patients treated with enalapril, mean arterial pressure (+5.2 mm Hg), systemic vascular resistance (+315 dynes x s/cm5), pulmonary arterial wedge pressure (-1.4 mm Hg), and mean pulmonary arterial pressure (-1.3 mm Hg) were greater compared with losartan (P<0.005, P=0.07, P<0.0001, and P<0.05 respectively) or placebo infusion (P< or =0.005 for all). There was a reduction in cardiac output after B9340 with enalapril compared with placebo (P<0.001) but not losartan. Bradykinin contributes to the systemic hemodynamic effects of long-term ACE inhibition in patients with heart failure. This mechanism may explain the apparent clinical differences between ACE inhibitors and angiotensin receptor blockers in the treatment of heart failure.

Systemic, pulmonary, and hepatosplanchnic effects of N-acetylcysteine during long-term porcine endotoxemia.

Controversial data have been reported on the effects of N-acetylcysteine in patients with septic shock. We therefore investigated the systemic, pulmonary, and hepatosplanchnic hemodynamic, gas exchange, and metabolic effects of N-acetylcysteine during long-term, volume-resuscitated, hyperdynamic porcine endotoxemia, which mimics the features of hyperdynamic human sepsis. Prospective, randomized, controlled experimental study. Investigational animal laboratory. Eighteen pigs were randomized to receive endotoxin alone (controls, n = 9) or endotoxin plus N-acetylcysteine (n = 9). Anesthetized, mechanically ventilated, and instrumented animals received continuous intravenous endotoxin and were resuscitated with hydroxyethylstarch to keep mean arterial pressure >60 mm Hg. After 12 hrs of endotoxemia, they were randomized to receive either placebo or N-acetylcysteine (150 mg/kg loading dose over 1 hr followed by 20 mg.kg-1.hr-1 for 11 hrs). Before as well as 12, 18, and 24 hrs after starting the endotoxin infusion, systemic, pulmonary, and hepatosplanchnic hemodynamics, oxygen exchange, and metabolism as well as nitric oxide, glutathione, and 8-isoprostane concentrations were assessed. N-acetylcysteine failed to improve any of the variables of the systemic, pulmonary, or hepatosplanchnic hemodynamics, gas exchange, and metabolism. Although N-acetylcysteine significantly elevated glutathione concentration, it did not influence the 8-isoprostane concentrations and even further reduced hepatic venous pH. Despite the increased glutathione concentration, N-acetylcysteine did not improve systemic, pulmonary, and hepatosplanchnic hemodynamics, oxygen exchange, and metabolism. When compared with previous reports in the literature, a different timing of N-acetylcysteine administration and/or an ongoing or even N-acetylcysteine-induced aggravation of oxidative stress may account for this result.