Effects of NKH477 on renal functions and cyclic AMP production in anesthetized dogs

Tanahashi, Masayuki; Hara, Sunao; Yoshida, Makoto; Suzuki-Kusaba, Mizue; Yokoyama, Hirofumi; Hosono, Makoto; Hisa, Hiroaki; Satoh, Susumu

doi:10.1016/s0014-2999(99)00220-4

Cited by 14 publications

(18 citation statements)

References 29 publications

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“…Rolipram was able to restore RBF to Sham levels within 30 minutes, paralleling the acute restoration of cortical capillary perfusion. This increase in RBF was likely due to the ability of rolipram and other PDE inhibitors to reduce renal vascular resistance since renal vascular resistance would be predicted to decrease under conditions in which MAP is reduced yet RBF is increased (Sandner et al, 1999;Tanahashi et al, 1999). Our findings are in agreement with other studies showing that selective PDE4 inhibition can improved RBF by reducing renal vascular resistance in a rat model of LPS-induced AKI (Begany et al, 1996;Carcillo et al, 1996).…”

Section: Discussionsupporting

confidence: 90%

“…Reasons for the reduced efficacy of rolipram at the high dose are unknown but may be related to peripheral vasodilation and a worsening of septic shock. Rolipram is known to decrease MAP and increase heart rate (Tanahashi et al, 1999), and we did observe that the dose of 1 mg/kg reduced MAP following CLP even further despite acutely increasing heart rate. These findings support the notion that decreasing vascular resistance to improve the microcirculation in the septic patient may be more important in preserving organ function than simply raising MAP (Dubin et al, 2009;De Backer et al, 2013).…”

Section: Discussionmentioning

confidence: 47%

“…Previous studies have shown a rapid decline in RBF following CLP Wang et al, 2012). Rolipram (Sandner et al, 1999;Tanahashi et al, 1999) and other PDE-4 inhibitors (Begany et al, 1996;Carcillo et al, 1996) have been shown to increase renal blood flow by lowering renal vascular resistance. To evaluate the effects of rolipram on RBF in our model, rolipram or vehicle was given at 5.5 hours post-CLP and RBF was measured at 6 hours.…”

Section: Resultsmentioning

confidence: 98%

“…PDE4 is highly expressed in endothelial cells (Netherton and Maurice, 2005;Lugnier, 2006), and targeting PDE4 with inhibitors reduces vascular leakage (Miotla et al, 1998;Lin et al, 2011;Schick et al, 2012). In the kidney, several isoforms of PDE are expressed (Cheng and Grande, 2007), and inhibiting PDE4 has been shown to increase RBF by decreasing renal vascular resistance (Tanahashi et al, 1999). In a lipopolysaccharide (LPS) model of sepsis in the rat, PDE4 inhibition not only increased RBF but also acutely improved glomerular filtration rate (Begany et al, 1996;Carcillo et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Rolipram Improves Renal Perfusion and Function during Sepsis in the Mouse

Holthoff

Wang

Patil

et al. 2013

J Pharmacol Exp Ther

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Microcirculatory dysfunction is correlated with increased mortality among septic patients and is believed to be a major contributor to the development of acute kidney injury (AKI). Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, has been shown to reduce microvascular permeability and in the kidney, increase renal blood flow (RBF). This led us to investigate its potential to improve the renal microcirculation and preserve renal function during sepsis using a murine cecal ligation and puncture (CLP) model to induce sepsis. Rolipram, tested at doses of 0.3-10 mg/kg i.p., acutely restored capillary perfusion in a bell-shaped dose-response effect with 1 mg/kg being the lowest most efficacious dose. This dose also acutely increased RBF despite transiently decreasing mean arterial pressure. Rolipram also reduced renal microvascular permeability. It is noteworthy that delayed treatment with rolipram at 6 hours after CLP restored the renal microcirculation, reduced blood urea nitrogen and serum creatinine, and increased glomerular filtration rate at 18 hours. However, delayed treatment with rolipram did not reduce serum nitrate/nitrite levels, a marker of nitric oxide production, nor reactive nitrogen species generation in renal tubules. These data show that restoring the microcirculation with rolipram, even with delayed treatment, is enough to improve renal function during sepsis despite the generation of oxidants and suggest that PDE4 inhibitors should be evaluated further for their ability to treat septic-induced AKI.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 47%

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Rolipram Improves Renal Perfusion and Function during Sepsis in the Mouse

Holthoff

Wang

Patil

et al. 2013

J Pharmacol Exp Ther

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“…Colforsin stimulates mainly cardiac adenylyl cyclase, and in part, other tissue adenylyl cyclases (lung, brain, and kidney) type II, III and V 24 . Colforsin produces systemic and pulmonary vasodilation and increases renal blood flow 25,26 . These factors may contribute to decreasing afterload and preload in vivo, which may ultimately lead to hypotension.…”

Section: Discussionmentioning

confidence: 99%

Influence of Acidosis on Cardiotonic Effects of Colforsin and Epinephrine: A Dose-Response Study

Hagiya

Takahashi

Isaka

et al. 2013

Journal of Cardiothoracic and Vascular Anesthesia

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PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response

Świerczek

Wyska

Baś

et al. 2017

Naunyn-Schmiedeberg's Arch Pharmacol

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In recent years, phosphodiesterase (PDE) inhibitors have been frequently tested for the treatment of experimental inflammatory and immune disorders. It is suggested that anti-inflammatory properties of PDE inhibitors are related to their ability to increase cAMP levels. The aim of this study was to verify the hypothesis that cAMP may be a useful marker of pharmacological response following administration of non-selective PDE inhibitors (pentoxifylline and (±)-lisofylline) to endotoxemic rats. Male Wistar rats were administered LPS (1 mg kg−1, i.v.) simultaneously with either compound given at two doses (40 and 80 mg kg−1, i.v.). Levels of cAMP and both compounds in animal plasma were measured by the validated HPLC methods. Pharmacokinetic-pharmacodynamic analysis was performed using basic and modified indirect response (IDR) models II in Phoenix WinNonlin. The results of this study indicate that, in contrast to pentoxifylline, (±)-lisofylline demonstrates a non-linear pharmacokinetics in rats with endotoxemia. In vitro study using human recombinant PDE4B and PDE7A revealed the occurrence of additive interaction between studied compounds. Moreover, (±)-lisofylline is a more potent inhibitor of PDEs compared to pentoxifylline, as evidenced by lower IC50 values. Following administration of both compounds, levels of cAMP in rat plasma increased in a dose-dependent manner. The modified IDR model II better described cAMP levels over time profiles. The validity of the proposed marker was confirmed by measuring plasma TNF-α levels in the studied animals. In conclusion, cAMP may be used in future preclinical and clinical studies of some PDE inhibitors to evaluate the drug concentration–effect relationship.

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Effects of NKH477 on renal functions and cyclic AMP production in anesthetized dogs

Cited by 14 publications

References 29 publications

Rolipram Improves Renal Perfusion and Function during Sepsis in the Mouse

Rolipram Improves Renal Perfusion and Function during Sepsis in the Mouse

Influence of Acidosis on Cardiotonic Effects of Colforsin and Epinephrine: A Dose-Response Study

PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response

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