Regression of the systemic vasculature to the lung after removal of pulmonary artery obstruction

RATIONALE: Pulmonary artery occlusion stimulates angiogenesis in the systemic circulation of the ipsilateral lung and increases systemic- to-pulmonary blood flow. Whether this systemic neovascularization decreases after lung revascularization is unknown. OBJECTIVES: To assess the influence of lung revascularization on anatomy and flow of bronchial vessels supplying a chronically ischemic lung in piglets. METHODS: Piglets were studied before (control) and 5 wk after left pulmonary artery ligation and 5 wk after left pulmonary artery reimplantation into the pulmonary artery trunk. The systemic blood flow to the right and left lungs was measured using colored microspheres, and the bronchial vasculature was assessed using light-microscopic morphometry. Renal and total blood flow, systemic blood pressure, and pulmonary blood pressure were measured in each experimental condition. MEASUREMENTS AND MAIN RESULTS: Systemic blood flow to the left lung increased from 0.4 +/- 0.1 to 11.5 +/- 3.8 ml/min/g (p < 0.05) after left pulmonary artery ligation and returned toward the control value (1.2 +/- 0.6 ml/min/g) after revascularization, whereas it remained unchanged in the right lung. The number of bronchial vessels increased twofold in the ligated lung (p = 0.01), and did not decrease after reperfusion; however, vessel diameters decreased markedly. Renal and total blood flows, as well as mean pulmonary and systemic arterial pressures, were similar in the three experimental conditions. CONCLUSION: Revascularization after a period of left pulmonary artery occlusion normalizes the systemic blood flow to the left lung and induces partial loss of collateral vessels.     

Distribution of the collateral blood flow at the lateral border of the ischemic myocardium after acute coronary occlusion in the pig and the dog

Summary Residual blood flow in pigs (n=8) and dogs (n=11) was measured by tracer microspheres (⁵⁸Sr) 1 hour after occlusion of the left anterior descending coronary artery (LAD). Collateral blood flow was distinguished from overlap flow, defined as the blood flow of non-ischemic myocardium interdigitating into the ischemic area, by direct LAD injection of isotope-labelled microspheres (¹²⁵I) prior to ligation. In the center of the acutely ischemic pig myocardium the residual blood flow, i.e., the myocardial perfusion remaining after LAD occlusion, was 0.01±0.01 ml/min/g subendocardially and 0.02±0.01 ml/min/g subepicardially, as estimated with⁸⁵Sr-labelled microspheres. These values were significantly lower than the corresponding values for the dog, 0.13±0.05 ml/min/kg (p<0.05) subendocardially and 0.28±0.08 ml/min/g (p<0.01) subepicardially. In the lateral aspects of the ischemic area, calculations of overlap flow were made with the aid of the distribution of the microspheres injected into the LAD. Values of the residual blood flow were normalized and nonischemic myocardial perfusion was set to 100 units. In subepicardial layers of the myocardium with calculated overlap flows corresponding to 20, 50 or 80 units, respectively, the residual blood flow (overlap flow + collateral flow) actually measured in the pig was 31±4 55±4 and 75±7 units and in the dog 65±6, 79±5 and 91±2 units. The values for the dog were significantly different from the respective value for the pig (p<0.01). In the subendocardial layers the difference between the two species regarding residual blood flow was similar, although the difference was statistically significant only for myocardium with a calculated overlap flow of 80 units. When the calculated overlap flow was subtracted from the measured residual blood flow, the collateral blood flow was found to be extensive in the dog and virtually absent in the pig.When, in the dog, the collateral blood flow across the lateral border of the ischemic area was related to the amount of myocardium it supplies, it was found to be homogeneously distributed. Thus neither subendocardially nor subepicardially could a gradient of collateral blood flow be detected. It is concluded that in the pig the collateral blood flow is almost nil throughout the acutely ischemic myocardium, both in subendocardial and subepicardial layers. In contrast, the dog has an extensive collateral flow. No lateral gradient of this collateral blood flow could, however, be detected.     

Effects of nifedipine on collateral blood flow at the lateral border of the acutely ischemic myocardium

Summary In open-chest dogs (n=5) the effects of nifedipine (25 g/kg infused over a period of 15 min) on the collateral blood flow after left anterior descending coronary artery (LAD) ligation were separated from those on heterogeneous blood supply, i.e. flow of collateral origin plus flow in nonischemic myocardium projecting into the ischemic area. This separation was possible using a technique based on microspheres, allowing analysis of perfusion via the left anterior descending coronary artery (LAD). Secondary effects on the ischemic heart induced by the hypotensive effect of nifedipine per se were minimized by counterbalancing the blood pressure change with an intra-aortic balloon. Nifedipine increased non-ischemic myocardial blood flow in the subendocardium from 1.11±0.10 to 2.71±0.17 (p<0.001) and in the subepicardium from 1.12±0.08 to 3.95±0.49 (p<0.001) (ml/min/g, mean ±SE). Collateral blood flow in the centre of the ischemic area was not affected by nifedipine. In the subendocardium, it was 0.12±0.05 before and 0.09±0.09 after nifedipine, and in the subepicardium, the corresponding values were 0.21±0.10 and 0.29±0.04, respectively. At the lateral ischemic border, the nifedipine-induced increase in myocardial blood flow was only directed to the admixed normal tissue. When the blood flow was corrected for this overlapping non-ischemic tissue, no significant effect of nifedipine was measurable in the subendocardial blood flow, which was 0.12±0.03 before and 0.18±0.04 ml/min/g after drug administration. However, in the subepicardium, the collateral blood flow was significantly reduced from 0.33±0.09 to 0.15±0.05 (p<0.05). It is concluded that nifedipine was able to decrease collateral blood flow at the lateral border, while leaving the blood flow unaffected in the centre of the ischemic are.     

Intestinal blood flow in murine colitis induced with dextran sulfate sodium

The aim of this study was to assess whether colitis induced by dextran sulfate sodium (DSS; 10% in tap water for 7 days) in BALB/c mice is associated with changes in intestinal blood flow. After anaesthesia, systemic hemodynamic variable and regional blood flows and resistances in various organs were measured in both control and DSS-treated mice. Mean arterial blood pressure was significantly lower in DSS-treated mice than in controls (56 ± 4 vs 66 ± 3 mm Hg; P < 0.05), but no differences were found in regional blood flows to or vascular resistances in the lungs, liver, stomach, small intestine (upper, middle, and lower part), cecum, mesentery + pancreas, spleen, kidneys, brain, and skin. However, compared to the control mice, blood flows in the middle (0.88 ± 0.13 vs 0.55 ± 0.09 ml/min/g; P < 0.05) and distal (0.69 ± 0.11 vs 0.29 ± 0.05 ml/min/g; P < 0.05) colon were significantly higher, and vascular resistances in the proximal (0.87 ± 0.21 vs 1.36 ± 0.21 mm Hg min/ml/100 g; P < 0.05), middle (0.60 ± 0.10 vs 1.46 ± 0.35 mm Hg min/ml 100 g; P < 0.05) as well as distal (0.90 ± 0.25 vs 2.67 ± 0.49 mm Hg min/ml/100 g; P < 0.05) colon were significantly lower in mice with experimental colitis. Interestingly, there was a gradient in the intestinal blood flow in control mice from the upper small intestine (2.79 ± 0.72 ml/min/g) down to the distal colon (0.29 ± 0.05 ml/min/g); such a gradient was also present in the colitis mice. It is concluded that DSS-induced colitis in mice is associated with microcirculatory disturbances in the colon, mainly in its middle and distal parts.     

Changes in uterine and ovarian blood flow during the oestrous cycle in rats.

The rates of uterine and ovarian blood flow during the oestrous cycle in rats were measured using radioactive microspheres. Blood flow was highest in the ovaries and uteri during pro-oestrus and lowest during metoestrus. During pro-oestrus, mean ovarian blood flow was 676-2 +/- 183-6 (S.D.) ml/min/100 g wet tissue and mean uterine blood flow was 249-7 +/- 120-1 ml/min/100 g. During metoestrus mean ovarian blood flow was 117-4 +/- 19-8 ml/min/100 g and mean uterine blood flow was 38-5 +/- 7-4 ml/min/100 g. In ovariectomized rats, uterine blood flow was 28-7 +/- 10-5 ml/min 100 g.     

Cutaneous Blood Flow and Peripheral Resistance in Type II Diabetes as Compared to Intermittent Claudication Patients

Insulin deficient, type I diabetic patients have reduced skin blood flow reserve. It is not known whether these skin perfusion abnormalities also exist in non-insulin dependent (type II) diabetic patients. An additional open question is whether the reduced skin blood flow is due to increased resistance of the cutaneous microvasculature or to decreased peripheral perfusion pressure due to increased atherosclerosis in the diabetic population. We measured skin blood flow by laser Doppler flowmetry in patients with type II non-insulin treated diabetes. Limb systolic blood pressure was measured distally using a sensitive sonar Doppler device at the finger and toe. The ratio of pressure to flow was computed as an index of peripheral blood flow resistance. To assess the effect of cutaneous blood flow resistance, we elicited maximal vasodilation by increasing local skin temperature directly at the site of the laser Doppler probe. We compared blood flow and pressure in diabetic patients with the values in non-diabetic control patients. As a further control population, we also assessed these same parameters in non-diabetic patients with peripheral vascular disease, which may be expected to decrease large arterial blood flow pressure without directly affecting the microvasculature. There were 68 type II diabetic patients, 18 non-diabetic control subjects, and 25 non-diabetic patients with intermittent claudication. We measured skin blood flow at the dorsal surfaces of the finger and toe, sites with primarily nutritive capillary perfusion, and at the plantar surfaces of the finger and toe, where arteriovenous shunt perfusion predominates. Heat stimulated flow was markedly lower for the diabetic patients at the finger dorsal surface (16.5 ± 1.4 ml/min/100 g vs 29.8 ± 4.4 ml/min/100 g in the non-diabetic group (p < 0.05). The resistance index was 13.2 ± 1.9 in the diabetic patients and 6.8 ± 1.7 in the controls (p < 0.05). At the toe dorsum, basal temperature flow was significantly lower in the diabetic group (0.6 ± 0.1 ml/min/100 g) than in the non diabetic group (1.1 ± 0.2 ml/min/100 gm) with resistance index almost twice as high (379 ± 32) in the diabetic group versus non-diabetic controls (208 ± 36) [p < 0.01 for both comparisons]. With the local application of heat, there was a much larger increase in flow in the non-diabetic subjects than in the diabetic group. The resistance index dropped much more with heat stimulation for the non-diabetic patients (10.8 ± 3.3) than for the diabetic patients (50.6 ± 10.4) [p < 0.01] There was a lesser rise in flow at the toe pulp surface with heat in the diabetic patients (31.3 ± 3.0 ml/min/199 gm) than in the control subjects (45.4 ± 5.9 ml/min/100 gm; p < 0.05) with a higher resistance index (13 ± 4) than in the non-diabetic subjects (4 ± 1) [p < 0.05]. The claudication patients had substantially greater flow at the toe dorsal surface at basal temperature (2.2 ± 0.4 ml/min/100 gm) with significantly lower resistance index (126 ± 24) than the non-diabetic controls (p < 0.05). At 44°C, toe dorsum flow was significantly higher (17.8 ± 3.7 ml/min/100 gm) than in the diabetic patients with lower resistance index (17.0 ± 6.6) [p < 0.05]. Toe pulp flow at basal temperature was significantly higher (10.1 ± 2.0 ml/min/100 gm) than in either the diabetic (3.8 ± 0.6) or non-diabetic control groups (3.5 ± 1.4) [p < 0.05]. Skin blood flow is impaired in diabetes. The reduction is due to increased resistance in the capillary bed rather than to reduced perfusion pressure. The increased resistance was found only in the diabetic patients, not in the non-diabetic patients with peripheral vascular disease. To the contrary, there appeared to be a compensatory decrease in skin flow resistance in the patients with peripheral vascular disease. Thus, there is a small vessel disease which impairs cutaneous perfusion in diabetes, but there is no such effect on skin blood flow in non-diabetic patients with large vessel disease.     

Acute effects of ethanol on myocardial blood flow in the nonischemic and ischemic heart

To determine the effects of ethanol on myocardial blood flow in the non-ischemic and ischemic heart, coronary blood flow was measured with radionuclide-tagged microspheres in the anesthetized dog before and after intravenous administration of 1.7 g/kg body weight of ethanol. In non-ischemic dogs, at an average peak blood ethanol level of 225 ± 8 mg/dl (mean ± standard error of the mean), left atrial pressure increased from 5.7 ± 0.6 to 7.7 ± 0.8 mm Hg (p <0.01) and heart rate slowed from 179 ± 8 to 171 ± 8 min^?1 (p <0.001) but mean aortic pressure and cardiac output were unchanged. Average myocardial blood flow increased from 122 ± 5 to 143 ± 8 ml/min per 100 g (p <0.001). In dogs given ethanol after coronary occlusion, at an average peak blood ethanol level of 201 ± 13 mg/dl, left atrlal pressure increased from 6.3 ± 0.6 to 7.4 ± 1.4 mm Hg (p <0.05) but there was no significant change in heart rate, mean aortic pressure or peak positive first derivative of left ventricular pressure ($\text{dP}\text{dt}$). In these dogs, there was a significant change (F = 6.47, p <0.001) in the distribution of myocardial blood flow. In the nonischemic zone, blood flow increased from 118 ± 7 to 148 ± 14 ml/min per 100 g (p <0.005), whereas in the ischemie zone it declined from 30 ± 6 to 20 ± 5 ml/min per 100 g (p <0.02). Myocardial tissue demonstrating myocardial perfusion equal to or greater than 80 percent of preligation levels showed a significant increment of blood flow after ethanol; by contrast, myocardial tissue having blood flow levels equal to or less than 60 percent of preligation levels showed a significant decline in blood flow.Thus, ethanol increases coronary blood flow in the nonischemic myocardium. However, in the acutely ischemic heart, ethanol produces an unfavorable redistribution of myocardial blood flow with flow in the non-ischemic myocardium increasing, at least in part, at the expense of blood flow to ischemic myocardium, producing in effect a “coronary steal.”     

Acute ethanol does not protect against ischemic/ reperfusion injury in rabbit myocardium

Moderate use of alcohol has shown protective effects in coronary artery disease, while excessive use has been associated with cardiomyopathy and hypertension. Since alcohol is a vasodilator, we postulated that it might have protective effects when administered acutely in the setting of ischemia/reperfusion. Therefore, we studied the acute effects of alcohol on myocardial infarction in a rabbit model. Anesthetized, open chest rabbits were subjected to a 30 minute coronary artery occlusion followed by 4 hours of reperfusion. Rabbits were randomized to a control group (n = 20), receiving an infusion of 10 ml normal saline, intravenously, over 10 minutes via a Harvard pump, or an alcohol group (n = 20), receiving a diluted solution of 100% ethanol (1 ml/kg diluted in normal saline to 10 ml total solution) infused in a similar fashion. This infusion regimen resulted in an average blood alcohol level of 110 mg/dl (range 77–129) tested in five rabbits within the study. Ten minutes after infusion, a marginal branch of the circumflex artery was occluded. Regional myocardial blood flow during coronary occlusion and reperfusion was measured using radioactive microspheres. Myocardial ischemic area at risk (AR) was assessed by blue dye injection and myocardial necrosis (AN) by triphenyltetrazolium chloride (TTC) staining. The mean regional coronary blood flow in ischemic tissue was 0.04 ± 0.01 ml/min/g in the control group versus 0.03 ± 0.01 ml/min/g in the experimental group (p = NS) and averaged 1.74 ml/min/g (control) to 1.98 ml/min/g (alcohol) in the nonischemic tissue. All rabbits received comparable ischemic insult: Collateral blood flow and AR were similar in both groups. An overall analysis showed no significant reduction in infarct size (expressed as the percent of necrotic tissue within the area at risk) in the alcohol group (23 ± 3%) compared with the control group (27 ± 4%). In conclusion, alcohol did not reduce infarct size in the rabbit model.     

Effects of oral pretreatment with metoprolol on left ventricular wall motion,infarct size,hemodynamics, and regional myocardial blood flow in anesthetized dogs during thrombotic coronary artery occlusion and reperfusion

Summary Objectives. To study the effects of oral pretreatment with metoprolol over 3 days on hemodynamics, left ventricular function, regional myocardial blood flow, and infarct size in an anesthetized dog model of thrombotic occlusion of the anterior descending coronary artery treated with thrombolysis.Methods. Ten dogs received 200 mg metoprolol (Selozok) orally and 8 dogs received placebo for 3 days twice daily and 1 hour before the experiment. Under general anesthesia, thrombotic occlusion was provoked by the copper-coil technique. Intracardiac pressures and their derivatives, cardiac output (thermodilution method), regional coronary blood flow (microspheres), global and regional left ventricular function (ventriculography), and infarct size (triphenyltetrazolium staining) were measured. Measurements were performed during control, after 60 minutes of occlusion, and after 30 and 90 minutes of reperfusion. Thrombolysis was performed in all dogs 60 minutes after occlusion by intravenous infusion of 10 µg/kg/min of rt-PA for 30 minutes.Results. During control cardiac output was lower, total peripheral resistance higher, and Tau and the left ventricular isovolumic relaxation time greater in the metoprolol group. During occlusion and after reperfusion, there were no significant hemodynamic differences between both groups. Blood flow to the area at risk and circumflex territory during occlusion were, respectively, 12.8±5.80 ml/100 g/min versus 9.65±8.35 ml/100 g/min (p>0.05) and 42.58±7.86 ml/100 g/min versus 61.52±20.43 ml/100 g/min (p=0.01) in the metoprolol- and placebo-treated dogs. The ratios of flow area at risk/circumflex territories in the epicardial, midmyocardial, and endocardial layers were, respectively, 0.44±0.20, 0.19±0.09, and 0.20±0.13 in the metoprolol- versus 0.24±0.16, 0.08±0.06, and 0.06±0.07 (p0.04) in the placebo-treated dogs. The ratio of flow endocardium/epicardium was higher (p0.02) in the active treatment group during the control period, both in the area at risk and circumflex territory; this was also the case in the circumflex territory at the end of the experiment (p=0.003). Thirty minutes after occlusion, blood flow to the three layers of the area at risk rose to 2–3 times control values in both groups; a significant increase above control values also occurred in the circumflex territory. After 90 minutes reperfusion, blood flow to both territories was similar in both groups but was comparable to the control; however, in necrotic tissue of the subendocardial layer of both groups, flow fell below control values (p<0.05). End-systolic volume rose from 21.2±7.4 ml to 36.1±11.5 ml (p<0.05), end-diastolic volume remained constant (46.0±13.8 vs. 47.9±12.1 ml; p>0.05), and ejection fraction fell from 53.9±8.3% to 25.8±10.2% (p<0.05) at the end of the experiment in the metoprolol group. Respective figures for the placebo group were 19.4±7.9 versus 27.9±10.9 (p<0.05), 38.5±13.0 versus 42.1±11.0 (p>0.05), and 50.6±5.7 versus 35.5±11.7 (p<0.05). Fractional shortening of the chords analyzed was similar in both groups during the control period; it fell significantly at the end of the experiment in three chords of the metoprolol group and in five chords of the placebo group. The apical chord in the placebo, but not in the metoprolol, dogs was dyskinetic: fractional shortening was –0.86±9.7 versus 7.5±13.5% (p>0.05). The area at risk was 41.6±10.6 cm² in metoprolol- and 40.5±7.2 cm² in placebo-treated dogs (p>0.05); the infarct size, expressed as a percentage of the area at risk, was 29.0±22.5% and 45.3±23.6% (p=0.02), respectively.Conclusions. Oral pretreatment with metoprolol limited infarct size and improved regional left ventricular function, probably due to its negative chronotropic and inotropic effects, and also due to an enhancement of collateral flow from the circumflex territory to the area at risk.     

Effect of complement depletion on O2 supply and consumption in ischemic dog myocardium

Summary The purpose of this study was to determine whether depletion of serum complement can decrease the severity of an ischemic episode by improving regional O₂ supply and conumption parameters in the ischemic region of the heart. Fourteen anesthetized dogs with serum complement intact or depleted (100 U/kg cobra venom factor given 8 hrs before) were subjected to left anterior descending coronary artery (LAD) occlusion for 6 hrs. Myocardial blood flows were determined before and 6 hrs after LAD occlusion using radioactive microspheres. Regional arterial and venous O₂ saturations were determined using microspectrophotometry. In control animals, flow decreased from 122±42 to 13±14 ml/min/100 g (mean±SD) in the occluded LAD region. With complement depletion, LAD occlusion resulted in a flow reduction in the ischemic region (38±29 ml/min/100 g), but to a lesser degree than seen in the same region in control animals, especially in the subendocardium. O₂ consumption was decreased in the ischemic region of both treatment groups, though O₂ consumption was higher in this region in complement depleted animals compared to the values in control animals. The O₂ supply/consumption ratio was decreased similarly in the ischemic region of control and complement depleted groups. Thus, with complement depletion, flow to the ischemic zone was improved but this region was still flow restricted. The flow increase during complement depletion was sufficient to allow an increased O₂, utilization in the ischemic region.     

Regional myocadial blood flow and cardiac mechanics in dog hearts with CO2 laser-induced intramyocardial revascularization

Summary Laser-induced intramyocardial revascularization (LIR) has been used to promote direct communications between blood within the ventricular cavity and that of the existing myocardial vasculature in an attempt to increase perfusion in patients with ischemic heart discase. This study was conducted to measure the effects of LIR channels on regional myocardial flood flow (microspheres), cardiac mechanics (sonomicrometers), and myocardial tissue pressures in 18 dogs. Under baseline hemodynamic conditions (mean HR=165.2±11.4 bpm, LVP=123.6±22.9/4.0±1.8 mmHg, AoP=112.8±27.1/77.0±22.5 mmHg), myocardial blood flow in laser-treated tissue (mean =1.11±.10 cc/min/gm before laser; .71±.19 cc/min/gm after laser) was reduced as compared to blood flow in control tissue (mean=1.12±.15 cc/min/gm before laser; 1.25±.22 cc/min/gm after laser). Regional myocardial systolic shortening (11.32%±3.82% before laser; 7.49%±2.86% after laser) was decreased by 33%. During simultaneous reversible ligation of the LAD and LCCA for 2 min, when intramyocardial channels represented the only tissue access for the injected microspheres, blood flow in laser-treated tissue was not increased above that of the control non-lasered tissue. However, regional blood flow was greater in laser-treated ischemic tissue (mean=.61±.12 cc/min/gm) than in untreated ischemic areas (mean=.04±.03 cc/min/gm) when left ventricular pressure (LVP) was acutely elevated (mean SLVP=207.0±16.1 mmHg). Using these measurements, a model is proposed to predict regional systolic pressure gradients between the left ventricular cavity and coronary intramyocardial vasculature required to permit restoration of blood flow to ischemic myocardium. We conclude that improved perfusion via laser-induced intramyocardial channels does not occur in otherwise normal myocardium exposed to acute coronary ligation and only small improvements in perfusion are noted when LVP is significantly elevated. Consideration of further clinical application of this approach is seriously cautioned awaiting additional experimental studies.This study was supported by U.S. Public Health Service Grant R01 HL32897-01 from the National Heart, Lung, and Blood Institute, by grants in aid from the American Heart Association, and by the Fulbright-Hays Scholarship Grant.     

Effect of magnesium on ischemic and reperfusion arrhythmias in a canine model with diminished collateral blood flow

Summary To assess the effects of elevated serum magnesium on ischemic and reperfusion arrhythmias, the left anterior descending coronary artery was cannulated and perfused by a shunt from a carotid artery in 20 open-chest anesthetized dogs. Ischemia was caused for 30 minutes by shunt occlusion and retrograde diversion of collateral blood flow. Dogs (10/group) were treated prior to occlusion with either saline or MgSO₄ (100 mg/kg IV). Plasma magnesium rose from 0.72±0.05 mM to 3.89±0.29 mM before occlusion (p<0.01) and fell to 3.28±0.21 mM just before reperfusion (p<0.01). Compared to saline, magnesium significantly slowed heart rate (113±4 beats/min vs. 124±3 beats/min, p<0.05), lowered arterial blood pressure (90±2 mmHg vs. 111±4 mmHg, p<0.05), and reduced myocardial blood flow to the ischemic zone before the occlusion (59±7 ml/min/100 g vs. 83±5 ml/min/100 g, p<0.01). The incidence of ventricular tachycardia during occlusion was 80% in the saline group and 70% in the magnesium group (p=1.0). The time required for a monophasic complex to develop in an electrogram over the ischemic zone was 4.5±0.24 minutes in the saline group and was not altered by magnesium (4.6±0.18 minutes). The incidence of reperfusion-induced ventricular fibrillation was 100% in both groups. The results suggest that acute infusion of magnesium offers little protection against ventricular tachyarrhythmias evoked by occlusion or reperfusion in a canine model of myocardial ischemia with diminished collateral blood flow.     

Effects of chronic,urea-induced osmotic diuresis on kidney weight and function in rats

Summary To study the effects of chronic osmotic diuresis which were not associated with hyperglycaemia on the rat kidney, osmotic diuresis was induced by i. v. infusion of urea. A 5 mol/l urea solution was continuously infused at a rate of 100 ml · kg^–1 · day^–1 on the basis of body weight on day 0. Duration of infusion was 2, 6, 10 or 14 days. Control rats received continuously infused Ringer's solution. Urea-treated groups developed osmotic diuresis (urine flow = about 0.04 ml · min ^–1 · 100 g body weight^–1) comparable to that in rats with experimental diabetes mellitus induced by i. v. streptozotocin (55 mg/kg), however urea-induced osmotic diuresis was not associated with blood glucose level increases. Compared with their controls, rats receiving urea for 2–14 days had markedly increased kidney weight. Rats receiving urea for 10 days showed greatest kidney weight increase, 0.565 ± 0.044 g/100 g body weight (mean ± SD), representing a 53% increase compared with the control (0.369 ± 0.034 g/100 g body weight). Kidney weight was associated with increases in kidney protein content. In contrast, none of control kidney weight values differed significantly from day 0 values (=normal rats; 0.387 ± 0.028 g/100 g body weight). Creatinine clearance values in urea-treated groups were also higher than those in controls. The maximum value, 0.65 ± 0.17.ml · min^–1 · 100 g body weight^–1, was recorded in the 14-day group and was significantly higher than the corresponding control value (0.34 ± 0.07 ml · min^–1 · 100 g body weight^–1) (p <0.001). Urea clearance values were also significantly higher in urea-treated groups than in respective controls. This study suggests that osmotic diuresis may induce renal hypertrophy/hyperplasia and glomerular hyperfiltration immediately after development of diabetes.Abbreviations DM Diabetes mellitus - ID inner diameter - OD outer diameter     

The effects of ventilation with positive end-expiratory pressure on the bronchial circulation

We studied the effects of ventilation with 10 cm H2O PEEP for 2 h in dogs with temporary unilateral pulmonary arterial occlusion (TUPAO) on bronchial blood flow to the occluded lung using the microsphere dispersion technique. We found that blood flow to the occluded left lung in dogs was 9.9 ml/min (0.122 ml X min-1 X g-1). Within 30 min following the addition of 10 cm H2O PEEP blood flow fell by 70-80% (to 2.3 ml/min) caused both by a 3-fold decrease in vascular conductance and a 25% fall in systemic blood pressure. The reduction in left bronchial blood flow persisted for at least 2 h. We conclude from these data that ventilation with PEEP in the presence of pulmonary artery occlusion has a severe, persistent adverse effect on bronchial blood flow. This reduction in bronchial blood flow is beyond what can be explained by the changes in airway pressure. The additional increase in bronchial vascular resistance may be caused by the increase in lung volume, by reflex bronchial vasoconstriction, or by release of mediators locally.     

Cardiac tamponade in dogs with normal coronary arteries. II. Myocardial flow and metabolism with moderate and severe hemodynamic impairment

Summary To determine the effects of cardiac tamponade on myocardial blood flow and its distribution, dogs were prepared with indwelling pericardial catheters. Hemodynamic, myocardial blood flow, and myocardial metabolic data were collected in 5 closed-chest, spontaneously breathing animals with normal blood volumes and hemoglobin concentrations and 6 with acute anemia. Instillation of an average of 89.0±14.9 ml of modified Normosol® into the pericardial space in dogs with normal hemoglobin levels produced mild tamponade with a modest decline in aortic pressure (119.5±14.3 to 96.8±12.1 mm Hg) and significant rises in left and right atrial and pericardial pressures to 7–8 mm Hg. Increasing the pericardial volume to 124.0±13.6 ml produced hypotension (mean aortic pressure 86.2±10.5 mm Hg) and rises in the left and right ventricular filling pressures and pericardial pressure to 10–11 mm Hg. Total myocardial blood flow fell from 1.19±0.18 to 0.73±0.17 ml/min/g (p<0.02) during mild tamponade, and fell further to 0.56±0.17 ml/min/g (p<0.05) with more severe tamponade. Despite these declines, the left ventricular wall inner/outer flow ratio and left ventricular flow as a proportion of total cardiac output were unchanged. In dogs with anemia more severe tamponade was created, with consequently more marked hemodynamic abnormalities. However, the relative changes in myocardial blood flow and inner/outer flow ratio were similar. Myocardial metabolic parameters could be evaluated only in the dogs with less severe tamponade. The coronary arteriovenous oxygen difference changed little during induced tamponade, and, therefore, quantitated myocardial oxygen consumption declined in proportion to the fall in myocardial flow. Furthermore, myocardial lactate extraction and the lactate/pyruvate ratio were not affected by cardiac tamponade. Thus, these experiments cannot support the hypothesis that myocardial ischemia is a pathophysiologic factor in the production of abnormal hemodynamics in cardiac tamponade.Dr. Cohen is the recipient of a Research Career Development Award from the National Heart, Lung and Blood Institute Grant HL-00281.This study was supported in part by National Heart, Lung and Blood Institute Grant HL-17809.     

New chronic pancreatitis model with diabetes induced by cerulein plus stress in rats

To establish a new experimental model of chronic pancreatitis (CP) with diabetes, we investigated pancreatic endocrine function, blood flow, and histopathology in CP induced by repetition of cerulein injection plus water immersion stress in rats. CP rats were treated with water immersion stress for 5 hr and two intraperitoneal injections of 20g/kg body weight of cerulein once a week for 16 weeks. In the CP group, pancreatic contents of protein, amylase, elastase, and lipase significantly decreased to 64, 38, 23, and 68% of the control group, respectively. In oral glucose tolerance test (glucose 2 g/kg body wt), blood glucose level in the CP group was 212.1±97.8 mg/dl (mean±sd) at 30 min and was significantly higher than the control group (126.3±15.4 mg/dl) (P<0.05). Two of seven rats in the CP group showed an obvious diabetic pattern with a blood glucose level over 200 mg/dl at 120 min. The basal level of serum insulin in the CP group was 640.1±148.7 pM, significantly lower than in the control group (1133.4±242.0 pM) (P<0.001). However, insulin content in the pancreas was 12.37±1.72 nmol/pancreas and was preserved compared with the control group (10.24±1.94 nmol/pancreas). In CP rats, winding and dilatation of surface blood vessels and gland atrophy were evident. Marked fibrosis, fatty changes, and destruction of lobular architecture were also demonstrated microscopically, although the structure of each pancreatic islet was preserved and each islet was fully stained with anti-insulin antibody. In the CP group, pancreatic blood flow by the hydrogen gas-clearance method was 197.6±33.0 ml/min/100 g, which was significantly less than the control group (276.2±19.1 ml/min/100 g) (P<0.001). Thus, we conclude that the CP model induced by cerulein plus stress is a new CP model with diabetes in rats, in which the glucose tolerance was impaired without loss of insulin reserve.     

The effects of enoximone (MDL-17043) on forearm venous circulation in healthy volunteers and patients with heart failure

Summary The effect of intravenous enoximone on forearm venous circulation was studied in ten healthy volunteers (group A) and in ten patients with NYHA class III–IV congestive heart failure (group B). Distensibility of the forearm capacitance vessels was assessed from pressure-volume curves by venous occlusion plethysmography using a mercury-in-rubber strain gauge. Three recordings each at 3-min intervals were obtained before the infusion and again 20 min after completion of the infusion. Venous volume changes (VV) at congesting pressures of 10, 20, and 30 mmHg before and after enoximone were compared. Forearm muscle blood flow was also measured by venous occlusion plethysmography; electrocardiogram, heart rate, and cuff blood pressure were recorded throughout. Enoximone at a dose of 1 mg/kg body weight was infused over 10 min through a peripheral vein in group A and via a central line in group B. In group A, the effect of the injection vehicle was also assessed.VV₁₀, VV₂₀, and VV₃₀ did not differ from baseline values after enoximone in both groups A and B. The vehicle caused a small but significant degree of venoconstriction in group A (VV₂₀, 2.64±0.9 to 2.48±0.83 ml/100 ml,P<0.05; VV₃₀, 3.47±1.27 to 3.33±1.20 ml/100 ml,P<0.05), which could be explained by an acute response to local pain from the infusion. This effect was not evident following enoximone, perhaps as a result of its counterbalancing vasodilating action to venoconstriction induced by acute pain. Muscle blood flow increased in both groups (group A, 3.05±0.33 to 4.62±1.32 ml/100 ml/min,P<0.01; group B, 2.33±0.93 to 3.13±0.95 ml/100 ml/min,P<0.02) after enoximone and did not change in group A after vehicle (3.08±1.50 to 2.73±0.87,P—not significant).It is concluded that enoximone at the dose studied does not exert appreciable effects on the forearm venous system in normal subjects or in patients with heart failure.     

Effect of vasopressin on phasic coronary blood flow

Summary The effects of vasopressin on the coronary circulation have been studied with regard to its general hemodynamic effects. Aortic blood pressure (BP), left ventricular pressure (LVP), aortic blood flow (AoBF), and circumflex blood flow (CBF), were measured in 12 open-chest dogs, under control conditions and during vasopressin infusion (25 mU/kg/min). During vasopressin infusion, the mean aortic blood pressure (MBP) was increased from 104±23 mm Hg to 161±23 mm Hg. The diastolic blood pressure (DBP) was more increased (+55%) than the systolic blood pressure (SBP) (+40%). AoBF was decreased from 2.169±0.408 l/min to 1.118±0.303 l/min; and the heart rate was decreased by 18%. The total combined left ventricular power did not change significantly. The increase in total peripheral resistance (TPR) (+200%) was the main change in impedance spectrum. The mean circumflex coronary blood flow (MCBF) was decreased from 48±8.6 ml/min to 33.4±9.7 ml/min. This decrease was more important in the diastolic circumflex blood flow (DCBF) (–33%) than in the systolic one (–0.8%). The diastolic pressure time index (DPTI) was more increased than the systolic pressure time index (SPTI). The DPTI/SPTI ratio was increased from 0.91 to 1.3.Long diastoles, induced by vagus nerve stimulation, have permitted to characterise the relationship between pressure and coronary blood flow during diastole. This relationship was linear under basal condition, and during vasopressin perfusion. This made it possible to determine the critical closing pressure (Pf0), and the coronary conductance (the slope of the regression curve). Vasopressin induced an increase in Pf0, from 33.7±95 to 77.4±16.07 mm Hg (p<0.001), and a decrease in coronary conductance, from 0.8±0.32 to 0.5±0.1 ml/min/mm Hg. The effect of an acute change in perfusion pressure on the coronary flow, under control conditions and during vasopressin infusion was studied by opening a large arteriovenous fistula. Unclamping of the fistula, under control conditions, allowed to realize an acute fall in DBP from 82.5±6.36 to 35.5±9.19 mm Hg, and in DCBF, from 58.5±9.2 to 20±9.8 ml/min. During vasopressin infusion, a similar fall in perfusion pressure lead to a zero diastolic circumflex blood flow, for a diastolic aortic blood pressure of 56±12 mm Hg. However, vasopressin did not affect the delayed active coronary vasodilatation.     

Noninvasive measurement of portal venous blood flow in patients with cirrhosis

The present study aims to evaluate the usefulness of combined pulse Doppler-real-time ultrasonography as a noninvasive method for the measurement of portal blood flow in man. This measurement technique was performed on 12 healthy subjects and 20 patients with portal hypertension. Ten patients (group 1) were evaluated prior to and after ingestion of a standard meal (Ensure Plus) or placebo. In the remaining 10 patients (group 2), the effects of isosorbide dinitrate (5 mg/SL) administration or placebo were studied. In group 1, food intake caused a significant increase of portal blood flow (from 1038±539 to 1572±759 ml/min,P<0.02); this effect was due to a significant rise in mean blood velocity (from 18.5±3.7 to 23.9±3.9 cm/sec,P<0.02). In group 2, isosorbide dinitrate significantly reduced portal blood flow (from 985±491 to 625±355 ml/min,P<0.05); a significant decline of mean blood velocity (from 18.8 ±4.5 to 14.5±2.5 cm/sec,P<0.02) was observed. Placebo administration had no significant hemodynamic effects in either group. Our results suggest that Doppler measurements gave accurate noninvasive estimations of portal blood flow and that this technique may be used to monitor physiological and pharmological stimuli in patients with portal hypertension.     

Effects of Prostaglandin E1 Infusion on Limb Hemodynamics and Vasodilatory Response in Patients with Arteriosclerosis Obliterans

It is well known that prostaglandin E1 (PGE1>) increases peripheral blood flow. The aim of this study was to investigate the effects of PGE1 infusion on the hemodynamics and vasodilatory response of the leg affected by intermittent claudication in patients with arteriosclerosis obliterans (ASO). Fourteen legs of 8 male patients with ASO were infused intravenously with PGE1 (120 µg/day) for 7 consecutive days. Before the infusion and 5 days after cessation of the infusion, resting skin and skeletal muscle blood flow in the calf and occlusion-induced reactive hyperemic flow were measured using plethysmography and a laser Doppler flowmeter. Clinical symptoms in the legs were assessed by treadmill exercise testing. Resting calf blood flow was found to have increased significantly (skin, from 2.6 ± 0.1 ml/min/100 g tissue to 2.9 ± 0.1 ml/min/100 g tissue, p > 0.02; skeletal muscle, from 3.1 ± 0.2 ml/min/dl tissue to 4.0 ± 0.5 ml/min/dl tissue, p > 0.02). There was also a significant reduction in the peripheral vascular resistance (–17.8 ± 7.2%, p > 0.05) 5 days after the cessation of infusion. The time to the half-maximum post peak of hyperemia was significantly elongated (from 34.6 ± 5.7 sec to 58.6 ± 9.2 sec, p > 0.01). Borg's score of the legs on exercise testing was markedly reduced, and symptom-free walking distance was increased by an average of 70.9 ± 15.6%. In conclusion, PGE1 infusion has vascular effects on not only resting calf blood flow but also hyperemic flow responses. These retentive effects may be due to alteration in vascular functions and/or rheological state as a result of PGE1-induced regular enhancement of blood flow, rather than the direct vasodilatory effect of the agent.