A system to simulate gas exchange in humans to control quality of metabolic measurements

The present experiments were designed to compare the behavior of cerebral blood flow (CBF) during acute moderate and severe hypotensive episodes induced by either ventricular tachycardias (VT) or by hemorrhage. Using the microsphere method CBF was determined in 20 Sprague-Dawley rats during sinus rhythm (Group A), in 28 animals during high-rate VT (Group B) and in 10 animals after hemorrhage (Group C). According to the decrease in blood pressure and with respect to the lower threshold of cerebral autoregulation Group B was divided into 2 subgroups (B1: 80-130 mmHg; B2: 50-80 mmHg) retrospectively. While CBF remained constant in Group B1 (0.98 +/- 0.3 ml g-1 min-1 vs. 1.01 +/- 0.32 in controls, NS), CBF decreased markedly during severely hypotensive VT in Group B2 (0.52 +/- 0.2 ml g-1 min-1, p < 0.001 vs. A; p < 0.05 vs. C) and during hypovolemic hypotension in Group C (0.77 +/- 0.22 ml g-1 min-1 vs. A; NS). Cerebrovascular resistance and autoregulation indices indicated a maintenance of CBF regulation during hypovolemic hypotension and a failure during normovolemic hypotension. These findings indicate that the autoregulatory ability of the brain is substantially more stable during hypovolemic hypotension than during normovolemic hypotension. Therefore, the hemodynamic sequelae of acute hypotensive episodes on CBF depend on the underlying cause of hypotension.     

Sustained left ansae subclaviae stimulation for a 5-hour period inhibits cesium-induced ventricular arrhythmogenesis in rabbits

The acute stimulation of the left ansae subclaviae (LAS) augments cesium chloride (Cs)- induced early afterdepolarizations (EADs) and ventricular arrhythmias. However, the effect of sustained cardiac sympathetic nerve stimulation on Cs-induced arrhythmogenesis remains to be elucidated. Three protocols were used. In protocol A, seven rabbits received continuous LAS stimulation for 5 h (study group), and were then given bolus injections of Cs at 5-min intervals (initial dose 1.5 mmol/kg, followed by repetitive doses 1 mmol/kg). Another eight rabbits received the same dose of Cs after a 5-h observation period without LAS stimulation (control group). The effects of 2 h of LAS stimulation were also assessed in five rabbits of each group. In protocol B, a bolus injection of Cs (1 mmol/kg) was administered during atrial pacing (cycle length: 250 ms) after a 5-h period with (study group, n = 5) or without (control group, n = 5) LAS stimulation, and the amplitude of Cs-induced EADs was measured. In protocol C, a bolus injection of isoproterenol (0.05 mg/kg) was given after a 5-h period with (study group, n = 5) or without (control group, n = 5) LAS stimulation to assess the sensitivity to beta-adrenergic stimulation. In protocol A, the cumulative doses of Cs required for the induction of ventricular tachycardia (VT) and fibrillation (VF) were significantly greater in the study group than in the control group (4.4 +/- 0.1 v 2.8 +/- 0.3 mmol/kg for VT, P<0.05; 5.8 +/- 0.3 v 4.1 +/- 0.4 mmol/kg for VF, P<0.05). However, 2 h of LAS stimulation did not influence the cumulative doses of Cs required for the induction of VT and VF. In protocol B, the amplitude of Cs-induced EADs was significantly lower in the study group than in the control group. In protocol C, the increase in rate-pressure product by isoproterenol was significantly less in study than in control groups (3492 +/- 612 v 6504 +/- 829, P<0.05). These results suggest that sustained LAS stimulation exerts a protective effect against Cs-induced arrhythmogenesis in the rabbit heart, which may be partially explained by desensitization to the beta-adrenergic stimulation.     

Hypotensive effects of [D-Tyr27,36, D-Thr32]Neuropeptide Y (27-36)

An analogue of the 10 C-terminal amino acids of neuropeptide Y (NPY) containing three D-isomeric substitutions (27-36-D) has been synthesized and its cardiovascular activity studied in Sprague-Dawley (SD) and spontaneously hypertensive (SHR) rats. Intravenous administration of 1000 nmol/kg 27-36-D decreases MAP in SHR (-59.9 +/- 5.0 mmHg) and SD rats (-44.4 +/- 4.7 mmHg). The hypotension produced by 1000 nmol/kg 27-36-D diminished by 71.2% following pretreatment with the histamine receptor antagonist diphenhydramine, although histamine depletion with compound 48/80 does not significantly alter this hypotension. These data suggest that NPY (27-36)-D produces a profound and sustained hypotension in two strains of rat which is partially attributable to activity at histamine receptors.     

Enhanced involvement of endothelin in the haemodynamic sequelae of endotoxaemia in conscious, hypertensive, transgenic ((mRen-2)27) rats

1. Age-matched (3-4 months old) male, heterozygous, hypertensive, transgenic ((mRen-2)27) rats (abbreviated to TG rats) and the normotensive control animals (homozygous, Hannover Sprague-Dawley rats (abbreviated to SD rats), were chronically instrumented for the assessment of regional haemodynamic responses to continuous lipopolysaccharide (LPS) infusion (150 microg kg(-1) h(-1), i.v.) 2. The early (1-2 h) hypotension in SD rats (-11+/-3 mmHg; n=7) was significantly less than that in TG rats (-35+/-3 mmHg; n=8), but by 24 h mean arterial blood pressure (MAP) in both strains of rat was not different from the pre-LPS value (SD rats: baseline, 108+/-3 mmHg; 24 h LPS, 112+/-4 mmHg; TG rats: baseline, 171+/-2 mmHg; 24 h LPS, 169+/-3 mmHg). At this stage in the SD rats there was a renal vasodilatation (delta vascular conductance, 29+/-10 [kHz mmHg(-1)]10(3)) but not in TG rats (delta vascular conductance 2+/-3[kHz mmHg(-1)]10(3)). 3. Co-infusion of LPS and the non-selective endothelin receptor antagonist, SB 209670 (600 microg kg(-1) bolus, 600 microg kg(-1) h(-1)) between 24 and 31 h in SD rats caused a fall in MAP of 16+/-2 mmHg accompanied by hindquarters vasodilatation (delta vascular conductance 11+/-3 (kHz mmHg(-1))10(3)). In TG rats, under the same conditions, the fall in MAP was -60+/-6 mmHg, and there were renal, mesenteric and hindquarters vasodilatations (delta vascular conductance, 23+/-5, 32+/-7, and 14+/-4 (kHz mmHg(-1))10(3), respectively). All effects, except the hindquarters vasodilatation, were greater in TG than in SD rats. 4. In TG rats infused with LPS alone for 31 h, between 24 and 31 h the fall in MAP was -17+/-4 mmHg, and the changes in renal, mesenteric and hindquarters vascular conductances were 5+/-3, -4+/-5, and 12+/-4 (kHz mmHg(-1)10(3), respectively. 5. Administration of the angiotensin (AT1)-receptor antagonist, losartan (10 mg kg(-1), i.v.) following co-infusion of LPS and SB 209670 between 24 and 31 h caused similar falls in MAP in SD and TG rats (-12+/-3 and -14+/-4 mmHg, respectively). 6. These results, together with previous findings, are consistent with a relative enhancement of the contribution of endothelin to the maintenance of cardiovascular status in endotoxaemic TG rats, particularly through a mesenteric vasoconstrictor action.     

Differences in caries recording with and without bitewing radiographs. A study on 5-year old children in the County of Bohusl?n, Sweden

OBJECTIVE: To evaluate the cerebral blood flow parameters assessed by transcranial Doppler during aortic cross-clamping and unclamping in patients undergoing abdominal aortic aneurysmectomy. METHODS: Invasive intraoperative monitoring of mean arterial pressure (MAP) and PaCO2, and right middle cerebral artery (RMCA) monitoring of blood flow parameters (mean velocity "Vm" and pulsatility index "PI") by transcranial Doppler were performed as well as evaluation of the four parameters during these subsequent periods: pre-cross-clamping, pre-unclamping, unclamping and 1-5-10-20 minutes after abdominal aortic unclamping. RESULTS: No significative changes of MAP, PaCO2, Vm and PI were noticed during the aortic cross-clamping period (77.5 +/- 18.5 SD minutes). During aortic unclamping Vm and MAP decreased (64 +/- 20 vs 52 +/- 20 cm/sec, p < 0.05, and 101 +/- 8 vs 80 +/- 15 mmHg, p < 0.01, respectively). At the 1th post-unclamping minute there was an increase from pre-unclamping values of Vm (75 +/- 20 cm/sec, p < 0.05) and PaCO2 (42 +/- 1.5 vs 36 +/- 2 mmHg, p < 0.05), with persistent reduction of MAP (92 +/- mmHg, p < 0.05), even more evident at the 5th post-unclamping minute (Vm = 93 +/- 25 cm/sec; PaCO2 = 46 +/- 1.2 mmHg, p < 0.001, and MAP returned to pre-unclamping value), in which there was also a decrease of PI (0.65 +/- 0.16 vs 0.78 +/- 0.2, p < 0.05). At the 10th minute Vm (83 +/- 24 cm/sec, p < 0.02) and PaCO2 (41 +/- 1.5 mmHg, p < 0.05) increments were present together with persistent reduction of PI (0.69 +/- 0.17, p < 0.05), while at the 20th post-unclamping minute also Vm, PaCO2 and PI returned to their pre-unclamping values. CONCLUSIONS: The Vm decrease at aortic unclamping might correlate with the acute changes in MAP (blood steal hypovolemia) and is likely due to an inadequate cerebral autoregulatory response to abrupt MAP changes. The arterial CO2 increase after aortic unclamping could lead to a dilation of cerebral arterioles and a rise of CBF (increase of Vm and decrease of PI). Transcranial Doppler is a simple and reliable technique for the monitoring of cerebral blood flow parameters and seems to be quite suitable for the recognition and the quantification of changes in these parameters induced by surgical manoeuvres able to produce hemodynamic instability.     

Cellular localization of kallistatin and tissue kallikrein in human pancreas and salivary glands

We studied the effects of the new antioxidant drug U-83836E during splanchnic artery occlusion (SAO) shock in the rat. Serum tumor necrosis factor (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure (MAP), survival rate and the responsiveness to acetylcholine of aortic rings were investigated. SAO shock produced a marked increase in serum TNF-alpha (241.4 +/- 18.2 U/ml vs Not Detectable in basal), reduced MAP (51.4 +/- 4 mmHg vs 85.1 +/- 5 mmHg), survival time (80 +/- 10 min vs > 240 min), WBC count (2.8 +/- 0.4 x 10(3)/mm3 cells vs 11.7 +/- 0.9 x 10(3)/mm3 cells) and blunted the responsiveness to ACh of aortic rings (60 +/- 3% tension vs 23 +/- 4% tension). The analogue of vitamin E, U-84836E, administered at onset of reperfusion, lowered serum TNF-alpha (38.4 +/- 6.5 U/ml; p < 0.001), improved MAP (67.5 +/- 3.8 mmHg; p < 0.001), WBC count (8.9 +/- 0.6 x 10(3)/mm3; p < 0.001), and survival time (235 +/- 15 min; p < 0.001), and restored the responsiveness to ACh of aortic rings (32 +/- 3.7% tension; p < 0.001). These preliminary data suggest that this new compound could be a promising drug in shock therapy.     

Antihypertensive effects of food-intake restriction in aortic coarctation hypertension

OBJECTIVE: To test the hypothesis that reductions in mean arterial pressure (MAP) induced by food-intake restriction in aortic coarctation hypertension are the result of a reduction of the sympathetic support of the MAP. We also wanted to determine whether the baroreflex control of the heart rate, and alpha- and beta-adrenergic responsivenesses were influenced by chronic food-intake restriction. METHODS: Four days after aortic coarctation, female Sprague-Dawley rats were assigned to a group that had access ad libitum to food (CON; n = 19) or to a food-intake-restricted group (FRG; n = 17) that was allowed 60% of the CON group's food intake per rat. After 3 weeks, carotid and jugular catheters were implanted for measurement of the MAP and infusion of drugs into conscious rats. The sympathetic contribution to the blood pressure was assessed by measuring the depressor response to ganglionic blockade by hexamethonium plus atropine (30.0 and 0.1 mg/kg intravenously). The baroreflex control of the heart rate was assessed by administering alternating bolus doses of phenylephrine and nitroprusside. The alpha-adrenergic sensitivity was assessed by measuring the response of the MAP to phenylephrine in areflexive rats (after ganglionic blockade), and the beta-adrenergic sensitivity was assessed by measuring the responses of the MAP and heart rate to isoproterenol administration both in reflexive and in areflexive rats. RESULTS: Four days after catheterization, both the MAP (CON 150 +/- 5 mmHg, FRG 116 +/- 4 mmHg) and the heart rate (CON 414 +/- 8 beats/min, FRG 365 +/- 11 beats/min) were significantly lower in rats of the FRG. That the sympathetic support of the MAP had diminished in FRG rats was evidenced by an attenuated depressor response to ganglionic blockade (40 +/- 3 versus 65 +/- 3 mmHg). FRG rats exhibited significantly greater reflex bradycardia in response to phenylephrine (slope -1.44+/- 0.07 versus -0.54 +/- 0.05 beats/min per mmHg), whereas their reflex tachycardia was not altered (slope -1.58 +/- 0.08 versus -1.53 +/- 0.13 beats/min per mmHg). FRG rats also displayed blunted responses of the heart rate and MAP to isoproterenol administration. CONCLUSION: Food-intake restriction attenuates the rise in MAP which occurs after aortic coarctation significantly. The antihypertensive effect of food-intake restriction may be mediated via a reduction in sympathetic tone.     

Relative bioavailability of carbinoxamine and phenylephrine from a retard capsule after single and repeated dose administration in healthy subjects

The present study was designed to investigate the role of cardiopulmonary reflex, more specifically the Bezold-Jarisch reflex, in experimental hypertension induced by chronic administration of Nw-nitro-L-arginine methyl ester (L-NAME) (0.5 mg/ml) added to the drinking water for 6 days. The study was performed in male Wistar rats (200-350 g), 9 animals per group. L-NAME ingestion caused a significant increase in resting mean arterial pressure (MAP: 182 +/- 4 mmHg) and heart rate (HR: 447 +/- 20 bpm) when compared to untreated rats (MAP: 112 +/- 3 mmHg and HR: 355 +/- 10 bpm). Cardiopulmonary receptors were chemically stimulated with bolus injections of 5-hydroxytryptamine (5-HT, 4-10 micrograms/kg, iv) followed by measuring the falls in diastolic arterial pressure (DAP) and HR in conscious and freely moving animals. As expected, the responses to intravenous injections of 5-HT consisted of a dose-dependent reduction in HR (from 26 +/- 14 to 175 +/- 25 bpm) and DAP (from 7 +/- 4 to 39 +/- 3 mmHg) in the control rats. Both bradycardia and diastolic hypotension were significantly accentuated in the L-NAME animals (approximately 30%). These data suggest that, in contrast to other models of hypertension, in the present one caused by inhibition of nitric oxide synthesis, the Bezold-Jarisch reflex is exaggerated. This neural dysfunction could be related to changes in the cardiac vagal efferent or effector.     

Immediate increase in circulating hepatocyte growth factor/scatter factor by heparin

Circulating levels of hepatocyte growth factor (HGF)/scatter factor have been recently found to be increased in the early phase of myocardial infarction, and it has been hypothesized that HGF plays a role in angiogenesis and collateral vessel growth. Heparin has also been shown to enhance angiogenesis and to improve collateral blood flow. This study was designed to study the effect of heparin on the release of HGF. In an experimental study, heparin was given to rats intravenously and plasma was collected for measurements of HGF by enzyme-linked immunosorbent assay. A dose-dependent increase in circulating HGF was measured with peak levels occurring 10 min after injection of 300 units/kg of heparin (15.4+/-2.0 ng/ml after v 0. 17+/-0.14 ng/ml before injection,P<0.0001). In a subsequent clinical study, 12 patients received 3000 units of heparin during cardiac catheterization. Circulating HGF increased steeply within 3 min of the injection. Comparable changes in plasma concentrations were measured in samples obtained from femoral vein (8.7+/-3.5 after v 0. 33+/-0.07 before injection P<0.05) or artery (10.5+/-3.2 ng/mlv 0. 27+/-0.05 P<0.01), pulmonary artery (9.1+/-2.0 ng/mlv 0.36+/-0.06 ng/ml,P=0.07 ) or right atrium (8.5+/-1.6 ng/mlv 0.42+/-0.11,P<0.01). This study suggests that heparin-induced effects such as the promotion of angiogenesis may be at least partly due to the release of HGF.     

Central interaction between carotid baroreceptors and skeletal muscle receptors inhibits sympathoexcitation

To determine the potential of an inhibitory interaction between the carotid sinus baroreflex (CSB) and the exercise pressor reflex (EPR), both pathways were activated to produce sympathoexcitation. It was hypothesized that, under conditions when the baroreflex increased sympathetic outflow, the interaction between CSB and EPR would be inhibitory. Bilateral carotid occlusion (BCO), electrically induced muscle contraction (EMC), and passive muscle stretch (PMS) were used to evoke sympathoexcitation. BCO decreased sinus pressure 50 +/- 5 mmHg, and the levels of muscle tension generated by EMC and PMS were 7 +/- 2 and 8 +/- 1 kg, respectively. This resulted in significant increases in mean arterial pressure (MAP) of 55 +/- 9, 50 +/- 7, and 50 +/- 6 mmHg (P = not significant, BCO vs. EMC vs. PMS) and in heart rate (HR) of 7 +/- 2, 19 +/- 4, and 17 +/- 2 beats/min (P < 0. 05, BCO vs. EMC and PMS). When BCO was combined with EMC or PMS, the reflex increase in MAP was augmented (80 +/- 8 and 79 +/- 10 mmHg; BCO+EMC and BCO+PMS, respectively; P < 0.05). However, summation of the individual MAP responses was greater than the response evoked during coactivation (106 +/- 11 and 103 +/- 12 mmHg, respectively, P < 0.05). Because summing the individual blood pressure responses exceeded the response during coactivation, the net effect was that the CSB and EPR interacted in an occlusive manner. In contrast, summation of the individual chronotropic responses was the same as the response evoked during coactivation. Moreover, there was no difference in summation of the individual MAP or HR responses when muscle afferents were activated by either EMC or PMS. In conclusion, the interaction between the CSB and the EPR in control of MAP was occlusive when both reflexes were stimulated to evoke sympathoexcitation. However, summation of the reflex changes in HR was simply additive.     

Effects of reperfusion on arrhythmias and death after coronary artery occlusion in the rat: increased electrical stability independent of myocardial salvage

OBJECTIVES: This study sought to delineate salvage-dependent from salvage-independent coronary reperfusion in acute myocardial infarction and the effects on spontaneously occurring arrhythmias and arrhythmic death in rats. BACKGROUND: Reperfusion of the infarct-related artery might increase electrical stability independently of salvage of ischemic myocardium. METHODS: In 98 conscious rats the electrocardiogram was monitored by telemetry for 48 h after MI, and all episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analyzed. Reperfusion at 45 min (RP45) (n = 15), 90 min (RP90) (n = 18) and 180 min (RP180) (n = 30) min was compared with permanent coronary artery occlusion (CAO) (n = 35) with respect to the post-reperfusion periods. RESULTS: RP45, RP90 and RP180 reduced the incidence of VT by 93%, 98% and 88% and VF by 89%, 97% and 92%, respectively (all p < 0.01 vs. CAO). The all-cause mortality rate was reduced from 47% (CAO) to 8% (RP45, p < 0.05) and 0% (RP90, p < 0.01); after RP180 it was 17% (CAO 42%, p = 0.08). All reperfusion regimens reduced arrhythmic deaths: 47% to 8% (RP45, p < 0.05), 47% to 0% (RP90, p < 0.01) and 42% to 8% (RP180, p < 0.05). Infarct size was identical to that during CAO (49 +/- 10% [mean +/- SD]) and RP180 (49 +/- 10%), whereas preferentially epicardial salvage occurred at RP45 (36 +/- 8%, p < 0.001) and RP90 (38 < 10%, p < 0.001). CONCLUSIONS: Early and late reperfusion reduce the incidence and duration of VT and VF in conscious rats with acute MI. Thereby, arrhythmia-related mortality is improved through the prevention of fatal VF episodes. Thus, reperfusion increases the electrical stability of the heart independently of myocyte salvage, as proposed by the open artery hypothesis.     

Tonic inhibition of renin secretion by the 12 lipoxygenase pathway: augmentation by high salt intake

Recent evidence suggests that lipoxygenase (LO) metabolites inhibit renin production in vitro. However, the physiological significance of this effect has not been determined. This study examined the role of the LO pathway in the regulation of plasma renin concentration (PRC) in vivo. The acute administration of two structurally unrelated LO inhibitors, phenidone (30 and 60 mg/kg) and esculetin (60 mg/kg), resulted in suppression of platelet 12 hydroxyeicosatetraenoic acid (12HETE) production, reduction in systemic arterial pressure and a 2- to 3-fold increase in PRC. To determine whether the esculetin-induced increase in PRC was secondary to hypotension, esculetin was also administered to rats preinfused with a pressor dose of norepinephrine. In these acutely hypertensive rats, esculetin still induced a 2.5-fold increase in PRC, whereas blood pressure remained over 40 mm Hg above basal levels. Further, esculetin (10(-6)M) increased renin release in renal slices from 150 +/- 10 to 310 +/- 20 ng/ml.h (P < 0.05) and this rise was entirely blocked in the presence of 12HETE (10(-7)M; 130 +/- 40 ng/ml.h). In rats placed on high salt intake, 12HETE concentration in renal slices from the outer cortex was considerably higher than in renal slices from salt-restricted rats (116.5 +/- 15.7 vs. 65 +/- 12 pg/mg protein; P < 0.05). Chronic administration of the LO inhibitor phenidone also resulted in an increase of PRC, which was independent of changes in blood pressure. On either high salt (3.15%0 or low salt (0.05%) diet phenidone-treated rats had higher PRC levels than the respective control groups [high salt 9.7 +/- 3.5 vs. 1.9 +/- 1.4 ng/ml.h; P < 0.05; low salt 33.2 +/- 5.3 vs. 19.4 +/- 3.10 ng/ml.h; P < 0.05]. The finding that LO blockers are potent stimulators of PRC in vivo suggests the existence of a physiological tonic inhibition of renin secretion by LO products that is operative under a wide range of salt intake. High salt intake enhances this inhibitory tone by increasing renal cortical 12 LO activity and, in fact, normal suppression of PRC during high salt diet does not occur in LO-blocked animals. Thus, the LO pathway exerts a tonic inhibitory effect on renin release, which appears particularly important for renin suppression during high salt intake.     

Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide

BACKGROUND: It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS: Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS: Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS: Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.     

Comparison of metoprolol and sotalol in preventing ventricular tachyarrhythmias after the implantation of a cardioverter/defibrillator

The purpose of this prospective study was to evaluate, on an intention-to-treat basis, the efficacy of d,l-sotalol and metoprolol with regards to the recurrence of arrhythmic events after implantable cardioverter defibrillator (ICD) implantation. After ICD implantation, 70 patients were randomly assigned to treatment with either metoprolol (mean dosage 104+/-37 mg/day in 35 patients) or d,l-sotalol (mean dosage 242+/-109 mg/day in 35 patients). During follow up ventricular tachycardia (VT), fast VT, and ventricular fibrillation (VF) episodes were calculated. Metoprolol treatment led to a marked reduction in the recurrence of arrhythmic events. Actuarial rates for absence of VT recurrence at 1 and 2 years were significantly higher in the metoprolol group compared with the d,l-sotalol group (83% and 80% vs 57% and 51%, respectively, p=0.016). The actuarial rates for absence of fast VT or VF were 80% in the metoprolol group compared with 46% in the d,l-sotalol group (p=0.002). During a follow up of 26+/-16 months, there were 3 deaths in the metoprolol group compared with 6 deaths in the d,l-sotalol group. Actuarial rates of overall survival were not significantly different in the 2 groups (91% vs 83%, p=0.287). In this prospective, randomized, controlled study the recurrence rate of ventricular tachyarrhythmias in patients treated with metoprolol was lower than in patients treated by d,l-sotolol.     

The effect of clonidine on cerebral blood flow velocity, carbon dioxide cerebral vasoreactivity, and response to increased arterial pressure in human volunteers

BACKGROUND: Because patients may be taking clonidine chronically or may be receiving it as a premedication before surgery, the authors investigated its effect on cerebral hemodynamics. METHODS: In nine volunteers, middle cerebral artery mean blood flow velocity (Vm) was measured using transcranial Doppler ultrasonography (TCD). CO2 vasoreactivity was measured before clonidine administration (preclonidine), 90 min after clonidine, 5 microg/kg orally, then following restoration of mean arterial pressure (MAP) to the preclonidine level. In addition, Vm was measured after a phenylephrine-induced 30-mmHg increase in MAP. RESULTS: After clonidine administration, Vm decreased from 62 +/- 9 to 48 +/- 8 cm/s (P < 0.01), and MAP decreased from 86 +/- 10 to 63 +/- 5 mmHg (P < 0.01; mean +/- SD). Clonidine decreased the CO2 vasoreactivity slope from 2.2 +/- 0.4 to 1.2 +/- 0.5 cm x s(-1) x mmHg(-1) (P < 0.05); restoring MAP to the preclonidine level increased the slope to 1.60 +/- 0.5 cm x s(-1) x mmHg(-1), still less than the preclonidine slope (P < 0.05). CO2 vasoreactivity expressed as a percentage change in Vm, decreased after clonidine, 3.5 +/- 0.8 versus 2.4 +/- 0.8 %/mmHg (P < 0.05); this difference disappeared after restoration of MAP, 3.1 +/- 1.2 %/mmHg. With a 30-mmHg increase in MAP, Vm increased by 13% before and after clonidine (P < 0.05). CONCLUSIONS: Clonidine, 5 microg/kg orally, decreases Vm and slightly attenuates cerebral CO2 vasoreactivity, therefore decreased cerebral blood flow and mildly attenuated CO2 vasoreactivity should be anticipated.     

Effects of norepinephrine on right ventricular function in septic shock patients

OBJECTIVE: To study the effects of norepinephrine on right ventricular function in patients with hyperdynamic septic shock. DESIGN: Prospective, open study. SETTING: A 15 bed ICU in a university hospital. PATIENTS: 9 patients with hyperdynamic septic shock (SBP < 90 mmHg, Cl > or = 4 l.min-1.m-2, SVRI < or = 850 dynes.s.cm-5m-2 and oliguria). INTERVENTIONS: Plasma volume expansion was used to correct a suspected volume deficit and then, norepinephrine infusion was started and titrated to restore systemic blood pressure to the normal range (mean infusion rate: 1.1 +/- 0.2 mcg.kg-1.min-1). Norepinephrine was the only vasoactive agent used in these patients. MEASUREMENTS AND RESULTS: A modified Swan-Ganz catheter mounted with a fast response thermistor was inserted in each patient, allowing repeated measurements of RVEDVI and RVEF. At time of inclusion to the study, all but one patient had elevated MPAP (23 +/- 4 mmHg) and RVEF < or = 50%, and all patients had RVEDVI > or = 90 ml.m-2. During norepinephrine infusion, MAP increased from 51 +/- 9 to 89 +/- 10 mmHg (p < 0.0001), PVRI increased from 204 +/- 35 to 286 +/- 63 dynes.s.cm-5.m-2 (p < 0.05), and despite this increase in right ventricular afterload, no detrimental effect in RVEF (36 +/- 11 to 36 +/- 10%) or in RVEDVI (116 +/- 30 to 127 +/- 40 ml.m-2) was observed. A Frank-Starling relationship for the right ventricle was constructed by plotting an index of ventricular performance (RVSWI) against an index of ventricular preload (RVEDVI). A significant upward shift to the right of the relationship was observed during norepinephrine infusion. CONCLUSION: It was concluded that norepinephrine exerted a favourable effect on right ventricular function.     

Comparative study of the effects of ouabain and digoxin on blood pressure of rats

OBJECTIVE: To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension. METHODS: Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured. RESULTS: After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group. CONCLUSIONS: Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.     

Effects of angiotensin II and losartan in the forearm of patients with essential hypertension

OBJECTIVE: Angiotensin II type 1 receptor-mediated constrictor effects may be modulated by hypertension-related vascular changes, changes in receptor function and in neurohumoral activity. DESIGN: The forearm blood flow (FBF) effects of angiotensin II, methoxamine, and losartan were investigated in essential hypertensive patients. Minimal forearm vascular resistance was measured to determine structural vascular changes. METHODS: Seven hypertensive patients were selected, and seven matched normotensives. Angiotensin II (0.01-10 ng/kg per min) was infused during predilatation by sodium nitroprusside (6.1 +/- 0.6 ng/kg per min) before and during losartan infusion (0.3-3 microg/kg per min). Methoxamine (0.2-2 microg/kg per min) was co-infused with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. FBF, measured by venous occlusion plethysmography, was expressed as the change in FBF ratio (FBFinfused arm/FBFnon-infused arm). RESULTS: Baseline FBF (infused arm) was increased by sodium nitroprusside from 2.56 +/- 0.80 to 5.46 +/- 0.92 (P<0.05) and from 2.66 +/- 0.25 to 5.42 +/- 0.40 ml/100 ml per min (P<0.05) in the hypertensive and normotensive group, respectively. Baseline forearm vascular resistance (FVR) was higher in the hypertensive than in the normotensive group [51 +/- 8 versus 33 +/- 3 mmHg/ (ml/100 ml per min); P<0.05]. Angiotensin II caused a maximal change in FBF ratio (Emax) by -70 +/- 3 and -72 +/- 6% in the hypertensive and normotensive group, respectively (NS). Tachyphylaxis did not occur. Infusions of losartan at 0.3, 1 and 3 microg/kg per min reduced the Emax values from -70 +/- 3 to -50 +/- 5, -45 +/- 5 and -15 +/- 2%, respectively, in the hypertensive group, and from -72 +/- 6 to -62 +/- 4, -45 +/- 2 and -32 +/- 2%, respectively, in the normotensive group (NS). Infusion of methoxamine significantly reduced the FBF ratio by -58 +/- 6 and -69 +/- 5% in the hypertensive and normotensive groups, respectively (NS). Minimal FVR, after forearm ischemia, was the same in hypertensives and normotensives, namely 3.2 +/- 0.7 and 3.2 +/- 0.4 mmHg/(ml per 100 ml per min), respectively (NS). CONCLUSIONS: Angiotensin II type 1- and alpha1-mediated vascular effects were unchanged by essential hypertension. Baseline FVR was greater in the hypertensives than in the normotensives, while minimal FVR was the same. These results indicate that the forearm vascular bed of the patient group studied does not show important structural and renin-angiotensin system-related functional changes as a result of hypertension.     

Effect of nitrovasodilators and inhibitors of nitric oxide synthase on ischaemic and reperfusion function of rat isolated hearts

1. The functional role of the nitric oxide (NO)/guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway in experimental myocardial ischaemia and reperfusion was studied in rat isolated hearts. 2. Rat isolated hearts were perfused at constant pressure with Krebs-Henseleit buffer for 25 min (baseline), then made ischaemic by reducing coronary flow to 0.2 ml min(-1) for 25 or 40 min, and reperfused at constant pressure for 25 min. Drugs inhibiting or stimulating the NO/cyclic GMP pathway were infused during the ischaemic phase only. Ischaemic contracture, myocardial cyclic GMP and cyclic AMP levels during ischaemia, and recovery of reperfusion mechanical function were monitored. 3. At baseline, heart rate was 287+/-12 beats min(-1), coronary flow was 12.8+/-0.6 ml min(-1), left ventricular developed pressure (LVDevP) was 105+/-4 mmHg and left ventricular end-diastolic pressure 4.6+/-0.2 mmHg in vehicle-treated hearts (control; n=12). Baseline values were similar in all treatment groups (P>0.05). 4. In normoxic perfused hearts, 1 microM N(G)-nitro-L-arginine (L-NOARG) significantly reduced coronary flow from 13.5+/-0.2 to 12.1+/-0.1 ml min(-1) (10%) and LVDevP from 97+/-1 to 92+/-1 mmHg (5%; P<0.05, n=5). 5. Ischaemic contracture was 46+/-2 mmHg, i.e. 44% of LVDevP in control hearts (n=12), unaffected by low concentrations of nitroprusside (1 and 10 microM) but reduced to approximately 30 mmHg (approximately 25%) at higher concentrations (100 or 1000 microM; P<0.05 vs control, n=6). Conversely, the NO synthase inhibitor L-NOARG reduced contracture at 1 microM to 26+/-3 mmHg (23%), but increased it to 63+/-4 mmHg (59%) at 1000 microM (n=6). Dobutamine (10 microM) exacerbated ischaemic contracture (81+/-3 mmHg; n = 7) and the cyclic GMP analogue Sp-8-(4-p-chlorophenylthio)-3',5'-monophosphorothioate (Sp-8-pCPT-cGMPS; 10 microM) blocked this effect (63+/-11 mmHg; P<0.05 vs dobutamine alone, n=5). 6. At the end of reperfusion, LVDevP was 58+/-5 mmHg, i.e. 55% of pre-ischaemic value in control hearts, significantly increased to approximately 80% by high concentrations of nitroprusside (100 or 1000 microM) or L-NOARG at 1 microM, while a high concentration of L-NOARG (1000 microM) reduced LVDevP to approximately 35% (P<0.05 vs control; n=6). 7. Ischaemia increased tissue cyclic GMP levels 1.8 fold in control hearts (P<0.05; n=12); nitroprusside at 1 microM had no sustained effect, but increased cyclic GMP approximately 6 fold at 1000 microM; L-NOARG (1 or 1000 microM) was without effect (n=6). Nitroprusside (1 or 1000 microM) marginally increased cyclic AMP levels whereas NO synthase inhibitors had no effect (n=6). 8. In conclusion, the cardioprotective effect of NO donors, but not of low concentrations of NO synthase inhibitors may be due to their ability to elevate cyclic GMP levels. Because myocardial cyclic GMP levels were not affected by low concentrations of NO synthase inhibitors, their beneficial effect on ischaemic and reperfusion function is probably not accompanied by reduced formation of NO and peroxynitrite in this model.     

Differential effects of endotoxaemia on pressor and vasoconstrictor actions of angiotensin II and arginine vasopressin in conscious rats

1. Regional haemodynamic responses to arginine vasopressin (AVP; 0.5, 1.0, 5.0 pmol i.v.) and angiotensin II (AII; 5.0, 10.0, 50.0 pmol i.v.) were measured in conscious Long Evans rats at various times (0, 2, 6 and 24 h) during infusion of lipopolysaccharide (LPS, 150 microg kg(-1) h(-1), i.v., n=9) or saline (n=9). Additional experiments were performed in vasopressin-deficient (Brattleboro) rats infused with LPS (n=7) or saline (n=8) to determine whether or not, in the absence of circulating vasopressin, responses to the exogenous peptides differed from those in Long Evans rats. 2. In the Long Evans rats, during the 24 h infusion of LPS, there was a changing haemodynamic profile with renal vasodilatation from 2 h onwards, additional mesenteric vasodilatation at 6 h, and a modest hypotension (reduction in mean arterial blood pressure (MAP) from 103+/-1 to 98+/-2 mmHg) associated with renal and hindquarters vasodilatation at 24 h. 3. In the Brattleboro rats, the changes in regional haemodynamics during LPS infusion were more profound than in the Long Evans rats. At 2 h and 6 h, there was a marked fall in MAP (from 103+/-3 mmHg; to 65+/-3 mmHg at 2 h, and to 82+/-4 mmHg at 6 h) associated with vasodilatation in all three vascular beds. After 24 h infusion of LPS, the hypotension was less although still significant (from 103+/-3 mmHg; to 93+/-4 mmHg, a change of 10+/-4 mmHg), and there was renal and hindquarters vasodilatation, but mesenteric vasoconstriction. 4. During infusion of LPS, at each time point studied, and in both strains of rat, pressor responses to AII and AVP were reduced, but the changes were less marked at 6 h than at 2 h or 24 h. The reduced pressor responses were not accompanied by generalized reductions in the regional vasoconstrictor responses. Thus, in the Long Evans rats, the renal vasoconstrictor responses to both peptides were enhanced (at 6 h and 24 h for AVP; at all times for AII), whereas the mesenteric vasoconstrictor response to AVP was unchanged at 2 h, enhanced at 6 h and reduced at 24 h. The mesenteric vasoconstrictor response to AII was reduced at 2 h, normal at 6 h and reduced at 24 h. The small hindquarters vasoconstrictor responses to both peptides were reduced at 2 h and 6 h, but normal at 24 h. 5. In the Brattleboro rats, the renal vasoconstrictor responses to both peptides were reduced at 2 h and enhanced at 6 h and 24 h, whereas the mesenteric vasoconstrictor response to AVP was normal at 2 h and 6 h, and reduced at 24 h. The response to AII was reduced at 2 h, normal at 6 h and reduced again at 24 h. There were no reproducible hindquarters vasoconstrictions to AVP in the Brattleboro rats. The small hindquarters vasoconstrictor responses to AII were unchanged at 2 h and enhanced at 6 h and 24 h. 6. In isolated perfused mesenteric vascular beds, removed after 24 h of LPS infusion in vivo, there was an increase in the potency of AVP in both strains (Long Evans, ED50 saline: 56.9+/-15.0 pmol, ED50 LPS: 20.4+/-4.8 pmol, Brattleboro, ED50 saline: 38.6+/-4.2, ED50 LPS: 19.6+/-2.9 pmol), but no change in the responses to AII. 7. These findings indicate that a reduced pressor response to a vasoconstrictor challenge during LPS infusion is not necessarily associated with a reduced regional vasoconstriction. The data obtained in the Brattleboro rats indicate a potentially important role for vasopressin in maintaining haemodynamic status during LPS infusion in Long Evans rats. However, it is unlikely that the responses to exogenous AVP (or AII) are influenced by changes in the background level of endogenous vasopressin, since the patterns of change were similar in Long Evans and Brattleboro rats. 8. The results obtained in isolated perfused mesenteric vascular beds differed from those in vivo, possibly due to the conditions pertaining with in vitro perfusion.