Hiromi Yamamoto

Open-loop dynamic and static characteristics of the carotid sinus baroreflex in rats with chronic heart failure after myocardial infarction

We estimated open-loop dynamic characteristics of the carotid sinus baroreflex in normal control rats and chronic heart failure (CHF) rats after myocardial infarction. First, the neural arc transfer function from carotid sinus pressure to splanchnic sympathetic nerve activity (SNA) and its corresponding step response were examined. Although the steady-state response was attenuated in CHF, the negative peak response and the time to peak did not change significantly, suggesting preserved neural arc dynamic characteristics. Next, the peripheral arc transfer function from SNA to arterial pressure (AP) and its corresponding step response were examined. The steady-state response and the initial slope were reduced in CHF, suggesting impaired end-organ responses. In a simulation study based on the dynamic and static characteristics, the percent recovery of AP was reduced progressively as the size of disturbance increased in CHF, suggesting that a reserve for AP buffering is lost in CHF despite relatively maintained baseline AP.

Contrasting effects of moderate vagal stimulation on heart rate and carotid sinus baroreflex-mediated sympathetic arterial pressure regulation in rats

AIMS To examine whether moderate efferent vagal nerve stimulation (VNS) attenuates the carotid sinus baroreflex-mediated arterial pressure (AP) regulation via its antagonism to the sympathetic system. MAIN METHODS Carotid sinus baroreceptor regions were isolated from the systemic circulation in eight anesthetized and vagotomized rats. A staircase-wise input was imposed on carotid sinus pressure (CSP) with or without efferent VNS (20Hz, 2ms, 1-4V), while the responses in AP, heart rate (HR), and splanchnic sympathetic nerve activity (SNA) were measured. KEY FINDINGS A multiple linear regression analysis indicated that VNS decreased the minimum HR in the CSP-HR relationship by 58.2±4.9 beats/min (P<0.01) from its reference value of 387.0±5.8 beats/min. Although VNS significantly decreased an intercept of the SNA-AP relationship, it did not affect parameters of the CSP-AP relationship or the CSP-SNA relationship significantly. The operating-point AP of the baroreflex was decreased by 2.8±1.0mmHg (P<0.01) during VNS, which was less than 3% of the reference value of 117.7±1.2mmHg. SIGNIFICANCE VNS, at an intensity of decreasing HR by approximately 13%, does not acutely attenuate the baroreflex-mediated sympathetic AP regulation.

Involvement of the mechanoreceptors in the sensory mechanisms of manual and electrical acupuncture

The modalities of acupuncture can be broadly classified into manual acupuncture (MA) and electroacupuncture (EA). Although MA has been reported to cause winding of tissue around the needle and subsequent activation of the sensory mechanoreceptors and nociceptors, the sensory mechanisms of acupuncture stimulation are not fully understood. To test the hypothesis that the involvement of the mechanoreceptors in the sensory mechanism is different in MA and EA, we examined the effects of a stretch-activated channel blocker gadolinium on the hemodynamic responses to hind limb MA and EA in anesthetized rats (n = 9). Gadolinium significantly attenuated the MA-induced bradycardic response (-22 ± 5 vs. -10 ± 3 bpm, P<0.05) and tended to attenuate the MA-induced depressor response (-30 ± 5 vs. -18 ± 4 mmHg, P = 0.06). On the other hand, gadolinium significantly attenuated both the EA-induced bradycardic (-22 ± 5 vs. -9 ± 4 bpm, P<0.01) and depressor responses (-32 ± 6 vs. -15 ± 5 mmHg, P<0.01). These results indicate that the mechanoreceptors are involved in the sensory mechanisms for both MA and EA.

Renal denervation mitigates cardiac remodeling and renal damage in Dahl rats: a comparison with β-receptor blockade

Chronic activation of the sympathetic nervous system (SNS) contributes to cardiac remodeling and the transition to heart failure (HF). Renal sympathetic denervation (RDN) may ameliorate this damage by improving renal function and sympathetic cardioregulation in hypertensive HF patients with renal injury. The efficacy may be comparable to that of chronic β-blocker treatment. Dahl salt-sensitive hypertensive rats were subjected to RDN in the hypertrophic stage. Another group of Dahl rats were subjected to sham operations and treated chronically with vehicle (CONT) or β-blocker bisoprolol (BISO). Neither RDN nor BISO altered the blood pressure; however, BISO significantly reduced the heart rate (HR). Both RDN and BISO significantly prolonged survival (22.2 and 22.4 weeks, respectively) compared with CONT (18.3 weeks). Echocardiography revealed reduced left ventricular (LV) hypertrophy and improved LV function, and histological analysis demonstrated the amelioration of LV myocyte hypertrophy and fibrosis in the RDN and BISO rats at the HF stage. Tyrosine hydroxylase and β1-adrenergic receptor (ADR) expression levels in the LV myocardium significantly increased only in the RDN rats, whereas the α1b-, α1d- and α2c-ADR expression levels increased only in the BISO rats. In both groups, renal damage and dysfunction were also reduced, and this reduction was accompanied by the suppression of endothelin-1, renin and angiotensin-converting enzyme mRNAs. RDN ameliorated the progression of both myocardial and renal damage in the hypertensive rats independent of blood pressure changes. The overall effects were similar to those of β-receptor blockade with favorable effects on HR and α-ADR expression. These findings may be associated with the restoration of the myocardial SNS and renal protection.

Electroacupuncture changes the relationship between cardiac and renal sympathetic nerve activities in anesthetized cats.

Electroacupuncture (EA) is known to affect hemodynamics through modulation of efferent sympathetic nerve activity (SNA), however, possible regional differences in the SNA response to EA remains to be examined. Based on the discordance between arterial blood pressure and heart rate changes during EA, we hypothesized that regional differences would occur among SNAs during EA. To test this hypothesis, we compared changes in cardiac and renal SNAs in response to 1-min EA (10 Hz or 2 Hz) of a hind limb in adult cats anesthetized with pentobarbital sodium. Renal SNA remained decreased for 1 min during EA (P<0.01 for both 10 Hz and 2 Hz). In contrast, cardiac SNA tented to decrease only in the beginning of EA. It increased during the end of EA (P<0.05 for 2 Hz) and further increased after the end of EA (P<0.01 both for 10 Hz and 2 Hz). There was a quasi-linear relationship between renal and cardiac SNAs with a slope of 0.69 (i.e., renal SNA was more suppressed than cardiac SNA) during the last 10 s of EA. The discrepancy between the renal and cardiac SNAs persisted after sinoaortic denervation and vagotomy. In conclusion, EA evokes differential patterns of SNA responses and changes the relationship between cardiac and renal SNAs.

Chronic vagal nerve stimulation improves baroreflex neural arc function in heart failure rats.

We tested whether 6-wk vagal stimulation (VS) treatment improved open-loop baroreflex function in rats after myocardial infarction (MI). The following three groups of Sprague-Dawley rats were examined: normal control (NC, n = 9), MI with no treatment (MI-NT, n = 8), and MI treated with VS (MI-VS, n = 7). Under anesthesia, a stepwise input ranging from 60 to 180 mmHg was imposed on isolated carotid sinus baroreceptor regions, while the responses in splanchnic sympathetic nerve activity (SNA) and arterial pressure (AP) were measured. The response range of percent SNA was greater in the MI-VS than in the MI-NT group (63.8 ± 4.9% vs. 33.1 ± 3.8%, P < 0.01). The slope of the AP response to percent SNA was not different between the MI-VS and MI-NT groups (0.611 ± 0.076 vs. 0.781 ± 0.057 mmHg/%). The difference in the response range of AP between the MI-VS and MI-NT groups did not reach statistical significance (40.7 ± 6.2 vs. 26.4 ± 3.5 mmHg). In conclusion, the 6-wk VS treatment significantly improved the baroreflex control of SNA, but the effect was limited for the baroreflex total-loop function due to the lack of significant improvement in the AP response to percent SNA.

Effects of cilnidipine on sympathetic outflow and sympathetic arterial pressure and heart rate regulations in rats

AIMS Cilnidipine is a unique Ca(2+) channel blocker that inhibits both L-type and N-type Ca(2+) channels. The present study aimed to assess the effects of intravenous cilnidipine on sympathetic outflow and sympathetic arterial pressure (AP) and heart rate (HR) regulations. MAIN METHODS Carotid sinus baroreceptor regions were isolated from the systemic circulation in anesthetized and vagotomized Wistar Kyoto rats. Changes in efferent sympathetic nerve activity (SNA), AP and HR in response to a stepwise input of carotid sinus pressure were examined before and during intravenous cilnidipine administration (30 μg/kg bolus+100 μg kg(-1)h(-1) infusion, n=6). KEY FINDINGS Cilnidipine significantly reduced the AP response range (from 68.0 ± 10.2 to 34.6 ± 4.1 mmHg, P=0.007) but did not affect the SNA response range (from 90.4 ± 10.3 to 84.7 ± 9.5%, P=0.297) or the HR response range (from 50.4 ± 10.1 to 48.1 ± 6.2 beats/min, P=0.719). SIGNIFICANCE Cilnidipine, at a depressor dose used in the present study, does not acutely suppress sympathetic outflow from the central nervous system. Also, it spared the sympathetic HR response, suggesting that N-type Ca(2+) channel blocking action at the cardiac sympathetic nerve endings may be a modest one.

Acute effects of intravenous nifedipine or azelnidipine on open-loop baroreflex static characteristics in rats.

AIMS To assess the acute effects of intravenous azelnidipine, a third-generation L-type calcium channel blocker, on sympathetic outflow from the central nervous system and to compare the effects of intravenous azelnidipine with those of intravenous nifedipine. MAIN METHODS In anesthetized Wistar Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in sympathetic nerve activity (SNA) and arterial pressure (AP) in response to a stepwise baroreceptor pressure input were examined before and during intravenous nifedipine or azelnidipine (for each: 100 μg/kg bolus followed by 300 μg/kg/h infusion, n = 6). KEY FINDINGS Nifedipine significantly reduced the range of the AP response from 76.8 ± 7.4 to 45.4 ± 7.0 mmHg (P < 0.01) but did not affect the range of the SNA response (from 84.4 ± 5.1 to 85.9 ± 10.2%) or the SNA maximum gain (from 2.26 ± 0.28 to 2.35 ± 0.55%/mmHg). Similarly, azelnidipine significantly reduced the range of the AP response from 62.4 ± 3.9 to 31.4 ± 4.1 mmHg (P<0.01) but did not affect the range of the SNA response (from 71.2 ± 5.5 to 74.9 ± 7.2%) or the SNA maximum gain (from 1.64 ± 0.17 to 2.08 ± 0.26%/mmHg). SIGNIFICANCE A depressor dose of nifedipine or azelnidipine does not have an acute sympathoinhibitory effect in normotensive Wistar Kyoto rats even when the level of SNA was varied over the entire operating range of the carotid sinus baroreflex.

Systematic understanding of acute effects of intravenous guanfacine on rat carotid sinus baroreflex-mediated sympathetic arterial pressure regulation

AIMS To assess the acute effects of intravenous guanfacine, an α2A-adrenergic agonist, on sympathetic outflow from the central nervous system and on sympathetic arterial pressure (AP) response. MAIN METHODS In anesthetized Wistar Kyoto rats, carotid sinus baroreceptor regions were isolated. Changes in electrical sympathetic nerve activity (SNA) and AP in response to a baroreceptor pressure input were examined before and after an intravenous administration of a high dose (100μg/kg, n=7) or a low dose (20μg/kg, n=5) of guanfacine. KEY FINDINGS The higher dose of guanfacine significantly narrowed the range of the AP response (86.8±6.4 to 38.4±12.9mmHg, P<0.01) but increased the minimum AP (79.3±7.5 to 93.2±8.7mmHg, P<0.05). In the neural arc, guanfacine reduced both the response range (90.4±2.3 to 33.4±10.7%, P<0.01) and the minimum SNA (11.4±1.9 to 2.6±1.5%, P<0.01). In the peripheral arc, guanfacine increased the intercept (67.6±7.1 to 92.8±8.5mmHg, P<0.01) without a significant effect on the slope. The lower dose of guanfacine weakened the effects on both the neural and peripheral arcs. SIGNIFICANCE Guanfacine suppressed SNA without a significant reduction of AP, which may be attributable to the peripheral vasoconstrictive effect. Reducing the dose of acutely administered intravenous guanfacine does not aid in separating the central sympathoinhibitory effect from the peripheral vasoconstrictive effect on AP in anesthetized rats in vivo.

Modification of autonomic balance by electrical acupuncture does not affect baroreflex dynamic characteristics

Background: We have demonstrated that modification of autonomic balance by electrical vagal stimulation delays progression of cardiac dysfunction and cardiac remodeling, and prolongs survival in rats with severe heart failure. We have also shown that we were able to modify autonomic balance by electrical acupuncture at the acupoint of Zusanli, potentially applicable for the treatment of heart failure. We examined the effect of the acupuncture on the dynamic characteristics of the baroreflex system to exclude the possible deleterious effect on orthostatic tolerance.