Pathophysiological role of platelets in acute experimental pancreatitis: influence of endothelin A receptor blockade

The potential pathophysiological role of platelet-endothelium interactions was investigated during ischemia/reperfusion (I/R), and the effect of a selective endothelin(A) receptor antagonist (ET(A)-RA) was evaluated in an acute pancreatitis model. Acute pancreatitis was induced by warm ischemia (60 min) in Wistar rats, and its effects with and without antagonist treatment were investigated. Equivalent sham-operated animals were also studied. Microcirculatory changes were assessed by in vivo microscopy, and serum levels for lipase/amylase and histological specimens were investigated. Capillary constriction to 83.7 +/- 6.7% of sham-operated diameters was observed after 60 min of ischemia. A capillary density of 56.8 +/- 9.3% of the sham-operated group (396.3 +/- 15.8 mm(-1)) was measured after reperfusion. Stagnant leukocytes (329.5 +/- 30.4%) and platelets (337.5 +/- 32.3%) increased in postcapillary venules (P < 0.05). Administration of the ET(A)-RA significantly reduced I/R injury. Capillary diameters were maintained (101.4 +/- 4.5%), and capillary density was improved to 73.3 +/- 7.6% of sham-operated animals (P < 0.05). Stagnant leukocytes (152.3 +/- 10.6%) and platelets (207.1 +/- 19.8%) in sinusoids and postcapillary venules were reduced (P < 0.05). The extent of acute pancreatitis was reduced in the therapy group as indicated by serum lipase/amylase values and histological tissue damage (P < 0.05). Thus, ET(A)-RA therapy was effective in reducing I/R-induced pancreatitis in this experimental model.     

Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure

In acute liver failure (ALF) patients that have raised increased intracranial pressure (ICP), mortality remains unacceptably high. There has been an explosion in the knowledge about the pathophysiological basis of raised ICP but treatment modalities are limited. Current therapy is aimed at reducing the circulating ammonia levels and attempts to reduce brain swelling which are only moderately effective. More recently, cerebral hyperemia has been suggested as being of major importance in the pathogenesis of increased ICP providing a new look at interventions such as hyperventilation, N-acetylcysteine, thiopentone sodium and propofol. More recently studies have focused upon the role of systemic inflammatory response in the pathogenesis of increased ICP and support the use of antibiotics prophylactically. The application of moderate hypothermia to treat uncontrolled intracranial hypertension seems promising and its exact place will be decided in a large trial being planned in USA and Europe. Early data from studies in an animal model suggests that albumin dialysis is a promising new tool to treat intracranial hypertension in patients with ALF. The recent advance in our understanding of the pathophysiological basis of intracranial hypertension has provided the platform for the discovery of new treatments.     

Early activation of cardiac and renal endothelin systems in experimental heart failure

We investigated the time course of the expression of cardiac and renal endothelin systems in tachycardia-induced heart failure in dogs. Eleven beagles underwent rapid pacing at a progressively increased rate over a period of 5 wk, with a weekly clinical examination, echocardiography, measurement of circulating and urinary endothelin-1 (ET-1), and myocardial and renal tissue biopsies. Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA. Cardiac and renal tissue ET-1 contents were evaluated by immunostaining and measured by radioimmunoassay at autopsy. Rapid pacing caused a progressive increase in end-systolic and end-diastolic ventricular volumes (P < 0.05) from week 2 together with a decrease in ejection fraction and in mean velocity of circumferential shortening (P < 0.05) from week 1. These changes were tightly correlated to myocardial ppET-1 and renal ETA receptor mRNA and less so to myocardial ECE-1 mRNA, and they occurred before any increase in plasma and urinary ET-1 (P < 0.05 from week 4) and clinical signs of heart failure. Renal ppET-1 did not change. Both cardiac and renal ET-1 peptide contents were increased at autopsy. We conclude that tachycardia-induced heart failure in dogs is characterized by an early activation of the cardiac and renal tissue endothelin systems, which occurs before any changes in circulating and urinary ET-1 and is closely related to altered ventricular function.     

The endothelin system and its role in acute myocardial infarction

Immediately after an acute myocardial infarction (AMI) or in models of ischemia-reperfusion injury, cardiac endothelin (ET) system is markedly activated, and plasma levels of ET are increased. In the heart, expression of the main components of the ET system (ET-1 peptide, both receptor subtypes ETA and ETB, though not endothelin converting enzyme) are increased both at the gene level and protein level, in the viable myocardium, and--even more substantially--in the necrotic area. Despite these conspicuous abnormalities, the role of ET in this setting remains unclear. In the absence of human data, most short-term studies in animals (in terms of hours to up to 8 days post-AMI) and in the reperfused ischemic heart, have found beneficial effects of ET receptor blockade on survival rate, incidence of arrhythmias, cardiac function, and morphology. In contrast, many studies in which a long-term ET inhibition was started immediately post-infarction and the late effects were examined in animals with ensuing chronic heart failure (14-100 days postinfarction), adverse effects were also observed, such as scar thinning, further ventricular dilation, or even a worse survival rate. It appears that the ET system plays a dual role during the early post-AMI period. At present, it is not clear whether the short-term beneficial effects or long-term adverse effects of ET receptor blockade would prevail. Acute use of short-acting ET receptor antagonists in patients with AMI complicated by an acute heart failure is an attractive possibility that also remains to be investigated.     

N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure

This study evaluated the effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, on the changes in renal function, intrarenal blood flow distribution (laser-Doppler flowmetry), and plasma peroxynitrite levels during the acute renal failure (ARF) produced by inferior vena cava occlusion (IVCO; 45 min) in anesthetized rats. Renal blood flow fell on reperfusion (whole kidney by -45.7%; cortex -58.7%, outer medulla -62.8%, and papilla -47.7%); glomerular filtration rate (GRF) also decreased (-68.6%), whereas fractional sodium excretion (FE(Na%)) and peroxynitrite and NO/NO plasma levels increased (189.5, 46.5, and 390%, respectively) after ischemia. Pretreatment with L-NAME (10 microg. kg(-1). min(-1)) aggravated the fall in renal blood flow seen during reperfusion (-60%). Pretreatment with NAC (150 mg/kg bolus + 715 microg. kg(-1). min(-1) iv) partially prevented those changes in renal function (GFR only fell by -29.2%, and FE(Na%) increased 119.4%) and laser-Doppler blood flow, especially in the outer medulla, where blood flow recovered to near control levels during reperfusion. These beneficial effects seen in rats given NAC seem to be dependent on the presence of NO, because they were abolished in rats pretreated with L-NAME. Also, the antioxidant effects of NAC prevented the increase in plasma peroxynitrite after ischemia. In conclusion, NAC ameliorates the renal failure and the outer medullary vasoconstriction induced by ICVO, effects that seem to be dependent on the presence of NO and the scavenging of peroxynitrite.     

Value of renal biopsy in acute intrinsic renal failure.

Eighty-four patients presented with acute renal failure and features suggesting a diagnosis of intrinsic renal disease other than "acute reversible renal failure." Renal biopsy proved valuable in establishing the diagnosis, in indicating the reversibility of the lesion, and in helping to decide on treatment.     

Endothelin and endothelin antagonists: Potential role in cardiovascular and renal disease

Endothelin-1 is a recently discovered peptide mainly released from endothelial cells. Hypoxia and ischemia as well as numerous factors such as angiotensin 11, thrombin and transforming growth factor ₁ stimulate the fomation of the peptide. On the other hand the synthesis of endothelin is inhibited by nitric oxide and atrial natriuretic peptide via the formation of cyclic guanosine monophosphate. Released from endothelial cells endothelin-1 mediates transient vasodilation followed by a profound and longlasting vasoconstriction. Endothelin is also a mitogen for smooth muscle proliferation. Endothelins exert their biological effects via activation of specific receptors. Two different receptors have been cloned from mammalian tissues (ET_A and ET_B receptors). On vascular smooth muscle cells both receptors mediate contractions. Endothelial cells only express ET_B receptors linked to the formation of nitric oxide and/or prostacyclin formation. Increased plasma concentrations of endothelin-1 have been described in a variety of diseases such as pulmonary hypertension, arteriosclerosis, renal failure, acute coronary syndromes, heart failure, migraine and vascular diseases.Recently an increasing number of endothelin receptor antagonists have been synthetized, which have been shown to inhibit endothelin-mediated vasoconstriction. Clinical studies are now ongoing to elucidate the pathophysiologic role of endothelin and the potential benefit of the blockade of the system in different disease states.     

Inhibition by calcium antagonism of circulating and renal endothelin in experimental congestive heart failure

Endothelin (ET) is a potent vasoconstrictor and sodium-regulating peptide whose tissue and plasma concentrations are increased in congestive heart failure (CHF). ET may mediate its vasoconstrictor and sodium-regulatory actions secondary to an increase in intracellular calcium. Calcium influx may augment ET synthesis. Although felodipine, a dihydropyridine calcium-channel antagonist, is effective in reducing vascular resistance in generalized vasoconstriction, its actions in CHF on circulating and local tissue ET remain undefined. The current studies were designed to determine the modulating actions of felodipine (oral, 40 mg/day for 7 days; n = 6) in an experimental canine model of CHF produced by chronic thoracic inferior vena caval constriction (TIVCC) compared with normal (n = 7) and TIVCC-alone (n = 7) dogs. We hypothesized that felodipine would decrease circulating and renal ET. Plasma ET was significantly increased in TIVCC compared with normal dogs (26 +/- 0. 5 vs. 12 +/- 0.7 pg/ml, P < 0.05) and was markedly decreased by felodipine compared with TIVCC alone (14 +/- 3 vs. 26 +/- 0.5 pg/ml, P < 0.05). Renal ET immunohistochemical staining demonstrated the presence of ET in normal kidney, which was markedly increased in renal cortex and medulla in TIVCC dogs. Renal cortical and medullary ET staining densities were markedly decreased with felodipine compared with those with TIVCC alone. In the TIVCC + felodipine group, cardiovascular hemodynamics also was markedly improved compared with the TIVCC-alone group [systemic vascular resistance: 27 +/- 2 vs. 44 +/- 3 resistance units (RU), P < 0.05; pulmonary vascular resistance: 3.3 +/- 0.1 vs. 5.7 +/- 0.4 RU, P < 0.05; cardiac output: 2.9 +/- 0.2 vs. 1.7 +/- 0.1 l/min, P < 0.05]. This study demonstrates important modulating inhibitory actions of felodipine on renal and plasma ET in an experimental model of CHF.