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At least 217 records · Page 12Linked to original sources
PubMed2004

Pushing the envelope in renal preservation; improved results with novel perfusate modifications for pulsatile machine perfusion of cadaver kidneys.

INTRODUCTION: Novel preservation techniques may diminish ischemia/reperfusion (I/R) injury. Our preservation laboratory has modified Belzer MPS for machine perfusion (MP) with prostaglandin E1 (PGE 1), nitroglycerin (NTG), and polyethylene glycol-superoxide dismutase (PEG-SOD) to attenuate I/R injury. We reviewed our recent experience using this novel formulation (NF) compared with standard perfusates. RESULTS: Between January 1998 and March 2000, 1060 consecutive kidneys were preserved in our laboratory. One hundred forty-eight kidneys (14%) were discarded. Fifty-eight percent of kidneys during this time period underwent MP (n = 532). En bloc kidney pairs were randomly assigned to pulsatile MP using Waters RM3 or MOX-100 perfusion systems using 1 of 3 perfusates; NF (NF; n = 119), Belzer MPS (MPS; n = 201), or Belzer II albumin gluconate (ALB; n = 212) Significant improvements in delayed graft function (DGF) rate were seen with NF versus other perfusates (8% vs 14% vs 19%, respectively; P =.03). At 6 months, graft survival was significantly improved with NF compared with MPS and ALB (96% vs 90% vs 87%, respectively; P =.03). NF also produced a significantly higher percentage of recipients with a serum creatinine level < or = 1.5 mg/dL. CONCLUSIONS: Novel modifications of standard MP perfusate improved outcomes after renal transplantation. Preservation-based interventions targeted to ameliorate I/R injury can improve outcomes and may allow expansion of the donor pool.

Adult↗
PubMed2005

Oxygenated machine perfusion preservation of predamaged kidneys with HTK and Belzer machine perfusion solution: an experimental study in pigs.

The objective of the present study was to evaluate the recently proposed aerobic machine preservation with the noncolloidal HTK solution by comparison with the colloidal Belzer machine perfusion solution (MPS) after procurement of marginal kidneys from non-heart-beating donors. Kidneys were harvested 40 minutes after cardiac arrest in German Landrace pigs and subjected to 18 hours of oxygenated hypothermic machine perfusion with either Belzer MPS or modified HTK via the renal artery (Psys < 40 mm Hg). During machine perfusion transrenal flow was approximatively twofold higher and calculated oxygen uptake was increased by 30% using the colloidal Belzer MPS, but overall enzyme release was comparable in both groups. After heterotopic transpantation with bilateral nephrectomy of the recipient, there were no differences with respect to initial tissue perfusion in vivo (evaluated by laser Doppler flowmetry) as well as urine production and median serum levels of urea or creatinine over 1 week of follow-up between grafts perfused with HTK or Belzer MPS. In conclusion, provision of oxygen during storage is possible by low-flow perfusion with HTK as with Belzer MPS.

Adenosine↗
PubMed2002

Increased pressure during retrograde cerebral perfusion in an acute porcine model improves brain tissue perfusion without increase in tissue edema.

BACKGROUND: There is a significant lack of scientific data to support the clinically accepted view that 25 to 30 mm Hg is the maximum safe perfusion pressure during retrograde cerebral perfusion (RCP). This study was designed to investigate whether perfusion pressure greater than 30 mm Hg during RCP is beneficial to the brain during prolonged HCA in an acute porcine model. METHODS: Sixteen pigs underwent 120 minutes of circulatory arrest in conjunction with RCP at a perfusion pressure of either 23 to 29 mm Hg (group L, n = 8) or 34 to 40 mm Hg (group H, n = 8) at 15 degrees C, followed by 60 minutes of normothermic cardiopulmonary bypass. Cortical blood flow and oxygenation were measured continuously with a laser flowmeter and near-infrared spectroscopy, respectively. Tissue water content was measured at the end of the experiments. RESULTS: Brain tissue blood flow was significantly higher in group H than in group L (16.8% +/- 4.1% vs 4.8% +/- 0.9% of baseline, p < 0.01) during RCP. Brain oxygen extraction in group L reached a maximum (approximately 70%) immediately after starting RCP, whereas in group H it increased gradually and reached a maximum at 120 minutes of RCP, indicating a greater supply of oxygen to tissue in group H than in group L. After RCP, the ability of brain tissue to use oxygen was better preserved in group H than in group L, as indicated by tissue oxygen saturation and the deoxyhemoglobin level. There was no significant increase in tissue water content in either group (group H 79.2% +/- 0.3%, group L 79.1% +/- 0.4%) relative to normal control pigs (78.7% +/- 0.1%). CONCLUSIONS: In this acute porcine model, increasing perfusion pressure from 23-29 to 34-40 mm Hg during RCP increases tissue blood flow and provides better tissue oxygenation, without increasing tissue edema. The optimal perfusion pressure for RCP needs to be further investigated.

Animals↗
PubMed1996

Surgery of the thoracic aorta with hypothermic circulatory arrest: experience with retrograde perfusion via the superior vena cava and demonstration of cerebral perfusion.

OBJECTIVE: Retrograde cerebral perfusion (RCP) via the superior vena cava has been described as an adjunctive technique to enhance the safety of hypothermic circulatory arrest (HCA), but perfusion of cerebral tissue in humans during RCP has not been demonstrated to date. We report our clinical experience with RCP and our attempt to demonstrate "true" perfusion of the brain. METHODS: Between April 1993 and June 1995, 49 thoracic aortic procedures were performed in 48 patients (male:female = 26:22) (emergency: elective = 25:24). The indications for surgery were acute type "A" dissection (18) chronic aneurysm (28) and infected valved conduit (3). Hypothermic circulatory arrest (15 degrees C) and RCP were implemented in all cases (mean HCA time 29 min, range 11-69) (mean RCP time 26 min, range 10-65). The 99mTechnetium labelled brain perfusion agent d,l, hexamethyl propylene amine oxime (99mTc-HMPAO) was administered (100 MBq) into the cardiotomy reservoir following institution of HCA (15 degrees C) in three consecutive patients and planar dynamic brain imaging with a portable gamma camera was commenced at the start of RCP. RESULTS: Six hospital deaths (12.2%) occurred in the emergency group due to atheromatous embolic stroke in one patient, sepsis in one, ruptured infrarenal aortic aneurysm in one, myocardial failure in one, renal failure in one and multi-system organ failure in one patient. The remaining patients suffered no major neurological complications (median Intensive Care Unit stay 1 day, range 1-5). Inspection of the images acquired showed 99mTc-HMPAO activity spreading quickly from the jugular bulb and the superior sagittal sinus throughout the cerebral white and gray matter. Time-activity curves calculated for both cerebral hemispheres showed homogeneous regional cerebral perfusion. CONCLUSIONS: Retrograde cerebral perfusion is easy to establish, "safe" and provides blood flow to the brain during HCA. The flow quantification and metabolic contribution of RCP require further investigation.

Adult↗
PubMed1998

EDRF does not mediate coronary vasodilation secondary to simulated ischemia: a study on KATP channels and N omega-nitro-L-arginine on coronary perfusion pressure in isolated Langendorff-perfused guinea-pig hearts.

Several authors have alluded to the possible involvement of EDRF (NO) in ischemia-induced coronary artery dilation. Alternatively, it has been suggested that opening of ATP-dependent K channels could play a key role in this context. We studied the effects of sulfonylureas and NG-nitro-L-arginine (LNNA), a specific inhibitor of endothelial NO (EDRF) synthesis, on ischemia-induced coronary vasodilation in isolated Langendorff-perfused guinea pig hearts arrested with 15 mM KCl in normal Tyrode, and isolated pig coronary arteries precontracted with 43 mM KCl. In Isolated Langerdorff-perfused guinea pig heart, when hypoxia was simulated by switching 100% O2 in the perfusate to 100% N2, coronary perfusion pressure (CPP) fell from 90 cm H2O by 45 +/- 5 cm H2O. In the presence of LNNA, a specific inhibitor of NO synthetase in endothelial cells, CPP dropped by 44 +/- 6 cm H2O (n = 6; +/- SEM, no statistically significant). On biochemical simulation of ischemia (addition of iodoacetate [IAA]), CPP dropped 40 +/- 6 cm H2O, and in experiments performed under the same conditions but in the presence of LNNA, CPP dropped by 38 +/- 5 cm H2O (n = 6; +/- SEM; not statistically significant). When ischemia was simulated metabolically by equimolar replacement of 10 mM glucose with 2-deoxyglucose (DOG), an inhibitor of glycolysis CPP decreased by 24 +/- 1 cm H2O (n = 6; +/- SEM) after 15 minutes. This fall in CPP was almost prevented by 20 microM glibenclamide, whereas in the presence of 20 microM LNNA the DOG-induced decrease in CPP was not significantly inhibited, and CPP decreased by 22 +/- 2.6 cm H2O (n = 6; +/- SEM). In isolated pig coronary artery rings, maximal tension, achieved by depolarizing the smooth muscle cells by 43 mM KCl, decreased by 37 +/- 7% upon simulated hypoxia by replacing 100% O2 with 100% N2 in the perfusate (n = 6; +/- SEM) in arteries with intact endothelium. In arteries without endothelium, maximal tension also dropped by 35 +/- 6% (not statistically significant). In the same experiments the decrease in tension could be largely inhibited in the presence of 50 microM glibenclamide. Our results clearly show that in isolated perfused guinea pig hearts, as well as in isolated pig coronary arteries, EDRF does not play a decisive role in the coronary dilatory response to hypoxia and ischemia.

Adenosine Triphosphate↗
PubMed1992

Concomitant stimulation by vasopressin of biliary and perfusate calcium fluxes in the perfused rat liver.

Changes in perfusate Ca2+ (measured with a Ca(2+)-selective electrode) and changes in bile calcium (measured by atomic absorption spectroscopy) were continuously and simultaneously monitored after infusion of (a) vasopressin, (b) glucagon and (c) both vasopressin and glucagon together to the perfused rat liver. Also monitored were perfusate glucose and oxygen concentrations and bile flow. Vasopressin induces a sharp, transient, pulse of increased bile flow and increased bile calcium within 1 min of infusion, concomitant with rapid changes in perfusate Ca2+ fluxes, glucose output and oxygen uptake. This is immediately followed by a decrease in both bile flow and bile calcium for as long as the hormone is administered. Changes induced by glucagon are a relatively slow onset of perfusate Ca2+ efflux and oxygen uptake, but rapid glucose output, and a small but significant and transient decrease in bile flow and bile calcium which, despite the continued infusion of the hormone, spontaneously and rapidly returns to normality. However, the greatest responses are observed after co-administration of both hormones. Coincident with the augmented perfusate Ca2+ fluxes (influx) seen in earlier work, there occurs within 1 min of vasopressin infusion a sharp increase in bile secretion and bile calcium greater in magnitude than that produced by vasopressin alone. Immediately thereafter bile secretion and bile calcium decline below basal values and remain there for as long as the hormones are administered. Glucagon and vasopressin therefore each have opposing effects on bile flow and bile calcium. However, the action of vasopressin is enhanced by the prior administration of glucagon. The data thus reveal features about the actions of glucagon and Ca(2+)-mobilizing hormones on bile flow and bile calcium not previously recorded and provide a novel framework around which the whole issue of hepato-biliary Ca2+ homoeostasis can be assessed in normal and diseased liver.

Animals↗
PubMedDate not supplied

Myocardial perfusion and angiographic correlations in patients with ST-segment elevation during dobutamine stress perfusion imaging.

BACKGROUND: There is scanty information on the angiographic and myocardial perfusion correlates of dobutamine-induced ST-segment elevation. METHODS AND RESULTS: We studied 39 patients who exhibited ST-segment elevation during dobutamine perfusion tomography and had recent coronary angiography performed (ie, within 3 months of the dobutamine study). Baseline characteristics, extent of coronary artery disease, relationship of Q waves to ST-segment elevation, ischemic burden, and angiographic findings were assessed. Twenty-nine patients (74%) had prior myocardial infarction, and 77% had abnormal Q waves at baseline. Ninety-three percent of patients had abnormal perfusion imaging. Eighty percent of patients had multivessel coronary artery disease. The left ventricular ejection fraction by contrast ventriculography was 35% +/- 7% (mean +/- SD), the perfusion defect size was 32% +/- 15%, and 73% of patients had some degree of myocardial ischemia. A predominance of ischemia (>50% reversibility) occurred in 38% of patients with Q waves and in 70% of those without Q waves. There was also good agreement between the site of ST-segment elevation and the site of ischemia by perfusion imaging (79%) and between the site of ST-segment elevation and the location of the vessel with significant coronary stenosis (95%). CONCLUSIONS: Patients with dobutamine-induced ST-segment elevation have a depressed left ventricular ejection fraction, a high frequency of multivessel disease, and markedly abnormal myocardial perfusion tomography. In patients with ST-segment elevation and abnormal Q waves, substantial scarring and superimposed ischemia coexist, whereas in patients without Q waves, ST-segment elevation usually denotes severe ischemia.

Adrenergic beta-Agonists↗
PubMed2005

Endoluminal pelvic perfusion with norepinephrine causes only minor systemic effects and diminishes the increase in pelvic pressure caused by perfusion.

OBJECTIVE: To evaluate the effect of endoluminal norepinephrine (NE) on transport pressures of the normal upper urinary tract of the pig and on plasma levels of NE in relation to possible systemic effects. MATERIAL AND METHODS: Six anaesthetized pigs weighing approximately 39 kg were studied. Transparenchymally, two 6-F catheters were introduced into the renal pelvis bilaterally to measure pressure and perfusion. Ultrasonic flow probes recorded renal arterial blood flow, and a transurethral 10-F catheter drained the bladder and monitored diuresis. In all six animals, the bilateral pelvic pressure response was examined at increasing perfusion rates (2, 4, 6, 8, 10 and 15 ml/min) and with increasing doses of NE (0, 5, 50 and 100 microg/ml). Arterial blood samples were analysed for NE, epinephrine and blood glucose. The systemic blood pressure, heart rate and electrocardiogram were registered. RESULTS: At all the investigated concentrations, endoluminal NE significantly diminished the increase in pelvic pressure caused by pelvic perfusion at all flow rates. At the lowest concentration of NE, no significant increase in the plasma level of NE was observed and the blood pressure did not increase. During perfusion with 50 and 100 microg/ml NE, plasma levels of NE increased significantly from 487+/-398 to 1798+/-910 and 2961+/-2093 pg/ml, respectively. This was accompanied by significant rises in mean systolic blood pressure from a baseline value of 95+/-10 mmHg to 111+/-20 and 118+/-23 mmHg, respectively. Heart rate, renal arterial blood flow and plasma levels of epinephrine and glucose did not change. CONCLUSIONS: Endoluminal NE diminished the increase in pelvic pressure caused by pelvic perfusion even at concentrations too low to cause significant changes in NE plasma levels or systemic effects. Very high NE concentrations in the perfusion fluid caused increased plasma levels and a modest but significant increase in blood pressure. Administration of endoluminal NE may be useful in upper urinary tract stone treatment and endoscopy.

Adrenergic alpha-Agonists↗
PubMed1985

Interaction of formaldehyde with glutathione in the isolated/ventilated perfused lung and the isolated perfused liver.

The interaction of formaldehyde (CH2O) with reduced glutathione (GSH) was evaluated in aqueous solution and in isolated perfused lungs and livers. Addition of CH2O (0-4.9 mM) to a solution of 0.17 mM GSH in 2 mM EDTA, pH 7.4, resulted in a time- and concentration-dependent depletion of GSH. Perfusion of livers with fortified Krebs-Ringer bicarbonate buffer containing 0.3-4.9 mM CH2O resulted in a dose-dependent depletion of GSH. Perfusion of isolated ventilated lungs with perfusate containing 4.9 mM CH2O resulted in a depletion of GSH to 75% of controls. However, lower concentrations of CH2O in the lung perfusate did not result in depletion of GSH. These results demonstrate that exposure to CH2O in aqueous solution or in the perfused lung and liver is capable of depleting endogenous GSH. However, the concentrations of CH2O required to yield a significant depletion of endogenous GSH exceed those encountered in vivo. Thus, it is unlikely that depletion of GSH by CH2O is a causal factor in formaldehyde-induced toxicity.

Animals↗
PubMed1992

Perfusion with anti-insulin gamma globulin indicates a B to A to D cellular perfusion sequence in the pancreas of the rhesus monkey, Macaca mulatta.

The cellular sequence of intraislet vascular perfusion has been shown to be important in the regulation of islet hormone secretion in the rat and dog islet. In order to test whether a B to A to D sequence of islet cellular perfusion is also present in a nonhuman primate, pancreata from the rhesus monkey, Macaca mulatta, were isolated and perfused in vitro in the presence and absence of anti-insulin gamma globulin. In the presence of the insulin antibody, efflux concentration of insulin decreased rapidly (-95 +/- 1.8%), whereas glucagon and somatostatin concentrations increased (111 +/- 28% and 239 +/- 38%, respectively). These results suggest the presence of a B-A-D cellular sequence of vascular perfusion within the monkey islet. The present results also strongly support the hypothesis that a B-A-D sequence of islet perfusion is important in the regulation of islet hormone secretion and further emphasize the central role of the B-cell in intraislet cellular interactions. The results also suggest that, despite differences in islet anatomy, a B-A-D order of islet cellular perfusion may be the preferred functional sequence among mammalian species.

Animals↗
PubMed2000

Vasomotion in critically perfused muscle protects adjacent tissues from capillary perfusion failure.

We analyzed the incidence and interaction of arteriolar vasomotion and capillary flow motion during critical perfusion conditions in neighboring peripheral tissues using intravital fluorescence microscopy. The gracilis and semitendinosus muscles and adjacent periosteum, subcutis, and skin of the left hindlimb of Sprague-Dawley rats were isolated at the femoral vessels. Critical perfusion conditions, achieved by stepwise reduction of femoral artery blood flow, induced capillary flow motion in muscle, but not in the periosteum, subcutis, and skin. Strikingly, blood flow within individual capillaries was decreased (P < 0.05) in muscle but was not affected in the periosteum, subcutis, and skin. However, despite the flow motion-induced reduction of muscle capillary blood flow during the critical perfusion conditions, functional capillary density remained preserved in all tissues analyzed, including the skeletal muscle. Abrogation of vasomotion in the muscle arterioles by the calcium channel blocker felodipine resulted in a redistribution of blood flow within individual capillaries from cutaneous, subcutaneous, and periosteal tissues toward skeletal muscle. As a consequence, shutdown of perfusion of individual capillaries was observed that resulted in a significant reduction (P < 0.05) of capillary density not only in the neighboring tissues but also in the muscle itself. We conclude that during critical perfusion conditions, vasomotion and flow motion in skeletal muscle preserve nutritive perfusion (functional capillary density) not only in the muscle itself but also in the neighboring tissues, which are not capable of developing this protective regulatory mechanism by themselves.

Animals↗
PubMed1993

Intrahypothalamic perfusion with interleukin-1-beta stimulates the local release of corticotropin-releasing hormone and arginine vasopressin and the plasma adrenocorticotropin in freely moving rats: a comparative perfusion of the paraventricular nucleus and the median eminence.

It is almost generally accepted that an acute-phase ACTH response induced by interleukin (IL)-1 is mediated principally by CRH release from the hypothalamus. However, the precise cellular site of action of IL-1 in activating the CRH neuronal system remains to be determined. Two likely candidates comprise the paraventricular nucleus (PVN) where CRH neuronal cell bodies are located, and the median eminence (ME) where their nerve endings are terminated. Therefore, in this study we performed a comparative perfusion of the ME and the PVN with increasing concentrations of recombinant human IL-1 beta utilizing the push-pull perfusion technique in freely moving rats. We measured the plasma ACTH and ME and PVN levels of CRH, and also of AVP, because AVP, another secretagogue of ACTH, has its cell body in the PVN and axon terminals partly in the ME. In control groups, the ME or the PVN was perfused with artificial cerebrospinal fluid between 12:00 and 15:00 h, and perfusates and blood samples were collected every 20 min. In the other groups, either the ME or the PVN was perfused with three increasing concentrations (0.1, 1.0, and 10 nM) of recombinant human IL-1 beta dissolved in artificial cerebrospinal fluid only between 13:00 and 14:00 h with all the other procedures run in the same way as in the controls. In the control perfusions, the hypothalamic release of CRH and AVP and the plasma ACTH did not change significantly during the entire period of observation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1977

Degradation of parathyroid hormone and fragment production by the isolated perfused dog kidney. The effect of glomerular filtration rate and perfusate CA++ concentrations.

The renal degradation of intact bovine parathyroid hormone (b-PTH 1-84) was studied with the isolated perfused dog kidney. Disappearance of b-PTH 1-84 from the perfusate occurred concomitantly with the appearance of smaller molecular weight forms of immunoreactive parathyroid hormone (PTH). These smaller molecular weight PTH fragments included both carboxyl and amino terminal regions of the PTH peptide. Perfusate from kidneys with lower glomerular filtration rates (GFR) contained b-PTH 1-84 for longer periods of time than kidneys with higher GFRs, and perfusate from kidneys with lower GFRs demonstrated greater accumulation of carboxyl terminal PTH fragments. Perfusate containing high Ca++ concentrations retarded, and perfusate with low Ca++ concentrations accelerated the rate of degradation of b-PTH 1-84 by the kidney. These studies, therefore document the production of PTH fragments during the course of intact hormone degradation by the kidney. They also demonstrate renal clearance of the PTH fragments produced and define the effects of glomerular filtration rate and calcium concentrations on degradation of intact hormone and the clearance of PTH fragments.

Animals↗
PubMed1986

The relationship between perfusion medium flow rate and steroid secretion in the isolated perfused rat adrenal gland in situ.

Using the in-situ, isolated, perfused rat adrenal preparation, we have investigated the effects of changes in the rate of perfusate flow through the gland, brought about both mechanically and by the use of vasoactive agents, in the absence of known adrenocortical stimulants. Adenosine caused a significant increase in the rate of perfusate flow through the adrenal, with a concomitant rise in corticosterone, but not aldosterone, secretion. Adrenaline, on the other hand, caused a decrease in the rate of perfusate flow through the gland, accompanied by a decrease in the rate of steroid secretion. Furthermore, increases in the rate of delivery of perfusate to the gland, brought about by increasing the peristaltic pump rate, caused a large increase in corticosterone secretion, although aldosterone was unaffected. Neither adenosine nor a mechanically increased rate of perfusate delivery increased steroid secretion by collagenase-dispersed rat adrenocortical cells superfused on a Sephadex column. These results suggest the existence of hitherto unsuspected intraglandular mechanisms for the control of steroid secretion.

Adenosine↗
PubMed1975

[Optimum perfusion pressure, renal resistance and oxygen consumption of kidney in hypothermic pulsating perfusion].

36 dog kidneys were perfused with different perfusion pressures (between 15 and 60 mm Hg) for 72 hrs and then transplanted. Hypothermic human albumin was the perfusion fluid. Kidneys perfused with a flow rate of 0.8 ml/g/min (21 mm Hg mean perfusion pressure) showed the smallest increase in kidney weight and the best function after transplantation. Renal vascular resistance was independent of the level of the perfusion pressure and renal oxygen consumption was independent of the applied flow rate.

Animals↗
PubMed2005

Distributed perfusion educational model: a shift in perfusion economic realities.

In recent years, a steady decline in the number of perfusion education programs in the United States has been noted. At the same time, there has been a parallel decline in the number of students graduated from perfusion educational programs in the United States. Also, as noted by several authors, there has been an increase in demand for perfusion graduates. The decline in programs and graduates has also been noted in anesthesia and surgical residency programs. The shift is caused by a combination of economic and clinical factors. First, decreased reimbursement has led to reallocation of hospital resources. Second, the original enthusiasm for beating heart coronary artery bypass surgery was grossly overestimated and has led to further reallocation of hospital resources and denigration of cardiopulmonary bypass. This paper describes two models of perfusion education programs: serial perfusion education model (SPEM) and the distributed perfusion education model (DPEM). Arguments are presented that the SPEM has some serious limitations and challenges for long-term economic survival. The authors feel the DPEM along with dependence on tuition funding can survive the current clinical and economic conditions and allow the profession to adapt to changes in scope of practice.

Allied Health Occupations↗
PubMed1986

Influence of basal perfusion pressure on vasoconstrictor and vasodilator responses induced sympathetically and reflexly in pump-perfused rat hindquarters.

The hindquarters of Wistar rats, under pentobarbital anesthesia, were vascularly isolated and perfused at a constant flow rate (6.25 ml/min) with autologous blood. Basal perfusion pressure varied from 60 to 140 mm Hg during the experimental procedure and among individual rats. The magnitude of the constrictor effect of i.a. norepinephrine was virtually constant and independent of the basal pressure. I.A. injection of acetylcholine and histamine; i.v. injection of norepinephrine; and stimulation of the lumbar sympathetic nerves with pulses of 0.03 msec or less, produced dilator responses in the perfused extremities. Stimulation with pulses of 0.1 msec or more resulted in a constrictor response followed by a dilator response. These dilator responses increased linearly and the constrictor responses decreased linearly as the basal pressure increased. Thus, the law of initial value of resistance held true for all dilator responses tested and for the constrictor responses evoked by stimulation of the lumbar sympathetic nerves. This result permitted normalization of these responses to predicted values at a reference perfusion pressure (100 mm Hg) by statistical analysis. The dilator response elicited by stimulation with shorter pulses and the constrictor response elicited by longer pulses had the same time course, which suggests that the constrictor response is probably compounded by a synchronous dilator mechanism. Hexamethonium, guanethidine and prazocin abolished the dilator responses elicited by neural stimulation and those induced by i.v. norepinephrine. These results indicate that the responsiveness of pump-perfused rat hindquarters varies with the existing perfusion pressure in a linear fashion according to the law of initial value of resistance except in the case of i.a. norepinephrine. Both the electrically- and reflexly-evoked dilator responses require intact ganglionic and alpha-adrenergic transmission.

Acetylcholine↗
PubMed1983

Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activities of harmol in the perfused rat liver preparation.

The role of zonal distributions of metabolic activities (sulfation and glucuronidation) in the liver on the kinetics of harmol conjugation was investigated. A computer simulation approach was adopted to better understand the effects of distributions of these conjugation activities in competition for a common drug substrate. Several distributions of the sulfation and glucuronidation systems were defined with respect to the flow path of blood; the conjugation activities along the flow path were in turn translated as time elapsed after entry of the substrate via blood into the organ. Realistic values of Km and Vmax for the sulfation and glucuronidation systems were assigned in the simulations. Directional flow, namely, normal vs. retrograde delivery of substrate was used as an additional variable. When the "center" of distribution of the sulfation system was anterior to that for glucuronidation, the steady-state hepatic extraction ratio of harmol (E) would increase, whereas the ratio of the steady-state rates of formation of harmol sulfate to harmol glucuronide (S/G ratio) would decrease when harmol was presented in a reversed direction (via retrograde perfusion), as compared with normal directional flow to the liver. The converse was true for an anterior distribution of the glucuronidation system; E would decrease, whereas S/G would increase with retrograde perfusion. To evaluate such zonal differences experimentally, perfusion studies were conducted in livers of male Wistar rats. A constant concentration of harmol (50 microM) was delivered under constant hepatic flow rate (10 ml/min/liver) by normal and retrograde perfusions to the same rat liver preparation. The steady-state hepatic E was higher (P less than .005) during retrograde perfusion than during normal perfusion, whereas the S/G ratio was significantly decreased (P less than .0005). The observations suggest an intercellular difference in the distribution of the two conjugating systems and are consistent with the view of the center of distribution for the sulfation system being anterior to the center of distribution for the glucuronidation system along the normal flow path of blood in the liver.

Alkaloids↗