Renal Substance P–Containing Neurons and Substance P Receptors Impaired in Hypertension

Abstract

Abstract-In normotensive rats, increased renal pelvic pressure stimulates the release of prostaglandin E and substance P, which in turn leads to an increase in afferent renal nerve activity (ARNA) and a contralateral natriuresis, a contralateral inhibitory renorenal reflex. In spontaneously hypertensive rats (SHR), increasing renal pelvic pressure failed to increase afferent renal nerve activity. The inhibitory nature of renorenal reflexes indicates that impaired renorenal reflexes could contribute to increased sodium retention in SHR. Phorbol esters, known to activate protein kinase C, increase afferent renal nerve activity in Wistar-Kyoto rats (WKY) but not in SHR. We examined the mechanisms involved in the impaired responses to renal sensory receptor activation in SHR. The phorbol ester 4␤-phorbol 12,13-dibutyrate increased renal pelvic protein kinase C activity similarly in SHR and WKY. Increasing renal pelvic pressure increased afferent renal nerve activity in WKY (27Ϯ2%) but not in SHR. Renal pelvic release of prostaglandin E increased similarly in WKY and SHR, from 0.8Ϯ0.1 to 2.0Ϯ0.4 ng/min and 0.7Ϯ0.1 to 1.4Ϯ0.2 ng/min. Renal pelvic release of substance P was greater (PϽ.01) in WKY, from 16.3Ϯ3.8 to 41.8Ϯ7.4 pg/min, than in SHR, from 9.9Ϯ1.7 to 17.0Ϯ3.2 pg/min. In WKY, renal pelvic administration of substance P at 0.8, 4, and 20 g/mL increased ARNA 382Ϯ69, 750Ϯ233, and 783Ϯ124% ⅐ second (area under the curve of afferent renal nerve activity versus time). In SHR, substance P at 0.8 to 20 g/mL failed to increase ARNA. These findings demonstrate that the impaired afferent renal nerve activity response to increased renal pelvic pressure is related to decreased release of substance P and/or impaired activation of substance P receptors. (Hypertension. 1998;31:815-822.)Key Words: afferent renal nerve activity Ⅲ receptors, sensory Ⅲ prostaglandins Ⅲ protein kinase C Ⅲ substance P Ⅲ rats, inbred SHR O bstruction to urine flow increases renal pelvic pressure and activates renal mechanoreceptors, resulting in an increase in ipsilateral ARNA.1-5 The increase in ARNA produces a fall in contralateral efferent renal sympathetic nerve activity (ER-SNA) and a contralateral diuresis and natriuresis, known as the contralateral inhibitory renorenal reflex. 2Accumulating evidence indicates that the renal nerves contribute to the pathogenesis of hypertension in SHR.6 Peripheral sympathetic nerve activity and, in particular, ERSNA is enhanced in SHR. The nature of the renorenal reflex, that is, a diuresis and natriuresis in association with decreased ERSNA, would suggest that an attenuation of this reflex would result in increased ERSNA leading to water and sodium retention, factors known to contribute to the hypertensive process. 7 Our previous studies in SHR demonstrated that increasing renal pelvic pressure failed to increase ARNA and thus failed to elicit a contralateral renorenal reflex in these rats. 8 The lack of an increase in ARNA in response to increased renal pelvic pressure suggested that the impairment of the reno...

Roles of central renin-angiotensin system and afferent renal nerve in the control of systemic hemodynamics in rats

“…[11][12][13][14]31 The reason for the discrepancy between our result and other studies is not clear. However, the present study also showed that blood pressure and RSNA were consistently increased in response to elevated pelvic pressure in the contralaterally nephrectomized rats.…”

“…It has been considered that the ARN activity is increased by stimulation of the sensory receptors in the kidney. And as the sensory receptors near the pelvic wall are distinctively sensitized to changes in the pelvic pressure [11][12][13] or backflow of the urine into the pelvis, 14 elevation of the pelvic pressure has been a useful tool to activate ARNs. [11][12][13] …”

Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of α1- and α2-adrenoceptors on renal sensory nerve fibers

“…The current studies would suggest that in conditions of decreased responsiveness of the renal sensory nerves, e.g., sodium retention, hypertension, and heart failure (19,21,22), reduced ARNA responses to acute increases in ERSNA would lead to impaired renorenal reflex inhibition of ER-SNA, which, in turn, would lead to elevated levels of ERSNA. In conditions of reduced sodium intake, this is an appropriate response leading to preservation of sodium balance.…”

Impaired Interaction Between Efferent and Afferent Renal Nerve Activity in SHR Involves Increased Activation of α 2 -Adrenoceptors

“…In SHR, stretching the renal pelvic wall failed to activate the renal sensory nerves despite marked increases in renal pelvic release of PGE 2 . 6 These findings, together with the lack of increases in substance P release in response to exogenous PGE 2 , 9 suggested that the impaired responsiveness of the renal sensory nerves in SHR involved a mechanism(s) downstream of activation of PGE 2 release. Subsequent studies confirmed this hypothesis.…”

“…1 In spontaneously hypertensive rats (SHR), there is an impairment of the responsiveness of the renal sensory nerves to various stimuli, including stretching of the renal pelvic wall and bradykinin. 6,7 In normotensive rats, renal mechanosensory nerve stimulation involves bradykinin-2 receptors, leading to activation of protein kinase (PK) C, induction of cyclooxygenase-2, and increased renal pelvic synthesis of prostaglandin (PG) E 2 . 8 PGE 2 activates the cAMP-PKA signal-transduction pathway, leading to increases in the release of substance P, which increases ARNA (Figure 1).…”