Cyclosporine Induces Progressive Attenuation of Baroreceptor Heart Rate Response and Cumulative Pressor Response in Conscious Unrestrained Rats

Shaltout, Hossam A.; Abdel‐Rahman, Abdel A.

doi:10.1124/jpet.102.048447

Cited by 15 publications

(10 citation statements)

References 34 publications

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“…The phenylephrine method is based on the open-loop model, in which the increases in RRI and BP are related according to a linear model, whereas the methods used in our study provide a closed-loop estimation of BRS, in which BP oscillations induce changes of RRI that in turn are able to modify BP (Pitzalis et al, 1998). Notably, phenylephrine at 10 g/kg, which falls within the doses used to construct the BRS curve by the Oxford method in reported studies, including ours (Gadegbeku et al, 2002;Shaltout and Abdel-Rahman, 2003), reduced the plasma NEFA level (Imura et al, 1971). Furthermore, the sequence BRS is an accepted measure for tonic parasympathetic cardiac control (Wang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of Fatty Acids Induced Suppression of Cardiovascular Reflexes in Rats

Shaltout¹,

Abdel‐Rahman²

2005

J Pharmacol Exp Ther

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A blunted baroreflex sensitivity (BRS), impaired heart rate variability (HRV), and high plasma nonesterified fatty acids (NEFA) are predictors of adverse cardiovascular outcomes. We tested the hypothesis that elevation of NEFA negatively impacts the cardiac baroreflex response and undertook spectral analyses and molecular studies to delineate the mechanism of action. We used two interventions to elevate serum NEFA: 1) overnight fasting (n ϭ 7) and 2) i.v. infusion of 1.2 ml/kg intralipid 20% ϩ heparin (I/H) over 10 min (n ϭ 9) in conscious unrestrained male rats. Elevated NEFA caused by fasting complemented by I/H infusion were associated with a concentration-dependent reduction in spontaneous BRS measured by spectral analysis [low-frequency ␣ and high-frequency ␣ (HF␣) indices] and sequence method and HRV measured by frequency domain as power of RR interval (RRI) spectra (low-frequency RRI and high-frequency RRI) and by time domain as standard deviation of beat-to-beat interval and root mean square of successive differences along with increase in blood pressure variability measured as standard deviation of mean arterial pressure and power of systolic arterial pressure spectra (low-frequency systolic arterial pressure). Because elevated NEFA suppressed the vagal component of the baroreflex response (HF␣), we tested the hypothesis that NEFA-evoked sequestration of myocardial muscarinic receptor (M2-mAChR) contributes to the reduced BRS. High NEFA level was accompanied by increased caveolar sequestration of cardiac M2-mAChRs without changing M2-mAChR protein expression. We report the first detailed analyses of NEFA's effect on the cardiac baroreflex and show that increased caveolar sequestration of cardiac M2-mAChRs constitutes a cellular mechanism for elevated NEFA-related deleterious cardiovascular outcomes.Sympathetic overactivity and depression of cardiac vagal function contribute to baroreflex dysfunction and may predispose to hypertension (Ketch et al., 2002), and these neural and hemodynamic abnormalities are associated with lifethreatening cardiac arrhythmias and sudden death (Hennersdorf and Strauer, 2001). Fluctuations in blood pressure (BP) and heart rate (HR) reflect the dynamic interplay of diverse physiological processes (Akselrod et al., 1985) and are acceptable measures for cardiovascular autonomic balance. Increased HR variability (HRV) and BP variability (BPV) and reduced HRV are predictors for mortality (Stein et al., 1994;Lombardi et al., 1996; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996;Palatini and Julius, 1997;Malliani and Montano, 2002). Spectral analysis of arterial BP and HR has provided new insight into the autonomic vascular and cardiac regulation (Cerutti et al., 1994). Analysis of BPV and HRV by the spectral approach, as well as by time domain techniques, represents a useful tool for the study of the mechanisms involved in cardiovascular regulation in both normal and diseased conditions (Parati et al., 1...

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Section: Discussionmentioning

confidence: 99%

“…The rats had free access to water and food. Arterial BP was measured according to the method used in our previous studies (Shaltout and Abdel-Rahman, 2003). Briefly, the rats were anesthetized with pentobarbital sodium (50 mg/kg, i.p.).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Fatty Acids Induced Suppression of Cardiovascular Reflexes in Rats

Shaltout¹,

Abdel‐Rahman²

2005

J Pharmacol Exp Ther

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“…The decrease in MSNA in response to chemoreflex inhibition was positively related to the duration after heart transplantation. We speculate that cyclosporine-related arterial baroreceptor attenuation, 34 and possibly the duration of systemic hypertension after the surgical procedure, may play a role. End-stage renal failure is accompanied by increased MSNA, which remains elevated in patients after renal transplantation with diseased native kidneys, 35 but decreases during peripheral chemoreceptor deactivation by acute hyperoxia.…”

Section: Discussionmentioning

confidence: 99%

Effects of Peripheral Chemoreceptors Deactivation on Sympathetic Activity in Heart Transplant Recipients

et al. 2005

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Abstract-Heart transplantation initially normalizes sympathetic hyperactivity directed at the muscle circulation. However, sympathetic activity increases with time after transplantation and the exact mechanisms responsible for sympathetic control in heart transplant recipients remain unclear. We examined the effects of peripheral chemoreflex deactivation caused by breathing 100% oxygen on muscle sympathetic nerve activity (expressed as number of burst per minute and mean burst amplitude), heart rate, and mean blood pressure in 13 heart transplant recipients, 13 patients with essential hypertension, and 10 controls. Heart transplant recipients disclosed the highest sympathetic activity, whereas it did not differ between controls and patients with essential hypertension (51Ϯ16 versus 37Ϯ14 versus 39Ϯ12 burst/min, respectively; PϽ0.05). Breathing 100% oxygen, in comparison with 21% oxygen, reduced sympathetic activity (Ϫ4Ϯ4 versus Ϫ1Ϯ2 burst/min, PϽ0.01; 85Ϯ9 versus101Ϯ8% of amplitude at baseline, PϽ0.001) and mean blood pressure (Ϫ4Ϯ5 versus ϩ3Ϯ6 mm Hg; PϽ0.05) in heart transplant recipients, decreased sympathetic activity (Ϫ4Ϯ4 versus 0Ϯ3 burst/min, PϽ0.05; 90Ϯ16 versus101Ϯ9% of amplitude at baseline, PϽ0.05) in patients with essential hypertension, but did not reduce sympathetic activity (2Ϯ4 versus 3Ϯ3 burst/min, PϭNS; 95Ϯ11 versus 95Ϯ13% of amplitude at baseline, PϭNS) in control subjects. The sympathetic response to hyperoxia was more marked in heart transplant recipients than in controls (85Ϯ9 versus 95Ϯ11% of baseline amplitude; PϽ0.05). The decrease in sympathetic activity was most evident in patients with the longest time after heart transplantation (rϭϪ0.75, PϽ0.01).In conclusion, tonic chemoreflex activation increases resting muscle sympathetic nerve activity and favors blood pressure elevation after heart transplantation. Key Words: chemoreceptors Ⅲ sympathetic nervous system Ⅲ transplantation C ongestive heart failure is associated with remarkably elevated muscle sympathetic nerve activity (MSNA). 1 Heart transplantation restores a close to normal cardiac function but does not always normalize MSNA. 2-5 Elevated MSNA after heart transplantation is associated with cyclosporine therapy 3 and increases as a function of time after transplantation. 2 Increased peripheral chemoreflex sensitivity has been demonstrated in humans and experimental animals with congestive heart failure. 6 -9 Whether this alteration in chemoreflex function is reversible when cardiac function is restored by heart transplantation is unknown. We hypothesized that increased peripheral chemoreceptor activation, possibly a lingering effect of heart failure, contributes to elevated MSNA in heart transplant recipients (HTRs). Accordingly, we studied the effects of hyperoxia, an intervention that acutely reduces afferent nerve traffic from the peripheral chemoreceptors, on MSNA in HTRs. Because the majority of HTRs are hypertensive 10 and enhanced peripheral chemoreflex sensitivity has been observed in hypertensive humans and in animal m...

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“…Arterial baroreceptor sensitivity is impaired because of chronic cyclosporine uptake. 29 The close proximity of baroreceptor and chemoreceptor neurons in the solitary and paramedian reticular nuclei in the medulla could explain the interactions between these reflexes 30,32 ; however, such an interference between baroreceptors and central chemoreceptors has not been described. Thus, although the surgical procedure improves cardiac function, which may favor normalization of central chemoreceptor sensitivity, it also alters inhibitory loops and necessitates drug treatments, which may suppress baroreflex restraint on peripheral chemoreflex control.…”

Section: Central Chemoreflex Sensitivitymentioning

confidence: 99%

Increased Peripheral Chemoreceptors Sensitivity and Exercise Ventilation in Heart Transplant Recipients

et al. 2006

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Background-Heart failure is characterized by increased ventilation during exercise, which is positively related to increased peripheral and central chemoreceptor sensitivity. Heart transplantation does not normalize the ventilatory response to exercise, and its effects on the chemoreflex control of ventilation remain unknown. We tested the hypothesis that chemoreceptor sensitivity is increased in heart transplant recipients (HTRs) and linked to exercise hyperpnea. Methods and Results-We determined the ventilatory, muscle sympathetic nerve activity (MSNA), and circulatory responses to isocapnic hypoxia and hyperoxic hypercapnia 7Ϯ1 years after transplantation in 19 HTRs with a normal left ventricular ejection fraction of 60Ϯ2%. Results were compared with those of 11 closely matched referent subjects. Sixteen patients and 10 referent subjects also underwent cycle ergometer exercise tests. HTRs compared with referent subjects presented higher MSNA (52Ϯ4 versus 34Ϯ3 bursts/min; PϽ0.01) and heart rates (83Ϯ3 versus 68Ϯ3 bpm; PϽ0.01) during room air breathing. The ventilatory response to hypoxia was higher in HTRs than in referent subjects (PϽ0.01, ANOVA). The increase in MSNA also was more marked during hypoxia in the HTRs than in the referent group (PϽ0.05, ANOVA

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Cyclosporine Induces Progressive Attenuation of Baroreceptor Heart Rate Response and Cumulative Pressor Response in Conscious Unrestrained Rats

Cited by 15 publications

References 34 publications

Mechanism of Fatty Acids Induced Suppression of Cardiovascular Reflexes in Rats

Mechanism of Fatty Acids Induced Suppression of Cardiovascular Reflexes in Rats

Effects of Peripheral Chemoreceptors Deactivation on Sympathetic Activity in Heart Transplant Recipients

Increased Peripheral Chemoreceptors Sensitivity and Exercise Ventilation in Heart Transplant Recipients

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