The role of histamine receptors in the release of renin

Transcription

1 Br. J. Phrmc. (1983), 79, The role of histmine receptors in the relese of renin J.G. Gerber & A.S. Nies Division of Clinicl Phrmcology, Deprtments of Medicine nd Phrmcology, University of Colordo Helth Sciences Center, Denver, Colordo 8262, U.S.A. 1 The effect of intrrenl histmine, dimprit (H2-gonist) nd 2-(2-pyridyl) ethylmine (Hl-gonist) on renin relese ws exmined in nesthetized dogs. 2 In dogs with intct kidneys, histmine nd dimprit dministrtion resulted in renl vsodilttion, two fold increse in urinry sodium excretion, nd no chnge in renl renin relese. 2(2-Pyridyl) ethylmine dministrtion resulted in renl vsodilttion, 25% decrese in urinry sodium excretion nd significnt increse in renin relese. 3 In dogs with non-filtering kidneys, dimprit dministrtion resulted in renl vsodilttion nd significnt increse in renin relese, while 2(2-pyridyl) ethylmine dministrtion resulted in renl vsodilttion but no chnge in renin relese. 4 Our dt suggest tht histmine is potentil prticipnt in the relese of renin through stimultion of H2-receptors, but it is wek gonist. 5 In ddition, the direct effect of histmine nlogues on renin relese is modulted by their effects on electrolyte excretion probbly by influencing the renl chemoreceptor relese of renin medited by the mcul dens. Introduction There re severl lines of evidence suggesting tht histmine my ply role in the control of renl physiology. Infusion of L-histidine into the renl rteries of dogs hs been shown to result in ipsilterl histmine synthesis demonstrting tht the kidney hs the rte limiting enzyme for histmine biosynthesis, histidine decrboxylse (Lindell & Schyer, 1958). A more direct demonstrtion of the presence of histidine decrboxylse hs been reported in the glomeruli of the rt kidney (Held & Hollis, 1976). Recently Torres, Northrup, Edwrds, Shh & Dous (1978) hve demonstrted tht histmine ctivtes denylte cyclse in the rt glomeruli, n effect blocked by H2-receptor ntgonists. In ddition, the ctul presence of H2-receptors hs been demonstrted in rt glomeruli by the use of [3H]-cimetidine s lignd (Chnsel, Oudinet, Nivez & Ardillou, 1982). In in vivo studies, infusion of histmine into the renl rteries of dogs resulted in renl vsodilttion, diuresis, ntriuresis but no chnge in glomerulr filtrtion rte (O'Brien & Willimson, 1971). Recently Bnks, Fondcro, Schwiger & Jcobson (1978) hve demonstrted tht the renl vsculture contins both Hl- nd H2-receptors nd tht these receptors hve different effects on renl function even though both receptors re involved in renl vsodilttion. One spect of renl physiology tht hs not been exmined crefully is the possible role of histmine in the control of renin secretion. More specificlly, we wnted to test the hypothesis tht H2-receptors re involved in renin relese becuse of the possibility tht renin secretion is cyclic AMP-dependent process (Dt & Whorton, 1982). We therefore first exmined the effect of histmine on renl renin relese, nd then exmined the contribution of H1- nd H2-receptors on the effect by the use of specific receptor gonists in both filtering nd non-filtering cnine kidneys. We included the non-filtering kidney preprtion to void ny chnges in the mcul dens sodium chloride flux tht could ffect renin relese during the infusion of histmine receptor gonists. Methods Animl preprtion A totl of 31 mongrel dogs of either sex weighing between 15 to 3 kg were used in this study. The dogs were divided into three groups. In group 1(n = 12) we determined the effect of intrrenl histmine diphosphte (1 yg kg- lmin-') on renin secretion, renl blood flow, sodium nd potssium excretion, ) The Mcmilln Press Ltd 1983

2 58 J.G. GERBER & A.S. NIES nd glomerulr filtrtion rte. In group 2 (n =11) we determined the effect of intrrenl dimprit (H2-gonist), 5 tg kg- lmin-t nd 2-(2-pyridyl) ethylmine (PEA, Hl-gonist), loopgkg-l min l on renin secretion, renl blood flow, sodium nd potssium excretion, nd glomerulr filtrtion rte. In group 3 (n = 8) we determined the effect of intrrenl dimprit, 5 flgkg1' min, nd PEA, 1 tig kg- min-' on renin secretion nd renl blood flow in dogs with non-filtering kidney. On the dy of the experiment, ll dogs were nesthetized with sodium pentobrbitone (3 mg/kg i.v.) nd supplemented s needed to mintin surgicl nesthesi. After endotrchil intubtion, the dogs were plced on Hrvrd pprtus respirtor nd ventilted with room ir. The right femorl rtery ws cnnulted for the continuous recording of blood pressure nd hert rte. The right femorl vein ws cnnulted for the dministrtion of inulin. The dogs in group 1 nd 2 hd the right nd left kidney exposed through flnk incisions. Both kidneys were denervted by cutting the renl nerves nd swbbing the rteries with 5% phenol solution. Both renl veins were cnnulted for blood withdrwl. A Stthm non-cnnulting electromgnetic flow probe ws plced round ech renl rtery nd blood flow ws monitored continuously with Stthm flowmeter. A 25 guge needle ws inserted into the left renl rtery for the infusion of histmine or histmine nlogues. The right nd left ureters were cnnulted for collection of urine for the determintion of sodium, potssium, nd inulin excretion rtes. One hour ws llowed for post surgicl stbiliztion before the ctul experiment ws begun. Forty-eight to 72 h before the experiment, the dogs in group 3 underwent septic surgery to produce non-filtering right kidney s described by Bline, Dvis & Witty (197). Through the right flnk, the ureter ws ligted nd severed, nd the renl rtery ws occluded for 2 h nd then relesed. The incision ws closed, 3, u of procine penicillin ws given intrmusculrly nd the dogs were llowed to recover. On the dy of the experiment, the dogs in this group hd the left kidney exposed nd surgiclly removed. The dogs were instrumented s in groups 1 nd 2 for infusion into the right renl rtery nd for mesurement of right renl blood flow, plsm renin ctivity nd rteril pressure. Experimentl design In groups 1 nd 2 fter the completion of surgery, sline solution contining sufficient inulin to mintin plsm levels t 15-2 ig/ml ws infused (.5 ml/min) into the femorl vein. One hour lter, bseline vlues for rteril pressure, right nd left renl blood flows, nd rteril nd right nd left renl venous blood smples for plsm renin ctivity were obtined t zero time, immeditely before the intrrenl infusion of histmine or histmine nlogues. Urine smples were collected from both ureters for determining urinry electrolytes nd inulin excretion rte for 1 min before beginning the infusion of histmine or nlogues. A plsm smple ws obtined for mesurement of inulin concentrtion in the middle of the urine collection period. In group 1, histmine 1 pig kg-i mint ws infused intrrenlly for 15 min. Urine ws collected for 1 min strting S min fter histmine infusion ws begn. Ten minutes fter the strt of the histmine infusion, plsm ws obtined from both renl veins for plsm renin ctivity nd femorl rtery for plsm renin ctivity nd inulin concentrtion. Group 2 dogs hd similr protocol to group 1 dogs except tht these dogs received 2 different infusions of histmine nlogues seprted by 6-75 min. Five dogs received n intrrenl dimprit infusion for 15 min first nd, fter 6-75 min recovery period, then received n intrrenl PEA infusion for 15 min with hemodynmic nd biochemicl monitoring s described for group 1 dogs. Six dogs received the PEA infusion first nd, fter 6-75 min recovery period, then received the dimprit infusion. In group 3, the men rteril pressure, renl blood flow nd renin secretion were monitored in the sme fshion s for the dogs followed by PEA infusion, nd PEA ws infused first in 4 dogs followed by dimprit infusion. Agin the infusions were continued for 15 min with plsm smples from the right renl vein nd femorl rtery obtined 1 min into the infusions. After the experiments in group 3, 1 ml of 5% indigo crmine ws injected into the renl rtery nd 15 min lter the kidney ws removed nd exmined grossly for the ppernce of blue discolortion of the tubules nd filtrtes. The bsence of colour indicted tht the kidneys were non-filtering. Blood smples collected from the femorl rtery nd renl veins were used for the determintion of plsm renin ctivity; 5 ml of blood ws collected into precooled collection vils contining.15 ml of 1% disodium edette (EDTA). Plsm renin ctivity ws determined by ngiotensin I rdioimmunossy using modifiction of the technique reported by Stockigt, Collins & Biglieri (1971). Net renin secretion ws clculted by the following formul: (renl venous plsm renin ctivity - rteril plsm renin ctivity) renl plsm blood flow. Inulin ws determined colorimetriclly by rection with nthrone in H2SO4 (Dvidson & Sckner 1963) by technique dpted for the Technicon Autonlyzer (Erley & Friedler, 1965). Urine sodium nd potssium concentrtion ws determined by flme photometry.

3 HISTAMINE AND RENIN RELEASE 59 Sttistics For the renl hemodynmic, renin secretion nd renl functionl dt in groups 1 nd 2 we used pired Student's t test compring chnges in the infused kidney to the contrlterl control kidney. For the renl hemodynmic, renin secretion, nd renl functionl dt in group 3 dogs, s well s the men rteril pressure chnges in ll the groups, we used Student's pired t test compring the infused period to the control period. Results re expressed s men ± s.e.men. A P vlue of less thn.5 ws considered significnt. Drugs Histmine diphosphte (Sigm Chemicl Compny, St. Louis, MO. U.S.A.), dimprit, nd 2-(2-pyridyl) ethylmine (PEA) (Smith, Kline & French Lbortories, Phildelphi, PA, U.S.A.) were dissolved in.9% w/v NCl solution (sline) nd infused intrrenlly t rte of.2 ml/min. Results In the filtering kidneys, histmine nd dimprit infusions were ssocited with ipsilterl renl vsodiltion, ntriuresis, kliuresis but no chnge in renin relese (Figure 1, Tble 1). On the other hnd, PEA infusion ws ssocited with renl vsodilttion but decresed excretion of sodium nd significnt stimultion of renl renin relese. The chnge in glomerulr filtrtion rte (GFR) fter PEA infusion ws not sttisticlly significnt but there ws clerly trend towrds decrese in most of the dogs studied. In contrst, in the non-filtering kidneys, preprtion where the mcul dens mechnism of renin relese is inctive, dimprit dministrtion resulted in significnt relese of renin while PEA ws inctive even though both histmine gonists cused renl vsodilttion without chnges in systemic hemodynmics. 4' 2 o 1 CD cr b b 4C co cj ) L., ) C') Cl c ).C ), C Histmine Dimprit PEA Dimprit PEA Filtering Non-filtering Figure 1 The effect of histmine, dimprit nd 2(2-pyridyl) ethylmine (PEA) on renin secretory rte in the filtering kidney is shown on the left side of the pnel. Open columns: bsl period; solid columns: infusion period. Both the infused (b) nd control kidneys () re included. The effect of dimprit nd PEA on renin secretory rte in the non-filtering kidneys is shown on the right. The results re expressed s the men of n = 12 for histmine, n = 11 for dimprit nd PEA for the filtering kidney, nd n = 8 for the non-filtering kidney. Asterisk signifies tht P<.5 using Student's pired t test.

4 6 J.G. GERBER & A.S. NIES Discussion ;Y Ce co Cc E. CO r. CO - r. 'e CO o l O) x.+.+ V., x S z ~ +1+1 N n "o N +1 l_ z +l +l W) t- +l-+ +1 Cl +1 C to cq -4-1 \ W) -) W) _-4 +l +l r- r- e +l Nl +1 W)~ +1 +l+ W) oc -) It I'* In W) tt It m +l +l +l +l +l +l C~ m d- It m m) I' m) m v) m) N- r-4 C l4 W) t- Cl4 cl ~c m C l4 "- Cl -.-C i U im C o Cl4 ' ~o C9 C4 Cl" C It ) P.% 4e to X t qz. o "so <> Ct '-PSCol t-.4 -! Q 2 4 ~UE o< Our dt indicte tht histmine could potentilly be involved in the relese of renin from the kidney. In ddition, it is the H2-receptor tht is most probbly responsible for the effect. Interestingly, in the filtering kidney neither histmine nor dimprit (H2- gonist) resulted in renin relese but in these preprtions the mcul dens mechnism of renin relese ws intct. If the two fold increse in sodium excretion ws secondry to decresed proximl tubulr sodium rebsorption, s hs been proposed for renl vsodiltor drugs, then the incresed delivery of sodium chloride to the mcul dens could hve inhibited the direct stimultory effect of these drugs on renin relese. The fct tht dimprit stimulted renin relese in the non-filtering kidney would support the inhibitory role of the mcul dens on the stimultory effect of dimprit in the filtering kidney. The effect of PEA on renin relese ws opposite to tht observed for dimprit. PEA stimulted renin relese in the filtering kidney but ws without n effect in the non-filtering kidney. Since PEA dministrtion ws ssocited with significnt ntintriuresis, the renin stimultory effect ws most probbly indirect nd vi the mcul dens. The ntintriuretic effect of PEA hs been described previously (Bnks et l., 1978). The mechnism for this decresed urinry sodium excretion hs not been chrcterized but is prtly relted to reduced glomerulr filtrtion rte. Our dt re comptible with the hypothesis tht histmine could contribute to the stimultion of renin relese from the kidneys. However, it is reltively wek stimultor of renin relese when compred to prostglndins E2, 12, nd isoprenline. Prostglndins E2 nd 12 will stimulte renin relese five to ten fold bove bsl levels when infused in the filtering kidney even though mrked ntriuresis is observed with the renl vsodilttion (Gerber, Brnch, Nies, Gerkens, Shnd, Hollifield & Otes, 1978). It is possible tht t higher infusion rtes histmine nd dimprit would hve stimulted renl renin relese in the filtering kidney but t higher infusion rtes there re chnges in systemic vsculr resistnce which would hve mde ccurte evlution of the direct effect of histmine more difficult. Histmine H2- receptor stimultion hs been shown to be coupled to denylte cyclse in mny systems including the rt renl glomeruli nd the mmmlin brin (Torres, et l., 1978; Nhorski, Rogers & Smith, 1974). Cyclic AMP nlogues nd compounds tht stimulte denylte cyclse hve been shown to cuse renin relese (Dt & Whorton, 1982). These fcts re consistent with our findings tht stimultion of the H2-receptors cn result in renin relese when the inhibitory influence of the mcul dens is excluded.

5 HISTAMINE AND RENIN RELEASE 61 We cn conclude from our dt tht histmine is potentil prticipnt in the relese of renin by the kidneys through stimultion of the H2-receptor, but it is wek gonist. In ddition, we hve demonstrted tht the direct effect of histmine nlogues on renin relese is modulted by their effects on electrolyte excretion, probbly by influencing the renl chemoreceptor relese of renin medited by the mcul dens. We would like to thnk Mr J.G. Pul (Smith, Kline & French) for the kind gift of the histmine nlogues. This work ws supported by NIH grnt HL2138. J.G.G. is n Estblished Investigtor of the Americn Hert Assocition. References BANKS, R.O., FONDACARO, J.D., SCHWAIGER, M.M. & JACOBSON, E.D. (1978). Renl histmine H1 nd H2 receptors: chrcteriztion nd functionl significnce. Am. J. Physiol., 235, F57-F575. BLAINE, E.H., DAVIS, J.O. & WHTY, R.T. (197). Renin relese fter hemorrhge nd fter suprrenl ortic constriction in dogs without sodium delivery to the mcul dens. Circultion Res., 27, CHANSEL, D., OUDINET, J.-P., NIVEZ, M.-P. & ARDAIL- LOU R. (1982). Histmine H2-receptors in rt renl glomeruli. Biochem. Phrmc., 31, DATA, J.L. & WHORTON, A.R. (1982). Renin relese: prostglndin-denylte cyclse reltionship. Fedn. Proc., 41, DAVIDSON, W.D. & SACKNER, M.A. (1963). Simplifiction of the nthrone method for the determintion of inulin in clernce studies. J. Lb. clin. Med., 62, EARLEY, L.E. & FRIEDLER, R.M. (1965). Studies on the mechnism of ntriuresis ccompnying incresed renl blood flow nd its role in the renl response to extrcellulr volume expnsion. J. clin. Invest., 44, GERBER. J.G., BRANCH, R.A., NIES, A.S., GERKENS, J.F., SHAND, D.G., HOLLIFIELD, J. & OATES, J.A. (1978). Prostglndins nd renin relese. II. Assessment of renin secretion following infusion of PGI2, E2 nd D2 into the renl rtery of nesthetized dogs. Prostglndins, 15, HEALD, J.I. & HOLLIS, T.M. (1976). Histidine decrboxylse-medited histmine synthesis in glomeruli from rt kidneys. Am. J. Physiol., 23, LINDELL, S.-E. & SCHAYER, R.W. (1958). Formtion of histmine in the kidney of the dog. Br. J. Phrmc., 13, NAHORSKI, S.R., ROGERS, K.J. & SMITH, B.M. (1974). Histmine H2-receptors nd cyclic AMP in brin. Life Sci., 15, O'BRIEN, K.P. & WILLIAMSON, H.E. (1971). The ntriuretic ction of histmine. Eur. J. Phrmc., 16, STOCKIGT, J.R., COLLINS, R.D. & BIGLIERII, E.G. (1971). Determintion of plsm renin concentrtion by ngiotensin I immunossy. Dignostic report of precise mesurement of sub-norml renin by hyperldosteronism. Circultion Res., (Suppl II), TORRES, V.E., NORTHRUP, T.E., EDWARDS, R.M., SHAH, S.V. & DOUSA, T.P. (1978). Modultion of cyclic nucleotides in isolted rt glomeruli. J. clin. Invest., 62, (Received July27, Revised December29, 1982.)