Circulatory and myocardial effects of endothelin.

The endothelin peptide family consists of the 21 amino acid isoforms endothelin-1, endothelin-2, endothelin-3, and sarafotoxin (a snake venom). Endothelin-1 has been isolated from the supernatant of endothelial cells and has subsequently been shown to be the most potent vasoconstrictor known to date and to be positively inotropic. This review summarizes some of the current literature pertaining to circulatory and myocardial effects of endothelins. Exogenously administered endothelin-1 has been demonstrated to increase peripheral resistance and blood pressure in a dose-dependent manner. However, during the first minutes of intravenous administration endothelins also decrease peripheral resistance and blood pressure, presumably due to the release of vasodilatory compounds such as nitric oxide, prostacyclin, and atrial natriuretic peptide. Endothelins appear to be involved in the pathogenesis of salt-dependent and renovascular animal models of experimental hypertension. Although endothelins appear to contribute to basal vascular tone, the role of endothelins in the pathophysiology of human hypertension remains unclear. In addition, a role has been suggested for endothelins in specific vascular lesions and inflammatory conditions (e.g., restenosis after coronary angioplasty, atherosclerotic coronary lesions, acute myocardial infarction, and vasculitis, glomerulonephritis). Endothelins are positively inotropic peptides in cardiac myocyte and papillary muscle preparations. They have also been demonstrated to induce hypertrophy of cardiac myocyte and may play an important role in ventricular processes that lead to chronic cardiac failure. The pathophysiological relevance of the endothelin system in human disease states is elucidated using selective (ET[A]) and nonselective (ET[A/B]) inhibitors of the endothelin receptors.

Nitric oxide synthase isoform III gene expression in rat liver is up-regulated by lipopolysaccharide and lipoteichoic acid.

This study was done to investigate the influence of Gram-negative and Gram-positive sepsis on the expression of the three isoforms of nitric oxide synthase (NOS) gene in rat liver and kidney. Male Sprague-Dawley rats were treated with lipopolysaccharide (LPS, 10 mg/kg i.v.) as an in vivo model for Gram-negative sepsis or lipoteichoic acid (LTA, 10 mg/kg i.v.) as an in vivo model for Gram-positive sepsis. Animals were killed 12 h and 24 h after i.v. treatment. NOS mRNA of the three isoforms was determined by RNase protection assay. NOS II gene expression was strongly induced after LPS or LTA treatment in rat liver and kidney, indicating the efficacy of this treatment to induce sepsis. We found no change of NOS I gene expression after LPS or LTA injection in rat liver and kidney. NOS III gene expression was increased about 8-fold 12 h and about 5-fold 24 h after induction of sepsis in the rat liver whereas in the kidney there was no significant increase in NOS III gene expression. After correction for length NOS III mRNA was about 4- and 40-fold more abundant 12 h and 24 h after LPS treatment than NOS II mRNA in the liver, respectively. Twelve and 24 h after LTA treatment NOS III mRNA was about 18- and 140-fold more abundant than NOS II in the liver. These findings suggest that NOS III is an even more potent source of NO than NOS II in the liver after stimulation with LPS or LTA.

Pharmacokinetic interaction between proton pump inhibitors and roxithromycin in volunteers.

BACKGROUND: Triple therapy including two antibiotics and a proton pump inhibitor is a rational approach to the treatment of Helicobacter pylori induced peptic ulcer disease. The interaction of antimicrobial therapy and acid suppression is not yet well elucidated. AIMS: To investigate the effects of proton pump inhibitors on roxithromycin levels in plasma and gastric tissue under steady-state conditions in volunteers. METHODS: In two crossover studies omeprazole 20 mg b.d., lansoprazole 30 mg b.d., roxithromycin 300 mg b.d., and the combination of roxithromycin with either omeprazole or lansoprazole were administered to 12 healthy volunteers over 6 days. Blood plasma levels of the drugs were measured. In addition, roxithromycin concentrations were also determined in gastric juice and gastric tissue obtained during endoscopy. RESULTS: The proton pump inhibitors and roxithromycin did not alter the blood plasma pharmacokinetics of each other. When compared to roxithromycin administered alone, its combination with a proton pump inhibitor significantly increased the roxithromycin concentrations in gastric juice (3.0-5.0 microg/mL vs. 0.3-0.4 microg/mL) and gastric tissue (antrum: 3.8-4.0 vs. 2.8 microg/g, fundus: 5.9-7.4 vs. 4.2-4.4 microg/g). CONCLUSIONS: Proton pump inhibitors and roxithromycin do not alter the systemic bioavailability of each other. However, proton pump inhibitors increase the local concentration of roxithromycin in the stomach which may contribute to the clinically proven synergic beneficial action in eradication therapy of H. pylori.

The effect of urapidil and ramipril on hyperglycemia in streptozotocin diabetic rats.

Angiotensin-converting enzyme inhibitors and alpha1-adrenoceptor antagonists improve glucose disposal in diabetes mellitus. We compared the effect of the antihypertensive hybrid drug urapidil [alpha1-adrenoceptor antagonist serotonin 1A (5-hydroxytryptamine 1A, 5-HT1A) receptor agonist] on hyperglycemia in streptozotocin diabetic rats with the angiotensin-converting enzyme inhibitor ramipril. 5-HT1A receptor agonists induce hyperglycemia. This could be an important disadvantage during treatment of diabetes mellitus with urapidil. Diabetes was induced by streptozotocin (70 mg/kg i.p.). Treatment for 7 days (ramipril 10 mg/kg p.o.; urapidil 20 mg/kg p.o.) significantly decreased mean blood glucose values (urapidil: 15.7+/-0.9 mmol/l, P=0.007; ramipril: 15.0+/-0.8 mmol/l, P=0.038 vs. diabetic control group: 18.7+/-1.0 mmol/l). Both drugs reduced significantly blood pressure, urinary glucose, water consumption, and food requirement. Serotonin concentration in the brain (medulla oblongata, pituitary) was not affected. A normalization comparable with healthy control rats was observed only in a diabetic control group with insulin therapy. In conclusion, our results demonstrate that the antihypertensive drug urapidil has no detrimental effect on hyperglycemia compared with the angiotensin-converting enzyme inhibitor ramipril in experimental diabetes mellitus despite its 5-HT1A receptor agonistic properties.

Clearance of moxifloxacin during continuous haemofiltration (CVVHF) in vitro.

BACKGROUND/AIMS: The clearance of moxifloxacin is reported to be unaltered in the presence of renal insufficiency. There is little information about the clearance of intravenous moxifloxacin in renal replacement therapies during intensive care. The aim of this study was to determine the clearance of moxifloxacin during continuous veno-venous haemofiltration (CVVHF) in vitro. METHODS: The elimination of moxifloxacin (reservoir with 600 mL of washed human erythrocytes, 100 mL of NaHCO3 and various amounts of Ringer solution and human albumin to give a total volume of 1000 mL, pH 7.35 +/- 0.5; haematocrit 41 +/- 2) during CVVHF in vitro with two filter conditions (during priming, after priming), three protein concentrations (human albumin: 0 g/L, 20 g/L, 40 g/L) and two filtration velocities [(i) standard condition: blood flow at 100 mL/min and turnover of 2 L/h; (ii) blood flow at 50 mL/min and turnover of 1 L/h] were investigated. RESULTS: A new filter needs 20 min of priming before moxifloxacin reaches a steady relative filtration rate. The sieving coefficient with 0 g/L albumin was 1.07, with 20 g/L 0.90 and with 40 g/L 0.80. Under standard filtration conditions (i) the renal clearance was between 26.7 and 35.7 mL/min, and under the altered conditions (ii) it was 15.2 mL/min. CONCLUSION: During CVVHF in vitro we found filtration clearances of moxifloxacin of the same order as its renal clearance in healthy subjects. The high sieving coefficient, nearly independent of blood protein concentration, would suggest that moxifloxacin is filtered almost as freely as creatinine. These results do not indicate a need for dose adjustment under appropriate haemofiltration conditions and normal hepatic function.

[Obstructive respiration disorders. An aneurysm of the ventilator tubing during general anesthesia]. / Obstruktive Ventilationsstörung. Beatmungsschlauchaneurysma im Verlauf einer Allgemeinanästhesie.

Technical problems during anaesthesia are important causes of anaesthesia-related deaths and brain damage. During general endotracheal anaesthesia for ophthalmic surgery (41-year-old man, ASA 1) we observed an increase in inspiratory pressure without other clinical changes. Disconnection and ventilation with a resuscitation bag showed normal inspiratory pressures. Inspection demonstrated an obstruction due to an aneurysm of the inner layer of the inspiratory tubing. The classification of this rare blockage of ventilation differs in the literature (pressure, hypoventilation, hypercarbia). In addition, it demonstrates the principal problem of clinical decision-making during anaesthesia based on monitoring information. Strategies for responding to alarms indicating hazards of ventilation must be based on immediate restoration of sufficient ventilation, and not primarily on detecting the cause.

Thiopentone and methohexitone enantiomers do not act stereoselectively on the oxidative response in human neutrophils in vitro.

To elucidate potential stereoselective effects of single barbiturate isomers, we compared the inhibitory potency of single thiopentone enantiomers, two isomer-enriched mixtures of methohexitone and racemic mixtures of both barbiturates on the fMLP-induced neutrophil oxidative response. A suppression of the response to 50% compared to control required a 100-fold therapeutic concentration of methohexitone, while therapeutic concentrations of the thiopentone racemate led to a significant inhibition (relative fluorescence of neutrophils 0.46 +/- 0.03 compared to fMLP controls). The racemate of thiopentone produced significantly greater inhibition than the single enantiomers. Stereoselectivity in favor of one isomer could not be shown for both barbiturates. The greater inhibition by the thiopentone racemate might suggest two separate binding sites for the enantiomers which are positively coupled.

Downregulation of angiotensin II type 1 receptors during sepsis.

Our study aimed to characterize the mechanisms underlying the attenuated cardiovascular responsiveness toward the renin-angiotensin system during sepsis. For this purpose, we determined the effects of experimental Gram-negative and Gram-positive sepsis in rats. We found that sepsis led to a ubiquitous upregulation of NO synthase isoform II expression and to pronounced hypotension. Despite increased plasma renin activity and plasma angiotensin (Ang) II levels, plasma aldosterone concentrations were normal, and the blood pressure response to exogenous Ang II was markedly diminished in septic rats. Mimicking the fall of blood pressure during sepsis by short-term infusion of the NO donor sodium nitroprusside in normal rats did not alter their blood pressure response to exogenous Ang II. Therefore, we considered the possibility of an altered expression of Ang II receptors during sepsis. It turned out that Ang II type 1 receptor expression was markedly downregulated in all organs of septic rats. Further in vitro studies with rat renal mesangial cells showed that NO and a combination of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) downregulated Ang II type 1 receptor expression in a synergistic fashion. In summary, our data suggest that sepsis causes a systemic downregulation of Ang II type 1 receptors that is likely mediated by proinflammatory cytokines and NO. We suggest that this downregulation of Ang II type 1 receptors is the main reason for the attenuated responsiveness of blood pressure and of aldosterone formation to Ang II and, therefore, contributes to the characteristic septic shock.

Elimination of methohexitone after long-term, high-dose infusion in patients with critically elevated intracranial pressure.

OBJECTIVE: To determine the plasma elimination of methohexitone in patients with critically elevated intracranial pressure (ICP) who received the drug in high doses for several days. DESIGN: Drug-monitoring study. SETTING: Intensive care unit at a university hospital. PATIENTS: Twelve intensive care unit patients with brain injuries who received methohexitone as a final therapeutic approach after routine therapy had proved to be insufficient in controlling critically elevated ICP. MEASUREMENTS AND MAIN RESULTS: Plasma samples were taken during methohexitone infusion, before cessation, and in distinct, short increments after discontinuation of the infusion. Methohexitone was determined in plasma by reverse-phase high-pressure liquid chromatography and photometric detection. The median duration of infusion of methohexitone was 137 hrs (minimum, 27 hrs; maximum, 445 hrs), with a median infusion rate of 62.5 microg/kg/min (minimum, 22.5 microg/kg/min; maximum, 116.2 microg/kg/min). Plasma concentrations of methohexitone at burst suppression under concomitant analgesic sedation ranged from 1.6 to 17.3 microg/mL (median, 4.7 microg/mL). After cessation of methohexitone infusion, the decline of plasma concentrations followed a biexponential function. Clearance rates, volume of distribution at steady state, context-sensitive half-time, and initial and terminal elimination half-times were calculated. Pharmacokinetic data showed remarkable interindividual variability that could not be correlated to the infusion rate, to the duration of the infusion, or to obvious differences in physiology or the disease states of these patients. Even in patients with high plasma concentrations who received the drug for a considerable length of time, the initial decline in plasma concentration was exponential, indicating redistribution. CONCLUSIONS: We conclude that the elimination kinetics of methohexitone after long-term, high-dose infusion in critically ill patients with brain injuries may favor the use of methohexitone over thiopentone for controlling critically elevated ICP by allowing for a more timely neurologic examination after cessation.

Renocortical expression of renin and of cyclooxygenase-2 in response to angiotensin II AT1 receptor blockade is closely coordinated but not causally linked.

Based on recent evidence that renin gene and cyclooxygenase-2 (COX-2) expression in the rat kidney cortex increase in parallel under a variety of conditions, this study aimed to characterize the causal linkage between COX-2 and renin expression. Therefore, we semi-quantitated renocortical renin and COX-2 gene expression when the renin-angiotensin system (RAS) was inhibited by the angiotensin II (Ang II) AT1 receptor antagonist candesartan (15 mg/kg per day) and when COX-2 activity was blocked by celecoxib (20 mg/kg twice a day) in three rat strains (Sprague-Dawley, WKY and SHR) at ages of 5, 9 and 15 weeks. We observed that candesartan increased renin mRNA in all rats at all ages, the amplitude of stimulation being inversely related to age. Candesartan increased COX-2 mRNA in all three strains at 5 weeks, and in SD and WKY rats also at 9 weeks. In 9-week-old SHR and in 15-week-old rats of all three strains candesartan did not influence COX-2 mRNA levels. For all rat strains, strain-specific strong linear correlations existed between renocortical COX-2 and renin mRNA levels, both with and without candesartan treatment. The additional feeding of candesartan-treated rats with celecoxib did not change renin mRNA or COX-2 mRNA levels, whilst the renal excretion of sodium and renal cortical prostaglandin E2 concentration decreased by 26% and 60%, respectively. In summary, these findings, obtained when the renin system was activated by AT1 receptor blockade, indicate that Ang II is not required to stimulate COX-2 expression and that COX-2 activity is not required to stimulate renin expression. However, the renocortical expression of renin and of COX-2 appear to be highly coordinated under basal conditions and during inhibition of RAS, suggesting the existence of a common denominator for renin and COX-2 expression that remains to be elucidated.

Effects of hypoxia on growth factor expression in the rat kidney in vivo.

There is accumulating evidence from in vitro studies suggesting that the genes of endothelin-1, PDGF, and VEGF are, like the erythropoietin gene, regulated by oxygen tension and by divalent cations. Hypoxia-induced stimulation of, such as endothelin-1, PDGF or VEGF might be involved in the pathogenesis of acute or chronic renal failure, and in renal "inflammatory" diseases (glomerulonephritis, vasculitis, allograft rejection). Hypoxia (8% O2) for six hours caused a 55-fold/1.6-fold increase of renal erythropoietin/endothelin-1 gene expression, whereas endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was unchanged. Carbon monoxide (0.1%) treatment for six hours stimulated renal erythropoietin gene expression 140-fold; however, endothelin-1, endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was not affected. Finally, cobalt treatment (60 mg/kg CoCl2) increased only renal erythropoietin/PDGF-B gene expression 5-fold/1.65-fold. These findings suggest that hypoxia is a rather weak stimulus for renal endothelin-1 gene expression, and that renal PDGF and VEGF gene expression in vivo is not sensitive to tissue hypoxia, in contrast to cell culture experiments. The in vivo regulation of endothelin-1, PDGF, and VEGF differs substantially from that of erythropoietin, suggesting that the basic gene regulatory mechanisms may not be the same.

Effect of three different doses of urapidil on blood glucose concentrations in the streptozotocin diabetic rat.

BACKGROUND AND OBJECTIVE: Diabetes mellitus associated with hypertension often causes perioperative complications. The alpha1-adrenoceptor antagonist/5-hydroxytryptamine-1A receptor agonist urapidil is an approved drug used in hypertension and hypertensive emergencies. 5-Hydroxytryptamine-1A (5-HT1A) receptor agonists impair glucose metabolism. To evaluate a possible dose-dependent hyperglycaemic effect of urapidil due to its 5-HT1A receptor agonistic properties, the effect of three doses of urapidil on hyperglycaemia in the streptozotocin diabetic rat was investigated. METHODS: Male Wistar-Kyoto rats were made diabetic by streptozotocin and randomly allocated to the following daily treatments for 7 days (n = 6 each): urapidil 6 mg kg(-1), urapidil 20 mg kg(-1), urapidil 60 mg kg(-1), insulin 4 IU kg(-1) subcutaneously. One diabetic group and one non-diabetic healthy group served as controls. RESULTS: Treatment for 7 days with urapidil 20 mg kg(-1) and urapidil 60 mg kg(-1) reduced mean glucose concentrations significantly (urapidil-20: 15.6 +/- 1.1 mmol L(-1), P = 0.023; urapidil-60: 15.8 +/- 0.8 mmol L(-1), P = 0.04) compared with diabetic controls (20.9 +/- 0.8 mmol L(-1)), whereas those after urapidil 6 mg kg(-1) were similar to diabetic controls. Insulin treatment normalized blood glucose concentrations. CONCLUSIONS: The alpha1-adrenoceptor antagonist/5-HT1A receptor agonist urapidil has no hyperglycaemic effect on experimental diabetes mellitus, even in high doses, despite its 5-HT1A receptor agonistic properties.

Effects of the angiotensin II type-1 receptor antagonist ZD7155 on angiotensin II-mediated regulation of renin secretion and renal renin gene expression, renal vasoconstriction, and blood pressure in rats.

Angiotensin II receptors have recently been subclassified as type-1 or type-2 receptors. The in vitro and in vivo effects of blocking the angiotensin II type-1 receptor with ZD7155, an angiotensin II type-1 selective receptor antagonist, have been studied in angiotensin II-mediated increases in cytosolic calcium in rat mesangial cells, in angiotensin II-induced renal and systemic vasoconstriction, and in angiotensin II-mediated regulation of renin secretion and renal renin gene expression. ZD7155 completely blocked the ability of angiotensin II to elicit an increase in free intracellular calcium concentrations in rat mesangial cells. In isolated perfused rat kidneys, ZD7155 completely abolished the angiotensin II-induced vasoconstriction and increased renin secretion to 700% of baseline levels. Furthermore, ZD7155 decreased systolic blood pressure by 16 mm Hg, increased plasma renin activity 3.7-fold, and stimulated renal renin gene expression 4.2-fold in Sprague-Dawley rats in vivo. Our results suggest that ZD7155 is a potent antagonist of the angiotensin II type-1 receptor, which mediates angiotensin II-induced increases of free intracellular calcium concentrations in (e.g., renal mesangial cells), constriction of the renal and systemic vasculature, and inhibition of renin secretion and synthesis.