Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure.

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure.

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (-30%) and medulla (-23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.

[The effect of a crown-ether derivative, ethmozine and etatsizin on the functioning of the calcium pools in the guinea pig myocardium]. / Vliianie proizvodnogo kraun-éfira, étmozina i étatsizina na funktsionirovanie kal'tsevykh pulov v miokarde morskikh svinok.

Analysis of the component structure of single contractions of papillary muscles in guinea pigs was used to study the effects of the crown ether derivative benzylase-15-crown-5 and the antiarrhythmic agents ethmozine and ethacizine. The negative inotropic effect of these compounds was shown to be associated with limited penetration of calcium ions from the sarcolemmal pool into cardiac cellular myoplasm.

[The anti-ischemic properties of crown ether derivatives]. / Protivoishemicheskie svoistva proizvodnykh kraun-éfirov.

Experiments on open-chest anaesthetized cats were made to test derivatives of crown ethers, such as benzylase-15-crown-5 and dibenzylase-15-crown-5 for their effects on myocardial ischemia and the functional status of a myocardial ischemic focus in temporary coronary occlusion during coronary spasm induced by dihydroergotamine and during coronary microthrombosis caused by ADP. When intravenously administered in doses of 0.5-15 mg/kg, the tested agents were found to enhance myocardial tolerance to ischemia, depressed ST segment in ischemia induced by coronary occlusion and administration of ATP, and prevented ST-segment depression during coronary spasm.

[The effect of verapamil on cardio- and hemodynamics in rats with various models of hypertension]. / Vliianie verapamila na kardio- i gemodinamiku krys s razlichnymi modeliami gipertenzii.

Rats with various models of hypertension (spontaneous, renal, neurogenic, adreno-regenerative) were used in experiments to study the effect of verapamil on parameters of cardio- and hemodynamics in its two-week oral administration. The antihypertensive effect of verapamil was most expressed in rats with spontaneous model of hypertension and initial hyperkinetic variant of circulation.

[The relationship between the magnitude of the negative inotropic action and chemical structure of crown-ether derivatives]. / Zavisimost' mezhdu velichinoi otritsatel'nogo inotropnogo deistviia i khimicheskoi strukturoi proizvodnykh kraun-éfirov.

The relationship between the inotropic effect and chemical structure of 15-crown-5 and 18-crown-6 derivatives was studied in experiments in open-chest anaesthesized cats, by using computer-aided analysis. The findings showed that the 15-crown-5 derivatives produced more pronounced cardiotropic effect and they were less toxic than 18-crown-6 derivatives. Computer-aided analysis revealed pharmacophoric groups which are responsible for cardiotropic (negative inotropic) activity in the series of crown ether derivatives.

[The anti-ischemic properties of verapamil and its effect on myocardial functional potentials in coronary artery occlusion]. / Antiishemicheskie svoistva verapamila i ego vliianie na funktsional'nye vozmozhnosti miokarda pri okkliuzii koronarnoi arterii.

The effect of verapamil on the functional state of the ischemic myocardium, the myocardial tolerance to ischemia and the processes of urgent adaptation of the heart in the coronary artery occlusion was investigated in the experiments on anesthetized open-chest cats. Verapamil was shown to exert the dose-dependent anti-ischemic action, to increase the myocardial tolerance to ischemia, to suppress the response to the physiological saline infusion and not to change adrenoreactivity of the ischemic myocardium at the coronary artery compression.

Renal effects of big endothelin-1 in experimental congestive heart failure.

The present study was designed to evaluate the effects of big endothelin (ET) on renal hemodynamics and excretory functions in rats with experimental congestive heart failure (CHF) produced by aortocaval fistula. Clearance studies were performed in control and in chronic (7 day) CHF rats. Administration of bit ET (1 and 3 nmol/kg, i.v.) to control rats caused an increase (29%) in mean arterial pressure (MAP) associated with a decrease (38%) in renal blood flow (RBF) and a marked increase (130%) in renal vascular resistance (RVR). These changes were accompanied by a decrease in glomerular filtration rate (GFR) and a significant increase in sodium excretion. In contrast, the effects of big ET on MAP and renal hemodynamics were blunted in CHF rats, and sodium excretion increased only minimally in response to big ET despite a significant increase in GFR. The data suggest that rats with CHF have reduced sensitivity to the vascular and renal action of ET.

[A comparative evaluation of the anti-ischemic action of verapamil in different models of myocardial ischemia]. / Sravnitel'naia otsenka antiishemicheskogo deistviia verapamila na razlichnykh modeliakh ishemii miokarda.

The effectiveness of the anti-ischemic effect of verapamil was studied on models of coronary spasm (the test with dihydroergotamine) and microthrombosis of the coronary arteries (the test with ADP). The results of the performed studies showed that verapamil exerts the anti-ischemic effect at administration of dihydroergotamine and ADP. The most pronounced effect of verapamil was demonstrated on the model of myocardial ischemia due to coronary spasm.

[An experimental study of the cardio- and hemodynamic effects of the carboxyl ionophore monensin]. / Eksperimental'noe izuchenie kardio- i gemodinamicheskikh éffektov karboksil'nogo ionofora monensina.

The effect of ionophore monensin on the main parameters of cardio- and hemodynamics was studied in the experiments on anesthetized cats. Monensin (0.075-0.375 mg/kg) administered intravenously in the increasing doses was shown to produce the dose-dependent elevation of arterial blood pressure, the increase of myocardial contractility and the total peripheral resistance. A single administration of monensin (0.375 mg/kg) was found to exert the two-phase action on the parameters of cardio- and hemodynamics.

Investigation of antiischemic properties and mechanism of action of azacrown ether derivative.

The influence of the azacrown ether derivative benzylaza-15-crown-5 on myocardial tolerance to ischemia and on the functional state of the zone of myocardial ischemia during coronary artery occlusion was investigated in experiments on anaesthetized open-chest cats. The compound tested produced a dose-dependent antiischemic effect and prevented the development of myocardial ischemia. In experiments on isolated guinea-pig papillary muscle benzylaza-15-crown-5 inhibited the first and second components of the isoproterenol-induced muscle contraction. The compound decreased the maximal contraction force and had no effect on the cardiac cycle duration and on the time necessary for reaching maximal tension. It is suggested that the protective effect of benzylaza-15-crown-5 during myocardial ischemia is mediated through the inhibition of calcium release from the sarcoplasmic reticulum.

[Effect of tranquilizers on myocardial function in stress injury]. / Vliianie trankvilizatorov na funktsional'noe sostoianie moikarda pri ego stressornom povrezhdenii.

Experiments on rats were performed to evaluate the action of diazepam (1 mg/kg), phenazepam (1 mg/kg), meprotan (25 mg/kg), mebicar (500 mg/kg), and phenibut (25 mg/kg) on myocardial function under stress-induced injury. Diazepam, phenazepam and phenibut protected the myocardium from stress by raising the functional reserves of the heart. Meanwhile meprotan and mebicar produced no stress-protective action on the heart under similar conditions.

Differential effect of endothelin-1 on renal regional blood flow: role of nitric oxide.

This study evaluated the effects of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively) and the interactions with other local vasoactive systems in the regulation of renal regional blood flow. CBF and MBF were measured simulataneously by laser-Doppler flowmetry in anesthetized Wistar rats. Administration of ET-1 (1.0 nmol/kg, i.v.) produced a decrease in CBF (delta = -20%) and at the same time increased MBF (delta = +24%). In the presence of nitric oxide (NO) blockade by L-NAME, the vasodilatory effect of ET-1 on MBF was completely blocked and actually reversed (delta = -19%), whereas the cortical vasconstrictor effect was potentiated (delta = -31%). Cycloxygenase inhibition with indomethacin attenuated the vasodilator effect of ET-1 on MBF (delta = +12%) but did not affect the changes in CBF. Therefore, ET-1 exerts a differential effect on intrarenal regional blood flow, i.e., a decrease in CBF and an increase in MBF. The medullary vasodilator action of the peptide is dependent on an intact NO system and, to a lesser extent, on prostaglandin synthesis.

Urinary neutral endopeptidase 24.11 activity: modulation by chronic salt loading.

Neutral endopeptidase (NEP) 24.11 is a zinc-metallopeptidase involved in the metabolism of several biologically active peptides including enkephalin, atrial natriuretic peptide, bradykinin, and endothelin. The enzyme is found in abundant amounts in the brush border of renal proximal epithelial cells. A soluble form of NEP was previously identified in human urine with characteristics similar to the renal enzyme. The present study further characterized the excreted form of NEP activity in urine of normal rats using a sensitive two-stage enzymatic assay. The response of urinary NEP to known inhibitors such as phosphoramidon and thiorphan, and its dependence on pH and salt concentration was studied. In addition, we evaluated the effects of acute and chronic changes in salt balance, induced by i.v. saline infusion and drinking of saline solution, on urinary NEP and on the activity of the enzyme in isolated proximal tubules. Our findings demonstrated that abundant NEP activity was detected in the urine of normal rats. Furthermore, chronic salt loading, but not acute salt infusion, was associated with increased activity of NEP in urine and in isolated proximal tubules, suggesting that the enzyme may be regulated by salt balance. Finally, the data suggest that urinary NEP may be used as an index of enzyme activity in the kidney.

Regulation of intrarenal blood flow in experimental heart failure: role of endothelin and nitric oxide.

Congestive heart failure(CHF) is associated with a marked decrease in cortical blood flow and preservation of medullary blood flow. In the present study we tested the hypothesis that changes in the endothelin (ET) and nitric oxide (NO) systems in the kidney may contribute to the altered intrarenal hemodynamics in rats with aortocaval fistula, an experimental model of CHF. Cortical and medullary blood flow were measured simultaneously by laser-Doppler flowmetry in controls and rats with compensated and decompensated CHF. As previously reported [K. Gurbanov, I. Rubinstein, A. Hoffman, Z. Abassi, O. S. Better, and J. Winaver. Am. J Physiol. 271 (Renal Fluid Electrolyte Physiol. 40): F1166-F1172, 1996], administration of ET-1 in control rats produced a sustained cortical vasoconstriction and a transient medullary vasodilatory response. In rats with decompensated CHF, cortical vasoconstriction was severely blunted, whereas ET-1-induced medullary vasodilation was significantly prolonged. This prolonged response was mimicked by IRL-1620, a specific ETB agonist, and partially abolished by NO synthase (NOS) blockade. In line with these findings, expression of ET-1, ETA and ETB receptors, and endothelial NOS (eNOS), assessed by RT-PCR, and eNOS immunoreactivity, assessed by Western blotting, was significantly higher in the medulla than in the cortex. Moreover, expression of ET-1 mRNA in the cortex and eNOS mRNA in the cortex and the medulla increased in proportion to the severity of heart failure. These findings indicate that CHF is associated with altered regulation of intrarenal blood flow, which reflects alterations in expression and activity of the ET and NO systems. It is further suggested that exaggerated NO activity in the medulla contributes to preservation of medullary blood flow in the face of cortical vasoconstriction in CHF.

Differential regulation of renal regional blood flow by endothelin-1.

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

Renal effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine, a novel selective inhibitor of neutral endopeptidase 24.11 (Neprilysin): comparison with SQ 28,603.

The effects of 2-mercaptoacetyl-L-leucyl-L-phenylalanine (MA-LF) on the activity of neutral endopeptidase and on renal hemodynamics and excretory function were investigated in experiments in vitro and in vivo. In vitro studies showed that the compound effectively inhibited purified bovine kidney neutral endopeptidase (Ki = 0.012 microM), while having slight influence on the activity of angiotensin I converting enzyme (Ki = 0.14 microM). In experiments on normal anesthetized rats (thiobutabarbital sodium salt, 100 mg/kg), IV administration of MA-LF (20 and 60 mg/kg) produced a dose-dependent increase in absolute rate and fractional excretion of sodium (+324% and +299%, respectively) and urinary flow rate (+261%), but did not change renal and systemic hemodynamics. Renal excretory effects of the new compound were comparable to those of the selective neutral endopeptidase inhibitor SQ 28,603. These results demonstrate that MA-LF is a potent neutral endopeptidase inhibitor with prominent natriuretic and diuretic properties.

[Effect of tranquilizers on the course of myocardial ischemia and on myocardial resistance to hypoxia in coronary artery occlusion]. / Vliianie trankvilizatorov na techenie ishemii miokarda i na ustoichivost' miokarda k gipoksii pri okkliuzii koronarnoi arterii.

It was shown that meprobamate and phenazepam protect the myocardium from hypoxia and decrease myocardial ischemia during coronary occlusion. Phenibut and mebicar reduce the tolerance to ischemia and increase the degree of ischemic injury to the heart. Diazepam has no effect on these processes.