Effects of transjugular intrahepatic portasystemic shunt (TIPS) on splanchnic and systemic hemodynamics,and hepatic function in patients with portal hypertension

The purpose of this study was to evaluate the short-term splanchnic and systemic hemodynamics and hepatic function after TIPS creation. Fifteen cirrhotics with portal hypertension underwent TIPS placement for treatment of variceal hemorrhage, and extensive hemodynamic studies including right heart catheterization, portal pressure measurement, hepatic blood flow, and indocyanine green (ICG) clearance were performed before and 1 month after the procedure. Self-expandable metal stents (Strecker 11 mm diameter) were placed in all cases. Portasystemic gradient significantly diminished (18.3±4.2 vs 8±2.8; 54%±18 mm Hg) after the technique, mainly due to a decrease in portal pressure, and remained stable in the final study. Cardiac output and mean arterial pressure increased (6.2±1.4 vs 8.2±1.8 liters/min, 80.1±10.1 vs 91±11.2 mm Hg, respectively), and a decrease in systemic vascular resistance was registered (1018±211 vs 872±168 dyne/sec/cm⁵); the hepatic blood flow and ICG clearance also decreased significantly (1.5±0.7 vs 0.68±0.2 liters/min, 0.4±0.2 vs 0.24 ±0.06 liters/min, respectively). There was an increase in the preload at the final study, as evidenced by a marked increase in right atrial (3.1±1.6 vs 4.35±2.2 mm Hg, +15%,P<0.05), pulmonary arterial (12.2±2.4 vs 15.9±3.2 mm hg, +31.8%,P<0.001), and wedge pulmonary arterial pressures (6.9±2.4 vs 9.8±3.1 mm Hg, +53%,P<0.001). These results suggest that TIPS worsens the hyperdynamic syndrome associated to portal hypertension. Therefore, in patients with cardiac insufficiency, this procedure should be evaluated. TIPS also decreases the hepatic blood flow, inducing a mild worsening in liver function.Funded in part by the Fondo de Investigaciones Sanitarias de la Seguridad Social, grant 94/0240.     

Adenylate cyclase activation promotes the recruitment of coronary vasodilator reserve and improves subendocardial contractility during coronary hypoperfusion

Summary This study was designed to examine the effects of an adenylate cyclase activator, NKH477, on epicardial and endocardial contraction and coronary blood flow (CoF) in the presence or absence of ischemia and to compare it to those of adenosine. We measured coronary pressures (CoP), coronary blood flow, epicardial and endocardial wall thickening (i.e., %EPWT and %ENWT, respectively, by sonomicrometry) in 18 anesthetized dogs. The left circumflex coronary artery was perfused with arterial blood using a pressure controlled servo pump. Propranolol (0.5 mg/kg) and atropine (0.25 mg) were used to minimize the neurogenic effects. CoP decreased from 100 mm Hg to 40 mm Hg with and without drugs. At CoP of 100 mm Hg, intracoronary infusion of NKH477 (10^–8 M/kg/min) produced a two-fold increase in CoF, but there were no changes in either the %EPWT or the %ENWT. During coronary hypofusion at coronary pressures equal to 40 mm Hg, NKH477 increased CoF from 16±2 to 28±4 mL/min (p<0.05) and improved %ENWT significantly from 6±7 to 23±7% (p<0.05). However %EPWT was not improved by NKH477. On the other hand, the intracoronary infusion of adenosine (10 g/kg/min) increased CoF from 16±5 to 21±6 mL/min (p<0.05) at CoP of 40 mm Hg. However, this dose of adenosine failed to improve %ENWT (16±10% vs. 14±10%, n.s.). Thus, the improvement of subendocardial function by NKH477 might be related to the improvement of subendocardial perfusion which could be induced by the potentiation of endogenously released adenosine as well as the direct vasodilator effect. This contrasts with the effects of exogenously administered adenosine, which failed to improve subendocardial contractility.     

Changes of Colonic Mucosal Microcirculation and Histology in Two Colitis Models: An Experimental Study Using Intravital Microscopy and a New Histological Scoring System

This study investigated capillary blood flow (CBF) and pathomorphological alterations in the mucosa of different bowel segments at different times after disease onset in rats with colitis induced by either trinitrobenzensulfonic acid (TNBS) or mitomycin-C. CBF was determined by intravital microscopy using fluorescein-labeled erythrocytes. The histological degree of inflammation was assessed by a new scoring system. Severe acute histological changes were found in the distal colon 24 hr after induction of TNBS colitis (score: 8.9 ± 1.0). CBF was increased (2.9 ± 0.05 vs. 2.6 ± 0.04 nl/min in healthy controls). The histological alterations persisted until day 3 (8.5 ± 0.9) when CBF significantly decreased (1.8 ± 0.05 nl/min). After 15 days, moderate acute inflammation was still detectable histologically (5.4 ± 1.3), but CBF had returned to normal values. In mitomycin-C colitis, changes developed mainly in the proximal colon: After three days, there was mild inflammation (2.8 ± 1.2) with normal CBF (2.5 ± 0.1 nl/min). After seven days, the inflammation had increased (4.8 ± 1.1), while CBF had decreased (1.5 ± 0.06 nl/min). These changes persisted for six weeks (5.3 ± 0.7; 1.2 ± 0.05 nl/min). These data suggest that disturbed colonic microcirculation may play an important role in the pathogenesis of inflammatory bowel disease regardless of the histopathomorphological alterations.     

Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina

OBJECTIVES: We designed a study to explore the effect of glycoprotein (GP) IIb/IIIa blockade on the atherosclerotic plaque and distal coronary vasculature. BACKGROUND: Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined. METHODS: Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty. RESULTS: Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 +/- 16.9 vs. 6.1 +/- 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 +/- 7.5 vs. 6.8 +/- 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 +/- 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 +/- 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 +/- 3.0 vs. 4.3 +/- 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration. CONCLUSIONS: These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.     

Reduced myocardial blood flow resulting from dynamic changes in coronary artery stenosis

To evaluate the interaction of coronary vasomotor tone and stenosis, we studied the effects of ergonovine and adenosine on partially obstructed coronary arteries in 6 closed chest dogs. Coronary stenosis was created by partially inflating a balloon catheter with a distal lumen in the left anterior descending or circumflex coronary artery. Stenotic resistance was calculated as the mean pressure gradient across the stenosis divided by the mean blood flow measured with 15 micron radioactive microspheres. Coronary artery vasoconstriction, induced by ergonovine (0.6 mg i.v.), caused a small, but nonsignificant, increase in stenotic resistance (1.42 ± 0.25 to 2.68 ± 0.64 mm Hg/ml per min) and had no effect on myocardial blood flow. Coronary arteriolar dilation induced by adenosine increased stenotic resistance (1.52 ± 0.25 to 9.01 ± 2.49 mm Hg/ml per min, P < 0.05) and the pressure gradient across the stenosis (18.8 ± 3.0 to 41.3 ± 7.5 mm Hg, P < 0.05). Adenosine increased myocardial blood flow from 0.52 ± 0.05 ml/min per g to 1.43 ± 0.20 ml/min per g (P < 0.05) in the regions supplied by unstenosed arteries, while in the region perfused by the stenosed artery blood flow fell from 0.51 ± 0.06 to 0.29 ± 0.13 ml/min per g (P < 0.05), with the endocardium most severely affected (0.55 ± 0.04 ml/min per g to 0.26 ± 0.09 ml/min per g, P < 0.05).Thus changes in severity of stenosis produced by altered coronary pressure and flow can influence blood flow to the myocardium. Such dynamic changes in coronary artery stenosis may be important in the pathogenesis of angina and myocardial infarction.     

Response of canine ileocolonic sphincter to intraluminal acetic acid and colonic distension

The aim was to determine the effect of intraluminal acetic acid and proximal colonic distension on canine ileocolonic sphincter pressure, ileal motility, and coloileal reflux. In six conscious dogs with an isolated ileocolonic loop, basal pressure of the ileocolonic sphincter was similar during ileal perfusion with 100 mM acetic acid at 1 ml/min (mean±sem=18±0.4 mm Hg) and with saline (18±0.5 mm Hg;P=0.81). Discrete clustered ileal contractions were more frequent with acetic acid, however, and when they propagated across the sphincter, sphincter pressure increased from 18±0.4 mm Hg to 36±1.3 mm Hg (P=0.002). Sphincter pressure was also greater during colonic perfusion with acetic acid (32±0.7 mm Hg) than during ileal perfusion with acetic acid or saline (P<0.017). Moreover, sphincter pressure gradually increased as the colon was distended with saline (slope=0.8 mm Hg/cm H₂O,P<0.017) or acetic acid (slope=0.5 mm Hg/cm H₂O,P<0.017), but the increase did not prevent coloileal reflux. In conclusion, ileal clustered contractions, colonic perfusion of acetic acid, and colonic distension all increased canine ileocolonic sphincter pressure.     

Effect of Viscous Fiber (Guar) on Postprandial Motor Activity in Human Small Bowel

Both caloric value and chemical composition ofa meal have been shown to regulate postprandial smallbowel motility in dog. In the same species, duration ofand contractile activity within the postprandial period also depends on mean viscosity. It isunknown, however, whether meal viscosity and fibercontent also regulate small bowel motor activity in man.In human volunteers, we therefore studied the effect of guar gum on small bowel motor response toliquid and solid meals. Twenty-six prolonged ambulatorysmall bowel manometry studies were performed in 12volunteers. A total of 620 hr of recording were analyzed visually for phase III of the MMC and avalidated computer program calculated the incidence andamplitude of contractions after ingestion of water (300ml), a pure glucose drink (300 ml/330 kcal) or a solid meal (530 kcal) with and without 5 g of guargum. Addition of 5 g of guar gum did not significantlydelay reappearance of phase III after ingestion of water(59 ± 11 vs 106 ± 21 min; P = 0.09).However, guar gum significantly prolonged duration ofpostprandial motility pattern both after the glucosedrink (123 ± 19 vs 199 ± 24 min; P <0.05) and after the solid meal (310 ± 92 vs 419± 22 min; P = 0.005). Contractile activity during these periods was not affected by guargum. This was true for mean incidence of contractionsafter water (1.9 ± 0.3 vs 1.8 ± 0.5min^-1), after the glucose drink (1.6 ±0.4 vs 1.7 ± 0.3 min^-1) and after the solid meal (2.4 ± 0.4 vs 2.6 ±0.4 min^-1). Likewise, mean amplitude ofcontractions was not affected by guar gum after water(22.8 ± 1.4 vs 20.9 ± 1.9 mm Hg), afterthe glucose drink (20.5 ± 1.4 vs 21.3 ±1.2), and after the solid meal (20.3 ± 1.5 vs 21.5± 1.6 mm Hg). Thus a guar gum-induced increase inchyme viscosity markedly prolonged duration ofpostprandial motor activity in the human small bowel.Contractile activity within the postprandial period, however, wasnot affected. We suggest that the postprandial motilitypattern persisted longer after the more viscous meals,because gastric emptying and intestinal transit were delayed by guar gum. We conclude that itis essential to define meal viscosity and fiber contentwhen studying postprandial small bowelmotility.     

Absorption and motility of the bypassed human ileum

The authors assessed absorption and motility of the human ileum after a prolonged period of disuse. In eight patients with ulcerative colitis, a manometric-catheter assembly was placed via the ileostomy into the unused portion of distal ileum two months after ileal pouch-anal anastomosis and temporary diverting loop ileostomy. The distal ileum was perfused at 5 ml/min with an isosmotic solution of either sodium chloride or ileal chyme diluted with sodium chloride for three hours before and three hours after a meal on two consecutive days. Absorption was measured, single and clustered pressure waves were identified and quantitated with the aid of a computer program, and a motility index was calculated. Mean absorption ± S.E.M. of both perfusates was poor on day 1 (–10±2 ml/25 cm × 30 min), and the meal induced no ileal motor response. By day 2, however, absorption of both perfusates was much improved (–1±2 ml/25 cm × 30 min; P<0.05), and the number of discrete clustered contractions and the motility index now clearly increased after the meal (2.6±0.6 vs. 7.2±1.0 clustered waves/hr; 7.5±0.5 vs. 9.7±0.2 motility units/30 min;P<0.05).The conclusion was that absorption and motility of the human ileum were impaired after two months of disuse, but that ileal absorption and motility improved one day after the introduction of isosmotic ileal perfusates.Supported in part by USPHS NIH Grants DK34988, DK18278 and DK07198, and the Mayo Foundation.     

Dopaminergic Control of Renal Tubular Function in Patients with Compensated Cirrhosis

In normal humans, plasma dopamine levels rise during head-out water immersion or saline intravenous infusion. Dopamine inhibits NA⁺,K⁺-ATPase activity in the proximal tubule and blunts aldosterone secretion leading to increased diuresis and natriuresis. The aim of this study is to evaluate the role of endogenous dopaminergic activity in the intrarenal sodium handling in patients with compensated liver cirrhosis. We studied nine healthy controls and 12 patients with Child-Pugh A cirrhosis during a normosodic diet for (1) dopaminergic activity, as measured by the incremental aldosterone responses 30 and 60 min after intravenous metoclopramide administration; (2) basal plasma levels of active renin and aldosterone; (3) 4-hr renal clearance of lithium (an index of fluid delivery to the distal tubule), creatinine, sodium, and potassium, first without and then with dopaminergic blockade with intravenous metoclopramide. The patients displayed greater endogenous dopaminergic activity, evidenced by higher incremental aldosterone responses compared with controls (+30 min: 160.2 ± 68.8 vs 83.6 ± 35.2 pg/ml, P < 0.01; +60 min: 140.5 ± 80.3 vs 36.8 ± 39.1 pg/ml, P < 0.01, respectively). In spite of this, patients and controls did not show significantly different basal aldosterone plasma levels, delivery of sodium to the distal nephron, or urinary excretion of sodium. In both groups the dopaminergic blockade with metoclopramide determined no change in sodium and potassium urinary excretion, but it caused a fall of the fluid and sodium delivery from the proximal tubule to the distal nephron among the patients (from 30.7 ± 9.3 to 14.4 ± 4.5 ml/min, P < 0.001; and from 4.25 ± 1.30 to 2.00 ± 0.64 meq/min, P < 0.001, respectively). In this group the natriuresis was maintained due to a reduction of the reabsorbed fraction of the distal sodium delivery (from 97.5 ± 1.9% to 89.8 ± 12.4%, P < 0.05). In conclusions, compensated cirrhotic patients display an increased endogenous dopaminergic activity compared with controls. This function is critical in maintaining the delivery of sodium to the distal nephron.     

A potential role for angiotensin II in obesity induced cardiac hypertrophy and ischaemic/reperfusion injury

Background The mechanisms for obesity induced myocardial remodelling and subsequent mechanical dysfunction are poorly understood. There is good evidence that angiotensin II and TNFα have strong growth promoting properties and are elevated with obesity. In addition, these two peptides may interact to exacerbate myocardial ischaemic/reperfusion injury.Hypothesis Obesity increases systemic and myocardial renin–angiotensin system (RAS) activity and TNFα levels and contributes to obesity induced cardiac remodelling and ischaemic/reperfusion injury.Methods Male Wistar rats were placed on a standard rat chow diet or cafeteria diet for 16 weeks. Two additional groups of rats received the respective diets and losartan (30 mg/ kg/d) in their drinking water. Hearts were perfused on the isolated working rat heart perfusion system and mechanical function was documented before and after 15 min normothermic total global ischaemia. Blood and myocardial samples were collected for angiotensin II, TNFα and NADPH oxidase activity determinations.Results The rats on the cafeteria diet became obese compared to rats on the standard rat chow (438 ± 5.9 g vs 393 ± 7.3 g for control, p < 0.05). Obesity was associated with elevated serum angiotensin II (0.050 ± 0.015 pmol/ml vs. 0.035 ± 0.003 pmol/ml, p < 0.05) and TNFα levels (42.8 ± 5.93 pg/ml vs. 13.18 ± 2.50 pg/ml, p < 0.05), and increased heart to body weight ratios (3.1 ± 0.04 mg/g vs. 2.8 ± 0.03 mg/g, p < 0.05). Losartan had no effect on body weight but decreased basal myocardial angiotensin II and TNFΑ levels as well as heart to body weight ratio in the obese and lean controls (2.5 ± 0.05 mg/g and 2.6 ± 0.04 mg/g relative to their controls, p < 0.05). Hearts from obese rats had lower reperfusion aortic outputs (AO) than their concurrent controls (18.42 ± 1.17 ml/min vs. 27.8 ± 0.83 ml/min, p < 0.05). Losartan improved aortic output recoveries in obese rats (23.0 ± 1.71 ml/min, p < 0.05).Conclusions Obesity increased serum angiotensin II and TNFα levels, blood pressure, and heart weight to body weight ratios. These changes were associated with decreased basal and post–ischaemic myocardial mechanical function. Chronic AT₁ receptor antagonism prevented the adverse changes in heart weight, mechanical function and susceptibility to ischaemic/reperfusion injury. Although current data do not exclude additional mechanisms for obesity induced cardiac remodelling, they suggest that angiotensin II may contribute to obesity induced cardiac remodelling and ischaemic/reperfusion injury.     

Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation

The active form of vitamin D, 1,25-dihydroxyvitamin D3, [1,25(OH)2D3] has potent actions on innate and adaptive immunity. Although endocrine synthesis of 1,25(OH)2D3 takes place in the kidney, the enzyme that catalyzes this, 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27b1 in humans, Cyp27b1 in mice), is expressed at many extra-renal sites including the colon. We have shown previously that colonic expression of CYP27b1 may act to protect against the onset of colitis. To investigate this further, we firstly characterized changes in Cyp27b1 expression in a mouse model of colitis. Mice treated with dextran sodium sulfate (DSS) showed weight loss, histological evidence of colitis, and increased expression of inflammatory cytokines. This was associated with decreased renal expression of Cyp27b1 (5-fold, P=0.013) and lower serum 1,25(OH)2D3 (51.8+/-5.9 pg/nl vs. 65.1+/-1.6 in controls, P<0.001). However, expression of CYP27b1 was increased in the proximal colon of DSS mice (4-fold compared with controls, P<0.001). Further studies were carried out using Cyp27b1 null (-/-) mice. Compared with+/-controls the Cyp27b1-/-mice showed increased weight loss (4.9% vs. 22.8%, P<0.001) and colitis. This was associated with raised IL-1 in the distal colon and IL-17 in the proximal and distal colon. Conversely, DSS-treated Cyp27b1-/-mice exhibited lower IL-10 in the proximal colon and toll-like receptors 2 and 4 in the distal colon. These data indicate that both local and endocrine synthesis of 1,25(OH)2D3 affect colitis in DSS-treated mice. Lack of Cyp27b1 exacerbates disease in this model, suggesting that similar effects may occur with vitamin D deficiency.     

Lactulose Feeding in Piglets (A Model for Persistent Diarrhea and Colitis Induced by Severe Sugar Malabsorption)

We sought to determine, in a piglet model,whether severe sugar malabsorption causes colonic injuryor inflammation. Twenty-four piglets were randomized toreceive either control formula (CON) or CON supplemented with lactulose (LAC) (N = 12 each group). Afterseven days, inflammation, apoptosis, and crypt cellproliferation were assessed in the proximal colon(cecum). Lactulose feeding caused persistent diarrhea. In both groups, breath H₂concentration was low, suggesting no increasedfermentation in the LAC group. Weight gain/volumeformula intake was identical in the CON and LAC groups(0.09 ± 0.13 and 0.09 ± 0.11 g/ml) respectively. Injury to thecolon did not occur, but inflammation of the colon(scale 0-5) was greater in LAC (score of 1.5 ±1.38) than in CON (0.42 ± 0.79; P < 0.05).Cell proliferation at the basal 40% of the crypt was 92% increasedin CON (labeling index 22.8 ± 9.9 vs 11.9± 2.8; P < 0.05). We conclude that persistentfeeding during severe sugar malabsorption permits weightgain but may cause colitis.     

SR140333, a Substance P Receptor Antagonist, Influences Morphological and Motor Changes in Rat Experimental Colitis

The etiology of inflammation, edema, and smoothmuscle contraction characteristic of inflammatory boweldisease is not clearly understood. There is evidencethat several neuropeptides, including substance P (SP), may play a role. In this study weevaluated the ability of a SP-antagonist (SR140333) tomodify the course of experimental colitis induced in therat by trinitrobenzene sulfonic acid (TNB). Colitis was induced in 24 rats using TNB applied byintrarectal enema. Twelve TNB-treated rats receivedSR140333, 0.1 mg/kg intraperitoneally, 30 min before theadministration of TNB and every 48 hr until death. Twelve rats receiving only intrarectal 0.9%saline served as controls. Rats of each group werekilled after 14 days. At day 14, the control groupshowed no signs of inflammation whereas the TNB-treated rats without SR140333 treatment exhibited awell-established colitis. The TNB-treated group had ahigher level of inflammation, as seen histologically andby the significantly greater weight of colon strips, compared to the controls (0.30 ± 0.09 gvs 0.13 ± 0.03 g, P < 0.001) and to theSR140333-treated rats (0.30 ± 0.09 g vs 0.14± 0.05 g, P < 0.001). In addition, smoothmuscle contractility was significantly reduced in the inflamedcolons of TNB-treated rats when compared with thecontrols (carbachol: 42.7 ± 20.3 vs 254.2± 69.78 mg/mm²± 10.02 vs 89.45± 23.17 mg/mm² 11.4 ± 2.2 vs 98.32 ± 33.57mg/mm²1). However, SR140333-treated ratsshowed a recovery from inflammation and motoralterations caused by TNB (carbachol: 150.9 ±46.1 mg/mm²1; SP: 32.5 ± 9.4 mg/mm²5; KCl:125.7 ± 36.1 mg/mm²1). In conclusion,treatment with SP antagonist SR140333 reduces theseverity of colitis and has beneficial effects on theconcomitant alterations of contractility. Thus, theblockade of substance P may represent a possibility inthe treatment of intestinal inflammation.     

Attenuation of the systemic and coronary hemodynamic effects of cocaine in conscious dogs: propranolol versus labetalol

Summary The interaction of cocaine with myocardial and vascular adrenoceptors is incompletely understood. The systemic and coronary hemodynamic effects of intravenous cocaine (1.5 mg/kg) were examined in dogs with and without pretreatment with propranolol (2 mg/kg i.v.) or labelatol (5 mg/kg i.v.) on different days. A total of 24 experiments was completed (three sets of experiments) using eight dogs chronically instrumented for measurement of aortic and left-ventricular pressure, left-ventricular dP/dt, subendocardial segment length, coronary blood flow, and cardiac output. Myocardial oxygen consumption was estimated from the pressure work index (PWI). Cocaine significantly (p<0.05) increased heart rate (+51±17 bpm), mean arterial pressure (+72±10 mm Hg), left-ventricular systolic and end-diastolic pressures (+56±9 and +14±6 mm Hg, respectively), coronary blood flow (+32±10 ml/min) and the PWI (+10.0±2.3 ml O₂/min/100 g). Significant reductions in stroke volume (–9±5 ml) and percent segment shortening (–7.1±1.7) were observed. These changes returned to control after 30 min. After pretreatment with propranolol, the cocaine-mediated increases in mean arterial pressure, left-ventricular systolic pressure, rate-pressure product, and the pressure work index (4.4±0.7 ml O₂/min/100 g) were significantly (p<0.05) less than those observed with cocaine alone. Cocaine also reduced contractility [dP/dt₅₀ (–341±80 mm Hg/s)] and increased systemic vascular resistance (+2703±339 dyn·s·cm^–5) in the resence of propranolol. Labetalol abolished the cocainemediated increases in heart rate and coronary blood flow and significantly attenuated the increases in mean arterial pressure, left-ventricular systolic pressure, cardiac output, rate-pressure product, and calculated myocardial oxygen consumption when compared to results obtained with cocaine alone. The results demonstrate that a portion of the basic dynamic effects of cocaine is mediated by stimulation of alpha and beta adrenoceptors. Combined alpha and beta adrenergic blockade reduces the hemodynamic effects of cocaine more than beta blockade alone. During antagonism of the sympathomimetic response of cocaine, direct negative inotropic actions of this drug are unmasked.This work was supported by US PHS grants HL 36144 and HL 32911, Anesthesiology Research Training Grant GM 08377, and VA Medical Research Funds.     

PMN-elastase in assessment of patients with inflammatory bowel disease

PMN-elastase is a proteinase released by activated neutrophils. PMN-elastase was determined in two independent populations with inflammatory bowel disease. In an unselected population of 70 consecutive patients with Crohn's disease and 24 patients with ulcerative colitis with different degrees of disease activity plasma PMN-elastase levels were statistically significantly higher in patients with active than in patients with inactive disease [Crohn's disease: 80.5±33.2 ng/ml vs 60.1±24.6 ng/ml (means±sd),P=0.0017; ulcerative colitis: 98.2±54.9 ng/ml vs 59.2±16.8 ng/ml,P=0.026]. PMN-elastase levels in feces were also higher in patients with active Crohn's disease (23.6±15.3 ng/g vs 13.6±12.5 ng/g,P=0.0021) and active ulcerative colitis (46.5±60.5 ng/g vs 20.2±25.0 ng/g,P=0.46), but the difference reached significance only in Crohn's disease. Correlation of disease activity and PMN-elastase in individual patients showed a statistically significant correlation between plasma and fecal elastase concentrations and disease activity in ulcerative colitis (plasma:r=0.72,P<0.001; feces:r=0.423,P<0.001) but not fecal elastase concentrations (r=0.0083,P=0.485) correlated significantly with disease activity. Plasma PMN-elastase correlated weakly with fecal PMN-elastase levels in Crohn's disease (r=0.431,P<0.01) and in ulcerative colitis (r=0.515,P=0.05). In 28 patients with highly active Crohn's disease [median severity activity index (SAI) 203] and 11 patients with highly active ulcerative colitis [median Rachmilewitz index (RI) 14] studied before and four weeks after steroid therapy, treatment lowered the median SAI to 140 and the median RI to 4.5. Mean plasma elastase concentrations decreased concomitantly from 83±44.9 ng/ml to 61.8±25.8 (P=0.0035) in patients with Crohn's disease and from 110±49.5 to 71.6±28.8 ng/ml (P=0.0069) in patients with ulcerative colitis. In conclusion, there is a release of PMN-elastase in active IBD, which can be detected in plasma as well as in feces. Plasma elastase levels reflect disease activity in patients with IBD. The variation of the data and the large overlap between different groups, however, strongly reduce the clinical value.This research was supported by the SFB 154 of the Deutsche Forschungsgemeinschaft. V. Gross is supported by a Heisenberg-Stipendium of the Deutsche Forschungsgemeinschaft.     

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.     

Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes

Aims/hypothesis Type 2 diabetes often results in diabetic nephropathy, which is preceded by an elevated glomerular filtration rate (GFR). This study was designed to develop a mouse model of Type 2 diabetes and to elucidate the glomerular events in the early stages of diabetic nephropathy.Methods Four-week-old mice were fed a normal or high-fat (42% of total calories from fat) diet, and body weight, blood glucose, insulin, leptin, lipids and GFR were monitored from 9 to 21 weeks or longer after the feeding programme. Mesangial cell dedifferentiation was accessed by alpha-smooth muscle actin staining. Glomerular hypertrophy was determined using image analysis with haematoxylin–eosin staining. Matrix deposition was determined by type IV collagen staining.Results After 9 weeks, mice fed a high-fat diet weighed more than mice fed a normal diet (30.5±1.2 vs 22.3±0.5 g, p<0.05), and mice fed a high-fat diet were hyperinsulinaemic (283.9±69.7 vs 102.9±36.4 pmol/l, p<0.05), hyperglycaemic (8.0±0.6 vs 6.5±0.2 mmol/l, p<0.05) and their leptin levels were increased six-fold (1.48±0.45 vs 0.25±0.03 ng/ml, p<0.05). After 13 weeks, mice fed a high-fat diet showed hyperfiltration (GFR; 440±60 vs 210±10 µl/min, p<0.05). During the early stages of diabetic nephropathy, mesangial cell dedifferentiation was evident, shown by increased expression of alpha-smooth muscle actin in the glomeruli. After 9 weeks, mice fed a high-fat diet already demonstrated increased type IV collagen deposition. After 13 weeks, they developed enlarged glomerular tufts compared with those of their age-matched controls.Conclusions/interpretation The results of this study suggest that collagen IV deposition precedes the hyperfiltration and enlargement of glomeruli in early-stage diabetic nephropathy. Dedifferentiation of mesangial cells may be associated with collagen IV deposition.     

Hemodynamic effects of acute and chronic administration of vapreotide in rats with cirrhosis

The aim of this study was to assess the hemodynamic effects of acute and chronic administration of vapreotide, a somatostatin analog, in rats with intrahepatic portal hypertension induced by dimethylnitrosamine (DMNA) administration. Acute effects were evaluated at baseline and 30 min after placebo (N = 13) or vapreotide (8 g/kg/hr, N = 13) infusions in DMNA rats. Chronic hemodynamic effects were evaluated using subcutaneous implants for five weeks in anesthetized DMNA rats (placebo: N = 13, vapreotide: N = 13) and in sham rats (placebo: N = 10, vapreotide: N = 10). Hemodynamic measurements included splenorenal shunt blood flow (SRS BF) by the transit time ultrasound (TTU) method and cardiac output by the combined dilution–TTU method. Acute administration of vapreotide significantly decreased SRS BF (–17.3 ± 19 vs –1.1 ± 14%, P < 0.05) and portal pressure (–8 ± 9 vs 0 ± 8%, p < 0.05) compared to placebo without systemic effects. Chronic administration of vapreotide significantly reduced the increase in SRS BF (2.4 ± 1.5 vs 1.2 ± 1.0 ml/min, P < 0.05) and cardiac index (50 ± 15 vs 33 ± 10 ml/min/100 g, P < 0.0001) while portal pressure and blood flow, and mean arterial pressure were not significantly changed compared to placebo. In conclusion, the acute administration of vapreotide decreased collateral circulation blood flow while chronic administration attenuated its development. Vapreotide seems to have a vasoconstrictive effect on collateral circulation.     

Olmesartan, but not amlodipine, improves endothelium-dependent coronary dilation in hypertensive patients.

OBJECTIVES: We aimed to compare the effects of the angiotensin II receptor blocker (ARB) olmesartan versus the calcium channel blocker (CCB) amlodipine on coronary endothelial dysfunction in patients with hypertension. BACKGROUND: Angiotensin II receptor blockers are thought to have greater beneficial effects than CCBs on coronary vasomotion by directly blocking action of angiotensin II. METHODS: Twenty-six patients with untreated essential hypertension were prospectively assigned to treatment with either olmesartan (27.7 +/- 12.4 mg/day, n = 13) or amlodipine (5.6 +/- 1.5 mg/day, n = 13) for 12 weeks. Changes of corrected myocardial blood flow (DeltaMBF) and coronary vascular resistance (DeltaCVR) from rest to cold pressor were measured by using 15O-water and positron emission tomography before and after treatment. Blood biomarkers including lipids, glucose, insulin, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and superoxide dismutase (SOD) were also measured. RESULTS: Olmesartan and amlodipine reduced blood pressure (BP) to the same extent (-28.7 +/- 16.2 mm Hg vs. -26.7 +/- 10.8 mm Hg). In the olmesartan group, DeltaMBF tended to be greater (-0.15 +/- 0.19 ml/g/min vs. 0.03 +/- 0.17 ml/g/min, p = 0.09 by 2-way analysis of variance), and DeltaCVR was significantly decreased (7.9 +/- 23.5 mm Hg/[ml/g/min] vs. -16.6 +/- 18.0 mm Hg/[ml/g/min], p < 0.05) after treatment, whereas these parameters did not change in the amlodipine group (DeltaMBF: -0.15 +/- 0.12 ml/g/min vs. -0.12 +/- 0.20 ml/g/min; DeltaCVR: 6.5 +/- 18.2 mm Hg/[ml/g/min] vs. 4.8 +/- 23.4 mm Hg/[ml/g/min]). Serum SOD activity tended to increase (4.74 +/- 4.77 U/ml vs. 5.57 +/- 4.74 U/ml, p = 0.07 by 2-way analysis of variance) only in the olmesartan group. CONCLUSIONS: Olmesartan, but not amlodipine, improved endothelium-dependent coronary dilation in hypertensive patients independent of BP reduction. These beneficial effects on coronary vasomotion might be via an antioxidant property of ARBs.     

Extrinsic denervation causes a transient proabsorptive adrenergic hypersensitivity in the canine proximal colon

Our aim was to determine if extrinsic denervation alters the absorptive response of the colon to proabsorptive and prosecretory stimuli. Ten dogs underwent enteric isolation of a 50-cm proximal colonic segment; five were also randomized to undergo extrinsic denervation (DEN). At 2 and 13 wk postoperatively, net absorptive fluxes (mean ± sem) of water and electrolytes were determined during basal conditions and during proabsorptive low-dose (0.3 g/kg/min) or high-dose (3 g/kg/min) norepinephrine or prosecretory VIP (500 pg/kg/min). The net absorptive flux of water under basal conditions was decreased in DEN versus neurally intact controls at two weeks (4.0 ± 0.6 vs 6.6 ± 0.7 l/min/cm, P = 0.03) but did not differ at 13 weeks (5.0 ± 1.0 vs 5.7 ± 0.9, P > 0.05). Low- and high-dose norepinephrine increased water absorption in both groups at two weeks; the change in flux for high-dose norepinephrine was greater in DEN versus controls (4.1 ± 1 vs 2.1 ± 0.6 l/min/cm, P = 0.04). Net absorptive fluxes of Na⁺ and Cl^– followed these trends. VIP did not alter absorption of water or electrolytes. Extrinsic denervation of the proximal colon causes a decrease in net colonic absorption and a transient, proabsorptive adrenergic hypersensitivity in colonic absorption of water and electrolytes. VIP does not have a net secretory effect in the proximal canine colon.