EFFECTS OF SARAFOTOXIN S6c ON RENAL HAEMODYNAMICS AND URINE FORMATION IN ANAESTHETIZED DOGS

Matsuo, Gen; Matsumura, Yasuo; Tadano, Kiyoshi; Hashimoto, Takashi; Morimoto, Shiro

doi:10.1111/j.1440-1681.1997.tb01232.x

Cited by 16 publications

(16 citation statements)

References 19 publications

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“…26 In the present study, we cannot identify the downstream of ET B receptor stimulation, but CF after ischemia/reperfusion markedly increased after treatment with big ET-1, possibly implicating vasorelaxing factor(s). In addition, we have recently reported that nitric oxide has an inhibitory effect on NE overflow after cardiac ischemia/reperfusion.…”

Section: Discussioncontrasting

confidence: 61%

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

et al. 2010

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Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET A receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/ reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt max ) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET B receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET A receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET B receptors to exert its related beneficial actions. Keywords: big endothelin-1; endothelin-1; ischemia/reperfusion; norepinephrine INTRODUCTION Endothelin-1 (ET-1) was originally found as a 21-amino-acid vasoconstrictor peptide produced by vascular endothelial cells. 1 This peptide is most abundant in the cardiovascular system, and at least two distinct ET receptors, ET A and ET B , have been identified. ET A receptors mediate vasoconstriction and cell proliferation, whereas ET B receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin. 2 There is accumulating evidence that ET-1 is closely related to the pathogenesis and development of several cardiovascular diseases. 3,4 It has been demonstrated that ischemia increases ET-1-binding sites in cardiac membranes. 5 In addition, we have recently noted that left ventricular ET-1 content is increased by ischemia/reperfusion in isolated rat hearts, and postischemic cardiac dysfunction is improved by suppressing the ET-1 biosynthesis. 6 These findings imply that endogenously generated ET-1 plays an important role in the pathophysiology of myocardial ischemia/reperfusion. Indeed, both selective

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Section: Discussioncontrasting

confidence: 61%

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

et al. 2010

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“…Furthermore, the ability of the ET B receptor to reduce renal tubular transport has been attributed to increasing NO (22). Matsuo and colleagues (17) have also reported that S6c infusion in the renal artery of anesthetized dogs results in a natriuretic and diuretic effect that is also associated with increases in urinary excretion of NO metabolites, nitrate and nitrite. A lingering question has been which NOS isoform could be involved in the proexcretory effects of ET B receptor stimulation.…”

Section: Discussionmentioning

confidence: 89%

“…Nitric oxide (NO) is thought to act as the downstream mediator of renal ET B receptor activation, because total NO synthase (NOS) inhibition can inhibit ET B receptor-dependent responses both in vivo (17) and in vitro (22). However, which NOS isoform is mainly involved in ET B -mediated diuretic and natriuretic responses remains unclear because all three NOS isoforms are expressed in tubules within the renal medulla (18,33).…”

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confidence: 99%

Renal medullary ET_Breceptors produce diuresis and natriuresis via NOS1

Nakano¹,

Pollock²,

Pollock³

2008

American Journal of Physiology-Renal Physiology

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(ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ET B receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ETB receptor stimulation in vivo. Infusion of the ETB receptor agonist sarafotoxin S6c (S6c: 0.45 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ETB receptor-deficient rats.), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-, a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ET B receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway. sodium excretion; nitric oxide synthase 1; guanosine 3Ј,5Ј-cyclic monophosphate; protein kinase G ENDOTHELIN-1 (ET-1), originally described as being released from vascular endothelial cells (46), is now known to be produced by many cell types and exerts a variety of biological effects in various organ systems (27). The renal medulla is a major site of ET-1 synthesis in the body (14,42). Considerable evidence has accumulated in recent years to demonstrate the physiological importance of renal medullary ET-1 in the control of arterial pressure and salt sensitivity. In inner medullary collecting duct (IMCD) cells, ET-1 reduced ouabain-sensitive Na-K-ATPase (47) and amiloride-sensitive sodium channel (6) activities. Furthermore, ET-1 inhibits chloride flux in isolated thick ascending limbs, an effect blocked by an ET B , but not ET A , antagonist (22). These in vitro studies suggest that activation of the renal medullary ET B receptors by ET-1 could play an important role in the regulation of salt and water excretion. Indeed, rats or mice lacking functional ET B receptors display salt-sensitive hypertension (2, 7). Early studies showed that low-dose infusion of ET-1 could produce a direct natriuretic and diuretic effect in vivo without any associated changes in blood pressure (28). A more definitive study demonstrating the physiological significance of renal ET-1 in control of sodium excretion comes from the observation that mice lacking specific expression of ET-1 within the renal collecting duct develop hypertension that is salt dependent (1).Nitric oxide (NO) is thought to act as the downstream mediator of renal ET B receptor activation, because total NO synthase (NOS) inhibition can inhibit ET B receptor-dependent responses both in vivo (17) and in vitro (22). However, which...

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“…ETA and ETB receptors expressed in tubular cells contribute to the regulation of electrolyte and water homeostasis, which have profound implications for regulation of arterial blood pressure. There is conflicting data regarding the presence and function of ETA and ETB in specific nephron segments, but the main conclusion is that ETA serves as vasoconstrictor in the vascular beds effecting RBF, GFR and mainly cortical RBF whereas ETB are more involved in the regulation of water and sodium homeostasis by regulating medullary RBF and directly inhibiting tubular transport [47,48]. ETBmediated natriuresis and diuresis are reported to involve several different cellular signaling pathways, including protein kinase C, mitogen activated protein kinase and cyclooxygenase.…”

Section: The Endothelin Systemmentioning

confidence: 99%

The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling

Franzén¹

2016

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PrefaceThis thesis is the reflection of me, my work and my experiences. It has mostly been frustration but apparently I managed to stay alive the whole way through.For some it might have seemed easy but I am convinced that a big part has been extreme luck. I don't consider it my skill that it has sometimes run smoothly, because mostly it has been Murphy all over the place. Research is very much about luck. The luck to get the "right" animal batch, the luck to have equipment that isn't broken, the luck to have reviewers who like your paper, the luck that no one interferes with your settings, the luck to actually get results, etc etc. I could go one forever… Anyway, here it is. My work. To be understood or not. AbstractDiabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes. It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice. The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed. The final part of this thesis was to invest...

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EFFECTS OF SARAFOTOXIN S6c ON RENAL HAEMODYNAMICS AND URINE FORMATION IN ANAESTHETIZED DOGS

Cited by 16 publications

References 19 publications

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Renal medullary ET_Breceptors produce diuresis and natriuresis via NOS1

The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling

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EFFECTS OF SARAFOTOXIN S6c ON RENAL HAEMODYNAMICS AND URINE FORMATION IN ANAESTHETIZED DOGS

Cited by 16 publications

References 19 publications

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Renal medullary ETBreceptors produce diuresis and natriuresis via NOS1

The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling

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Renal medullary ET_Breceptors produce diuresis and natriuresis via NOS1