PGE<sub>2</sub> increases substance P release from renal pelvic  sensory nerves via activation of N-type calcium channels

Abstract-In rats fed high sodium diet, increasing renal pelvic pressure Ն3 mm Hg activates renal mechanosensory nerves, resulting in a renorenal reflex-induced increase in urinary sodium excretion. The low activation threshold of the renal mechanosensory nerves suggests a role for natriuretic renorenal reflexes in the regulation of arterial pressure and sodium balance. If so, interruption of the afferent renal innervation by dorsal rhizotomy (DRX) at T 9 -L 1 would impair urinary sodium excretion and/or increase arterial pressure during high dietary sodium intake. DRX and sham-DRX rats were fed either a high or a normal sodium diet for 3 weeks. Mean arterial pressure measured in conscious rats was higher in DRX than in sham-DRX rats fed a high sodium diet, 130Ϯ2 vs 100Ϯ3 mm Hg (PϽ0.01). However, mean arterial pressure was similar in DRX and sham-DRX rats fed a normal sodium diet, 115Ϯ1 and 113Ϯ1 mm Hg, respectively. Steady-state urinary sodium excretion was similar in DRX and sham-DRX rats on high (17.9Ϯ2.2 and 16.4Ϯ1.8 mmol/24 h, respectively) and normal (4.8Ϯ0.3 and 5.0Ϯ0.4 mmol/24 h, respectively) sodium diets. Studies in anesthetized rats showed a lack of an increase in afferent renal nerve activity in response to increased renal pelvic pressure and impaired prostaglandin E 2 -mediated release of substance P from the renal pelvic nerves in DRX rats fed either a high or a normal sodium diet, suggesting that DRX resulted in decreased responsiveness of peripheral renal sensory nerves. In conclusion, when the afferent limb of the renorenal reflex is interrupted, a high sodium diet results in increased arterial pressure to facilitate the natriuresis and maintenance of sodium balance. Key Words: renal nerves Ⅲ hypertension, sodium dependent Ⅲ sodium, dietary Ⅲ urine Ⅲ natriuresis I n the kidney, the majority of renal sensory nerves containing substance P are located in the renal pelvic wall. 1,2 The afferent renal nerves project to the ipsilateral dorsal root ganglia at the T 6 -L 2 level, with the majority of cell bodies of the afferent renal nerves being at the T 9 -L 1 level. 3,4 The renal sensory nerves are activated by increases in renal pelvic pressure within the physiologic range. 5 The increase in afferent renal nerve activity (ARNA) produced by the increased renal pelvic pressure leads to a reflex decrease in efferent renal sympathetic nerve activity (ERSNA) and diuresis and natriuresis, ie, a renorenal reflex response. 6 Increasing renal pelvic pressure elicits a series of events eventually leading to increases in ARNA. Among the various mechanisms activated by increased renal pelvic pressure is stimulation of bradykinin-2 receptors that activate protein kinase C, which leads to activation of cyclooxygenase-2 and increased prostaglandin E 2 (PGE 2 ) synthesis. 7-9 PGE 2 activates cAMP, which leads to a calcium-dependent release of substance P from the renal sensory nerves. 10,11 Substance P increases ARNA by stimulating neurokinin-1 receptors. 12 The responsiveness of renal sensory nerves is modulated by...

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“…The experiments were started after a 130-minute equilibration period. 5,10,11 Effects of PGE 2 on Substance P Release…”

Section: Substance P Release From An Isolated Renal Pelvic Wall Prepmentioning

confidence: 99%

“…7-9 PGE 2 activates cAMP, which leads to a calcium-dependent release of substance P from the renal sensory nerves. 10,11 Substance P increases ARNA by stimulating neurokinin-1 receptors. 12 The responsiveness of renal sensory nerves is modulated by dietary sodium, being suppressed by a low and enhanced by a high sodium (HNa) diet.…”

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confidence: 99%

Dietary Sodium Loading Increases Arterial Pressure in Afferent Renal–Denervated Rats

2003

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“…1,2,6,7,9,10 In brief, after anesthesia, renal pelvises dissected from the kidneys were placed in wells containing 400 L of HEPES buffer (pH 7.4), 37°C, containing indomethacin (0.14 mmol/L) to minimize the influence of endogenous PGE 2 on substance P release. Each well contained the pelvic wall from 1 kidney.…”

Section: Substance P Release From An Isolated Renal Pelvic Wall Prepamentioning

confidence: 99%

“…5,6 PGE 2 leads to activation of the cAMP-protein kinase A transduction pathway and a release of the neuropeptide substance P, which activates the afferent renal nerves by stimulating neurokinin-1 receptors in the renal pelvic area. 1,7,8 The responsiveness of the afferent renal nerves is enhanced by high-sodium diet and suppressed by low-sodium diet because of an interaction between prostaglandin (PG) E 2 (PGE 2 ) and angiotensin (Ang) II at the peripheral renal sensory nerve endings. 7,9,10 In conditions of high-sodium diet, characterized by low endogenous Ang II, 11 there is little or no inhibition of the PGE 2 -mediated activation of adenylyl cyclase.…”

mentioning

confidence: 99%

“…1,7,8 The responsiveness of the afferent renal nerves is enhanced by high-sodium diet and suppressed by low-sodium diet because of an interaction between prostaglandin (PG) E 2 (PGE 2 ) and angiotensin (Ang) II at the peripheral renal sensory nerve endings. 7,9,10 In conditions of high-sodium diet, characterized by low endogenous Ang II, 11 there is little or no inhibition of the PGE 2 -mediated activation of adenylyl cyclase. Conversely, in conditions of low-sodium diet, high endogenous Ang II activity reduces the PGE 2 -mediated activation of adenylyl cyclase via a pertussis-toxin (PTX)-sensitive mechanism leading to an impairment of the renorenal reflexes.…”

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confidence: 99%

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Activation of Endothelin-A Receptors Contributes to Angiotensin-Induced Suppression of Renal Sensory Nerve Activation

2007

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Abstract-Activation of renal mechanosensory nerves is enhanced by a high-sodium diet and suppressed by a low-sodium diet. Angiotensin (Ang) II and endothelin (ET)-1 each contributes to the impaired responsiveness of renal mechanosensory nerves in a low-sodium diet. We examined whether stimulation of ETA receptors (Rs) contributes to Ang II-induced suppression of the responsiveness of renal mechanosensory nerves. In anesthetized rats fed a low-sodium diet, renal pelvic administration of the Ang type I receptor (AT1-R) antagonist losartan enhanced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mm Hg from 7Ϯ2% to 15Ϯ2% and the prostaglandin (PG) E 2 -mediated substance P release from 0Ϯ1 to 8Ϯ1 pg/min. Adding the ETA-R antagonist BQ123 to the renal pelvic perfusate containing losartan did not produce any further enhancement of the ARNA response or PGE 2 -mediated release of substance P (17Ϯ3% and 8Ϯ1 pg/min). Likewise, renal pelvic administration of BQ123 and BQ123ϩlosartan resulted in similar enhancements of the ARNA responses to increased renal pelvic pressure and PGE 2 -mediated substance P release. In high-sodium-diet rats, pelvic administration of Ang II reduced the ARNA response to increased renal pelvic pressure from 27Ϯ4% to 8Ϯ3% and the PGE 2 -mediated substance P release from 9Ϯ0 to 1Ϯ1 pg/min. Adding BQ123 to the renal pelvic perfusate containing Ang II restored the increases in ARNA and the PGE 2 -mediated substance P release toward control (27Ϯ6% and 7Ϯ1 pg/min). In conclusion, stimulation of ETA-R plays an important contributory role to the Ang II-mediated suppression of the activation of renal mechanosensory nerves in conditions of low-sodium diet. Key Words: ETA-receptors Ⅲ AT1-receptors Ⅲ afferent renal nerves Ⅲ PGE 2 Ⅲ substance P Ⅲ BQ123 Ⅲ losartan T he majority of the afferent renal nerves are located in the renal pelvic wall. 1-3 Activation of these nerves by increases in renal pelvic pressure results in increases in afferent renal nerve activity (ARNA) leading to reflex decreases in efferent renal sympathetic nerve activity and diuresis and natriuresis, that is, a renorenal reflex response. 4 Among the various mechanisms activated by stretching the renal pelvic wall is induction of cyclooxygenase-2 resulting in increased renal pelvic synthesis of PGE 2 . 5,6 PGE 2 leads to activation of the cAMP-protein kinase A transduction pathway and a release of the neuropeptide substance P, which activates the afferent renal nerves by stimulating neurokinin-1 receptors in the renal pelvic area. 1,7,8 The responsiveness of the afferent renal nerves is enhanced by high-sodium diet and suppressed by low-sodium diet because of an interaction between prostaglandin (PG) E 2 (PGE 2 ) and angiotensin (Ang) II at the peripheral renal sensory nerve endings. 7,9,10 In conditions of high-sodium diet, characterized by low endogenous Ang II, 11 there is little or no inhibition of the PGE 2 -mediated activation of adenylyl cyclase. Conversely, in conditions of low-sodium diet, ...

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Neural Control of Renal Function

Johns

Kopp

DiBona

2011

Comprehensive Physiology

240

186

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The kidney is innervated with efferent sympathetic nerve fibers that directly contact the vasculature, the renal tubules, and the juxtaglomerular granular cells. Via specific adrenoceptors, increased efferent renal sympathetic nerve activity decreases renal blood flow and glomerular filtration rate, increases renal tubular sodium and water reabsorption, and increases renin release. Decreased efferent renal sympathetic nerve activity produces opposite functional responses. This integrated system contributes importantly to homeostatic regulation of sodium and water balance under physiological conditions and to pathological alterations in sodium and water balance in disease. The kidney contains afferent sensory nerve fibers that are located primarily in the renal pelvic wall where they sense stretch. Stretch activation of these afferent sensory nerve fibers elicits an inhibitory renorenal reflex response wherein the contralateral kidney exhibits a compensatory natriuresis and diuresis due to diminished efferent renal sympathetic nerve activity. The renorenal reflex coordinates the excretory function of the two kidneys so as to facilitate homeostatic regulation of sodium and water balance. There is a negative feedback loop in which efferent renal sympathetic nerve activity facilitates increases in afferent renal nerve activity that in turn inhibit efferent renal sympathetic nerve activity so as to avoid excess renal sodium retention. In states of renal disease or injury, there is activation of afferent sensory nerve fibers that are excitatory, leading to increased peripheral sympathetic nerve activity, vasoconstriction, and increased arterial pressure. Proof of principle studies in essential hypertensive patients demonstrate that renal denervation produces sustained decreases in arterial pressure.

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PGE₂ increases substance P release from renal pelvic sensory nerves via activation of N-type calcium channels

Cited by 30 publications

References 16 publications

Dietary Sodium Loading Increases Arterial Pressure in Afferent Renal–Denervated Rats

Dietary Sodium Loading Increases Arterial Pressure in Afferent Renal–Denervated Rats

Activation of Endothelin-A Receptors Contributes to Angiotensin-Induced Suppression of Renal Sensory Nerve Activation

Neural Control of Renal Function

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PGE2 increases substance P release from renal pelvic sensory nerves via activation of N-type calcium channels

Cited by 30 publications

References 16 publications

Dietary Sodium Loading Increases Arterial Pressure in Afferent Renal–Denervated Rats

Dietary Sodium Loading Increases Arterial Pressure in Afferent Renal–Denervated Rats

Activation of Endothelin-A Receptors Contributes to Angiotensin-Induced Suppression of Renal Sensory Nerve Activation

Neural Control of Renal Function

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PGE₂ increases substance P release from renal pelvic sensory nerves via activation of N-type calcium channels