Motivated by previous indications that beta-adrenergic signaling can regulate tumor cell gene expression in model systems, we sought to determine whether similar dynamics occur in primary human ovarian cancer. DNA microarray analyses of 10 ovarian carcinomas identified 266 human transcripts that were differentially expressed in tumors from patients with elevated biobehavioral risk factors (high depressive symptoms and low social support) relative to grade-and stage-matched tumors from low-risk patients. Promoter-based bioinformatic analyses confirmed increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-κB/ Rel, STAT, and Ets family transcription factors. Consistent with increased beta-adrenergic signaling, high biobehavioral risk patients also showed increased intra-tumor concentrations of norepinephrine (but no difference in plasma norepinephrine). These data show that genome-wide transcriptional profiles are significantly altered in patients with high behavioral risk profiles, and they identify betaadrenergic signal transduction as a likely mediator of those differences.

Increased renal pelvic pressure or bradykinin increases afferent renal nerve activity (ARNA) via PGE(2)-induced release of substance P. Protein kinase C (PKC) activation increases ARNA, and PKC inhibition blocks the ARNA response to bradykinin. We now examined whether bradykinin mediates the ARNA response to increased renal pelvic pressure by activating PKC. In anesthetized rats, the ARNA responses to increased renal pelvic pressure were blocked by renal pelvic perfusion with the bradykinin B(2)-receptor antagonist HOE 140 and the PKC inhibitor calphostin C by 76 +/- 8% (P < 0.02) and 81 +/- 5% (P < 0.01), respectively. Renal pelvic perfusion with 4beta-phorbol 12,13-dibutyrate (PDBu) to activate PKC increased ARNA 27 +/- 4% and renal pelvic release of PGE(2) from 500 +/- 59 to 1, 113 +/- 183 pg/min and substance P from 10 +/- 2 to 30 +/- 2 pg/min (all P < 0.01). Indomethacin abolished the increases in substance P release and ARNA. The PDBu-mediated increase in ARNA was also abolished by the substance P-receptor antagonist RP 67580. We conclude that bradykinin contributes to the activation of renal pelvic mechanosensitive neurons by activating PKC. PKC increases ARNA via a PGE(2)-induced release of substance P.

Renal mechanoreceptor (MR) activation by increased ureteral pressure (increases UP) results in an increase in afferent renal nerve activity (ARNA) that is blocked by substance P receptor blockade and prostaglandin (PG) synthesis inhibition. To examine the interaction between substance P and PGs, the release of substance P and PGE into the renal pelvis was studied before and during renal pelvic perfusion with indomethacin. Before indomethacin, increases UP increased ARNA 43 +/- 6% and renal pelvic release of substance P from 11 +/- 3 to 29 +/- 8 pg/min and PGE from 319 +/- 71 to 880 +/- 146 pg/min. Indomethacin blocked the increases in ARNA and release of substance P and PGE produced by increases UP. Time control experiments showed reproducible increases in ARNA and release of substance P and PGE during increases UP. Mechanical stimulation of the renal pelvic wall in vitro resulted in an increase in PGE release from 110 +/- 8 to 722 +/- 152 pg/min, which was abolished by indomethacin, suggesting a de novo PGE synthesis. The data suggest that increases UP results in a renal pelvic release of PGE, which facilitates the release of substance P and activation of renal pelvic MR.

In anesthetized rats, renal pelvic administration of bradykinin results in a prostaglandin (PG)-dependent increase in afferent renal nerve activity (ARNA). We now measured renal pelvic release of PGE and substance P during renal pelvic administration of bradykinin. Bradykinin increased ARNA and renal pelvic release of PGE by 497 +/- 252 pg/min and substance P. by 10.7 +/- 7.2 pg/min. Renal pelvic perfusion with indomethacin abolished the bradykinin-mediated increase in ARNA and reduced renal pelvic release of PGE and substance P by 76 +/- 11 and 72 +/- 8%, respectively. To examine whether the increased substance P release contributed to bradykinin-mediated activation of renal sensory receptors, renal pelvis was perfused with the substance P-receptor antagonists CP-96,345, CP-99,994, or RP-67580. The ARNA response to bradykinin was reduced 73 +/- 11, 55 +/- 12, and 64 +/- 10% by CP-96,345, CP-99,994, and RP-67580, respectively. The inactive enantiomers CP-96,344 and RP-68651 had no effect. These data suggest that bradykinin increases renal pelvic release of PGE, which facilitates the release of substance P, which in turn stimulates substance P receptors. Thus the ARNA response to bradykinin is largely mediated by activation of substance P receptors.

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...