Biomedical subjects

Masanori Takaoka

Publications and source records attributed to Masanori Takaoka.

At least 19 recordsLinked to original sources

PubMed2006

Role of gp91phox-containing NADPH oxidase in the deoxycorticosterone acetate-salt-induced hypertension.

NADPH oxidase plays an important role in vascular oxidative stress in hypertensive diseases. We evaluated whether NADPH oxidase-dependent superoxide (O(2)(-)) production is involved in the deoxycorticosterone acetate (DOCA)-salt-induced hypertension, using mice which are genetically deficient in gp91phox, an NADPH oxidase subunit protein (gp91(-/-) mice). Two weeks after the DOCA-salt treatment, systolic blood pressure was significantly elevated in wild-type mice, but not in gp91(-/-) mice. After a 5-week treatment period, wild-type mice developed high blood pressure, with a systolic blood pressure of 127 +/- 3 mm Hg, compared with 107 +/- 4 mm Hg in gp91(-/-) mice. Aortic O(2)(-) production in wild-type DOCA-salt-treated mice was significantly higher than that in wild-type sham mice, whereas there were no significant differences in aortic O(2)(-) production between gp91(-/-) DOCA-salt-treated and sham mice. These findings suggest that vascular O(2)(-) overproduction via gp91phox-containing NADPH oxidase is one of the crucial factors in the development of DOCA-salt-induced hypertension.

Animals↗

PubMed2006

Renoprotective effects of l-carnosine on ischemia/reperfusion-induced renal injury in rats.

We examined the renoprotective effects of l-carnosine (beta-alanyl-l-histidine) on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. In vehicle (0.9% saline)-treated rats, renal sympathetic nerve activity (RSNA) was significantly augmented during the renal ischemia, and renal function was markedly decreased at 24 h after reperfusion. Intracerebroventricular injection of l-carnosine (1.5 and 5 pmol/rat) to ischemic ARF rats dose-dependently suppressed the augmented RSNA during ischemia and the renal injury at 24 h after reperfusion. N-alpha-Acetyl-l-carnosine [N-acetyl-beta-alanyl-l-histidine; 5 pmol/rat intracerebroventricular (i.c.v.)], which is resistant to enzymatic hydrolysis by carnosinase, did not affect the renal injury, and l-histidine (5 pmol/rat i.c.v.), a metabolite cleaved from l-carnosine by carnosinase, ameliorated the I/R-induced renal injury. Furthermore, a selective histamine H(3) receptor antagonist, thioperamide (30 nmol/rat i.c.v.) eliminated the preventing effects by l-carnosine (15 nmol/rat intravenously) on ischemic ARF. In contrast, a selective H(3) receptor agonist, R-alpha-methylhistamine (5 pmol/rat i.c.v.), prevented the I/R-induced renal injury as well as l-carnosine (5 pmol/rat) did. These results indicate that l-carnosine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppressing the enhanced RSNA during ischemia. In addition, the present findings suggest that the renoprotective effect of l-carnosine on ischemic ARF is induced by its conversion to l-histidine and l-histamine and is mediated through the activation of histamine H(3) receptors in the central nervous system.

Acute Kidney Injury↗

PubMed2006

Sesamin metabolites induce an endothelial nitric oxide-dependent vasorelaxation through their antioxidative property-independent mechanisms: possible involvement of the metabolites in the antihypertensive effect of sesamin.

Sesamin, a major lignan in sesame seeds and oil, has been known to lower blood pressure in several types of experimental hypertensive animals. A recent study demonstrated that sesamin metabolites had in vitro radical-scavenging activities. Thus, we determined whether the antioxidative effect of sesamin metabolites modulate the vascular tone and contribute to the in vivo antihypertensive effect of sesamin. We used four demethylated sesamin metabolites: SC-1m (piperitol), SC-1 (demethylpiperitol), SC-2m [(1R,2S,5R,6S)-6-(4-hydroxy-3-methoxyphenyl)-2-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane], and SC-2 [(1R,2S,5R, 6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane]. SC-1, SC-2m, and SC-2, but not SC-1m, exhibited potent radical-scavenging activities against the xanthine/xanthine oxidase-induced superoxide production. On the other hand, SC-1m, SC-1, and SC-2m produced endothelium-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings, whereas SC-2 had no effect. The SC-1m- and SC-1-induced vasorelaxations were markedly attenuated by pretreatment with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (NOARG), or a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. Neither SC-1m nor SC-1 changed the expression level of endothelial NOS protein in aortic tissues. The antihypertensive effects of sesamin feeding were not observed in chronically NOARG-treated rats or in deoxycorticosterone acetate-salt-treated endothelial NOS-deficient mice. These findings suggest that the enhancement of endothelium-dependent vasorelaxation induced by sesamin metabolites is one of the important mechanisms of the in vivo antihypertensive effect of sesamin.

Animals↗

PubMed2006

Effects of pre- and post-ischemic treatments with FK409, a nitric oxide donor, on ischemia/reperfusion-induced renal injury and endothelin-1 production in rats.

We have demonstrated that ischemic acute renal failure (ARF) is attenuated by pre-ischemic treatment with a spontaneous nitric oxide (NO) donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409). In the present study, we evaluated the effect of post-ischemic treatment with FK409 on ARF, compared with the pre-ischemic treatment effect. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated ARF rats markedly decreased. In addition, increases in renal contents of endothelin-1 (ET-1), a deleterious mediator in the pathogenesis of ischemic ARF, were evident in untreated ARF rats at 24 h after reperfusion. Pre-ischemic treatment with FK409 (1 or 3 mg/kg, i.v.) at 5 min before ischemia attenuated ischemia/reperfusion-induced renal dysfunction and increased ET-1 contents after reperfusion. In contrast, post-ischemic treatment with FK409 (3 or 10 mg/kg, i.v.) at 6 h after reperfusion aggravated the renal injury, but did not affect the increased ET-1 content after reperfusion. These results suggest that pre-ischemic treatment with FK409 exerts renoprotective effects on ischemic ARF, probably through the suppression of renal ET-1 overproduction, whereas post-ischemic treatment with the NO donor worsens the ischemia/reperfusion-induced renal injury, through mechanisms unrelated to the ET-1 production after reperfusion.

Animals↗

PubMed2006

Antihypertensive effect of angiotensin I-converting enzyme inhibitory peptides from a sesame protein hydrolysate in spontaneously hypertensive rats.

Sesame peptide powder (SPP) exhibited angiotensin I-converting enzyme (ACE) inhibitory activity, and significantly and temporarily decreased the systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs) by a single administration (1 and 10 mg/kg). Six peptide ACE inhibitors were isolated and identified from SPP. The representative peptides, Leu-Val-Tyr, Leu-Gln-Pro and Leu-Lys-Tyr, could competitively inhibit ACE activity at respective Ki values of 0.92 microM, 0.50 microM, and 0.48 microM. A reconstituted sesame peptide mixture of Leu-Ser-Ala, Leu-Gln-Pro, Leu-Lys-Tyr, Ile-Val-Tyr, Val-Ile-Tyr, Leu-Val-Tyr, and Met-Leu-Pro-Ala-Tyr according to their content ratio in SPP showed a strong antihypertensive effect on SHR at doses of 3.63 and 36.3 microg/kg, which accounted for more than 70% of the corresponding dosage for the SPP-induced hypotensive effect. Repeated oral administration of SPP also lowered both SBP and the aortic ACE activity in SHR. These results demonstrate that SPP would be a beneficial ingredient for preventing and providing therapy against hypertension and its related diseases.

Administration, Oral↗

PubMed2006

Differential effects of different statins on endothelin-1 gene expression and endothelial NOS phosphorylation in porcine aortic endothelial cells.

It has been reported that 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors (statins) produce a variety of cardiovascular protective effects independent of their ability to lower total and low-density lipoprotein cholesterol. Recent studies have also reported that statins produce pleiotropic effects through improved endothelial function, enhanced fibrinolysis, and antithrombotic actions. In the present study, we examined the effects of pitavastatin, pravastatin, atorvastatin, and cerivastatin on endothelin (ET)-1 production in cultured porcine aortic endothelial cells (PAECs). Treatment with cerivastatin but not pitavastatin, pravastatin, or atorvastatin decreased basal and TNF-alpha-stimulated ET-1 release from PAECs in a dose-dependent manner (1-10 microM). Northern blot analysis showed that cerivastatin markedly suppressed prepro ET-1 mRNA expression in both conditions. In addition, these inhibitory effects of cerivastatin on ET-1 release and prepro ET-1 mRNA expression were completely abolished by simultaneous treatment with 200 microM mevalonate. Furthermore, cerivastatin did not have any effects on endothelial nitric oxide synthase (eNOS) protein levels, but induced eNOS phosphorylation at Ser1177. From these findings, it is most likely that cerivastatin suppresses ET-1 production, possibly through an increase in eNOS activity and the subsequent nitric oxide production in PAECs. These findings also suggest that cerivastatin may have beneficial effects on ET-1-related diseases.

Animals↗

PubMed2005

Opposite effects of pre- and postischemic treatments with nitric oxide donor on ischemia/reperfusion-induced renal injury.

We have demonstrated previously that preischemic treatment with FK409 [(+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide], a spontaneous nitric oxide (NO) donor, markedly improves ischemia/reperfusion-induced renal injury. However, there is conflicting information (renoprotective or cytotoxic) as to the contribution of NO to ischemic acute renal failure (ARF). In the present study, we investigated the effect of postischemic treatment with FK409 (1, 3, and 10 mg/kg i.v.) at 6 h after reperfusion on ischemic ARF, in comparison with the preischemic treatment effect. Ischemic ARF was induced by clamping of the left renal artery and vein for 45 min, followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in ARF rats markedly decreased at 24 h after reperfusion. Histopathological examination of the kidney of ARF rats revealed severe renal damage. In contrast to the renoprotective effect by preischemic treatment, postischemic treatment with FK409 aggravated the ischemia/reperfusion-induced renal dysfunction and histological damage. Immunohistochemical analysis of renal sections obtained from ARF rats revealed positive staining for nitrotyrosine, a biomarker of peroxynitrite formation, in injured tubular cells, and more intense staining was observed in renal tissues from the animals that received postischemic treatment with FK409. On the other hand, the formation of nitrotyrosine, neutrophil infiltration into renal tissues, and renal superoxide production, all of which were enhanced in ARF rats, were efficiently attenuated by the preischemic treatment with FK409. These results demonstrate that, although preischemic treatment with an NO donor is renoprotective, postischemic treatment with the same agent aggravates the ischemia/reperfusion-induced renal injury, probably through peroxynitrite overproduction.

Acute Kidney Injury↗

PubMed2005

Protective effect of nitric oxide on ischemia/reperfusion-induced renal injury and endothelin-1 overproduction.

To elucidate the role of nitric oxide (NO) in the pathogenesis of ischemic acute renal failure, we examined the effects of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and N(G)-nitro-L-arginine methyl ester (L-NAME) as a NO donor and a non-selective NO synthase inhibitor on ischemia/reperfusion-induced renal injury and renal endothelin-1 content. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage. In addition, increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2, 6, and 24 h after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, i.v.) attenuated ischemia/reperfusion-induced renal dysfunction, histological damage, and endothelin-1 overproduction after reperfusion. In contrast, pretreatment with L-NAME (1 or 10 mg/kg, i.v.) aggravated renal injuries of acute renal failure rats at 24 h after reperfusion, and the effect is accompanied by further increases in the renal endothelin-1 content at 2 and 6 h, but not at 24 h, after reperfusion. These results suggest that suppressive effects of NO on the renal endothelin-1 overproduction induced by ischemia/reperfusion in an early phase are probably responsible for the protective effect of NO against ischemic acute renal failure.

Animals↗

PubMed2005

Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts.

BACKGROUND: Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion-induced NE overflow and cardiac dysfunction using a selective ET(A) receptor antagonist (ABT-627), a selective ET(B) receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene. METHODS AND RESULTS: According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion-induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET(B) receptor-deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na+/H+ exchanger (NHE). CONCLUSIONS: Pharmacological blockade or genetic deficiency of ET(B) receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET(A) receptor activation. ET(A)/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

Amiloride↗

PubMed2005

Preventive effect of flavangenol on ischemia/reperfusion-induced acute renal failure in rats.

The effects of flavangenol on ischemia/reperfusion-induced acute renal failure (ARF) in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Pre-ischemic treatment with flavangenol (3-30 mg/kg, i.v.) attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damage, such as tubular necrosis and proteinaceous casts in tubuli, which were also significantly suppressed by the administration of flavangenol. These findings suggest that flavangenol supplementation may be a promising candidate for treatments to improve the ischemia/reperfusion-induced renal injury.

Acute Kidney Injury↗

PubMed2005

Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats.

The effects of dietary supplementation of L-carnosine (beta-alanyl-L-histidine) on ischemia/reperfusion-induced acute renal failure (ARF) in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Prior feeding of L-carnosine-containing diet (0.0001 w/w%) for 2 weeks attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, which were also significantly suppressed by the dietary supplementation of L-carnosine. These findings strongly suggest that L-carnosine supplementation is useful as a prophylactic treatment in the development of the ischemic ARF.

Animals↗

PubMed2005

Xanthoangelol D isolated from the roots of Angelica keiskei inhibits endothelin-1 production through the suppression of nuclear factor-kappaB.

Transcription factor nuclear factor-kappa B (NF-kappaB) has been demonstrated to be important in regulating various gene expressions such as cytokines, adhesion molecules, and endothelin-1 (ET-1) in vascular endothelial cells. In the present study, we show the effects of xanthoangelol, xanthoangelol D, E, and F, which isolated from the root of Angelica keiskei KOIDZUMI (Umbelliferae), on NF-kappaB activation and ET-1 gene expression in cultured porcine aortic endothelial cells (PAECs). Treatments of xanthoangelol D but not xanthoangelol, xanthoangelol E and F markedly suppressed both of basal and tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activation in PAECs. To clarify the mechanism of xanthoangelol D-induced suppression on NF-kappaB activation, we evaluated the effects of xanthoangelol D on phosphorylation and degradation of IkappaBalpha, an inhibitory protein bound to NF-kappaB, and obtained evidence that xanthoangelol D selectively suppresses the phosphorylation of IkappaBalpha rather than the degradation of phosphorylated IkappaBalpha. In addition, xanthoangelol D significantly attenuated basal and TNF-alpha-induced prepro ET-1 mRNA expression in PAECs. These results suggest that xanthoangelol D may be useful for the treatment of various vascular diseases involved NF-kappaB activation.

Angelica↗

PubMed2005

Tempol protects against ischemic acute renal failure by inhibiting renal noradrenaline overflow and endothelin-1 overproduction.

The effects of tempol, a superoxide dismutase mimetic, on ischemia/reperfusion-induced acute renal failure (ARF), noradrenaline (NA) overflow and endothelin-1 (ET-1) overproduction in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine concentration, and fractional excretion of sodium, NA concentrations in renal venous plasma, and renal ET-1 contents were determined. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Pre-ischemic treatment with tempol (10, 100 mg/kg, i.v.) dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, which were also significantly suppressed by the tempol treatment. There was a significant increase in NA concentrations in renal venous plasma after the ischemia/reperfusion, and this increase was markedly suppressed by the treatment with tempol. In addition, tempol treatment significantly attenuated the increment of ET-1 content in the kidney exposed to the ischemia/reperfusion. These findings suggest that tempol improves the post-ischemic renal injury by inhibiting the neural activity of renal sympathetic nerve and ET-1 overproduction.

Acute Kidney Injury↗

PubMed2005

Selective endothelin ET(B) receptor antagonist improves left ventricular function but exaggerates degeneration of cardiomyocytes in J2N-k hamsters.

BACKGROUND: Endothelin-1 (ET-1) receptor antagonist is expected to improve the prognosis of patients with heart failure, but the role of the ET(B) receptor in cardiac function and structure is complicated. In the present study the NADPH diaphorase activity and ET-1 content in the failing heart treated with ET(A) or ET(B) receptor antagonist were evaluated in a model of dilated cardiomyopathy. METHODS AND RESULTS: Selective ET(A) receptor antagonist, ABT-627 (10 mg/kg per day), or selective ET(B) antagonist, A-192621 (30 mg/kg per day), was given to 22-week-old J2N-k cardiomyopathic hamsters for 8 weeks. The effects of ABT-627 and A-192621 on cardiac function, left ventricular (LV) histology, ET-1 content and NADPH diaphorase activity in the LV were evaluated. Treatment with ABT-627, but not A-192621, significantly decreased ET-1 content and NADPH diaphorase activity. Although the improvement of LV function was modest, ABT-627 prevented tissue damage in J2N-k hamsters. In contrast, A-192621 worsened the degeneration of cardiomyocytes despite improving hemodynamic parameters. CONCLUSIONS: Selective ET(A) antagonist, but not ET(B) antagonist, reduced the ET-1 content as well as the NADPH diaphorase activity, and preserved the fine structure of LV myocardium in cardiomyopathic hamsters. Long-term blockade of ET(B) receptor might worsen the degeneration of cardiomyocytes through the ET-1/ET(A) system even if LV function could be improved.

Animals↗

PubMed2004

Preventive effect of Y-27632, a selective Rho-kinase inhibitor, on ischemia/reperfusion-induced acute renal failure in rats.

We evaluated the effects of Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate], a selective Rho-kinase inhibitor, on ischemic acute renal failure. Ischemic acute renal failure in rats was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after the contralateral nephrectomy. Y-27632 administration (1, 10, and 100 microg/kg, i.p.) before ischemia dose-dependently attenuated the ischemia/reperfusion-induced renal dysfunction and histological damage, such as tubular necrosis. The ischemia/reperfusion-induced renal dysfunction was also overcome by postischemic treatment with Y-27632 at 100 microg/kg, i.p. Myeloperoxidase activity in the kidney after ischemia/reperfusion was significantly increased, being the maximal level at 6 h after the reperfusion, and this increase was also suppressed by Y-27632 (100 microg/kg, i.p.). These results indicate that Y-27632 prevents the development of ischemia/reperfusion-induced acute renal failure, and the effect is related to the suppression of the enhanced myeloperoxidase activity in an early phase after reperfusion, thereby suggesting that the Rho/Rho-kinase pathway plays a key role in the pathogenesis of ischemic acute renal failure.

Acute Kidney Injury↗

PubMed2004

Endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning.

We determined whether endothelial nitric oxide synthase (eNOS) plays an important role in the renal protective effect of ischemic preconditioning (IP) against the ischemia/reperfusion-induced acute renal failure (ARF) by using eNOS-deficient (eNOS(-/-)) and wild-type (eNOS(+/+)) mice. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. IP, which consists of three cycles of 2-min ischemia followed by 5-min reperfusion, was performed prior to 45-min ischemia. In eNOS(+/+) mice, IP treatment markedly attenuated the ischemia/reperfusion-induced renal dysfunction and significantly improved histological renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Constitutive nitric oxide synthase activity in the kidney without IP was markedly decreased 6 h after reperfusion, but this decreased response was not observed in eNOS(+/+) mice with IP treatment. The improvement of renal dysfunction in eNOS(+/+) mice with IP treatment was abolished by pretreatment with N(G)-nitro-l-arginine, a nonselective NOS inhibitor, whereas aminoguanidine, an inducible NOS inhibitor, had no effect. Finally, no protective effects of IP on ischemia/reperfusion-induced renal dysfunction and histological damage were observed in eNOS(-/-) mice. These findings strongly support the view that eNOS-mediated NO production plays a pivotal role in the protective effect of IP on ischemia/reperfusion-induced ARF.

Animals↗

PubMed2004

Role of endothelin ETB receptor in partial ablation-induced chronic renal failure in rats.

We investigated the role of endothelin ET(B) receptor in the remnant kidney model of chronic renal failure, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ET(B) receptor gene. After 5/6 nephrectomy, systolic blood pressure and renal functional parameters were measured for 12 weeks. At the end of the experimental period, arterial blood sample, remnant kidney, heart and aorta were collected and used for biochemical measurements and histopathological studies. The ET(B)-deficient sl/sl rats exhibited earlier and higher increases in systolic blood pressure, urinary protein excretion, blood urea nitrogen and plasma creatinine concentration, compared with cases in wild-type rats. Histopathologic examination of the kidney revealed glomerular and tubular lesions, alterations of which were more severe in sl/sl than in wild-type rats. While aortic endothelin-1 contents were increased similarly in both groups, the level of renal endothelin-1 content was significantly elevated in sl/sl rats, but not in the wild-type rats. These results suggest that enhanced endothelin-1 production is at least partly responsible for the increased susceptibility to partial ablation-induced chronic renal failure in ET(B) receptor-deficient rats and that ET(B) receptor-mediated actions are protective against vascular and renal injuries in this disease.

Animals↗

PubMed2004

Role of histamine H3 receptors during ischemia/reperfusion in isolated rat hearts.

Histamine H3 receptors are involved in regulating the release of norepinephrine (NE), in both central and peripheral nervous systems. We investigated the effect of R-alpha-methylhistamine (R-HA), a selective H3 receptor agonist, and thioperamide (Thiop), a selective H3 receptor antagonist, on ischemia/reperfusion-induced changes in carrier-mediated NE release and cardiac function in isolated rat heart. Hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Ischemia/reperfusion evoked massive NE release, which was markedly suppressed by the treatment with desipramine (DMI), a neuronal NE transporter blocker. Ischemia/reperfusion-induced cardiac dysfunction (decreases in left ventricular developed pressure, LVDP, and the first derivative of left ventricular pressure, dP/dt, and a rise in left ventricular end diastolic pressure, LVEDP) was also improved by the DMI treatment. The treatment with R-HA also significantly decreased the excessive NE release induced by the ischemia/reperfusion, improved the recovery of LVDP and dP/dt, and suppressed the rise in LVEDP. Thiop did not affect NE release and cardiac function after the reperfusion. When R-HA was administered concomitantly with Thiop, R-HA failed to attenuate ischemia/reperfusion-induced NE release and cardiac dysfunction. Thus, it seems likely that the ischemia/reperfusion-induced carrier-mediated NE release in rat hearts is negatively regulated by the activation of H3 receptors, probably located on cardiac noradrenergic nerve endings.

Adrenergic Uptake Inhibitors↗