Serotonergic mechanisms mediate renal sympathoinhibition during severe hemorrhage in rats

Morgan, Donald A.; Thorén, Peter; Wilczynski, E A; Victor, Ronald G.; Mark, Allyn L.

doi:10.1152/ajpheart.1988.255.3.h496

Cited by 38 publications

(37 citation statements)

References 12 publications

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“…Our echocardiographic demonstration that a marked reduction in left ventricular end-systolic dimension (approaching cavity obliteration) during hemodialysis preceded, rather than followed, the onset of vasodepressor syncope is consistent with this ventricular afferent hypothesis. However, multiple, redundant, and as yet unidentified mechanisms also may be involved ( 14,30,(41)(42)(43) …”

Section: Discussionmentioning

confidence: 99%

Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension.

et al. 1992

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Acute hypotension is an important complication of hemodialysis, but the underlying mechanisms remain poorly understood. Because hemorrhage-induced hypovolemia can trigger a sudden decrease in sympathetic activity resulting in bradycardia and vasodilation, we hypothesized that hemodialysis-induced hypovolemia also can trigger the same type of vasodepressor reaction, which would exacerbate the volume-dependent fall in blood pressure. We therefore measured blood pressure, vascular resistance, and sympathetic nerve activity (intraneural microelectrodes) during sessions of maintenance hemodialysis in 7 patients with and 16 patients without a history of hemodialysis-induced hypotension. During hemodialysis, blood pressure at first remained unchanged as calf resistance increased in both hypotension-resistant (from 37±4 to 49±5 U, P < 0.05) and hypotension-prone (from 42±6 to 66±12 U, P < 0.05) patients; sympathetic activity increased comparably in the subset of patients in whom it could be measured. With continued hemodialysis, calf resistance and sympathetic activity increased further in the hypotension-resistant patients, but in the hypotensionprone patients the precipitous decrease in blood pressure was accompanied by decreases in sympathetic activity, vascular resistance, and heart rate as well as symptoms of vasodepressor syncope. On an interdialysis day, both groups of patients increased vascular resistance normally during unloading ofcardiopulmonary baroreceptors with lower body negative pressure and increased heart rate normally during unloading of arterial baroreceptors with infusion of nitroprusside. These findings indicate that in a group of hemodialysis patients without diabetes or other conditions known to impair autonomic reflexes, hemodialysis-induced hypotension is not caused by chronic uremic impairment in arterial or cardiopulmonary baroreflexes but rather by acute, paradoxical withdrawal of sympathetic vasoconstrictor drive producing vasodepressor syncope. (J. Clin.

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Section: Discussionmentioning

confidence: 99%

Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension.

et al. 1992

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“…Serotonin is present in high concentrations in renal parenchyma (44) and may act directly or indirectly in the regulation of renal function (45). However, characterization and distribution of 5-HT receptors in the kidney is unknown.…”

Section: Discussionmentioning

confidence: 99%

Short-term regulation of Na+/K+ adenosine triphosphatase by recombinant human serotonin 5-HT1A receptor expressed in HeLa cells.

Middleton¹,

Raymond²,

Whorton³

et al. 1990

J. Clin. Invest.

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Agonist occupancy of the cloned human serotonin (5-HT)1A receptor expressed in HeLa cells stimulates Na+/K+ ATPase activity as assessed by rubidium uptake. The purpose of the study was to determine which of the receptor-associated signaling mechanisms was responsible for this effect. 5-HT stimulated Na+/K+ ATPase 38% at 2 mM extracellular potassium, an effect characterized by a decrease in apparent Ko5 from 2.8±0.3 to 1.8±0.3 mM potassium without a significant change in apparent V,,,. The EC50 for the transport effect was -3 uM 5-HT. The response was pertussis toxin-sensitive but did not involve inhibition of adenylate cyclase, as stimulation of Na+/K+ ATPase by 5-HT was observed in the presence of excess dibutyryl cAMP. Protein kinase C was not required for the response since short-term incubation with the phorbol esters phorbol 12 myristate, 13 acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) did not mimic the 5-HT effect. Moreover, 5-HT increased Na+/K+ ATPase activity after inactivation of protein kinase C by overnight incubation with PMA. 5-HT and the sesquiterpene lactone thapsigargin increased cytosolic calcium in this cell model, and the EC50 for 5-HT corresponded with that for stimulation of Na+/K+ ATPase. Both thapsigargin and A23187, a calcium ionophore, also increased Na+/K+ ATPase activity in a dose-responsive fashion. The response to 5-HT, thapsigargin, and A23187 was blocked by conditions that removed the cytosolic calcium response. By two-dimensional gel electrophoresis, we established evidence for a calcium-sensitive but protein kinase C-independent signaling pathway. We conclude that the 5-HTIA receptor, which we have previously shown to stimulate phosphate uptake via protein kinase C, stimulates Na+/K+ ATPase via a calcium-dependent mechanism. This provides evidence for regulation of two separate transport processes by a single receptor subtype via different signaling mechanisms. (J. Clin.

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“…It is well documented that phenyl biguanide stimulates chemosensitive vagal afferents, but whether stimulation of these presumably 5-HT 3 receptor agonist-sensitive vagal fibers can interact with mechanosensitive vagal afferents in the control of ERSNA is unknown. Morgan et al 12 provided evidence that serotonergic mechanisms are essential for the vagal reflex inhibition of ERSNA during acute severe hypotensive hemorrhage but not during acute intravenous volume expansion. However, whether vagal responsiveness to serotonergic stimuli is altered during conditions with chronically increased cardiac filling pressure is unknown.…”

Section: Sympathoinhibitory Responses To 2-methylserotonin During Chamentioning

confidence: 99%

Sympathoinhibitory responses to 2-methylserotonin during changes in sodium intake.

1993

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The vagal-mediated reflex responses elicited by the selective serotonin type 3 receptor agonist 2-methylserotonin were examined by administration (625, 12.5, 25, and 50 /ig/kg i.v.) of 2-methylserotonin to sinoaortic-denervated rats with either Intact or sectioned vagi. To study the influence of dietary sodium intake on 2-methylserotonin-induced vagal reflex responses, we performed experiments in rats fed either a high or low sodium diet Left ventricular end-diastolic pressure was significantly higher in animals on high than low salt diet However, mean arterial pressure and heart rate were similar in high and low salt groups. In rats with Intact vagi, 2-methylserotonin produced a dose-dependent increase in afferent vagal nerve activity and a dose-dependent decrease in efferent renal sympathetic nerve activity, mean arterial pressure, and heart rate. The sympathoinhibitory responses of decreased efferent renal sympathetic nerve activity, mean arterial pressure, and heart rate were abolished by vagotomy and were not affected by changes in dietary sodium intake. We conclude that the sympathoinhibitory effect of 2-methylserotonin is due to stimulation of vagal afferents with inhibitory action on peripheral sympathetic nerve activity and that the sympathoinhibitory responses are unaffected by changes in dietary sodium intake. 2 -4 5-HT 3 receptors have been demonstrated on both afferent (vagus nerve, nodose ganglion, dorsal root ganglion, pain afferents) and efferent (superior cervical ganglion, cardiac sympathetic nerve endings, enteric neurons) neurons and at several locations in the brain. elicits an excitatory effect by stimulating an inward current of cations leading to depolarization.6 Phenyl biguanide is known to mimic the effect of 5-HT on peripheral neurons, and the cardiovascular effects of phenyl biguanide are blocked by the selective 5-HT 3 receptor antagonist MDL 72222 or vagotomy, suggesting that the cardiovascular effects of peripheral 5 -HT 3 receptor stimulation are mediated via vagal afferents. 7 -10 In the present study, we tested this hypothesis by examining the sympathoinhibitory responses to peripheral administration of the selective 5-HT 3 receptor agonist 2-methyl-5-HT in rats with and without vagotomy.Studies of cardiac vagal afferents have shown that they do not show similar responses to mechanical stimulation (e.g., volume expansion) and chemical stimulation (e.g., phenyl biguanide).11 This has created the concept of two distinct types of unmyelinated vagal afferents, mechanosensitive and chemosensitive. Both types can affect efferent renal sympathetic nerve activity (ERSNA), but the physiological role of chemosensitive vagal afferents remains unknown. It is well documented that phenyl biguanide stimulates chemosensitive vagal afferents, but whether stimulation of these presumably 5-HT 3 receptor agonist-sensitive vagal fibers can interact with mechanosensitive vagal afferents in the control of ERSNA is unknown. Morgan et al 12 provided evidence that serotonergic mechanisms are essential f...

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Serotonergic mechanisms mediate renal sympathoinhibition during severe hemorrhage in rats

Cited by 38 publications

References 12 publications

Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension.

Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension.

Short-term regulation of Na+/K+ adenosine triphosphatase by recombinant human serotonin 5-HT1A receptor expressed in HeLa cells.

Sympathoinhibitory responses to 2-methylserotonin during changes in sodium intake.

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