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Angiotensin II inhibition increases diuresis during acute sympathetic activation in intact and denervated kidneys in rats with chronic myocardial infarction

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Abstract

We examined urine excretion during primary acute sympathetic activation (PASA) in Wistar–Kyoto rats with myocardial infarction (MI). The rats underwent unilateral renal denervation (RDN) 7 weeks after coronary artery ligation. 4–10 days later, an acute experiment was performed under anesthetized conditions (n = 8 rats). Isolated carotid sinus pressure was changed stepwise from 60 to 180 mmHg, and the relationship between the arterial pressure (AP) and the normalized urine flow (nUF, urine flow normalized by the body weight) was examined. After obtaining the control data, an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) was intravenously administered. The effects of RDN, telmisartan, and heart weight (biventricular weight) on the relationship between AP and nUF were examined using multiple regression analyses. Regarding the slope of nUF versus AP (nUFslope), the constant term of the regression was positive (0.315 ± 0.069 μL·min−1·kg−1·mmHg−1), indicating that nUF increased with AP. The heart weight had a negative effect on nUFslope (P < 0.05), suggesting that the severity of MI was associated with the impairment of urine excretion. Telmisartan increased nUFslope by 0.358 ± 0.080 μL·min−1·kg−1·mmHg−1 (P < 0.001), whereas RDN had no significant effect on this parameter. The results indicate that unilateral RDN was unable to abolish the effect of the renin–angiotensin system on urine excretion during PASA. Circulating or locally produced angiotensin II, rather than ongoing renal sympathetic nerve activity, played a dominant role in the impairment of urine excretion during PASA in rats with chronic MI.

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Acknowledgements

This study was partly supported by grants from Grants-in-Aid for Scientific Research (JSPS KAKENHI 20K20622), Salt Science Research Foundation (2029, 2125), and Takeda Medical Research Foundation. Part of this work was carried out by a research grant from NTT research, Inc. The authors confirm that these parties had no influence in the study design, contents of the article, or selection of this journal.

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Authors and Affiliations

  1. Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, 564-8565, Japan

    Toru Kawada, Meihua Li, Can Zheng, Kazunori Uemura, Masaru Sugimachi & Keita Saku

  2. Innovation Center, Terumo Corporation, Kanagawa, 259-0151, Japan

    Satoru Suehara & Satoshi Sawada

Authors
  1. Toru Kawada
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  2. Meihua Li
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  3. Satoru Suehara
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  4. Satoshi Sawada
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  5. Can Zheng
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  6. Kazunori Uemura
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  7. Masaru Sugimachi
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  8. Keita Saku
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Contributions

TK: conceived and designed the study. TK and ML: performed the experiments. TK: analyzed data. TK, ML, SSu, SSa, CZ, KU, MS, and KS: interpreted the results of the experiments. TK: prepared the figures and drafted the manuscript. TK: edited and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toru Kawada.

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Funding

Japan Society for the Promotion of Science, 20K20622, Toru Kawada,Salt Science Research Foundation, 2029, 2125, Toru Kawada, Takeda Medical Research Foundation, Toru Kawada.

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The authors declare no conflict of interest regarding this study.

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Appendix

Appendix

The line representing the relationship between AP and nUF in each condition was drawn based on the following equation (Eq. A1).

$$nUF={nUF}_{intercept}+{nUF}_{slope}\times AP,$$
(A1)

where nUFintercept and nUFslope were determined using values listed in Table 3. For the control data on the intact side, the mean values of C were adopted, and the relationship between AP and nUF was described by the following equation (Eq. A2).

$$nUF=0.82+0.315\times AP.$$
(A2)

For the control data on the denervated side, the mean values of BRDN were considered, and the relationship between AP and nUF was obtained by the following equation (Eq. A3).

$$nUF=\left(0.82+7.47\right)+\left(0.315-0.087\right)\times AP.$$
(A3)

For the data after the administration of telmisartan on the intact side, the mean values of BTLM were considered, and the relationship between AP and nUF was obtained by the following equation (Eq. A4).

$$nUF=\left(0.82-16.53\right)+\left(0.315+0.358\right)\times AP.$$
(A4)

For the data after the administration of telmisartan on the denervated side, the mean values of BRDN and BTLM were considered, and the relationship between AP and nUF was obtained by the following equation (Eq. A5).

$$nUF=\left(0.82+7.47-16.53\right)+\left(0.315-0.087+0.358\right)\times AP.$$
(A5)

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Kawada, T., Li, M., Suehara, S. et al. Angiotensin II inhibition increases diuresis during acute sympathetic activation in intact and denervated kidneys in rats with chronic myocardial infarction. Heart Vessels 37, 1636–1646 (2022). https://doi.org/10.1007/s00380-022-02110-2

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