No abstract

To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits:(1) the effects of intravenous infusion of L-or D-arginine (15 to 200 jimol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of A fO -monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 /imol/kg per minute) increased renal blood flow by 9±2 and 16±3 mL/min (P<.05, respectively) and decreased renal sympathetic nerve activity by 12±4% and 19±3% of control (P<.05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal E ndothelium-derived relaxing factor (EDRF) relaxes vascular smooth muscle. 1 Nitric oxide (NO) is synthesized from endogenous L-arginine 2 in various tissues 3 and accounts for the biological actions of EDRF.4 Accumulating evidence has revealed that EDRF/NO plays an important role in regulating renal blood flow (RBF).5 ' 6 Possible mechanisms such as a direct action on vascular smooth muscle tone, suppression of adrenergic nerve transmission in the blood vessels, and inhibition of the release of vasoactive substances have been proposed for the NO-mediated modulation of RBF. 79 There are also potential interactions among these regulatory mechanisms.10 For example, recent studies in anesthetized animals suggest that there is an interaction between sympathetic nerve activity and NO. Lacolley et al 11 have suggested that normal sympathetic discharge plays an important role in modulating the synthesis or release of vascular NO. It has also been reported that NO has a role in the central regulation of sympathetic tone.12 However, it is known that anesthesia alters sympathetic nerve activity 13 and has effects on responses to NO synthesis inhibitors, 14 soReceived October 14, 1993; accepted in revised form May 4, 1994.From the Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.Correspondence to Takao Saruta, MD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.O 1994 American Heart Association, Inc. Although there is evidence that exogenous L-arginine produces a vasodilator action by increasing NO production, 1516 to our knowledge there is no direct evidence that the effect of exogenous L-arginine on renal sympathetic nerve activity (RSNA) contributes to the modulation of RBF in conscious animals. The aim of the present study was to determine whether a sympathetic neural mechanism contributes to changes in RBF elicited by nondepressor doses of L-arginine in conscious rabbits. Therefore, we investigated the RBF and RSNA responses to nondep...

Impalred baroreflex function 1s a factor responslble for poor prognosis m myocardlal infarction patients Usmg loglstlc function curves, we calculated the maximal gam of the baroreflex control of renal sympathetic nerve actlvlty (RSNA) and heart rate m conscious Wlstar-Kyoto and spontaneously hypertensive rats whose left anterior descending artery had been ligated 4 weeks earlier We further investigated whether 3-week oral treatment with the anglotensm II type 1 receptor antagonist TCV-116 would Improve the baroreflex m rats with myocardlal infarction The maximal gam of the mean arterial pressure-RSNA relation m spontaneously hypertensive rats with myocardlal mfarctlon and treated with vehicle (1 7tO 1% control per mm Hg) was smaller than the gam m sham-operated hypertensive rats (2 3-+0 1% control per mm Hg) After 3-week oral treatment with TCV-I 16, the maximal gam of the arterial pressure-RSNA relation in hypertensive rats with myocardlal I t has been reported that baroreflex function 1s lmpaired in hypertension, I-? that MI 1s associated with an impaired baroreflex, and that the blunted baroreflex in MI IS involved m sudden death or fatal arrhythmia 4-h Recently, It has been reported that mtravenously injected Ang II receptor antagonist improves the blunted baroreflex m MI In normotensive rats7 and that lmprovement in baroreflex by blockade of the remn-anglotensm system has a favorable influence on the long-term outcome of patients with Ml 5,*,Q Thus, baroreflex dysfunction 1s considered a crltlcal factor in the poor prognosis of MI patients Moreover, smce a recent study examining the relation between blood pressure and mortality among men with prior MI showed that the percentage of men dymg from coronary artery disease was much higher In the hypertensive group, 10 It 1s important to examme whether high blood pressure exacerbates the influence of MI on baroreflex functionIn the present study, we compared the baroreflex function of conscious WKY and SHR whose left coronary artery had been ligated 4 weeks earher We also tested the hypothesis that long-term oral treatment with the Ang II receptor antagonist TCV-116 would improve the baroreflex controls of RSNA and HR m WKY and SHR with MI MethodsMale IS-week-old SHR and age-matched WKY were purchased from Charles River Japan Co, Atsugi, Japan All surglcal and experimental procedures were m accordance with institutional dmmal care gmdelmes Rats were housed singly m cages m a room with constant temperature and a 12-hour light/dark cycle Myocardial InfarctionWe used a previously described technique' 11 13 involving IIgatlon of the left coronary artery to produce chronic MI With rats under ether inhalation anesthesia, the heart was exteriorized via a left thoracotomy, and the left antenor descending artery was ligated between the pulmonary outflow tract and left atrium The heart was returned to Its normal position, the thorax was closed, and the an was removed Sham control rats underwent the same procedure but did not have then left coronary artery ligated ...

We here report a case of nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent gastric cancer developed acute kidney injury associated with kidney enlargement and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy findings. Immunohistochemistry revealed expression of programmed cell death-ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules. Among infiltrating immune cells, aggregation of T cells was more extensive than that of B cells, with CD4 T cells outnumbering CD8 T cells, consistent with the relative numbers of these cells in the circulation. Treatment with methylprednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function and reduction in the number of circulating CD4 T cells. Prompt administration of high-dose corticosteroid is thus recommended after diagnosis of this adverse event of nivolumab treatment by kidney biopsy.

This study was designed to elucidate how central and peripheral arginine vasopressin (AVP) interacts with the sympathetic nervous system and the renin-angiotensin system to maintain blood pressure in two-kidney, one-clip hypertensive rabbits. We recorded renal sympathetic nerve activity (RSNA) in the conscious state as an index of sympathetic nervous system function. The changes in mean arterial pressure, heart rate, and RSNA were recorded continuously for 60 minutes after intravenous administrations of captopril (2.5 mg/kg) and nicardipine (3.2 micrograms.kg-1.min-1) in eight identical rabbits. Despite equivalent reductions in mean arterial pressure (10 +/- 1 mm Hg), the increase in RSNA was significantly larger with captopril than that with nicardipine, and the plasma concentration of AVP was elevated (from 100% to 255 +/- 24%) with captopril. Mean arterial pressure was reduced, and RSNA was increased by intravenous infusion of AVP antagonist d(CH2)5Tyr(Me)AVP (n = 8), whereas vertebral artery infusion of the antagonist (n = 6) did not change RSNA. During central and peripheral infusions of AVP antagonist, RSNA was exaggerated by blood pressure reduction with nicardipine as well as with captopril. Increases in RSNA induced by captopril and nicardipine were larger by central infusion of AVP antagonist than by intravenous infusion. The decrease in mean arterial pressure by captopril (30 +/- 4 mm Hg) in eight sinoaortic-denervated hypertensive rabbits was larger than that in hypertensive rabbits with intact baroreflex. These data suggest that compensatory activation of RSNA was revealed by central and peripheral attenuation of AVP and that the sympathetic nervous system became the most important mechanism for blood pressure maintenance in the absence of AVP. The interaction of AVP with the sympathetic nervous system may be independent of the state of the renin-angiotensin system, since the exaggeration of RSNA by AVP antagonist was qualitatively the same with nicardipine as with captopril. In conscious renal-hypertensive rabbits, AVP in the central nervous system played a substantial role when blood pressure was reduced, although it did not contribute to blood pressure maintenance in the basal condition.