Measurement of pulmonary blood flow by fractal analysis of flow heterogeneity in isolated canine lungs

Regional heterogeneity of lung blood flow can be measured by analyzing the relative dispersion (RD) of mass (weight)-flow data. Numerous studies have shown that pulmonary blood flow is fractal in nature, a phenomenon that can be characterized by the fractal dimension and the RD for the smallest realizable volume element (piece size). Although information exists for the applicability of fractal analysis to pulmonary blood flow in whole animal models, little is known in isolated organs. Therefore, the present study was done to determine the effect of blood flow rate on the distribution of pulmonary blood flow in the isolated blood-perfused canine lung lobe by using fractal analysis. Four different radiolabeled microspheres (141Ce, 95Nb, 85Sr, and 51Cr), each 15 microns in diameter, were injected into the pulmonary lobar artery of isolated canine lung lobes (n = 5) perfused at four different flow rates (flow 1 = 0.42 +/- 0.02 l/min; flow 2 = 1.12 +/- 0.07 l/min; flow 3 = 2.25 +/- 0.17 l/min; flow 4 = 2.59 +/- 0.17 l/min), and the pulmonary blood flow distribution was measured. The results of the present study indicate that under isogravimetric blood flow conditions, all regions of horizontally perfused isolated lung lobes received blood flow that was preferentially distributed to the most distal caudal regions of the lobe. Regional pulmonary blood flow in the isolated perfused canine lobe was heterogeneous and fractal in nature, as measured by the RD. As flow rates increased, fractal dimension values (averaging 1.22 +/- 0.08) remained constant, whereas RD decreased, reflecting more homogeneous blood flow distribution. At any given blood flow rate, high-flow areas of the lobe received a proportionally larger amount of regional flow, suggesting that the degree of pulmonary vascular recruitment may also be spatially related.     

Effect of starvation on organ blood flow in the senescent rat

Since the first true hernioplasty performed by Edoardo Bassini more than 100 years ago (1884) all surgical reconstruction techniques have shared a common defect i.e. tension on suture line. This is the first etiologic factor of recurrent hernia. On the contrary by the use of modern prosthetic materials (mesh and plug) it is now possible to marriage all hernia repairs without distorting normal body anatomy and avoid undesirable tensions. The technique proposed is simple, efficient, characterized by a rapid performing procedure, giving way to an excellent clinical outcome: postoperative pain relief permitting the patient to resume in a short time his normal physical activities. In this paper the authors present their experience in wall defects reconstruction by means of outpatient surgery and in general anesthesia in the period spanning from 1994 to 1996. Five different types of hernia mesh in hernioplasty procedures were evaluated and used.     

The effect of remifentanil on cerebral blood flow velocity

High concentrations of lidocaine induce irreversible conduction block with little effect on resting membrane potential (Em). We assumed the mechanism of persistent neurologic deficit caused by local anesthetics may result from neural death, as represented by the loss of Em. We investigated the effects of lidocaine on Em and action potential (AP) in single crayfish giant axons in vitro. Axons were perfused with two doses of lidocaine for either 15 or 30 min, and they were continuously washed. No axons exposed to 80 mM lidocaine for 30 min showed recovery of AP and Em. Those exposed to 40 mM for 30 min and 80 mM for 15 min showed a return to baseline for Em, but no recovery of AP. Those exposed to 40 mM lidocaine for 15 min showed full recovery of Em and AP immediately after washing. The membrane depolarization was significantly greater during exposure to 80 mM lidocaine for 30 min than in other groups. We conclude that lidocaine has a direct neurotoxic effect on crayfish giant axons and that the generation of AP is more vulnerable than the maintenance of Em. The irreversibility of AP and Em is dose- and time-dependent. IMPLICATIONS: Highly concentrated lidocaine induced an irreversible conduction block and a complete loss of resting membrane potential in crayfish giant axons in vitro. Our results may represent a possible explanation for various grades of local anesthetic-induced neurotoxicity in clinical cases if the same toxicity occurs in mammalian nerves in vivo.     

The effect of dexmedetomidine on nutrient organ blood flow

The alpha 2-adrenergic agonist dexmedetomidine decreases not only heart rate, myocardial contractility, and oxygen demand, but also cardiac output (Q). To investigate whether this reduction in Q could critically impair perfusion of individual organs, we studied the effect of dexmedetomidine on nutrient blood flow to the heart, brain, kidney, spleen, skin, intestine, liver, and arteriovenous anastomoses using the radioactive microsphere technique. Studies were conducted in 14 dogs with an open chest and anesthetized with either chloralose/urethane (CU) or fentanyl/halothane (FH), to create different baseline conditions. Hemodynamic variables, organ blood flow, arterial and mixed venous oxygen, and lactate content were measured before and after administration of 0.1, 1, and 10 micrograms/kg dexmedetomidine intravenously (IV). After 10 micrograms/kg dexmedetomidine Q decreased in both groups by 50%. The decrease in blood flow varied greatly between the organs. While flow through arteriovenous anastomoses and skin decreased by 70% to 90%, renal blood flow decreased by 30%, cerebral blood flow only when baseline blood flow was high (FH dogs), and left ventricular blood flow only in the CU group, where the largest decrease in hemodynamic variables occurred. Oxygen consumption decreased only in CU dogs, but so did arterial lactate levels. These data indicate that dexmedetomidine causes considerable redistribution of Q, predominantly reducing blood flow to less vital organs and shunt flow.     

The effect of chronic hypertension on skin blood flow

OBJECTIVE: To determine whether the cutaneous microvasculature of the spontaneously hypertensive rat (SHR) is affected by chronic hypertension. DESIGN: We used laser Doppler techniques to measure skin blood flow in 22 SHR and in 22 non-hypertensive Wistar-Kyoto (WKY) rats over a 1-year time span, beginning at age 3 months. Sites of measurement included the back, leg, and root of the tail, areas with a predominantly nutritive perfusion, and the plantar surface of the paw, which has a large contribution from large arterioles and venules. Flow was measured at basal skin temperature and at the maximally heat-stimulated condition of 44 degrees C. Systolic tail arterial blood pressures were measured concurrently. RESULTS: At baseline, systolic blood pressures were considerably higher in the SHR (190 +/- 4 mmHg) than they were in the WKY rats (138 +/- 2 mmHg). Skin blood flow values at the three nutritive sites were similar in the two species. However, at 44 degrees C, flow was significantly higher at the paw in the SHR (46.8 +/- 3.5 versus 34.3 +/- 2.2 ml/min per 100 g). We attribute this difference to the effect of high perfusion pressure on large arterioles. During the 1-year measurement period, there was no appreciable change in blood flow in the WKY rats. In contrast, the SHR showed a steady progressive decline in skin blood flow at all sites. The largest decline was at the paw with a rate of fall of about 2.4%/month. After 1 year, there was no difference between paw blood flow in the SHR (27.5 +/- 1.8 ml/min per 100 g) and in the WKY rats (27.6 +/- 1.9 ml/min per 100 g). CONCLUSIONS: Skin blood flow reserve falls in response to chronic hypertension. The rate of fall is greater at sites with significant arteriovenous perfusion that at nutritive sites.     

Reduction of infarct volume by halothane: effect on cerebral blood flow or perifocal spreading depression-like depolarizations

Halothane is a strong inhibitor of potassium evoked spreading depression (SD) in cats. In the current study, we investigate halothane effects on induction of perifocal SD-like depolarizations, CBF, and infarct evolution in focal ischemia. Calomel and platinum electrodes measured cortical direct current potential and CBF in ectosylvian, suprasylvian, and marginal gyri. Left middle cerebral artery occlusion (MCAO) induced permanent focal ischemia for 16 hours in artificially ventilated cats (30% oxygen, 70% nitrous oxide) under halothane (0.75%, n = 8) or alpha-chloralose anesthesia (60 mg/kg intravenously, n = 7). Under alpha-chloralose, MCAO induced severe ischemia in ectosylvian and suprasylvian gyri(mean CBF < 10 mL/100 g/min), and direct current potentials turned immediately into terminal depolarization. In marginal gyri, CBF reduction was mild (more than 20 mL/100 g/min), and in six of seven animals, frequent SD-like depolarizations turned into terminal depolarization at a later stage of the experiments. Under halothane, MCAO induced severe ischemia (less than 10 mL/100 g/min) and immediate terminal depolarization only in ectosylvian gyrus. In suprasylvian gyrus, residual CBF remained significantly higher (more than 10 mL/100 g/min) than under alpha-chloralose, whereas in marginal gyri, CBF did not differ between groups. Compared with chloralose, the number of transient depolarizations was significantly reduced in marginal gyrus, and in suprasylvian gyrus transient but significantly longer depolarizations than in marginal gyrus were recorded. Except for one animal, transient depolarizations did not turn into terminal depolarization under halothane, and infarct volume reduction was particularly seen in suprasylvian gyrus. We conclude that halothane, the most commonly used anesthetic in studies of experimental brain ischemia, has protective properties, which may depend on both cerebrovascular and electrophysiologic influences.     

Role of nitric oxide in the effect of blood flow on neointima formation

PURPOSE: Neointima formation after arterial injury is inhibited by increased blood flow. The object of this study was to determine whether nitric oxide mediates the effect of increased blood flow on neointima formation. METHOD: Balloon catheter-denuded rat carotid arteries were exposed to increased blood flow or control blood flow by ligation of the contralateral carotid artery. Beginning 2 days before balloon denudation, rats were given either saline vehicle alone or the nitric oxide synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) at a dose of 10 mg/kg/day or 2 mg/kg/day intraperitoneally. The normalized neointima area was measured 14 days after denudation. RESULTS: Blood flow was significantly increased by ligation of the contralateral carotid artery for all drug treatments (p<0.008). In rats given saline vehicle only, normalized neointima area was significantly reduced after increased blood flow compared with control blood flow (0.33+/-0.04 compared with 0.48+/-0.03; p=0.006). Systolic blood pressure was significantly elevated by treatment with high-dose L-NAME (p=0.002 compared with vehicle), but was not altered by low-dose L-NAME (p=NS compared with vehicle). Normalized neointima area was not significantly reduced after increased carotid blood flow for rats treated with either dose of L-NAME (p=NS). CONCLUSION: The inhibition of neointima formation by increased blood flow was abolished with hypertensive and nonhypertensive doses of the nitric oxide synthase inhibitor L-NAME, which suggests that the L-NAME effects are independent of systemic hemodynamic alterations. It is concluded that flow-induced inhibition of neointima formation is mediated in part by nitric oxide.     

The isolated supported canine heart: a model for the evaluation of drug effects on regional myocardial blood flow

The present investigation was designed to determine the effect of propranolol on regional myocardial blood flow and oxygen consumption (MVO2) in the isolated supported dog heart preparation perfused at a constant coronary blood flow. The transmural distribution of blood flow, determined by the radioactive microsphere technique, was expressed as the epicardial/endocardial blood flow ratio (epi/endo). Propranolol (0.5 mg/kg i.v.) produced a significant decrease in heart rate and myocardial contractile force and an increase in coronary artery perfusion pressure due to an increase in coronary vascular resistance. These hemodynamic changes were accompanied by significant decreases in epi/endo (increased endocardial perfusion) and MVO2. Reduction of perfusion pressure to control by a decrease in total coronary blood flow produced no further change in epi/endo or MVO2. However, increasing heart rate to control increased epi/endo to predrug levels. Contractile force and MVO2 remained reduced below control. Norepinephrine infusion (1 mug/min intracoronary) produced a significant increase in heart rate and contractile force and decrease in perfusion pressure. These changes were accompanied by an increase in epi/endo and MVO2. Propranolol (0.5 mg/kg i.v.) abolished the response to norepinephrine. Propranolol may produce beneficial effects in angina pectoris by a decrease in epi/endo (via a reduction in heart rate) and MVO2 and by beta adrenergic blockade of the deleterious effects of catecholamines.     

The effect of diazoxide on uterine blood flow in pregnant sheep

Diazoxide, a labor inhibiting agent, was administered intravenously at various rates to seven pregnant, near-term sheep to evaluate its effect on cardiovascular and uterine hemodynamics. Uterine blood flow was measured with electromagnetic flow transducers. Rapid administration of diazoxide resulted in a profound maternal tachycardia with hypotension, an increase in uterine vascular resistance, and a significant decrease in uterine blood flow. With slow infusion of the drug, the changes in heart rate and blood pressure were minimized, uterine vascular resistance was decreased, and uterine blood flow was maintained. Therefore, slow infusion appears to be the preferred method for inhibiting labor with diazoxide.     

The antiulcer effect of corticosteroids and the blood flow in the gastric mucosa

Owing to the short wavelengths of X-radiation X-ray microscopes allow higher resolution than optical microscopes. In contrast to electron microscopes, X-radiation can be used to study relatively thick aqueous specimens in their natural environment. X-ray microscopes require intense X-radiation, which is best provided by electron storage rings, as well as efficient X-ray optics. X-ray microscopes with zone plate optics are installed at the storage ring BESSY in Berlin for studies in the fields of biology, medicine, biophysics, colloid chemistry, and soil sciences.     

Chronic blockade of nitric oxide synthase and endothelin receptors during pregnancy in the rat: effect on reactivity of the uterine artery in vitro

Complex tibial condylar fractures are intraarticular fractures with associated lesions of capsule and ligaments, menisci, soft tissue envelope and neurovascular structures. They are in general produced by a high-energy trauma and are usually part of a polytraumatized patient. The frequency for the associated lesions are up 50% for the collateral ligaments, and up to 40% for the cruciate ligaments and the menisci, respectively. The paper presents the crucial steps of clinical and radiological assessment and outlines a concept of treatment, documented by two illustrative cases.     

Effect of acute and chronic arecoline treatment on cerebral metabolism and blood flow in the conscious rat

To investigate the structural contribution of the light chain of anti-DNA antibodies to fine specificity, the VKappa genes of two monoclonal anti-DNA antibodies, termed H241 and H102, were cloned and sequenced. H102 and H241 are independently derived from MRL-lpr/lpr mice and differ in their fine specificity: H241 binds dsDNA and normal glomeruli in vitro and deposits in the kidney in vivo, whereas H102 binds only ssDNA and does not deposit in the kidney. Both are encoded by nearly identical VH genes but different N and D regions. Our previous results have demonstrated that the VH gene for H102 and H241 encodes eight other anti-DNA antibodies that also differed in fine specificity. This suggested that the gene product encoded by the VH 102/241 gene, may have intrinsic affinity for DNA, but is unlikely to determine fine specificity or nephritogenicity. In the present study we examined whether the VKappa gene might account for the difference in nephritogenicity. The complete nucleotide and deduced amino acid sequence of VK 102 and VK241 revealed that they are very dissimilar to each other (< 60% homology). VK 241 defined a new member of the VKappa gene family and was moderately homologous to two other VK genes encoding anti-DNA antibodies and to one VK gene encoding an anti-histone antibody all from lupus strains of mice. In addition, sequence diversity in the VK CDR1 region and position 96 of the CDR3 region was observed that may be of significance in determining fine specificity. VK 102 was highly homologous to two other VKappa genes, VKs17.2 and VK C8.5, both encoding anti-DNA antibodies and members of the VK20 gene family. It was striking that all three members of the VK 20 gene family code for DNA reactivity. This suggests that certain VKappa genes may also be used to repeatedly code for anti-DNA reactivity.     

Effects of excitatory amino acids on cerebral oxygen consumption and blood flow in rat

The oncogene Tpr-Met is a constitutively active form of the hepatocyte growth factor/scatter factor (HGF/SF) receptor Met. It comprises the intracellular moiety of Met linked to the dimerization domain of the nuclear envelope protein Tpr, thus functioning as a constitutively activated Met. HGF/SF is responsible for various biological processes including angiogenesis and wound healing, in which secreted serine protease urokinase-type plasminogen activator (uPA) is implicated. The action of HGF/SF on cells is mediated by the autophosphorylation of Met on two carboxyterminal tyrosine residues, Y1349VHVNATVY1356VNV. The two tyrosine residues provide docking sites for various effector molecules, suggesting that multiple signaling pathways are activated to exert biological effects of HGF/SF [Ponzetto et al., Cell (1994) 77: 261]. We found that Tpr-Met efficiently activates the uPA gene via a SOS/Ras/extracellular signal regulated kinase (ERK)-dependent signaling pathway. Mutation of Y1356, which abrogates GRB2 binding, reduced the induction to half of the control level, while mutation of Y1349 showed little effect on uPA induction, suggesting an important but partly replaceable role for GRB2 in Met-dependent uPA gene induction. Mutation of both Y1349VHV and Y1356VNV into optimal PI 3-kinase sites resulted in a residual induction of about one quarter of the control level, suggesting a potential role for PI 3-kinase. Dose-response analysis of the Tpr-Met showed a biphasic curve. These results suggest that the interplay among different signaling molecules on the receptor is important for full induction of the pathway leading to the activation of the uPA gene.     

The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size

The disposition of nifurtimox was studied in the rat isolated perfused liver using a recirculating system. The drug was administered as a bolus (5.0, 15.0 or 30.0 micrograms mL-1), and its disappearance was monitored by analysing perfusate samples. In all experiments perfusate disappearance was monoexponential, and no significant difference was found between the three doses for the elimination constant (0.016, 0.011 and 0.012 min-1, respectively), half-life (46.6, 65.8 and 66.8 min, respectively), extraction rate (0.128, 0.091 and 0.099, respectively) and distribution volume (41.1, 47.3 and 30.7 mL g-1, respectively). At 30 micrograms mL-1 the hepatic clearance was lower than the other concentrations of nifurtimox (0.66, 0.51 and 0.34 mL min-1 g-1, respectively). Relatively little parent drug was recovered from the liver at the end of the perfusions. In summary, nifurtimox is cleared slowly from the rat isolated perfused liver, is poorly extracted by hepatocyte cells and is completely metabolized from 2 to 4 h after perfusion.     

Endothelin-1 regulates tone of isolated small arteries in the rat: effect of hyperendothelinemia

Chronic elevation of plasma endothelin-1 (ET-1) levels has been reported in several pathological conditions. To investigate the consequences of increased circulating ET-1 on vascular responsiveness, Sprague-Dawley rats (n=16) were chronically instrumented with a minipump delivering ET-1 at a constant dose for 7 days. Plasma ET-1 levels were more than doubled in treated (0.98+/-0.09 pmol/L; P<.05) versus untreated sham-operated rats (0.43+/-0.04 pmol/L), whereas systolic arterial blood pressure increased (139+/-5 versus 128+/-4 mm Hg in untreated rats; P<.05). After rats were killed, segments of middle cerebral (MCA) and mesenteric (MES) arteries were mounted on an isometric myograph. ET-induced contraction was shifted to the right in ET-1-treated animals and not modified by BQ123 (an ET(A) receptor antagonist); bosentan (ET(A/B) receptor antagonist) prevented ET-1-induced contraction in both groups. After inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine (L-NNA), both phenylephrine and oxymetazoline (an alpha2-adrenoceptor agonist) induced MCA contraction. The sensitivity to phenylephrine was decreased in ET-1-treated compared with control rats (P<.05). Sensitivity to phenylephrine-induced contraction was decreased by BQ123 in control rats only. In contrast, L-NNA revealed greater oxymetazoline-induced contractions in treated compared with control MCA rings (P<.05); this potentiation was blunted by bosentan but unaffected by BQ123. Removal of the endothelium revealed a direct constrictor effect of oxymetazoline that was insensitive to L-NNA alone or combined with bosentan; however, oxymetazoline induced significantly lower constriction in treated rat MCA segments. Responses to oxymetazoline were also blunted in treated compared with untreated denuded MES arteries. In conclusion, chronic elevated plasmatic ET-1 decreases smooth muscle cell sensitivity to contractile agonists both in MCA and MES rings. In cerebral vessels, endothelial alpha2-adrenoceptor-dependent stimulation induced greater contractile responses in treated rats which were sensitive to bosentan, suggesting that oxymetazoline stimulates ET-1 release from the endothelium. This may represent a compensatory mechanism for the loss of smooth muscle sensitivity.