bq-123 and Ischemia

Ischemia and subsequent reperfusion are known to impair renal function. We examined several agents that might prevent renal impairment or enhance the recovery of renal function after ischemia/reperfusion injury in rats. Different degrees of preventive effects were observed in rats treated with captopril, BQ-123 (endothelin type A receptor antagonist), sodium nitroprusside (SNP, a nitric oxide donor), and losartan (angiotensin II type 1 receptor antagonist). Only minimal changes in renal morphology were observed after treatment with losartan, SNP, captopril, and BQ-123 compared with control animals. On the other hand, lesions were prominent in the N(G)-nitro-L-arginine-methyl ester (L-NAME)- and L-arginine-treated rats. The Na(+)-K(+) ATPase activity of ischemic kidneys was, however, preserved in all treatment groups, except in those treated with L-arginine and L-NAME, which showed a marked reduction in Na(+)-K(+) ATPase activity. Our post-treatment data suggest that losartan and SNP have the greatest potential for therapeutic use to mitigate post-ischemic renal damage and functional impairment.

Topics: Adenosine Triphosphatases; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Arginine; Captopril; Ischemia; Kidney; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitroprusside; Peptides, Cyclic; Rats, Wistar; Renal Insufficiency; Reperfusion; Reperfusion Injury

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin A Receptor Antagonists; Humans; Ischemia; Leg; Microcirculation; Peptides, Cyclic; Peripheral Vascular Diseases; Systole

Insufficient perfusion of distal flap areas, which may lead to partial necrosis, still represents a challenge in reconstructive surgery. In the process of microvascular and endothelial dysfunction, endothelins (ETs) and their receptors may play an important role. Therefore, the aim of the study was to investigate in a chronic in vivo model the effect of various ET-receptor antagonists in critically perfused flap tissue.. A random pattern musculocutaneous flap was elevated in the back of 25 C57BL/6 mice and fixed into a dorsal skinfold chamber. Repetitive intravital fluorescence microscopy was performed over a 10-day observation period, assessing arteriolar diameter, arteriolar blood flow (aBF), functional capillary density (FCD), the area of tissue necrosis, and the development of newly formed blood vessels. ET-receptor blockers were administrated intraperitoneally 30 min before induction of ischemia, as well as daily during the subsequent 4-day period, including (1) BQ-123, a specific ET-A-receptor antagonist (ET-A = 1 mg/kg), (2) BQ-788, a selective ET-B-receptor antagonist (ET-B = 1 mg/kg), and (3) PD-142893, a nonselective ET-AB-receptor antagonist (ET-AB = 0.5 mg/kg). Animals receiving saline only served as controls (n = 7).. Despite an increase in aBF during the 10-day observation period (day 1 = 1.92 +/- 0.29 nl/s; day 10 = 4.70 +/- 1.64 nl/s), the flaps of saline-treated controls showed a distinct decrease in FCD (94 +/- 12 cm/cm(2)). This perfusion failure resulted in flap necrosis of 52 +/- 3%. Selective blockade of the ET-B receptor caused a further increase in aBF already at day 1 (2.97 +/- 0.42 nl/s), which persisted during the following 10-day observation period (day 10 = 5.74 +/- 0.69 nl/s). Accordingly, adequate FCD could be maintained (day 10 = 215 +/- 8 cm/cm(2); p < 0.05 vs control), resulting in a significant reduction in flap necrosis (day 10 = 25 +/- 4%; p < 0,05). In contrast, neither selective blockade of the ET-A receptor nor nonselective ET-A- and ET-B-receptor blockade were able to significantly affect aBF when compared to controls (day 1 = ET-A = 1.39 +/- 0.10 nl/s; ET-AB = 1.53 +/- 0.80 nl/s; n.s.). Accordingly, flap necrosis after ET-A- and ET-AB-receptor inhibition did not differ from that of controls (day 10 = ET-A: 46 +/- 10%; ET-AB = 51 +/- 7%).. Our data show that only selective ET-B-receptor inhibition is capable of maintaining nutritive perfusion and, hence, reducing necrosis in critically perfused flap tissue. Accordingly, administration of ET-B-receptor antagonists may be considered in the treatment of critically perfused flaps.

Topics: Animals; Arterioles; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Graft Survival; Ischemia; Mice; Mice, Inbred C57BL; Microcirculation; Microscopy, Fluorescence; Models, Animal; Necrosis; Oligopeptides; Peptides, Cyclic; Piperidines; Regional Blood Flow; Surgical Flaps; Time Factors; Venules

In this study, the effects of BQ123 (an ET(A) receptor antagonist), bosentan (a nonselective ET(A)-ET(B) antagonist), and phosphoramidon (an endothelin converting enzyme inhibitor) were investigated on intestinal mucosal lesion formation and changes in tissue PGE2 and LTC4 levels due to intestinal ischemia-reperfusion (I/R) injury in rats. Following 30 min of ischemia, the substances were given via the inferior caval vein, and 10 min later the intestine was subjected to reperfusion for 30 min. The intestinal specimens were evaluated both microscopically and the tissue PGE2 and LTC4 levels were obtained for each group. The histopathologic examination revealed a significant reduction in tissue injury in both BQ123 and phosphoramidon pretreated groups compared with the control group. Bosentan, on the contrary, did not decrease the injury. The pharmacologic examination revealed a significant reduction of PGE2-like activity in both BQ123 and phosphoramidon pretreated groups, compared with the control group, while LTC4-like activity remained unchanged except for an increase in the bosentan pretreated group.

Topics: Animals; Bosentan; Dinoprostone; Endothelin Receptor Antagonists; Endothelins; Female; Glycopeptides; Histocytochemistry; Intestinal Mucosa; Intestines; Ischemia; Leukotriene C4; Male; Peptides, Cyclic; Rats; Reperfusion Injury; Sulfonamides

Endothelin (ET) is a potent vasoconstrictor that has been implicated in the pathogenesis of acute renal failure (ARF). In order to investigate the potential role of ET in ARF in the dog, the effect of a mixed ETA and ETB receptor antagonist, (+/-)-SB 209670, [(1RS-2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-5- (prop-1-yloxy) indane-2-carboxylic acid], and a selective ETA antagonist, BQ123, were evaluated in anesthetized uninephrectomized dogs undergoing 60 min of renal occlusion. (+/-)-SB 209670 (1 microgram/kg/min) and BQ123 (10 micrograms/kg/min) were infused directly into the renal artery (intrarenal) for 30 min before renal occlusion, during occlusion and for 60 min after reperfusion at doses that inhibited the renal vasoconstrictor effects of intrarenal renal artery infusions of ET-1. Renal occlusion resulted in a significant reduction in inulin clearance (from 26.2 +/- 1.8 to 3.2 +/- 1.1 ml/min). This response was significantly (P < .05) attenuated by (+/-)-SB 209670 (from 23.5 +/- 2.2 to 7.6 +/- 2.0 ml/min) but not by BQ123 (from 23.5 +/- 1.7 to 4.9 +/- 1.2 ml/min). Endogenous creatinine clearance showed the same pattern. After renal artery occlusion, fractional sodium and fractional potassium excretions were increased significantly. (+/-)-SB 209670, but not BQ123, resulted in a significant reduction in fractional sodium; however, neither compound altered fractional potassium excretion. The data suggest that ET receptor antagonists, possibly by altering tubular sodium reabsorption, may be beneficial in ischemia-induced ARF.

Topics: Acute Kidney Injury; Animals; Dogs; Endothelin Receptor Antagonists; Endothelins; Female; Glomerular Filtration Rate; Indans; Ischemia; Kidney; Male; Peptides, Cyclic; Renal Circulation

Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg.min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicle-treated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na+ and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism. Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Na+ reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance.

Topics: Acute Kidney Injury; Animals; Endothelin Receptor Antagonists; Glomerular Filtration Rate; Infusions, Intravenous; Ischemia; Kidney; Male; Nephrectomy; Peptides, Cyclic; Potassium; Rats; Rats, Sprague-Dawley; Renal Artery; Sodium; Time Factors

Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators regulating this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1) in hemorrhagic shock-induced gastric mucosal damage in rats.. ET-1 contents in plasma and gastric mucosa were measured and gastric mucosal damage was evaluated during a control period, 60 minutes of ischemia, 15 minutes of reperfusion, and 30 minutes of postreperfusion. Next, effects of BQ-123, an endothelinA receptor antagonist, on the gastric mucosal damage and hemodynamics were studied.. Both plasma and mucosal ET-1 significantly increased after ischemia and reperfusion compared with the control values, but only mucosal ET-1 continued to increase after reperfusion, leading to the development of gastric mucosal damage. BQ-123, administered just before reperfusion, reduced mucosal damage in the postreperfusion period dose-dependently and improved mean gastric mucosal blood flow and mucosal hemoglobin oxygen saturation during the 30-minute postreperfusion period.. These results suggest that endogenous ET-1 plays an important role in the pathogenesis of hemorrhage shock-induced gastric mucosal damage through impairment of mucosal microcirculation. Further, endothelinA antagonists may have therapeutic benefits for shock-induced gastric mucosal damage.

Topics: Animals; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; Gastric Mucosa; Hemodynamics; Ischemia; Male; Osmolar Concentration; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Reperfusion; Shock, Hemorrhagic; Stomach

In the isolated perfused rat kidney, endothelin (ET) added to the perfusate at concentrations ranging from 50 to 500 pmol/l resulted in a dose-dependent reduction in renal perfusate flow (RPF) and inulin clearance (CIn). The decrease in RPF (17 +/- 3 vs. 34 +/- 3 ml.min-1 x g-1; P < 0.01 compared with control) and CIn (89 +/- 13 vs. 317 +/- 19 microliters.min-1 x g-1; P < 0.01 compared with control) by ET (500 pmol/l) was prevented by the ET antagonist BQ-123 (10 microM), with full recovery of RPF [36 +/- 2 vs. 34 +/- 3 ml.min-1 x g-1; not significant (NS) compared with control] and CIn (299 +/- 51 vs. 317 +/- 19 microliters.min-1 x g-1; NS compared with control). In the absence of ET, perfusion of the kidney with a similar concentration of BQ-123 (10 microM) did not induce any changes in RPF (36 +/- 5 vs. 34 +/- 3 ml.min-1 x g-1; NS compared with control) or CIn (320 +/- 14 vs. 317 +/- 19 microliters.min-1 x g-1; NS compared with control). After 60 min of arterial clamping, BQ-123 (10 microM) given before the onset of ischemia and during reflow improved CIn (88 +/- 4 vs. 19 +/- 3 microliters.min-1 x g-1; n = 6, P < 0.01) and net tubular sodium reabsorption (TNa) compared with no treatment. On the other hand, the same dose (10 microM) of BQ-123 given only during the reperfusion period was not effective in preventing the decreases in either CIn or TNa.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Absorption; Acute Kidney Injury; Animals; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; In Vitro Techniques; Inulin; Ischemia; Kidney Tubules; Male; Peptides, Cyclic; Perfusion; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion

The current study was undertaken to define a biological role for the endothelin-A receptor in a clinically relevant model of altered systemic and renal function produced by suprarenal aortic cross-clamping. This model is associated with profound systemic and renal vasoconstriction, acute renal failure, and a significant increase in circulating endothelin. Studies were performed in three groups of anesthetized mongrel dogs. Group 1 (n = 5) underwent aortic cross-clamping for 1 hour; group 2 (n = 5) underwent aortic cross-clamping for 1 hour in the presence of BQ-123, a specific antagonist of the endothelin-A receptor; group 3 (n = 4) received BQ-123 alone. The marked systemic and renal vasoconstriction associated with aortic cross-clamping in group 1 was markedly attenuated in group 2 in the presence of BQ-123. Unlike the vasoconstrictor response, BQ-123 did not attenuate the decrease in glomerular filtration rate associated with this model. Under unstimulated conditions in group 3, BQ-123 had no actions on systemic or renal hemodynamics. In conclusion, the current study demonstrates that the systemic and renal vasoconstriction associated with aortic cross-clamping are in part mediated through the interaction of endothelin and the endothelin-A receptor. This study demonstrates the functional importance of increased endogenous endothelin in the regulation of vascular tone in this pathophysiological state.

Topics: Animals; Aorta; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Endothelins; Heart Rate; Hemodynamics; Ischemia; Kidney; Myocardial Ischemia; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Vascular Resistance; Vasoconstriction

To elucidate the pathophysiological role of endogenous endothelin (ET), we examined the effects of the newly synthesized ETA receptor-selective antagonist, BQ-123, on ischemic acute renal failure induced by bilateral clamping of renal artery and vein followed by reperfusion in rats. BQ-123, when given by i.v. infusion of 0.5 mg/kg per min for 2.5 h during the pre- and post-ischemic period, was found to prevent the decrease in creatinine clearance and increases in blood urea nitrogen, plasma creatinine and the fractional excretion of sodium. Morphological observation also showed an effect of BQ-123, i.e. prevention of proximal tubular (S3 segment) necrosis. At 2 h after the start of reperfusion, the ET-1 content in the kidney increased to its maximal level. At this time, the Ca2+ content in the mitochondrial fraction of the renal cortex increased, with a concomitant increase in blood urea nitrogen. However, these increases were limited by treatment with BQ-123. Thus, BQ-123 was effective to both prevent mitochondrial Ca2+ accumulation in the early phase of ischemic acute renal failure and protect proximal tubular cells from post-ischemic degeneration. We conclude that ET may be at least partially involved in the pathogenesis of tubular cell injury in this acute renal failure model.

Topics: Acute Kidney Injury; Animals; Calcium; Endothelin Receptor Antagonists; Endothelins; Ischemia; Kidney; Male; Mitochondria; Peptides, Cyclic; Rats; Rats, Sprague-Dawley