Biomedical subjects

H Iwao

Publications and source records attributed to H Iwao.

At least 73 records · Page 4Linked to original sources

PubMed1997

Imidapril inhibits increased transforming growth factor-beta1 expression in remnant kidney model.

To elucidate the effect of imidapril, an angiotensin-converting enzyme inhibitor, on molecular events in progressive glomerulosclerosis, we administered imidapril to 5/6 nephrectomized rats and measured the glomerular expression of genes for transforming growth factor (TGF)-beta1, fibronectin and collagen IV. Glomerular TGF-beta1, fibronectin and collagen IV mRNAs in nephrectomized rats were significantly higher than those in sham-operated rats. Treatment with imidapril for 10 weeks significantly reduced the enhanced glomerular expression of TGF-beta1 and collagen IV mRNA in nephrectomized rats, and prevented the associated proteinuria and glomerulosclerosis. Thus, imidapril may arrest progressive glomerulosclerosis by inhibiting the expression of TGF-beta1 and collagen IV.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activities are continuously and differentially increased in aorta of hypertensive rats.

We first examined the activities of extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs) in the aorta of hypertensive rats. In Dahl salt-sensitive (DS) rats, chronic hypertension caused by a high-salt diet was followed by sustained activation of aortic p42ERK and p44ERK. p46JNK and p55JNK activities were also increased in hypertensive DS rats, but returned to control levels earlier than ERKs, suggesting that ERKs and JNKs may be independently activated in hypertensive rats. In stroke-prone spontaneously hypertensive rats (SHRSP) which spontaneously develop hypertension under a low salt-diet, aortic p42ERK and p44ERK activities were progressively increased with the development of hypertension, compared with control normotensive rats. p46JNK and p55JNK activities in SHRSP were increased, with a different time course from ERKs. Thus, we first demonstrated that ERKs and JNKs activities are chronically and differentially increased in the aorta of hypertensive rats, suggesting the involvement of these kinases in hypertensive vascular diseases.

Animals↗

PubMed1997

Inhibition of nitric oxide synthase causes cardiac phenotypic modulation in rat.

Cardiac gene expressions of collagen and contractile proteins were examined in rats treated with a nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), for 3 weeks. The rats became hypertensive, which caused left ventricular hypertrophy. Among the mRNAs examined, beta-myosin heavy chain was increased and alpha-myosin heavy chain was decreased in both left and right ventricles, whereas skeletal alpha-actin and atrial natriuretic polypeptide were increased in the left ventricle only. Furthermore, coadministration of losartan with L-NAME lowered blood pressure and caused regression of left ventricular hypertrophy, but did not affect beta- and alpha-myosin heavy chain mRNA levels, indicating that L-NAME directly regulates beta- and alpha-myosin heavy chain mRNA.

Angiotensin II↗

PubMed1997

Differences in expression of sarcoplasmic reticulum Ca2+-ATPase and Na+-Ca2+ exchanger genes between adjacent and remote noninfarcted myocardium after myocardial infarction.

Although cardiac failure can develop over time after myocardial infarction, the mechanism responsible for this is still unknown. The change of intracellular Ca2+ transport protein, such as sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+-Ca2+ exchanger (Na+-Ca2+), or cardiac phenotypic modulation of contractile protein in noninfarcted myocardium may have a important role. However, the time course in gene expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+-Ca2+ exchanger (Na+-Ca2+), and contractile protein in the adjacent and remote noninfarcted myocardium after myocardial infarction has not been examined. At 1, 3 weeks and 3 months after myocardial infarction, hemodynamics were measured and mRNA of the left ventricle was analyzed. Left ventricular end-diastolic volume and weight increased both with time. Ascites became apparent at 3 months after infarction. SR-Ca2+ mRNA levels in the adjacent noninfarcted myocardium were 0.7- (P<0.01), 0.9- (N.S.), and 0.7-fold (P<0.01) of control, and Na+-Ca2+ mRNA levels were 2.1- (P<0.01), 1.4- (P<0.01), and 0.8-fold (P<0.01) of control, at 1, 3 weeks and 3 months after infarction, respectively. beta-Myosin heavy chain (MHC) mRNA was increased to 2.1- (P<0.01), 1.5- (P<0.01), and 1.4-fold (P<0.01), and alpha-skeletal actin was increased to 2.4- (P<0.01), 3.8- (P<0.01), and 1.6-fold (P<0.01) control levels, at 1 week, 3 weeks and 3 months, respectively. In contrast, alpha-MHC mRNA level was decreased at 1 week and 3 months after infarction. alpha-cardiac actin mRNA level did not change over time after infarction. In the remote non-infarcted myocardium, beta-MHC, alpha-skeletal actin, and Na+-Ca2+ mRNA levels were increased, but SR-Ca2+, alpha-MHC, and alpha-cardiac actin mRNA did not change after infarction. These findings suggest that: (1) intracellular Ca2+ handling system after myocardial infarction may be different between adjacent and remote non-infarcted myocardium: and that (2) both decreased gene expression of SR Ca2+-ATPase and Na+-Ca2+ exchanger in the adjacent non-infarcted myocardium may progress cardiac dysfunction.

Animals↗

PubMed1997

Increased expression of transforming growth factor-beta1 during gastric ulcer healing in rats.

This study was done to investigate the expression and localization of transforming growth factor-beta1 (TGF-beta1) in the gastric ulcerated tissues produced by acetic-acid during the healing process, by northern blot analysis and immunohistochemical technique. Ulcerated TGF-beta1 mRNA levels were significantly increased from days 3 to 18, in a similar manner to extracellular matrix proteins, and returned to control levels at the scarred phase. Immunoreactive TGF-beta1 was localized in epithelial cells beneath proliferative zone in intact tissues. In ulcerated tissues, TGF-beta1 was localized in macrophages in the ulcer bed and in fibroblasts or myofibroblasts in the granulation tissues. Treatment with prostaglandin E1 (PGE1) further stimulated ulcerated TGF-beta1 expression, being associated with the acceleration of gastric ulcer healing, while treatment with indomethacin reduced TGF-beta1 expression, being accompanied by the delayed ulcer healing. The combination of PGE1 and indomethacin reversed the indomethacin-induced decrease in ulcerated TGF-beta1. Thus, TGF-beta1 may be implicated in the acceleration of gastric ulcer healing.

Acetic Acid↗

PubMed1997

Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats.

1. Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats. 2. Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 mumol kg-1, for 20 min) induced a very small fall in blood pressure. Similarly, a non-selective ETA/ETB receptor antagonist, TAK-044 (12.5 mumol kg-1, for 20 min) slightly decreased blood pressure. A selective ETB receptor antagonist, BQ-788 (0.5 mumol kg-1, for 20 min) had no effect of blood pressure. 3. FR139317 and TAK-044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ-788 significantly reduced renal blood flow by 18.2 +/- 2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ-788 was not observed when combined with FR139317. 4. Pretreatment with a nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 37 mumol kg-1, i.v.) and a cyclo-oxygenase inhibitor ibuprofen (44 mumol kg-1, i.v.) completely abolished the BQ-788-mediated renal vasoconstriction. 5. These results indicate that activation of ETB receptors by endogenous ET acts as a physiological brake for the ETA-mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.

Animals↗

PubMed1997

Rapid expression and specific localization of tenascin in gastric ulcer healing in rats.

This study was done to investigate the gene expression and localization of tenascin in ulcerated gastric tissues during the healing process with Northern blot analysis and immunohistochemical technique. Gastric ulcers in rats were produced by acetic acid. Tenascin mRNA levels in the ulcerated tissue were significantly increased in a biphasic manner (12 h and day 5), preceding the increase in collagen type IV and laminin mRNA levels, and returned to control levels on day 11. In intact tissues, tenascin was mainly localized in the basement membrane above the proliferative zone, in contrast to the predominant localization of collagen type IV and laminin below the proliferative zone. On the ulcer margin from 12 h to day 5, tenascin was abundantly observed in the lamina propria around nonproliferating new epithelial cells, but collagen type IV and laminin were not seen in this lamina propria. On day 7, tenascin, expressed in the lamina propria, was replaced by collagen type IV and laminin. Thus, the rapid expression and unique localization of tenascin suggest the important role of tenascin in gastric ulcer healing.

Animals↗

PubMed1997

Characteristics of diabetes, blood pressure, and cardiac and renal complications in Otsuka Long-Evans Tokushima Fatty rats.

To characterize the molecular mechanism of cardiac and renal complications in non-insulin-dependent diabetes mellitus (NIDDM), we examined the gene expression of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new animal model for human NIDDM, at the ages of 14 weeks (prediabetic stage), 30 weeks (NIDDM stage), and 54 weeks (IDDM stage). Tissue mRNA levels were measured by Northern blot analysis. In 14-week-old OLETF rats, cardiac mRNAs for transforming growth factor-beta1 (TGF-beta1) and extracellular matrix, including collagen types I, III, and IV and laminin, were significantly increased compared with control rats (Long-Evans Tokushima Otsuka rats). Cardiac beta-myosin heavy chain (MHC) mRNA of OLETF was increased at 30 and 54 weeks of age, whereas alpha-MHC mRNA of OLETF was inversely decreased at 54 weeks. Marked perivascular fibrosis was seen in the hearts of OLETF rats from 30 weeks of age. In the kidney of OLETF rats, glomerular TGF-beta1 expression was temporally increased at 30 weeks of age, followed by glomerulosclerosis characterized by mesangial proliferation, thickening of the basement membrane, and nodular lesions. Blood pressure of OLETF rats remained higher than that of control rats from the prediabetic stage to the IDDM stage. Thus, in OLETF rats, cardiac fibrosis-related gene expressions were already enhanced at the prediabetic stage, which supports the involvement of these gene expressions in cardiac perivascular fibrosis. The antithetical change in beta- and alpha-MHC expressions seems to participate in the decreased cardiac contractility seen in diabetes. Furthermore, TGF-beta1 may also contribute to glomerulosclerosis of OLETF rats. OLETF rats seem to be a useful model to study the mechanism of hypertension and cardiac and renal complications in NIDDM.

Animals↗

PubMed1997

Angiotensin blockade improves cardiac and renal complications of type II diabetic rats.

Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new model of human non-insulin-dependent diabetes mellitus (NIDDM), we examined the role of local angiotensin II in cardiovascular and renal complications of NIDDM. OLETF rats were orally given cilazapril (an angiotensin-converting enzyme inhibitor, 1 or 10 mg/kg), E4177 (an angiotensin AT1 receptor antagonist, 10 mg/kg), or vehicle for 26 or 40 weeks (from the age of 20 to 46 or 60 weeks). Cardiac mRNAs were measured by Northern blot analysis, and the thickening of the coronary arterial wall and the degree of perivascular fibrosis were determined by an image analyzer. Cilazapril or E4177 did not significantly affect body weight or plasma glucose and insulin levels of OLETF rats, indicating the minor effects on diabetes itself. However, both drugs significantly and similarly prevented coronary microvascular remodeling (the increase in wall thickening and perivascular fibrosis in coronary arterioles and small coronary arteries) in OLETF rats, and they were associated with the suppression of cardiac transforming growth factor-beta1 expression. Both drugs suppressed not only the increase in left ventricular weight but also the downregulation of cardiac alpha-myosin heavy chain expression in OLETF rats. Glomerulosclerosis and glomerular hypertrophy in OLETF rats were improved by cilazapril and E4177 to a comparable extent. These results, taken together with the fact that OLETF rats show normal plasma renin levels, support that the AT1 receptor is involved in the pathogenesis of cardiac and renal complications in NIDDM.

Albuminuria↗

PubMed1997

Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats.

The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin AT1 receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin AT1 receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Ca(2+)-ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Ca(2+)-ATPase expression. Unlike the left ventricle, the significant downregulation of alpha-myosin heavy chain and transforming growth factor-beta 3 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-beta 3. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that AT1 receptor partially contributed to volume overload-induced changes in cardiac gene expression and that AT1 receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy.

Actins↗

PubMed1997

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Animals↗

PubMed1997

Involvement of angiotensin II in cardiovascular and renal injury: effects of an AT1-receptor antagonist on gene expression and the cellular phenotype.

OBJECTIVES: We investigated the effects of an angiotensin II type 1 (AT1)-receptor antagonist on experimental cardiac hypertrophy, vascular thickening and nephrosclerosis, in order to determine the involvement of this receptor in the development of cardiovascular and renal damage. DESIGN: Accumulating evidence indicates that various growth-related genes, growth factors and extracellular matrix components play a central part in the pathogenesis and development of cardiovascular and renal diseases, either by regulating cell growth and migration or by promoting tissue fibrosis. MATERIALS AND METHODS: Stroke-prone spontaneously hypertensive rats were given candesartan cilexetil, a specific non-peptide AT1-receptor antagonist, for 10 weeks, and cardiac phenotypic and fibrosis-related gene expression and aortic and mesenteric arterial gene expressions were determined. Balloon-injured carotid arteries and deoxycorticosterone acetate (DOCA)-salt hypertensive rats were also similarly examined. RESULTS: Treatment of hypertensive rats with an AT1-receptor antagonist led to the regression of cardiac hypertrophy, suppression of cardiac phenotypic changes to a fetal phenotype and an increase in fibrosis-related gene expression in the hypertrophied heart. Balloon injury-induced neointima formation in the rat carotid artery was prevented by the AT1-receptor antagonist, which was associated with the inhibition of the induction of proto-oncogenes such as c-fos, c-jun and Egr-1 and of increased fibronectin gene expression. Furthermore, the AT1-receptor antagonist prevented either the phenotypic modulation of glomerular cells or an increase in transforming growth factor-beta 1 expression in an experimental model of nephrosclerosis. CONCLUSIONS: AT1-receptor antagonists in vivo potently inhibit the expression of the growth-related and extracellular matrix genes, as well as cellular phenotypic modulation. These molecular effects of the AT1-receptor antagonist may contribute to their protective effects on cardiovascular and renal diseases.

Angiotensin II↗

PubMed1996

Contribution of local renin-angiotensin system to cardiac hypertrophy, phenotypic modulation, and remodeling in TGR (mRen2)27 transgenic rats.

BACKGROUND: The transgenic rat TGR(mRen2)27, carrying the mouse Ren-2 gene, is a new model to elucidate the role of the local renin-angiotensin system in vivo. However, the role of the local renin-angiotensin system in the heart remains to be determined in TGR(mRen2)27. METHODS AND RESULTS: TGR(mRen2)27 were treated with various antihypertensive drugs for 6 weeks to examine the effects on cardiac hypertrophy and gene expression. Cardiac mRNAs were examined by Northern blot analysis. In TGR(mRen2)27, left ventricular hypertrophy was associated with a decrease in alpha-myosin heavy chain expression of 31% and an increase in skeletal alpha-actin and atrial natriuretic polypeptide expression by 2.6- and 21-fold, respectively (P < .05), thereby showing the shift of myocardium to a fetal phenotype. Furthermore, cardiac collagen and laminin expressions were increased in TGR(mRen2)27 (P < .05), suggesting the occurrence of cardiac remodeling. Although treatment of TGR(mRen2)27 with a high dose of TCV-116 (angiotensin AT1 receptor antagonist) or manidipine (calcium antagonist) combined with atenolol (beta 1-adrenergic receptor blocker) completely normalized blood pressure, TCV-116 regressed cardiac hypertrophy and suppressed the changes in cardiac mRNA levels of TGR(mRen2)27 much more potently than manidipine with atenolol. Furthermore, the inhibitory effects of a low dose of TCV-116 on cardiac hypertrophy and altered gene expressions of TGR(mRen2)27 were greater than those of doxazosin (alpha 1-adrenergic receptor blocker) combined with atenolol, despite their similar hypotensive effects. CONCLUSIONS: Our present observations provide evidence that the cardiac renin-angiotensin system in TGR(mRen2)27 is responsible for cardiac hypertrophy, phenotypic modulation, and remodeling.

Actins↗

PubMed1996

High resolution localization of endothelin receptors in rat renal medulla.

The cellular localization of endothelin receptors in the inner medulla of the rat kidney was investigated by using high resolution light and electron microscopic autoradiography, with the microwave irradiation fixation methods. Kidney slices were incubated with 125I-endothelin-1 alone or with selective ligands for the endothelin ETB and/or ETA receptors for light microscopic autoradiography. At the microscopic level, 125I-endothelin-1 was found to bind specifically to the glomeruli, arterioles and peritubular spaces in the cortex and vasa recta and surrounding tissues in the inner medulla. These bindings were also observed when the tissue slices were incubated in the presence of IRL1620 (ETB receptor agonist) or 97-139 (ETA receptor antagonist). Electron microscopic autoradiography using 125I-endothelin-1 in the inner medulla revealed silver grains over endothelial cells of the vasa recta and interstitial and collecting duct cells. No grains were detected over inner lining cells of the thin limbs of Henle's loop. These interstitial cells contained abundant microorganelles and lipid droplets, and had extensive cytoplasmic processes that closely related to the basement membranes of the vasa recta and loop of Henle. These findings demonstrate that type 1 interstitial cells are also primary sites for endothelin receptors as well as endothelial cells of the vasa recta and collecting duct cells in the inner medulla.

Animals↗

PubMed1996

Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats.

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Role of angiotensin-converting enzyme, adrenergic receptors, and blood pressure in cardiac gene expression of spontaneously hypertensive rats during development.

We undertook this study to investigate the regulatory mechanism of cardiac gene expression in spontaneously hypertensive rats (SHR) during development. We measured cardiac mRNAs by Northern blot analysis. In 9-week-old SHR at the very early stage of cardiac hypertrophy, the expression of various cardiac genes related to the regulation of cardiac contraction and relaxation was already significantly changed compared with control Wistar-Kyoto rats, indicating that cardiac molecular changes are responsible for cardiac remodeling or the modulation of cardiac performance in SHR. We gave various types of antihypertensive drugs, at oral doses causing a mild and comparable hypotensive effect, to 27-week-old SHR to examine the effects on the altered cardiac gene expression. Imidapril, an angiotensin-converting enzyme inhibitor, normalized the increased gene expression of atrial natriuretic polypeptide and collagen types I and III and the decreased expression of alpha-myosin heavy chain in SHR heart. Atenolol (a beta 1-blocker) combined with doxazosin did not affect cardiac ANP and alpha-myosin heavy chain expression of SHR but normalized the increased collagen expression. In contrast, despite a hypotensive effect comparable to these two drug treatments, doxazosin (an alpha 1-blocker) alone or manidipine (a calcium antagonist) did not normalize these altered gene expressions of SHR. These results show that the cardiac renin-angiotensin system is involved in the altered cardiac gene expression in SHR. The beta 1- but not alpha 1-adrenergic receptor is also responsible for the increased cardiac collagen expression in SHR.

Actins↗

PubMed1996

Selective blockade of endothelin receptor subtypes on systemic and renal vascular responses to endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist, in anesthetized rats.

By using BQ-788 as a selective endothelin ETB-receptor antagonist and FR139317 as a selective endothelin ETA-receptor antagonist, we have characterized the receptor subtypes mediating the systemic and renal vascular effects of endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist (succinyl-[Glu9,Ala11,5]-endothelin-1(8-21)), in anesthetized rats. Bolus intravenous injection of endothelin-1 (0.5 nmol/kg) and IRL1620 (1.65 nmol/kg) produced a transient fall in systemic blood pressure followed by a sustained increase. The initial fall in blood pressure observed after endothelin-1 and IRL1620 administration was completely blocked by BQ-788 (0.5 mumol/kg, i.v.), whereas the pressor response was blocked by FR139317 (0.8 mumol/kg, i.v.). Renal blood flow was decreased and calculated renal vascular resistance was dramatically increased by endothelin-1 and IRL1620. The reduction of renal blood flow by endothelin-1 was significantly suppressed by FR139317 but potentiated by BQ-788. Both BQ-788 and FR139317 partially blocked the renal vasoconstriction by IRL1620. Pretreatment by BQ-788 itself decreased renal blood flow by 14.1%. These results indicate that the systemic depressor responses induced by endothelin-1 and IRL1620 are mediated through the endothelin ETB-receptor, and the pressor responses are mediated through the endothelin ETA-receptor. In the renal vasculature of anesthetized rats, it is suggested that vasoconstriction is mediated through both endothelin ETA- and ETB-receptors and that endothelin ETB-receptors may be also involved in vasodilating responses to endothelin peptides.

Anesthesia↗

PubMed1996

Role of platelet-activating factor and prostanoids in hemodynamic changes in rat experimental endotoxic shock.

The present experiments were conducted to elucidate the role of platelet-activating factor (PAF) and cyclooxygenase products in the cardiovascular responses to endotoxin in anesthetized rats. Endotoxin (10 mg/kg, i.v.) induced hypotension that was accompanied by a decrease in cardiac output and an increase in calculated total peripheral resistance, suggesting that this hypotension mainly resulted from the reduced cardiac output. The endotoxin-induced decrease in cardiac output and hemoconcentration was significantly attenuated by TCV-309 (a PAF receptor antagonist), ibuprofen (a cyclooxygenase inhibitor) or S-1452 (a thromboxane A2/prostaglandin H2-receptor antagonist). During the 3-hr observation period following endotoxin administration, ibuprofen and S-1452 showed only early protection and TCV-309 showed late attenuation of the endotoxin-induced hypotension. Tachycardiac responses to endotoxin were only blocked by ibuprofen but not by TCV-309 or S-1452. These results suggest that both PAF and cyclooxygenase product(s), including thromboxane A2, mediate the decrease in cardiac output and hypotension in rat experimental endotoxic shock. Cyclooxygenase product(s) other than thromboxane A2 or prostaglandin endoperoxide may be involved in the endotoxin-induced increase in heart rate.

Animals↗