saralasin and Disease-Models--Animal

Topics: Animals; Blood Pressure; Captopril; Disease Models, Animal; Disease Susceptibility; Dogs; Humans; Hypertension; Injections, Intraventricular; Oligopeptides; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Saralasin; Stress, Psychological

Topics: Acromegaly; Adult; Age Factors; Animals; Arteriosclerosis; Blood Volume; Cardiovascular Diseases; Child; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Disease Models, Animal; Humans; Hypercalcemia; Hypertension; Natriuresis; Renin-Angiotensin System; Risk; Saralasin; Sympathetic Nervous System; Thyroid Diseases

Topics: Adrenal Glands; Adrenergic beta-Antagonists; Aldosterone; Angiotensin II; Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Humans; Hydrocortisone; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney; Renin; Saralasin; Teprotide

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

Topics: Amino Alcohols; Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Models, Molecular; Molecular Structure; Rats; Seizures; Structure-Activity Relationship

Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents Ito,fast and IK,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in Ito,fast and IK,slow. Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored Ito,fast and IK,slow to control levels. The number of Ito.fast or IK,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For Ito,fast but not IK,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces Ito,fast and IK,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current densities. Second, the hypertrophic program can modify signaling between the angiotensin receptor and target current.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Cells, Cultured; Disease Models, Animal; Heart Diseases; Hypertrophy; Membrane Potentials; Mice, Inbred C57BL; Myocytes, Cardiac; Patch-Clamp Techniques; Pressure; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Saralasin; Stress, Physiological

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

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.

Topics: Acute Disease; alpha-Amylases; Angiotensin Receptor Antagonists; Animals; Ceruletide; Disease Models, Animal; Edema; Injections, Intravenous; Lipase; Necrosis; Pancreatitis; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Saralasin

In the present study, we use valsartan, a highly selective antagonist for angiotensin(1) (AT(1)) receptor subtype, to investigate the effect of AT(1) receptor on the plasma glucose metabolism in streptozotocin-induced diabetic rats (STZ-diabetic rats).. The plasma glucose concentration was assessed by glucose oxidase method and plasma insulin was measured using enzyme-linked immunosorbent assay. Systolic blood pressure (SBP) was determined by the tail-cuff method. The intravenous glucose challenge test (IVGCT) was carried out to evaluate the effect of valsartan on the glucose utilization in vivo. The mRNA levels of the subtype 4 form of glucose transporter (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in the liver were detected by Northern blotting analysis. Moreover, the protein levels of GLUT4 in isolated soleus muscle and hepatic PEPCK were investigated using Western blotting analysis.. A single intravenous injection of valsartan decreased the plasma glucose concentrations in a dose-dependent manner in STZ-diabetic rats. Plasma glucose-lowering action of valsartan also observed in normal rats although in a way not so effective as that in STZ-diabetic rats. Valsartan at the dose of 0.2 mg/kg that produced the maximal plasma glucose-lowering activity in STZ-diabetic rats is also effective to lower the SBP. However, oral treatment with nifedipine or nicorandil in STZ-diabetic rats at the dose sufficient to decrease SBP showed no change of plasma glucose. Otherwise, infusion of saralasin (10 microg/kg per min) into STZ-diabetic rats produced a plasma glucose-lowering activity similar to that by valsartan at 0.2 mg/kg. Moreover, valsartan (0.2 mg/kg) significantly attenuated the raise of plasma glucose induced by IVGCT in normal rats. Repeated intravenous administration of valsartan (0.2 mg/kg) in STZ-diabetic rats resulted in the lowering of plasma glucose after 3 days. The mRNA and protein levels of GLUT4 in the soleus muscle were increased after repeated intravenous administration of valsartan in STZ-diabetic rats for 3 days. Moreover, similar repeated treatment with valsartan reversed the elevated mRNA and protein levels of PEPCK in the liver of STZ-diabetic rats.. These results suggest that the plasma glucose-lowering activity of AT(1) receptor antagonism was associated with an increase in the glucose utilization in peripheral tissue and/or a reduction in hepatic gluconeogenesis in the absence of insulin.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Glucose; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Gene Expression; Glucose Tolerance Test; Glucose Transporter Type 4; Hyperglycemia; Liver; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Nicorandil; Nifedipine; Phosphoenolpyruvate Carboxykinase (GTP); Rats; Rats, Wistar; RNA, Messenger; Saralasin; Tetrazoles; Valine; Valsartan

Fetal plasma angiotensin II levels are 10 times the levels found in adults. Despite these high levels, central injection of angiotensin II may stimulate fetal swallowing and increase fetal arterial blood pressure. We postulated that the high rate of spontaneous fetal swallowing and normal fetal pressor regulation may be dependent, in part, on central angiotensin II. In view of the potential dipsogenic role of both type 1 and type 2 angiotensin II receptors, we examined the central effect of the nonselective angiotensin II receptor antagonist saralasin on fetal swallowing and cardiovascular responses.. Six time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and intracerebroventricular catheters, electrocorticograms, and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. After an initial 2-hour baseline period (0 to 2 hours), saralasin (1 mL, 64 microg) was injected intracerebroventricularly (2 to 4 hours). After 4 hours the dose of saralasin was repeated together with angiotensin II (1 mL, 6.4 microg), and the fetuses were monitored for a final 2 hours. Four fetuses also underwent an identical control study (on an alternate day) in which saralasin was replaced with artificial cerebrospinal fluid.. Blockade of central angiotensin II receptors by intracerebroventricular saralasin significantly reduced mean (+/- SEM) spontaneous fetal swallowing (1.3 +/- 0.1 to 0.4 +/- 0.1 swallows per minute; P <.001) but did not alter fetal mean blood pressure (50 +/- 5 versus 56 +/- 5 mm Hg). Intracerebroventricular angiotensin II, in the presence of saralasin, did not affect swallowing (0.6 +/- 0.1 swallows per minute) or fetal blood pressure. In the control study, intracerebroventricular artificial cerebrospinal fluid did not change fetal swallowing (0.9 +/- 0.1 versus 1.0 +/- 0.1 swallows per minute), whereas intracerebroventricular angiotensin II significantly increased swallowing activity (1.0 +/- 0.1 versus 2.0 +/- 0.1 swallows per minute; P <.001) and fetal blood pressure (51 +/- 2 to 59 +/- 3 mm Hg; P =.003).. Tonic activity of central angiotensin II receptor stimulation contributed to the high rate of basal ovine fetal swallowing but not fetal basal blood pressure. Angiotensin II-mediated fetal dipsogenic and pressor responses are a result of specific angiotensin II receptor binding in central brain regions. These results indicate that fetal exposure to angiotensin II antagonists or angiotensin-converting enzyme inhibitors may have adverse effects on fetal and amniotic fluid homeostasis.

Topics: Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiovascular System; Deglutition; Disease Models, Animal; Female; Fetal Blood; Fetus; Heart Rate; Injections, Intraventricular; Pregnancy; Pregnancy, Animal; Probability; Receptors, Angiotensin; Reference Values; Saralasin; Sensitivity and Specificity; Sheep

We examined the effects of U-97018, an AT1 receptor antagonist, on the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin II (AII) in conscious normotensive rats in comparison to losartan, EXP 3174, EXP 655, and saralasin. In an i.c.v. study, U-97018, losartan, and EXP 3174 reduced the pressor response. EXP 655, an AT2 selective antagonist, also inhibited the pressor response to i.c.v. AII. U-97018 combined with EXP 655 did not fully eliminate the pressor response to i.c.v. AII. Moreover, saralasin, a nonselective peptide AII antagonist, also failed to abolish the pressor response to i.c.v. AII. Therefore, both AT1- and AT2-receptors probably are functional in inhibiting the pressor response to i.c.v. AII and that a part of the i.c.v. AII-induced pressor response occurs through non-AT1- and non-AT2-receptors. In an intravenous (i.v.) study, U-97018, losartan, and EXP 3174 reduced the pressor response to i.c.v. AII. At 10 mg/kg orally (p.o.), which is an antihypertensive dose in spontaneously hypertensive rats (SHR), neither U-97018 nor losartan reduced the pressor response to i.c.v. AII even at 180 min after administration. This result indicates that neither U-97018 nor losartan, at the oral antihypertensive dose, reaches the brain in sufficient amount to affect the pressor response to i.c.v. AII.

Topics: Administration, Oral; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Imidazoles; Injections, Intravenous; Injections, Intraventricular; Losartan; Male; Pyridazines; Pyridines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Saralasin; Tetrazoles

We have previously shown that rats with congenital, unilateral hydronephrosis exhibit a reduction in GFR that returns to normal when either the renin angiotensin system or thromboxane A2 (TxA2) is blocked. The current study defines the single nephron defect in congenital, unilateral hydronephrosis and evaluates the roles of angiotensin II (Ang II) and TxA2 in this renal derangement. Renal micropuncture experiments were performed on the right kidney of rats from an inbred colony with unilateral right-sided hydronephrosis (HYDRO), or non-affected litter mates (CONTROL). In addition, four separate groups of hydronephrotic animals were treated with either the TxA2 receptor antagonist SQ-29548 (SQ), one of two Ang II receptor antagonists [saralasin (SAR) or DuP-753 (DUP)]; or combined treatment with DuP-753 and SQ-29,548 (S&D). SNGFR was significantly reduced (P < 0.05) in HYDRO compared to CONTROL (17.6 +/- 2.0 vs. 35.9 +/- 3.7 nl/min, respectively). Treatment with SQ-29,548 normalized SNGFR (29.0 +/- 3.0 nl/min), while saralasin and DuP-753 resulted in only a partial recovery of function (25.6 +/- 1.6 and 27.8 +/- 1.4 nl/min, respectively). Combined SQ-29,548 and DuP-753 treatment resulted in full recovery of SNGFR to 32.9 +/- 4.4 nl/min. The glomerular ultrafiltration coefficient (Kf) was reduced (P < 0.05) approximately 45% in HYDRO compared to CONTROL (1.64 +/- .08 vs. 2.84 +/- .22 nl/min/mm Hg, respectively). Kf returned to control levels in SAR, DUP and SQ, and increased above control in S&D (5.58 +/- 1.6 nl/min/mm Hg). There were no differences (P > 0.05) in hydrostatic or oncotic pressures across the glomerular capillary between any of the groups studied. The observation that Kf increases above CONTROL with combined blockade of TxA2 and Ang II suggests that these regulatory hormones decrease Kf via independent mechanisms. These data indicate that the reduction in SNGFR in congenital, unilateral hydronephrosis is a result of a marked fall in Kf that is mediated by both Ang II and TxA2.

Topics: Angiotensin II; Animals; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Fatty Acids, Unsaturated; Glomerular Filtration Rate; Hydrazines; Hydronephrosis; Imidazoles; Kidney Glomerulus; Losartan; Male; Rats; Rats, Inbred Strains; Rats, Wistar; Saralasin; Tetrazoles; Thromboxane A2

Hypertension was produced in cynomolgus monkeys by reducing blood flow to the left kidney by 60% via renal artery stenosis (2-kidney, 1-clip). Significant increases in mean arterial blood pressure (MABP) were observed within two to three weeks. Maximum increase (from 95 +/- 6 mmHg to 130 +/- 7 mmHg) occurred at about four to six weeks following renal artery stenosis and was sustained for more than 24 weeks. Plasma renin activity (PRA) was elevated concomitantly with the increase in MABP. PRA was raised to 42 +/- 3 ng angiotensin I/ml/hr six weeks after renal artery stenosis from a control PRA of 3 +/- 0.7 ng angiotensin I/ml/hr. At six months post renal artery stenosis, PRA was 33.4 +/- 4.2 ng angiotensin I/ml/hr. The angiotensin II (AII) receptor antagonist saralasin, the angiotensin I converting enzyme inhibitor captopril, and the renin inhibitor CGP 38,560 produced sustained reductions in MABP. The antihypertensive response to the renin inhibitor CGP 38,560 was associated with a reduction in PRA of greater than 99%, and a greater than 90% reduction in immunoreactive AII. These studies demonstrate that high-renin hypertension can be induced in the cynomolgus monkey. This pathological model provides a useful method for investigating the antihypertensive effects of agents which antagonize the renin-angiotensin system in a nonhuman primate.

Topics: Angiotensin II; Animals; Blood Pressure; Captopril; Disease Models, Animal; Hypertension, Renovascular; Macaca fascicularis; Male; Oligopeptides; Renal Artery Obstruction; Renin; Saralasin

During acute angiotension II (Ang II) infusion (200 ng/kg/min i.v.) into anesthetized rats, mean arterial pressure rose from 124 +/- 1 to 154 +/- 2 mm Hg. The peptidic Ang II antagonist saralasin lowered arterial pressure in a dose-dependent manner. The maximal decrease in pressure was similar to that observed after the Ang II infusion was discontinued. The nonpeptide Ang II antagonist, 4'-[( 2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole-1-yl] methyl) [1,1'-biphenyl] -2-carboxylic acid (SC-48742), lowered acutely elevated arterial pressure to a level similar to that on discontinuation of the angiotensin infusion. Chronic (8 days) infusion of Ang II (20 ng/kg/min i.v.) increased mean arterial pressure from 116 +/- 3 to 164 +/- 7 mm Hg, which then decreased to 121 +/- 6 mm Hg on termination of the infusion. Saralasin (10 micrograms/kg/min, a maximally effective dose during acute angiotensin infusion) decreased mean arterial pressure from 168 +/- 7 to 141 +/- 3 mm Hg, a pressure significantly higher (p less than 0.05) than the pressure observed after the angiotensin infusion was discontinued. SC-48742 decreased mean arterial pressure from 167 +/- 7 to 127 +/- 3 mm Hg, a pressure not statistically different from the minimum pressure observed after the angiotensin infusion was terminated. The mechanism of blood pressure elevation during acute high dose or chronic low dose Ang II infusion is different, the latter having a significant neural component as measured by the response to trimethaphan. The peptidic antagonist saralasin was fully effective in lowering acute angiotensin hypertension but only partially effective during chronic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Imidazoles; Infusions, Intravenous; Male; Rats; Rats, Inbred Strains; Saralasin

We studied the response of the renin-angiotensin system (RAS) to a surgically created ventricular septal defect (VSD) in immature ovines and also the role of angiotensin II in the pathophysiology of VSD in the chronically instrumented ovine. Plasma renin activity (PRA) was increased from 2.39 +/- 1.1 to 3.78 +/- 1.4 ng/ml/hr (p less than 0.05, n = 17) after VSD but not after sham procedure. The change in PRA was positively correlated with the amount of left-to-right shunt through the VSD (r = 0.74, p less than 0.05). Inhibition of angiotensin II effect with saralasin (10 micrograms/kg/min) or angiotensin II production with captopril (2 mg/kg) lowered systemic resistance (Rs) by 14% and 34%, respectively (p less than 0.05), and raised pulmonary resistance (Rp) by 35% and 77%, respectively (p less than 0.05). Thirty minutes following captopril, the ratio of pulmonary to systemic flow (Qp/Qs) decreased from 3.31 +/- 0.18 to 2.15 +/- 0.18 (p less than 0.05) while total pulmonary flow fell from 7.15 +/- 0.38 to 5.92 +/- 0.34 l/min/M2 (p less than 0.05, n = 11). Systemic flow increased from 2.17 +/- 0.14 to 2.86 +/- 0.33 l/min/M2 (p less than 0.05) despite a reduction in left atrial pressure (17.3 +/- 1.0 vs. 13.0 +/- 1.7, p less than 0.01). Reinfusion of angiotensin II (0.02 micrograms/kg/min) into the central aorta after captopril returned the hemodynamics to baseline including a rise in Rs and fall in Rp. Exogenous angiotensin II alone (0.08 micrograms/kg/min) or a threefold stimulation in PRA with furosemide (2 mg/kg) caused little hemodynamic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Captopril; Disease Models, Animal; Furosemide; Heart Septal Defects, Ventricular; Hemodynamics; Renin; Renin-Angiotensin System; Saralasin; Sheep; Sheep Diseases

A unilateral model of puromycin aminonucleoside (PAN)-induced albuminuria was produced in Munich-Wistar rats to examine the mechanisms responsible for renal salt retention. 2 wk after selective perfusion of left kidneys with PAN (n = 8 rats) or isotonic saline (control, n = 7 rats), increases in albumin excretion and decreases in sodium excretion were demonstrated in PAN-perfused but not in nonperfused kidneys of PAN-treated rats although systemic plasma protein concentration remained at control level. Total kidney glomerular filtration rate (GFR) and superficial single nephron (SN) GFR were also reduced selectively in PAN-perfused kidneys, on average by approximately 30%, due primarily to a marked decline in the glomerular capillary ultrafiltration coefficient (Kf), which was also confined to PAN-perfused kidneys. Values for absolute proximal reabsorption (APR) were also selectively depressed in PAN-perfused kidneys, in keeping with a similarly selective decline in peritubular capillary oncotic pressure measured in these kidneys, the latter also a consequence of the fall in Kf. In a separate group of seven PAN-treated rats, however, no differences were detected between PAN-perfused and nonperfused kidneys in the absolute amount of sodium reaching the early (0.77 +/- 0.09 neq/min vs. 0.74 +/- 0.08, P greater than 0.40) and late portions of superficial distal tubules (0.31 +/- 0.02) neq/min vs. 0.32 +/- 0.05, P greater than 0.50), despite the lesser filtered load of sodium in PAN-perfused kidneys. Suppressed sodium reabsorption in both proximal convoluted tubules and short loops of Henle of PAN-perfused kidneys contributed to this equalization of sodium delivery rates to the late distal tubule, as did comparable reabsorption along distal convolutions. In two additional groups of PAN-treated rats, infusion of saralasin (0.3 mg/kg per h, i.v.) led to substantial increases in total kidney GFR and SNGFR in PAN-perfused but not in nonperfused kidneys. Despite these increases in total and SNGFR, urinary sodium excretion by PAN-perfused kidneys remained at a level far below that for nonperfused kidneys, again indicating that the antinatriuresis characterizing the PAN-perfused kidney is due to alterations in sodium handling by the tubules rather than changes in GFR. These results therefore indicate (a) that reductions in Kf and depressed sodium reabsorption by proximal tubules and Henle's loop segments in this model are brought about by intrarenal rather than circ

Topics: Animals; Disease Models, Animal; Glomerular Filtration Rate; Hemodynamics; Kidney Glomerulus; Kidney Tubules, Proximal; Microscopy, Electron; Nephrotic Syndrome; Rats; Saralasin; Sodium

An attempt was made to produce one-clip, one-kidney hypertension in the rat with diabetes insipidus (DI). Renal artery constriction in unilaterally nephrectomized DI rats (DI-clip) resulted in an increased blood pressure in all 9 rats, but this response was only transient in 3 rats. The magnitude of the hypertension was less in the DI-clip rats than in Long-Evans rats subjected to the same protocol (LE-clip). Infusion of saralasin i.v. at doses of 10 and 30 micrograms/kg . min. 4 to 6 weeks after surgery was without effect on mean arterial pressure in LE-clip and control DI rats, but substantially lowered blood pressure in the DI-clip rats (p less that 0.05 - 0.01). It is concluded that vasopressin is not essential for the production of one-clip, one kidney hypertension in the rat, and that, in the DI rat, the renin-angiotensin system is an important factor in this form of hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Diabetes Insipidus; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension, Renal; Hypertension, Renovascular; Hypothalamic Diseases; Male; Muridae; Saralasin; Vasopressins; Water-Electrolyte Balance

The blood pressure response to different doses of methylprednisolone was examined in the rat. It is concluded that doses varying from 2.5 mg/kg/week to 20 mg/kg/week of this agent caused clear-cut elevations in arterial pressure. The methylprednisolone-induced arterial hypertension was accompanied by elevation in Plasma Renin Activity and administration of captopril or saralasin caused significant drops in systemic arterial pressure. Concomitant long term administration of captopril and methylprednisolone caused a delay in appearance and smaller elevations in arterial pressure. It is concluded the methylprednisolone in the rat causes arterial hypertension which is at least partially dependent upon renin angiotensin system activation. However elevated blood pressure levels were noticeable even during chronic captopril administration leading to the conclusion that other mechanism (s) may participate in the pathogenesis of this experimental model of hypertension in rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Captopril; Disease Models, Animal; Hypertension; Male; Methylprednisolone; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Saralasin

During fetal life, the autonomic nervous system is not fully mature, and it is likely that hormonal mechanisms play an important role in controlling cardiovascular function. In chronically instrumented fetal sheep, hemorrhage increased plasma renin activity and plasma angiotensin concentration significantly from 6.7 +/- 2.5 to 15.2 +/- 3.1 ng.ml-1.h-1 and from 74 +/- 19 to 182 +/- 43 pg/ml, respectively. Both mean arterial and venous blood pressures decreased initially from 45 to 35 Torr and from 3.5 to 2.5 Torr, respectively; then both returned to control values. Fetal heart rate decreased initially from 174 beats/min and then increased to 186 beats/min. To determine whether angiotensin had a role in mediating these responses to hemorrhage, we hemorrhaged a second group of fetuses before and during infusion of saralasin, a competitive antagonist of angiotensin. Hemorrhage during infusion of saralasin decreased heart rat from 170 to 145 beats/min and further decreased mean arterial pressure to 30 Torr. Cardiac output decreased from 436 +/- 25 to 368 +/- 30 ml.min-1.kg-1, and umbilical-placental blood flow decreased from 205 +/- 20 to 145 +/- 10 ml.min-1.kg-1. We conclude that the renin-angiotensin system plays a major role in the response to hemorrhage in fetal sheep.

Topics: Angiotensin II; Animals; Blood Pressure; Disease Models, Animal; Female; Fetal Blood; Fetal Diseases; Fetus; Heart Rate; Hematocrit; Hemorrhage; Pregnancy; Renin; Saralasin; Sheep

1. The peptide converting enzyme inhibitor captopril was given (1.25 mg/kg intravenously) to normal and nephrectomized rats and rats with renovascular and deoxycorticosterone hypertension. 2. Captopril lowered blood pressure to a small extent in normal and nephrectomized rats. Bradykinin infusion in nephrectomized animals, however, potentiated the vasodepressor action of captopril. 3. Captopril produced a major blood pressure fall in the early stages of Goldblatt two-kidney one-clip hypertension: even when hypertension had been present for more than 4 months, a substantial vasodepressor action was seen. Rats with deoxycorticosterone-induced hypertension also showed a significant blood pressure fall. 4. Captopril was given to salt-loaded and salt-depleted rats in which the renin-angiotensin system had been blocked by infusion of the competitive angiotensin II antagonist saralasin. Captopril still lowered blood pressure in the salt-depleted group. 5. Captopril lowers blood pressure in situations where the renin-angiotensin system is not responsible for blood pressure maintenance. Further, the fall in blood pressure produced in Goldblatt two-kidney one-clip hypertension is greater than would be predicted on the basis of renin-angiotensin blockade. It is likely therefore that captopril lowers blood pressure by an action additional to angiotensin blockade. Bradykinin potentiation is one possible mechanism by which this may take place.

Topics: Angiotensin II; Animals; Blood Pressure; Bradykinin; Captopril; Disease Models, Animal; Female; Hypertension; Nephrectomy; Proline; Rats; Renin; Saralasin

In two-kidney Goldblatt hypertensive, spontaneously hypertensive, and normotensive control rats, the activity of the renin-angiotensin system was tested during variation of sodium balance. Acute, exactly calculable and selective changes in total body sodium were achieved by haemodialysing conscious rats, using dialysates with high and low sodium contents. The activity of the renin-angiotensin system was evaluated by blood pressure response to angiogtensin II blockade (saralasin bolus injection; 25 micrograms/kg b.w., i.v.) and plasma renin activity. During sodium-depletion, blood pressure maintenance became renin-dependent; sodium-loading caused a decrease of renin-angiotensin activity in renovascular hypertension. A weak direct correlation between depressor response to saralasin and the plasma renin activity could be established in the different sodium-depleted and sodium-loaded states.

Topics: Animals; Blood Pressure; Disease Models, Animal; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Rats; Renal Dialysis; Renin; Saralasin; Sodium

Determinants of glomerular ultrafiltration were studied by micropuncture in clamped (n = 11) and unclamped (n = 7) kidneys of two-kidney hypertensive rats and compared to 15 controls. Infusion of the angiotensin II antagonist and saralasin lowered the blood pressure significantly. Glomerular capillary pressure (PGC) in clamped kidneys was decreased to 56 +/- (SD) 3 vs. 61 +/- 3 mm Hg in controls. Early proximal flow rate (EPFR) was decreased to 20 +/- 1 vs. 26 +/- 2 nl/min in controls, at an unchanged single nephron filtration fraction (SNFF), indicating a reduced glomerular plasma flow (SNGPF). Preglomerular resistance (RA) was increased by 21%. In unclamped kidneys PGC was increased to 65 +/- 2 mm Hg. EPFR was increased to 32 +/- 2 nl/min, indicating, at an unchanged SNFF, an increased SNGPF. RA increased by 51%, whereas postglomerular resistance declined by 25%. The ultrafiltration coefficient was reduced by 24% in unclamped kidneys. Our results indicate that in clamped kidneys an increase of RA causes a reduction of PGC and hence a reduction of pressure at the baroreceptor site which may act as a trigger mechanism for renin release.

Topics: Animals; Disease Models, Animal; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Tubules, Proximal; Rats; Renal Artery Obstruction; Saralasin

1 Prolonged infusion (11 h) of both saralasin and angiotensin-converting enzyme inhibitor (SQ20881) gradually lowered BP in two-kidney hypertensive rats to levels similar to that in normotensive rats infused with dextrose. 2 Saralasin did not lower BP in DOCA-salt hypertensive rats. 3 These observations support the notion that in chronic renal hypertension, angiotensin II may maintain hypertension by a slowly developing action. 4 Plasma angiotensin II in rats infused with SQ20881 was suppressed relative to renin, but was not eliminated. 5 Chromatography of angiotensin II extracts from dogs infused with converting enzyme inhibitor (SQ14,225) showed that the very high levels of angiotensin I achieved after treatment with SQ14,225 can lead to falsely high estimated angiotensin II levels as a result of angiotensin I cross-reacting with the angiotensin II assay.

Topics: Angiotensin I; Angiotensin II; Angiotensin III; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Dogs; Female; Hypertension, Renal; Male; Oligopeptides; Proline; Rats; Saralasin; Teprotide

Amphotericin B (2.5 mg/kg, administered intravenously) increased vascular resistance (renal more than pulmonary more than systemic) and decreased glomerular filtration and urine flow 94% in 16 anesthetized female mongrel dogs. Dopamine decreased renal vascular resistance 31% in 14 dogs; when amphotericin B was given with dopamine, there was partial antagonism of amphotericin B-induced renal vasoconstriction. Saralasin partially antagonized amphotericin B-induced renal vasoconstriction in seven dogs. When amphotericin B was given during combined infusion of dopamine and saralasin in eight dogs, renal blood flow remained at initial control levels, urine flow increased above initial levels, and glomerular filtration decreased only 21% from initial values. Amphotericin B increased renal vascular resistance 296% when given alone but only 41% in dogs during injection of both dopamine and saralasin (P = 0.002). The antagonism of amphotericin B-induced renal effects by the combination of dopamine and saralasin was significant and specific for the renal vascular bed.

Topics: Amphotericin B; Angiotensin II; Animals; Anuria; Disease Models, Animal; Dogs; Dopamine; Female; Glomerular Filtration Rate; Kidney; Lung; Oliguria; Saralasin; Vascular Resistance

1. Synthesis of several pepstatin A derivatives was performed with the aim of increasing water solubility without altering the capacity to inhibit the renin-angiotensinogen reaction. 2. Pepstatinyl-arginine-O-methyl ester was studied in vitro and in vivo and compared with pepstatin A and with the arginine salt of pepstatin A. 3. This compound inhibited in vitro the reaction between purified hog renin and the synthetic renin N-acetyl-tetradecapeptide or the natural rat renin substrate. The inhibitory constant was of the same order of magnitude as that of pepstatin A. 4. In renal hypertensive rats, the bolus injection of pepstatinyl-arginine-O-methyl-ester or of the arginine salt of pepstatin decreased blood pressure to the same extent as a bolus injection of Sar1, Ala8-angiotensin II.

Topics: Animals; Disease Models, Animal; Hypertension, Renovascular; Male; Oligopeptides; Pepstatins; Rats; Renin; Saralasin; Solubility

Topics: Angiotensin II; Animals; Bile Ducts; Disease Models, Animal; Dogs; Female; Humans; Kidney Tubules; Ligation; Liver Cirrhosis, Experimental; Saralasin; Sodium

Topics: Angiotensin II; Animals; Blood Pressure; Disease Models, Animal; Dogs; Hypertension, Renal; Nephrectomy; Renin; Saralasin

Topics: Animals; Aorta, Abdominal; Aortic Coarctation; Blood Pressure; Disease Models, Animal; Dogs; Humans; Hypertension, Renal; Infant; Nephrectomy; Radiography; Renin; Saralasin

Changes in plasma renin activity (PRA) and sodium balance were studied in hypertensive rabbits and dogs with one renal artery constricted and the other kidney intact (two-kidney hypertension); aldosterone secretion was measured also in the chronic hypertensive rabbits. Both PRA and aldosterone secretion were normal in some chronic hypertensive rabbits but elevated in others. Sodium balance studies revealed that some severely hypertensive rabbits with elevated PRA were in spontaneous negative sodium balance. Unlike the rabbit, PRA was never increased in the chronic hypertensive dog and sodium balance was normal. Infusion of [Sar1, Ala8]angiotensin II (P-113) decreased arterial pressure and aldosterone secretion in those hypertensive rabbits with elevated PRA but not in those rabbits with normal PRA; P-113 also did not decrease arterial pressure in the chronic hypertensive dog unless sodium depletion was superimposed. In the conscious two-kidney dog, acute renal artery stenosis increased both arterial pressure and PRA within minutes, and P-113 blocked the rise in pressure associated with the increase in PRA. Therefore, although apparent species differences between the rabbit and the dog occur, the present data indicate that neither increased PRA nor excess salt retention is essential to the chronic maintenance of two-kidney hypertension in these two species; however, in the dog a role for angiotensin II in the acute phase is indicated.

Topics: Adrenal Cortex Hormones; Angiotensin II; Animals; Blood Pressure; Blood Urea Nitrogen; Disease Models, Animal; Dogs; Female; Hypertension, Renal; Male; Methods; Potassium; Rabbits; Renal Artery Obstruction; Renin; Saralasin; Sodium

Topics: Angiotensin II; Animals; Blood Pressure; Disease Models, Animal; Dogs; Enzyme Inhibitors; Humans; Hypertension; Pindolol; Propranolol; Rats; Renal Artery Obstruction; Renin; Saralasin

The effectiveness of beta-adrenergic blockade in preventing acute renal failure (A.R.F.) in rats was studied in the hypoxia model produced by unilateral nephrectomy and clamping of the contralateral renal artery for 70 minutes. Beta-adrenergic blockade effectively reduced the severity of A.R.F. in this experimental model. Treatment with a combination of propranolol and a synthetic angiotensin-II competitive inhibitor (P113) produced no further improvement. These results are consistent with the view that intrarenal release of renin is to some extent involved in the pathogenesis of A.R.F.

Topics: Acute Kidney Injury; Animals; Blood Specimen Collection; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Female; Kidney; Propranolol; Rats; Rats, Inbred Strains; Renin; Saralasin; Time Factors; Urea

An angiotensin II inhibitor was administered to rats with two-kidney Goldblatt hypertension. The inhibitor produced a marked drop in blood pressure after 5 weeks but no significant change after 15 weeks of hypertension. However, even after 15 weeks of hypertension, following sodium depletion by either diuretics or a low sodium diet, the animals again became renin dependent as readministration of the inhibitor induced a significant fall in blood pressure. The data indicate that two-kidney Goldblatt hypertension is initially renin dependent but subsequently becomes sodium volume dependent in a way similar, although more protracted, to that already described for one-kidney Goldblatt hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Depression, Chemical; Disease Models, Animal; Hypertension, Renal; Male; Rats; Renal Artery Obstruction; Renin; Saralasin; Sodium

Clonidine was nonhypotensive in conscious unrestrained rats maintained on a normal sodium intake. In contradistinction, clonidine caused a dose-related hypotension in conscious unrestrained rats subjected to sodium depletion via furosemide. The plasma renin activity of normal and sodium-depleted rats was reduced after the administration of clonidine (100 mug/kg, iv) by 22.8% and 34.4%, respectively. Intravenous infusion of an angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II, caused a significant reduction of arterial blood pressure in sodium-depleted rats but not in normal rats. Similarly, bilateral nephrectomy reduced arterial blood pressure and completely abolished the hypotensive effect of clonidine in sodium-depleted rats. Subcutaneous administration of chlorisondamine caused a significantly greater reduction of arterial blood pressure in sodium-depleted rats than it did in normal rats. Treatment of normal and sodium-depleted rats with 6-hydroxydopamine reduced the arterial blood pressure of both groups to approximately 85 mm Hg and completely abolished the hypotensive effect of clonidine in the sodium-depleted rats. The data presented in this paper are consistent with the conclusion that clonidine acts at some site in the sympathetic nervous system of sodium-depleted rats to inhibit renal nerve activity with a resultant suppression of renin secretion and a reduction of the angiotensin II-maintained arterial blood pressure. A similar sequence of events occurring in normal rats would not result in hypotension because their arterial blood pressure is not maintained by angiotensin II.

Topics: Animals; Blood Pressure; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Furosemide; Heart Rate; Hydroxydopamines; Hypertension; Hyponatremia; Hypotension; Male; Nephrectomy; Rats; Renin; Saralasin