Although suppression of sympathetic activity is suggested as one of the underlying mechanisms for the cardioprotective effects afforded by sodium–glucose cotransporter 2 (SGLT2) inhibitors, whether the modulation of glucose handling acutely affects sympathetic regulation of arterial pressure remains to be elucidated. In Goto–Kakizaki diabetic rats, we estimated the open-loop static characteristics of the carotid sinus baroreflex together with urine glucose excretion using repeated 11-min step input sequences. After the completion of the 2nd sequence, an SGLT2 inhibitor empagliflozin (10 mg kg−1) or vehicle solution was administered intravenously (n = 7 rats each). Empagliflozin did not significantly affect the baroreflex neural or peripheral arc, despite significantly increasing urine glucose excretion (from 0.365 ± 0.216 to 8.514 ± 0.864 mg·min−1·kg−1, P < 0.001) in the 7th and 8th sequences. The possible sympathoinhibitory effect of empagliflozin may be an indirect effect associated with chronic improvements in renal energy status and general disease conditions.
We examined urine excretion during primary acute sympathetic activation (PASA) in anesthetized Wistar-Kyoto rats. Since arterial pressure (AP) changes with sympathetic nerve activity (SNA) during PASA, urine excretion reflects a neurally-mediated antidiuretic effect combined with an effect of pressure diuresis. We hypothesized that preventing AP changes under PASA would enable the direct estimation of the neurally-mediated antidiuretic effect alone. We changed the isolated carotid sinus pressure stepwise from 60 to 180 mmHg and compared the relationship of normalized urine flow (nUF, urine flow normalized by body weight) versus SNA between conditions allowing and preventing baroreflex-mediated changes in the mean AP. The slope of the SNA-nUF relationship was nUFvar = 0.444 ± 0.074 μL·min−1·kg−1·%−1 when the mean AP was variable, whereas it was nUFfix = −0.143 ± 0.032 μL·min−1·kg−1·%−1 when the mean AP was fixed at 100 mmHg (n = 7 rats). The slope associated with the effect of pressure diuresis alone, calculated as nUFvar − nUFfix, was 0.586 ± 0.105 μL·min−1·kg−1·%−1. Hence, the potency of the neurally-mediated antidiuretic effect, | nUFfix| / ( nUFvar − nUFfix), was 0.235 ± 0.014 relative to the effect of pressure diuresis under PASA. Our findings would aid an integrative understanding of the effects of renal hemodynamic and sympathetic modulations on urine output function.
Aims To quantify in vivo the effects of the soluble guanylate cyclase (sGC) stimulator, vericiguat, on autonomic cardiovascular regulation in comparison with the nitric oxide (NO) donor, sodium nitroprusside. Methods In anesthetized Wistar–Kyoto rats, baroreflex-mediated changes in sympathetic nerve activity (SNA), arterial pressure (AP), central venous pressure (CVP), and aortic flow (AoF) were examined before and during the intravenous continuous administration (10 μg·kg−1·min−1) of vericiguat or sodium nitroprusside (n = 8 each). Systemic vascular resistance (SVR) was calculated as SVR = (AP–CVP) / AoF. Results Neither vericiguat nor sodium nitroprusside affected fitted parameters of the baroreflex-mediated SNA response. Both vericiguat and sodium nitroprusside decreased the AP mainly through their peripheral effects. Vericiguat halved the slope of the SNA–SVR relationship from 0.012 ± 0.002 to 0.006 ± 0.002 mmHg·min·mL−1·%−1 (P = 0.008), whereas sodium nitroprusside caused a near parallel downward shift in the SNA–SVR relationship with a reduction of the SVR intercept from 1.235 ± 0.187 to 0.851 ± 0.123 mmHg·min/mL (P = 0.008). Conclusion Neither vericiguat nor sodium nitroprusside significantly affected the baroreflex-mediated SNA response. The vasodilative effect of vericiguat became greater toward high levels of SNA and AP, possibly reflecting the increased sGC sensitivity to endogenous NO. By contrast, the effect of sodium nitroprusside was more uniform over the range of SNA. These results help better understand cardiovascular effects of vericiguat.
Background: The utilization of a combination of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and Impella, ECPELLA, has become widespread among patients with cardiogenic shock. The utilization of VA-ECMO in the presence of aortic regurgitation (AR) can result in significant left ventricular (LV) distention. Additionally, the implantation of Impella via the aortic valve frequently induces AR clinically. We established a simulation model and evaluated the impact of AR on hemodynamics under ECPELLA. Furthermore, assuming that the reverse flow of AR is strongly determined by aortic pressure (AP) level, we simulated a scenario where AP was further decreased. Methods: We employed Simulink® (Mathworks, Inc.). The systemic and pulmonary circulations were modeled using a 5-element resistance-capacitance network. Four cardiac chambers were represented by time-varying elastance. We compared the aortic regurgitant flow (Far), total systemic flow (Ftotal), and LV pressure-volume relationship under various severities of AR and varying Impella (0-3.7 L/min) and VA-ECMO (0-5 L/min) flows. AR grades were adjusted by the regurgitant resistance and classified as mild, moderate, and severe, mimicking a clinical scenario. Results: Without AR, ECMO significantly increased Ftotal and raised LV end-diastolic pressure (LVEDP). Impella increased Ftotal and decreased LVEDP. The concomitant presence of AR exacerbated the increase of LVEDP by ECMO and the reduction of LVEDP by Impella. Under ECPELLA support (VA-ECMO: 3 L/min) with mild AR, the increase of Impella support (1 to 3.5 L) increased Ftotal and Far, while decreasing LVEDP, indicating the prevention of AR-induced LV distention. Additionally, the presence of mild AR prevented the Impella-induced left ventricular suction that is commonly observed under ECPELLA support with high-flow VA-ECMO. In the case of moderate AR, while the hemodynamic trends were similar to those observed under mild AR, Impella was unable to prevent the increment of LVEDP to a critical level (< 20 mmHg). However, by decreasing AP through reducing resistance (e.g. vasodilators), both Far and LVEDP were dramatically reduced and Ftotal was increased under ECPELLA support. Conclusion: The concomitant presence of AR in ECPELLA condition increased LV load, while prevented LV suction. The use of vasodilator in ECPELLA with AR could attenuate AR, increase systemic perfusion, and reduce LV load. The optimal control of Impella and VA-ECMO flows and AP can maximize the hemodynamic and LV unloading impacts of ECPELLA. no funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Accentuated antagonism refers to a phenomenon in which the vagal effect on heart rate (HR) is augmented by background sympathetic tone. The dynamic aspect of accentuated antagonism remains to be elucidated during different levels of vagal nerve stimulation (VNS) intensity. We performed VNS on anesthetized rats (n = 8) according to a binary white noise signal with a switching interval of 500 ms at three different stimulation rates (low-intensity: 0-10 Hz, moderate-intensity: 0-20 Hz, and high-intensity: 0-40 Hz). The transfer function from VNS to HR was estimated with and without concomitant tonic sympathetic nerve stimulation (SNS) at 5 Hz. The asymptotic low-frequency (LF) gain (in beats·min−1·Hz−1) of the transfer function increased with SNS regardless of the VNS rate [low-intensity: 3.93 ± 0.70 vs. 5.82 ± 0.65 (P = 0.021), moderate-intensity: 3.87 ± 0.62 vs. 5.36 ± 0.53 (P = 0.018), high-intensity: 4.77 ± 0.85 vs. 7.39 ± 1.36 (P = 0.011)]. Moreover, SNS slightly increased the ratio of high-frequency (HF) gain to the LF gain. These effects of SNS were cancelled by the pretreatment of ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated channels, in another group of rats (n = 6). Although background sympathetic tone antagonizes the vagal effect on mean HR, it enables finer HR control by increasing the dynamic gain of the vagal HR transfer function regardless of VNS intensity. When interpreting the HF component of HR variability, the augmenting effect from background sympathetic tone needs to be considered.
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