Tadeusz J. Scislo

Differential arterial baroreflex regulation of renal, lumbar, and adrenal sympathetic nerve activity in the rat

Lumbar (LSNA), renal (RSNA), or adrenal sympathetic nerve activity (ASNA) is most commonly used as an index of sympathetic nerve activity in investigations of arterial baroreflex control in the rat. Although differential regulation of sympathetic outputs to different organs has been extensively studied, no direct and simultaneous comparisons of the full range of baroreflex reactivity have been described for these sympathetic outputs. Therefore, we compared steady-state sigmoidal baroreflex stimulus-response curves (via phenylephrine-nitroprusside infusion) for RSNA recorded simultaneously with LSNA or ASNA in urethan-chloralose-anesthetized male Sprague-Dawley rats. Characteristics of the baroreflex curves differed significantly between all three sympathetic outputs. ASNA exhibited the greatest range of baroreflex regulation, the highest upper level of activity, and the widest distribution of the gain over a broad range of mean arterial pressure (MAP). RSNA exhibited greater gain than LSNA. LSNA showed the smallest range and maximal inhibition in comparison to other sympathetic outputs. However, all three nerves responded similarly to baroreflex stimulation and unloading in the range in MAP close to the operating point. We conclude that baroreflex regulation of sympathetic activity shows wide regional variability in gain, range, and maximal inhibition. Therefore, the entire stimulus-response relationship should be considered in comparing regional sympathetic responses.Lumbar (LSNA), renal (RSNA), or adrenal sympathetic nerve activity (ASNA) is most commonly used as an index of sympathetic nerve activity in investigations of arterial baroreflex control in the rat. Although differential regulation of sympathetic outputs to different organs has been extensively studied, no direct and simultaneous comparisons of the full range of baroreflex reactivity have been described for these sympathetic outputs. Therefore, we compared steady-state sigmoidal baroreflex stimulus-response curves (via phenylephrine-nitroprusside infusion) for RSNA recorded simultaneously with LSNA or ASNA in urethan-chloralose-anesthetized male Sprague-Dawley rats. Characteristics of the baroreflex curves differed significantly between all three sympathetic outputs. ASNA exhibited the greatest range of baroreflex regulation, the highest upper level of activity, and the widest distribution of the gain over a broad range of mean arterial pressure (MAP). RSNA exhibited greater gain than LSNA. LSNA showed the smallest range and maximal inhibition in comparison to other sympathetic outputs. However, all three nerves responded similarly to baroreflex stimulation and unloading in the range in MAP close to the operating point. We conclude that baroreflex regulation of sympathetic activity shows wide regional variability in gain, range, and maximal inhibition. Therefore, the entire stimulus-response relationship should be considered in comparing regional sympathetic responses.

Purines and the nucleus tractus solitarius: effects on cardiovascular and respiratory function.

1. The roles of adenosine and adenosine 5′‐triphosphate in cardiorespiratory regulation by the nucleus tractus solitarius (NTS) have been evaluated in a range of experiments, using microinjections of selective agonists and antagonists of purinoceptors.

Experimental Biology 2000 Symposium on Differential Control of Sympathetic Outflow DIFFERENTIAL PATTERNS OF SYMPATHETIC RESPONSES TO SELECTIVE STIMULATION OF NUCLEUS TRACTUS SOLITARIUS PURINERGIC RECEPTOR SUBTYPES

1. Studies are described that indicate that stimulation of different purinergic receptor subtypes (A1, A2A and P2X) located in the sub‐postremal nucleus tractus solitarius (NTS) evokes qualitatively and quantitatively different regional haemodynamic and efferent sympathetic responses.

Activation of P2x-purinoceptors in the nucleus tractus solitarius elicits differential inhibition of lumbar and renal sympathetic nerve activity

Activation of P2x-purinoceptors in the nucleus tractus solitarius (NTS) via microinjection of alpha,beta-methylene ATP (alpha,beta-MeATP) elicits large dose-dependent decreases in mean arterial pressure (MAP) and heart rate (HR) and preferential dilation of the iliac vascular bed in comparison to renal and mesenteric vascular beds. We investigated whether sympathoinhibition contributes to the depressor responses and whether differential changes in regional sympathetic output occur. In 43 chloralose/urethane anesthetized male Sprague-Dawley rats, MAP, HR, renal (RSNA) and lumbar sympathetic nerve activity (LSNA) were recorded. Data were analyzed as both the maximum decrease and the integral of the decrease over the duration of the depressor response. Microinjection of alpha,beta-MeATP (25 and 100 pmol in 50 nl volume) into the subpostremal NTS caused significant and dose-dependent decreases in MAP, HR, RSNA and LSNA. However, the changes in RSNA were significantly greater than those observed in LSNA for both doses and both methods of analysis of data (maximum responses in delta %: 84 +/- 3 vs 62 +/- 4, and 93 +/- 3 vs 74 +/- 4 for low and high dose of alpha,beta-MeATP, respectively; integral responses in delta % x min: 32 +/- 4 vs 18 +/- 3 and 179 +/- 7 vs 134 +/- 14 for low and high dose of alpha,beta-MeATP, respectively). Blockade of P2-purinoceptors in the NTS by the specific P2-receptor antagonist suramin abolished responses to 100 pmol alpha,beta-MeATP and microinjections of vehicle did not alter neural nor hemodynamic parameters. We conclude that activation of P2x-purinoceptors in the NTS inhibits sympathetic nerve activity and evokes differential regional sympathetic responses. However, differential sympathoinhibition does not explain differential vascular responses to the activation of P2x-purinoceptors in the NTS.

Purinergic mechanisms of the nucleus of the solitary tract and neural cardiovascular control

Abstract Objectives: This review addresses the role of central purinergic receptors in the operation of the cardiovascular reflexes. Methods: Potential physiological role of purinergic receptors operating in the nucleus of the solitary tract (NTS) was assessed via comparison of the regional patterns of hemodynamic and sympathetic responses evoked by selective stimulation/inhibition of NTS purinergic receptor subtypes, with the patterns evoked by stimulation and unloading of arterial baroreceptors, and other known patterns of autonomic responses. The effects of sino-aortic denervation plus vagotomy and ionotropic glutamatergic blockade of NTS mechanisms on the patterns of the responses were also considered. Results: Selective stimulation of NTS A1 receptors with CPA evoked a pattern of regional autonomic responses consistent with inhibition of baroreflex mechanisms and facilitation/ disinhibition of chemoreflex mechanisms. Selective stimulation of NTS A2a receptors with CGS 21680-evoked pattern of the responses different than that evoked by stimulation of baroreflex afferents what remains in contrast to previous reports suggesting that NTS A2a receptors facilitate baroreflex transmission. The pattern of the responses was similar to that observed during hypotensive hemorrhage. Preferential, b -adrenergic iliac vasodilation evoked by stimulation of adenosine A2a receptors and preferential activation of sympathetic output to the adrenal medulla by both adenosine A1 and A2a receptors are consistent with contribution of these receptors to the defense response, stress and exercise. These observations support previous findings that NTS A1 receptors contribute to the hypothalamic defense response. The effects of stimulation and blockade of NTS P2x receptors with α, β-methylene ATP and suramin, respectively, suggested that neuronally-released ATP operating via P2x receptors may be a crucial co-transmitter with glutamate in mediating baroreflex responses. Discussion: The above observations strongly suggest that purinergic receptor subtypes operating in NTS circuitry are linked to specific afferent and descending mechanisms primarily integrated in the NTS.

Differential control of renal vs. adrenal sympathetic nerve activity by NTS A2a and P2x purinoceptors

Activation of adenosine A2a and ATP P2x purinoceptors in the subpostremal nucleus tractus solitarii (NTS) via microinjection of the selective agonists CGS-21680 and α,β-methylene ATP (α,β-MeATP), respectively, elicits large dose-dependent decreases in arterial pressure and heart rate, differential regional vasodilation, and differential inhibition of regional sympathetic outputs. With marked hypotensive hemorrhage, preganglionic adrenal sympathetic nerve activity (pre-ASNA) increases, whereas renal (RSNA) and postganglionic adrenal sympathetic nerve activity (post-ASNA) decrease. In this setting, adenosine levels in the brain stem increase. Therefore, we investigated whether stimulation of specific purinoceptors in the NTS may evoke differential sympathetic responses. RSNA was recorded simultaneously with pre-ASNA or post-ASNA in chloralose-urethan-anesthetized male Sprague-Dawley rats. CGS-21680 (2 and 20 pmol in 50 nl) inhibited RSNA and post-ASNA, whereas pre-ASNA increased markedly. α,β-MeATP (25 and 100 pmol in 50 nl) inhibited all sympathetic outputs. Sinoaortic denervation plus vagotomy markedly prolonged the responses to P2x-purinoceptor stimulation. Glutamate (100 pmol in 50 nl) caused differential inhibition of all sympathetic outputs similar to that evoked by α,β-MeATP. We conclude that NTS A2a-purinoceptor activation evokes differential sympathetic responses similar to those observed during hemorrhage, whereas P2x-purinoceptor and glutamate-receptor activation evokes differential inhibition of sympathetic outputs similar to arterial baroreflex responses.

Impaired arterial baroreflex regulation of heart rate after blockade of P2-purinoceptors in the nucleus tractus solitarius

Activation of P2x-purinoceptors in the nucleus tractus solitarius (NTS) via microinjection of ATP mimics baroreflex responses (bradycardia, hypotension); however, the physiological role of these receptors in cardiovascular control remains unclear. We tested whether blockade of these receptors attenuates arterial baroreflex control of heart rate (HR). Baroreflex-induced changes in HR (via graded i.v. infusion of phenylephrine and nitroprusside) were observed in seven alpha-chloralose/urethane anesthetized male Sprague-Dawley rats before and after microinjection of the purinergic P2 receptor antagonist suramin (0.5 nmol in 50 nL) into the subpostremal NTS. Before suramin, typical baroreflex changes in HR were observed (maximum gain, Gmax = 2.94 +/- 0.54 bpm/mmHg). Suramin markedly impaired baroreflex-induced changes in HR (gain = 0.02 +/- 0.08 and 0.18 +/- 0.09 bpm/mmHg for increases and decreases in mean arterial blood pressure, respectively); however, after 90-130 min, HR and baroreflex reactivity returned to control levels. Microinjections of vehicle into the same area did not alter baroreflex function. In addition, suramin did not alter the depressor responses to microinjections of glutamate into the same site of the NTS. We conclude that normal P2x-purinoceptor function in subpostremal NTS may be necessary for baroreflex regulation of HR.

Activation of A2a adenosine receptors in the nucleus tractus solitarius inhibits renal but not lumbar sympathetic nerve activity

The activation of adenosine A2a receptors in the nucleus tractus solitarius (NTS) via microinjection of the selective agonist CGS 21680 elicits long-lasting, dose-dependent decreases in mean arterial pressure (MAP) and heart rate (HR) and preferential dilation of the iliac vascular bed in comparison to the renal and mesenteric vascular beds. We investigated whether differential changes in regional sympathetic output occur with A2a receptor activation. In 24 chloralose/urethane anesthetized male Sprague-Dawley rats MAP, HR, renal (RSNA) and lumbar sympathetic nerve activity (LSNA) were recorded simultaneously. Data were analyzed as both the maximum decrease and the integral of the decrease over the duration of the depressor response. Microinjection of CGS 21680 (2 and 20 pmol in 50 nl volume) into the subpostremal NTS caused significant and dose-dependent decreases in MAP, HR and RSNA, however, did not significantly decrease LSNA in comparison to the effect of vehicle. Maximum responses of RSNA vs. LSNA in delta% of control values were: -32 +/- 4 vs. -9 +/- 2, and -59 +/- 4 vs. -19 +/- 5 for low (n = 9) and high (n = 8) doses of CGS 21680 respectively; integral responses of RSNA vs. LSNA in delta% x min were: -487 +/- 112 vs. -19 +/- 35 and -1258 +/- 164 vs. -175 +/- 126 for low and high doses of CGS 21680 respectively. Microinjections of vehicle (n = 7) did not alter integral hemodynamic or neural parameters. We conclude that activation of A2a adenosine receptors in the NTS evokes differential changes in visceral vs. somatic sympathetic nerve activity which cannot explain differential vascular responses in terms of simple sympathetic withdrawal. Lack of significant inhibition of LSNA combined with preferential vasodilation in hindquarter vascular bed suggests that active vasodilation may be triggered by activation of A2a adenosine receptors in the subpostremal NTS.

THE CO-EXISTENCE OF INSULIN-MEDIATED DECREASED MEAN ARTERIAL PRESSURE AND INCREASED SYMPATHETIC NERVE ACTIVITY IS NOT MEDIATED BY THE BARORECEPTOR REFLEX AND DIFFERENTIALLY BY HYPOGLYCEMIA

In this study we measured simultaneously and sequentially the lumbar sympathetic nerve activity (LSNA) or renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in response to insulin with co-existing hypoglycemia or with glucose replacement in normal rats. Sinoaortic denervation (SAD) was used to evaluate the influence of the baroreflex. LSNA, RSNA, MAP and HR were determined using an acquisition processor and computer software. Bolus insulin infusion where the blood glucose was allowed to decrease resulted in an immediate decrease in MAP. The HR decreased for approximately 15 min and subsequently increased. The LSNA increased immediately after insulin infusion peaking at 25 minutes and then recovered toward baseline. Insulin infusion with glucose replacement resulted in a decrease in MAP and HR. The LSNA progressively increased and was maintained throughout the experimental period. Insulin infusion with hypoglycemia increased RSNA and when hypoglycemia was prevented the RSNA decreased. SAD attenuated the decrease in MAP and LSNA response to insulin. Thus, insulin acts to decrease MAP while simultaneously increasing HR, LSNA and RSNA when hypoglycemia is allowed to occur. However, insulin acts to decrease HR and RSNA when euglycemia is maintained. The insulin-induced increase in LSNA is modulated by the baroreflex mechanism. We conclude that insulin has independent direct and indirect effects on LSNA, RSNA, MAP and HR that are modulated by glycemia and the baroreflex.

Activation of NTS A2a adenosine receptors differentially resets baroreflex control of renal vs. adrenal sympathetic nerve activity.

The role of nucleus of solitary tract (NTS) A(2a) adenosine receptors in baroreflex mechanisms is controversial. Stimulation of these receptors releases glutamate within the NTS and elicits baroreflex-like decreases in mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas inhibition of these receptors attenuates HR baroreflex responses. In contrast, stimulation of NTS A(2a) adenosine receptors increases preganglionic adrenal sympathetic nerve activity (pre-ASNA), and the depressor and sympathoinhibitory responses are not markedly affected by sinoaortic denervation and blockade of NTS glutamatergic transmission. To elucidate the role of NTS A(2a) adenosine receptors in baroreflex function, we compared full baroreflex stimulus-response curves for HR, RSNA, and pre-ASNA (intravenous nitroprusside/phenylephrine) before and after bilateral NTS microinjections of selective adenosine A(2a) receptor agonist (CGS-21680; 2.0, 20 pmol/50 nl), selective A(2a) receptor antagonist (ZM-241385; 40 pmol/100 nl), and nonselective A(1) + A(2a) receptor antagonist (8-SPT; 1 nmol/100 nl) in urethane/alpha-chloralose anesthetized rats. Activation of A(2a) receptors decreased the range, upper plateau, and gain of baroreflex-response curves for RSNA, whereas these parameters all increased for pre-ASNA, consistent with direct effects of the agonist on regional sympathetic activity. However, no resetting of baroreflex-response curves along the MAP axis occurred despite the marked decreases in baseline MAP. The antagonists had no marked effects on baseline variables or baroreflex-response functions. We conclude that the activation of NTS A(2a) adenosine receptors differentially alters baroreflex control of HR, RSNA, and pre-ASNA mostly via non-baroreflex mechanism(s), and these receptors have virtually no tonic action on baroreflex control of these sympathetic outputs.