Saralasin

Saralasin, a nonspecific angiotensin II receptor antagonist, attenuates oxidative stress and tissue injury in cerulein-induced acute pancreatitis.[Pubmed:12657946]

Pancreas. 2003 Apr;26(3):224-9.

INTRODUCTION: Free radical-mediated pancreatic injury is believed to play a key role in the pathogenesis of acute pancreatitis. Most of these studies have focused on the effects of antioxidant enzymes and free radical scavengers on improving the pancreatic injury. Recent findings showed that cerulein-induced acute pancreatitis was associated with an upregulation of a local pancreatic renin-angiotensin system in the pancreas. In the current study we hypothesized that inhibition of this renin-angiotensin system by Saralasin, a nonspecific antagonist for angiotensin II receptor, could attenuate the severity of cerulein-induced pancreatitis. METHODOLOGY: The effects of Saralasin on oxidative stress and tissue injury in cerulein-induced pancreatitis were assessed by histopathologic analysis and on the basis of biochemical changes of plasma alpha-amylase level, pancreatic glutathione status, oxidative modification of protein, and lipid peroxidation. RESULTS: Data from the biochemical analysis showed that intravenous injections of Saralasin at doses of 10 microg/kg to 50 microg/kg 30 minutes before the induction of acute pancreatitis significantly reduced pancreatic injury, as indicated by a decrease in plasma alpha-amylase activity in comparison with the cerulein-treated control. The effect of Saralasin was further manifested by significant suppressions of glutathione depletion, oxidative modification of proteins, and lipid peroxidation in cerulein-treated rat pancreas. Histopathologic examination findings were in agreement with the biochemical data. CONCLUSIONS: These data suggest that prophylactic administration of Saralasin can ameliorate the oxidative stress and tissue injury in cerulein-induced pancreatitis. Such a protective effect may provide new insight into the potential value of angiotensin II receptor antagonists in the clinical therapy for acute pancreatitis.

Saralasin and Sarile Are AT2 Receptor Agonists.[Pubmed:25313325]

ACS Med Chem Lett. 2014 Aug 18;5(10):1129-32.

Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither Saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists.

Differential effects of saralasin and ramiprilat, the inhibitors of renin-angiotensin system, on cerulein-induced acute pancreatitis.[Pubmed:12609748]

Regul Pept. 2003 Mar 28;111(1-3):47-53.

Acute pancreatitis is an inflammatory disease characterized by pancreatic tissue edema, acinar cell necrosis, hemorrhage and inflammation of the damaged gland. It is believed that acinar cell injury is initiated by the activation of digestive zymogens inside the acinar cells, leading finally to the autodigestion of the pancreas. Previous study in our laboratory demonstrated that cerulein-induced acute pancreatitis was associated with an up-regulation of local renin-angiotensin system (RAS) in rat pancreas. Therefore, the utilization of RAS inhibitors may provide a novel and alternative treatment for acute pancreatitis. By means of a rat model of cerulein-induced acute pancreatitis, results from the present study showed that an intravenous injection of Saralasin, an antagonist for angiotensin II receptors, at a dose of 40 microg/kg 30 min before the induction of acute pancreatitis significantly attenuated pancreatic edema. Results from the biochemical measurements showed that pretreatment with Saralasin at a dose of 20 microg/kg markedly reduced pancreatic injury, as evidenced by the decreased activities of alpha-amylase and lipase in plasma. However, the same recipe of ramiprilat, a specific inhibitor for angiotensin-converting enzyme, at a dose of 20 microg/kg did not provide any protective effect against acute pancreatitis. On the contrary, pretreatment with ramiprilat at a dose 40 microg/kg enhanced cerulein-induced pancreatic injury. Results from histopathological analysis of these RAS inhibitors further confirmed with those results as obtained from biochemical analysis. These data indicate that administration of Saralasin but not ramiprilat could be protective against acute pancreatitis and that activation of pancreatic RAS in acute pancreatitis may play a role in pancreatic tissue injury.

Intracerebroventricular administration of the angiotensin II receptor antagonist saralasin reduces respiratory rate and tidal volume variability in freely moving Wistar rats.[Pubmed:14575733]

Psychoneuroendocrinology. 2004 Jan;29(1):107-12.

The possible importance of intra-individual variations in respiratory rate and tidal volume has recently gained interest in psychiatric research, as a result of the observations that patients with panic disorder or premenstrual dysphoric disorder display enhanced respiratory variability as compared to controls. Although the role of brain neurotransmitters in the regulation of breathing has been extensively studied, as yet data on the central regulation of respiratory variability is sparse. Prompted by previous studies indicating that angiotensin II (ANG II) may influence ventilation as well as anxiety, we have studied the effect of intracerebroventricular administration of an ANG II receptor antagonist, Saralasin, on respiratory variability in unrestrained, freely moving male Wistar rats. Treatment with Saralasin, 5 mug dissolved in 1 mul saline followed by 9 mul saline in each lateral cerebral ventricle, did not influence tidal volume, but markedly reduced tidal volume variability (p=0.0005), as compared to saline injections (10 mul). Respiratory rate was reduced by Saralasin (p=0.02), and there was also a non-significant tendency for a reduction in respiratory rate variability. Both minute volume (p=0.005) and volume/10 s variability (p=0.0006) were reduced. It is suggested that ANG II in the brain of Wistar rats may regulate respiratory rate and tidal volume variability.

Saralasin suppresses arrhythmias in an isolated guinea pig ventricular free wall model of simulated ischemia and reperfusion.[Pubmed:7562511]

J Pharmacol Exp Ther. 1995 Sep;274(3):1379-86.

The effects of Saralasin on electrophysiological changes and arrhythmias induced by simulated ischemia and reperfusion were examined in an isolated tissue model. Segments of guinea pig right ventricles, stimulated regularly, were exposed to simulated ischemia for 15 min and then were reperfused with normal Tyrode's solution for 30 min. Transmembrane electrical activity and a high-gain electrogram were recorded. Arrhythmias and electrophysiological changes accompanying simulated ischemia and reperfusion in control preparations were compared to those in preparations treated with 0.1 or 1 microM Saralasin. Simulated ischemia caused abbreviation of action potential duration measured at 90% repolarization, abbreviation of endocardial effective refractory period (ERP) and prolongation of transmural conduction time. Premature ventricular beats, ventricular tachycardia and conduction block were observed in approximately 35% of control preparations during simulated ischemia. Rapid sustained or nonsustained ventricular tachycardia occurred in approximately 60% of control preparations in early reperfusion. The overall incidence of arrhythmias and the incidence of ventricular tachycardia in early reperfusion were significantly decreased by 1 microM but not 0.1 microM Saralasin. Saralasin (1 microM) prolonged the ERP in normoxic tissues, but it did not alter changes induced by ischemia or reperfusion in ERP or the action potential duration at 90% repolarization. Prolongation of transmural conduction time during ischemia and early reperfusion was significantly inhibited by both concentrations of Saralasin. However, only 1 microM Saralasin reduced the ratio of transmural conduction time to ERP enough to prevent arrhythmias. Our observations demonstrate that Saralasin exerts antiarrhythmic effects in myocardial reperfusion by a mechanism independent of circulatory and central actions.

Angiotensin II control of the renal microcirculation: effect of blockade by saralasin.[Pubmed:3747343]

Kidney Int. 1986 Jul;30(1):56-61.

The hydronephrotic rat kidney with intact circulation and innervation was split and spread out as a thin sheet in a tissue bath. The microvasculature was observed in vivo via television microscopy. We quantitated the effects of increasing concentrations (10(-9) to 10(-5) M) of Saralasin (angiotensin II antagonist) applied locally in the tissue bath on microvascular diameters and on relative glomerular blood flow (measured using fluorescent labeled RBCs). Saralasin produced an increase in preglomerular diameters which was largest (37 +/- 11%) in the interlobular artery (there was no dilation in the afferent arteriole near the glomerulus), an increase in postglomerular diameters which was largest (17 +/- 4%) in the efferent arteriole near the glomerulus, and an increase in blood flow (19 +/- 4%). If these types of findings would hold for the normal kidney, it would suggest a role for angiotensin II in the control of total renal blood flow, in the regional distribution of flow, and in the control of filtration fraction. We also made control micropressure measurements using the servo-nulling approach. Pressures measured were: afferent arteriole, 65 +/- 5 mm Hg; intraglomerulus, 50 +/- 5 mm Hg; and efferent arteriole, 19 +/- 3 mm Hg. These data indicate that there is major vascular resistance near the glomerulus, especially in the efferent arteriole.