Effect of (Sar1, Ala8)-angiotensin II and hypophysectomy on the intestinal resistance vessels and blood pressure following furosemide-induced volume depletion.

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Effect of [Sar1, Alas]-angiotensin I1 and hypophysectomy on the intestinal resistance vessels and blood pressure following f urosemide-induced volume depletion J. ROBERT MCNEILL,WII,L.IAM 6. WII,COX,AND RAOUI,REGNAULT Dt>purtmc>nt of PI~~trt?~trc'ology, Univcr.,a'tg o f S C I J X ( ~ ~ C ~ I ~ ' H ~ N I I . S ~ ~ k ~ t oSask., o t ~ C'c~nudu , S7N OW0 Received September 26, 1975

McNF-111-, J . R., WILCOX.W. C'., and ~ < ~ , G K A U L TK. , 1976. Fffect of [Sar', Alah]angiotensin I1 and hypophysectomy on the intestinal resistance vessels and blood pressure following furosemide-induced volume depletion. Can. J. Physiol. Pharmacol. 54, 373-380. Intravenous administration of furosemide ( 2 mg/kg) caused intestinal vasoconstriction in varioi~sgroups of pentobal-bital-anesthetired cats. [Sar'. Ala'l-angiotensin IT, a specific competitive antagonist of angiotensin 11, was infused 60 min after administration of furosemide, a time when the intestinal vasoconstrictor respome to the diuretic was maximal o r near maximal. In hypophysectomizcd animals, infusion of the antagonist abolished the intestinal vasoconstriction and caused a significant fall in arterial pressure even when the intestinal nerves and adrenal glands remained intact. In contrast. the antagonist had little effect when the pituitary gland remained intact. 'The results suggest that endogenous angiotensin and vasopressin are overlapping mechanisms which constrict the intestinal resistance vessels and support arterial pressure following furosemide-induced volume depletion. In the absence of one control system, the other compensate^ to maintain the responses. MCNFILL,J . R., WILCOX,W. C'. et KLLNAUIT.K. 1976. EfTect of [Sar', AIah]angiotensin I1 and hypophysectorny on the intestinal resistance vessels and blood pressure following furosemide-induced volume depletion. Can. J. Physiol. Pharmacol. 54, 373-380. L'administration intraveineuse de furosimide ( 2 mg/kg) provoqire ilne vasoconstriction intestinale dans diffkrents groupes de chats anesthesiks ail pentobarbital. L'angiotensine TI [Sar', Alah] un antagoniste cornpetitif specifique de l'angiotensine TI, est perfusk pendant 60 min, aprks administration de furoskmide, correspondant ail temps oil la vascoconstriction intestinale provoquCe par le diureticlue est maximale. C'hez les animaux hypophysectomisks, la perfusion de I'antagoniste abolit la vasoconstriction intestinale et provoque une chute significative dc la pression artkrielle, m h e lor5que les nerfs intestinaux et les glandes surrknale~sont intacts. Par contre, l'antagoniste a pcu d'effet lorsque l'hypophyse est intacte. Ces resultats suggZrent que I'angiotensine endogene et la vasopressine agissent en synergie pour contracter les vaisseaux de rksistance intestinale et pour permettre le maintien de la pression arterielle B la wite d'une hypovolemie provoqu6c par le fiirssemide. En absence d'un s y s t h e de contrhle, l'autre permet une compen5ation pour maintenir la rkponse. [Traduit par le journal]

Introduction Although the blood levels of circulating angiotensin and vasopressin increase in response to a decrease in blood volume (Ginsburg and Heller 1953; Weinstein et al. 1960; Scornik and Palladini 1964; Hodge et al. 1966; Share 1967; Beleslin et (11. 1967; Rosenthal et al. 1965; Rocha e Silva and Rosenberg 1969; Claybaugh and Share 1973; Cousineau et al. 1973) few vascular roles have been assigned to these circulating peptides. Since 1969 however, increasing evidence has implicated both the renin-angiotensin and vasopressin systems

as important mechanisms controlling arterial pressure following blood loss (Rocha e Silva and Rosenberg 1969; McNeill et al. 1970; Stark et al. I 9 7 1 McNeill 1972; Errington and Kocha e Silva 1974). The support of arterial pressure following blood loss is due in part to vasoconstriction of the intestinal and splenic resistance vessels and both endogenous angiotensin and vasopressin play major roles in the mechai~ismof the vasoconstriction of these two beds (McNeill et al. 1970; Stark et al. 1971 ) . Even the volume depletion induced by diuretic agents induces intestinal vasoconstric-


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tion and a role for angiotensin and vasopressin in the ~necharlismof this response was suggested by the observation that pretreatment of animals with SQ2088 1, an inhibitor of angioteaasin converting enzyme, prevented the intestinal vasoconstriction in hypophysectomized animals but not in animals in which the pituitary gland remained intact (McNeill 1974b). However these results have been criticized on the basis that SQ20881 is not specific for the angiotensin converting enzyme. The inhibitor also potentiates bradykinin depressor responses (Engel et al. 1972) and the possibility that the elfects of SQ20881 were in part due to potentiation of endogenous kinins cannot be rulcd out. T o define more clearly the role of the renin-angiotensin system in the response, [Sar1, Alas]-angiotensin 11, a specific competitive antagonist of angiotensiil I1 (Pals et ul. 1971), was infused in various groups of animals at a time when the intestinal vasoconstrictor response to furosemide was maximal o r near rnaximal. The effect of the antagonist on the intestinal resistance vessels and on blood pressure was carried out both in hypophysectomized animals and in animals with the pituitary gland intact.

Methods Cats weighing between 1.7 and 4.2 kg were ane5thetized by intraperitoneal injection of sodium pentobarbital (Nembutal, Abbott Lab) (30 mg/kg). Superior mesenteric arterial flow was recorded from a noncannulating electromagnetic flow probe (Statham Inst. Co., Oxnard. CA.) and arterial pressure was recorded from cnrmnulae in the femoral artery and in a branch of the superior mesenteric artery downstream from the flow probe and clamp. Urine was collected from a cannula advanced into the bladder. These methods have been described in detail elsewhere (McNeill 1974h). The parameters in all aninlals were recorded for 30 rnin before and for 105 nlin following intravenous administration of furosemide (2.0 naglkg). The responses of the intestinal resistance vessels were calculated in condiactance units (ml (min kg nam Hg)-') ( 1 mm Mg ( 0 'C) -s 133.322 Pa) (Stark 1968). The conductance at variolas times before and after furosemide was expressed as a percentage of the control conductance value calculated imnlediately before the administration of the drug. All values were expressed as the mean f SE. Certain cats were subjected to intestinal denervation, adrenalectomy and(or) hypophysectomy. These procedures have been described in detail previously (McNeiIII et nl. 1970). Most animals were infused with

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[Sar', Ala'l-angiotcnsin IT (Norwich Pharmacal. Co., Norwich, N.Y.), a specific competitive antagonist 0% angiotensin II. The antagonist was inftased intravenoimsly ( 18 pglmin) for 15 min beginning 60 rnin after administration of fiaroscmide, a time when thc intestinal vasoconstrictor response to the diuretic was maxirnal or near maximal. In preliminary experin~ents with the antagonirt, 4 pg/min caused a 90% reduction and B O pg/mirm a 100% rediaction in the intestinal vasoconstrictor rcsponse to angiotensin I1 ( H ypertensin, Ciba) ( 1.0 pg/rnin). This dose of antagonist had no effect on the intestinal vasoconstrictor response to vasopressin ( Pitressin, Parke, Davis and Co. ) 4 85 mU/ min) nor on the response to stimulation of the intcstinal nerves (10 V. 2 ms, 4 / s ) .

Results Eftects of Furnse~nide The responses to furosemide were studied in five animals (2.9 _t. 0.2 kg) in which the intestinal nerves, adrenal glands and pituitary gland remained intact (group 1 ) . [Sar1, Alayangiotensin I1 was not administered to these animals. The results are shown in Fig. i . Before furosemide, superior mesenteric arterial flow was 2 1.5 -t- 1.4 rnl rnin-l kg-l and superior inesenteric arterial conductance was 0.164 -t0.0 16 ml (min kg mm Hg) -I. Following lurosemide superior mesenteric arterial conductance fell and the values for superior inesenteric arterial conductance (ml (min kg mm Hg)-I) rccorded 15 min after furosernide were significantly different from the cc~rrespondingcontrol values rccorded immecjiately before administration of furosemide ( p = 0.002, paired d test). Thereafter the vasoconstrictor response was well maintained. There was little change in arterial pressure during the course of the experiment. These findings were very similar to those reported previously wB~en it was shown that the intestinal vasoconstrictor response was primarily dependent on the volume depletion produced by furosemide (McNeill 1974b). In subsequent experimei~ts the effect of [Sar1, Ah\]-angiotensin I1 011 this intestinal vasoconstrictor response to f urosemide-induced volume depletion was studied in animals subjected to intestinal denervation, adrenalectomy and (or) hypophysectomy. Effec-t of [Sar1, Alas]-cr17giotctzsinI I in Benervated Adrenalectornized and Mypophysecdornized A nintuls Six cats (2.1 t 0.2 kg) were subjected to


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FIG.1. Values (mean zk SE) for femoral arterial pressure, superior mesenteric arterial conductances expressed as percentages of control conductance values (i.e. time 0 values), and cumulative urine volume before and after furosemide administration (2.0 mg! kg, iv) in five cats with intact organ systems (group 1) .

FIG.2. Effect of [Sar', Ala'l-angiotensin I1 (10 p g i min, iv) on femoral arterial pressure and superior nlesenteric arterial conductance following furosemide administration ( 2 mglkg, iv) in six cats subjected to intestinal denervation, adrenalectomy and hypophysectomy (group 2 ) .

acute intestinal denervation, adrenalectomy, and hypophysectomy (group 2). The responses to furosemide are shown in Fig. 2. The values for urine volume (ml,/kg) were not significantly differentfrom the corresponding values in group 1 ( p = 0.060-0.922, unpaired t test). Before furosemide, superior mesenteric arterial flow was 37.4 k 5.3 n ~min-' l kg-I and superior mesenteric arterial conductance was 0.283 +0.040 1x11 ( rnin kg mm Hg ) -I. Following furosemide, intestinal vasoconstriction occurred and the conductance values (percentage control) for the first 60 ~ n i nfollowing the diuretic were not significantly different from the corresponding values in group 1 ( p = 0.074-0.550, unpaired t test). Thus intestinal dencrvation, adrenalectomy and hypophysectomy did not significantly reduce the intestinal vasoconstrictor response to furosemide-induced volume

depletion, suggesting other factors could mediate the response. Infusion of [Sar1, Ala3]-angiotensin 11, during the intestinal vasoconstrictor response, caused an increase in superior mesenteric arterial conductance and a fall in arterial pressure (Fig. 2 ) . During the infusion of the antagonist the values for conductance (percentage control) and arterial pressure, recorded at 65, 70 and 75 min after furosemide, were significantly different from the corresponding values in group 1 (p = 0.0004-0.0008, unpaired t test). Following cessation of the infusion, conductance and arterial pressure returned towards their pre-infusion values. Thus infusion of [Sar1, Alay-angiotensin I1 abolished the intestinal vasoconstriction in these animals suggesting that the presence of renin-angiotensin system alone was sufficient to ensure the


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FIG.3. Effcct of [Sar', Alas]-angiotensin I1 ( 10 pgI min, iv) on femoral arterial pressure and supcrior rnesenteric arterial conductance following furosemide administration ( 2 mg/kg, iv) in six cats subjected to hypophysecton~y(group 3 ) .

full intestinal vasoconstrictor response to furosemide. Effect of [Sar1, Alas]-nngiotensin II in Hypophysectomized Animals The responses to furosemide were studied in six cats (3.0 t 0.3 kg) in which the pituitary gland was removed (group 3 ) . The intestinal innervation and adrenal glands remained intact. The responses to the diuretic are shown in Fig. 3. The values for urine voluine were not significantly different from those in group 1 or group 2 ( y = 0.228-0.996, unpaired t test). Before furosemide superior mesenteric arterial flow was 25.7 k 1.9 ml inin-I kg-I and superior mesenteric arterial conductance was 0.180 +- 0.022 ml (min kg mm Hg)-I. Following furosemide, intestinal vasoconstriction occurred and the conductance values (percentage control) for the first 60 min after the diuretic were not significantly different from

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those in group 1 or group 2 ( p = 0.055-0.904, unpaired t test j . Thus hypophysectomy alone did not significantly reduce the intestinal vasoconstriction and other factors could mediate the response. Infusion of [Sar1, Alav-angiotensin 11 during the intestinal vasoconstrictor response caused an increase in superior nlesenteric arterial conductance and a fall in arterial pressure (Fig. 3 ) . During infusion of the antagonist the values for conductance and arterial pressure (percentage control j recorded at 65, 70 and 75 min after furosemide were significantly different from the corresponding values in group 1 ( p = 0.00005-0.0004, unpaired t test). The values for conductance were not significailtly different from those in group 2 ( y = 0.193-0.688) although the peak fall in arterial pressure (75min values expressed as percentages of 60-inin values) was slightly less than that which occurred in group 2 ( y = 0.045). Cessation of the i~lfusionwas followecf by a return of conductance and arterial pressure towards preinfusion values. Thus [Sar1, Alas]-angiotensin I1 abolished the intestinal vasoconstriction in hypophysectomized animals even when the intestinal innervation and adrenal glands remained intact. Eflect of JSarl, Alay-angiotensitz II in Denervuted Adrennlectovrtized Animals Six cats (2.7 2 0.2 kg) were subjected to intestinal denervation and adrenalectomy (group 3 ) . The pituitary gland was left intact. The responses to furosemide are shown in Fig. 4. The diuresis caused by the drug was similar to that which occurred in other groups of aninlaIs. Before furosemide superior mesenteric arterial flow was 34.2 4.0 ml min-I k g 1 and superior mesenteric arterial conductance was 0.261 2 0.029 ml (min kg mm Hg) - I . Following furosemidc intestinal vasoconstriction occurred and the conductance values (percentage control) for the first 60 min after the drug were not significantly different from the corresponding values in previous groups of animals ( y = 0.1 11-0.954, unpaired t test). Thus intestinal denervation and adrenalectomy did not reduce the intestinal vasocsnstriction and other factors could mediate the response. In contrast to the results obtained in group 2 and group 3. infusion of [Sar1, Alas]-angio-

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conductance to increase to 16 5 4.8% of the pre-infusion control values. In one additional animal, [Sar1, Alah]-angiotensin I1 was infused before and at various times after bilateral nephrectomy. After nephrectomy, the intestinal vasodilator effect of the antagonist gradually diminished and it had no effect on superior rnescnteric arterial conductance when infused 3 h after both kidneys had been removed. In a secoild animal the effect of the antagonist was conlpIetely abolished 15 min after intravenous administration of SQ2088 1 ( 1.0 ing/kg) . Thus when the major source of renin was removed or when angiotensin converting enzyme was inhibited, [Sar1,Alax]-angiotensin had no effect on the intestinal resistance vessels.

Discussion Previously, we studied the response of the intestinal resistance vessels to furosemide-induced volume depIetion (McNeill 1974h). The vasoconstriction was dependent on the volumc I ' ' l ' ' I I I 1 - 3 0 -15 0 15 30 45 60 75 90 105 depletion produced by the diuretic since t nephrectomy or replacement of urinary losses MINUTES prevented the response. The possibility that the FIG.4. Effect of [Sar', Alay-angiotensin IT (10 pg/ renin-angiotensin and vasopressin systems min, iv) on femoral arterial pressure and superior might play important roles in the mechanism of mesenteric arterial conductance following furosemide administration ( 2 mg/kg, iv) in six cats subjected to the intestinal vasoconstriction was suggested by intestinal denervation and adrenalectomy (group 4 ) . the observation that pretreatment of animals with SQ2088 1, an inhibitor of angiotensin converting enzyme, abolished the vasoconstriction tensin 11 caused little change in conductance in hypophyscctomized animals but not in anior arterial pressure. The vaIues for conductance mals in which the pituitary gland remained and arterial pressure recorded at 65, 70 and 75 min after furosemide were not significantly dif- intact. However, a report of this work (McNeill ferent from the corresponding values in group 1974u) was criticized partly because the effects of the drug were not readily reversible but 1 (p = 0.206-0.563, unpaired t test). Thus [Sar1, Alax]-angiotensin 11 did not significantly more importantly, because SQ20881 is not reduce the intestinal vasoconstriction in specific for angiotensin converting enzyme. The denervatcd adrenalectomized animaIs and the agent has been shown to potentiate bradykinin presence of an intact pituitary gland was SUE- depressor responses (Engel et ul. 1972) and cient to maintain the vasoconstrictor response thc possibility that the effects of SQ20881 were in part due to potentiation of endogenous to furosemidc-induced volume depIetion. kinins cannot be ruled out. Eflect of [Surl, AlaH]-angiotensin II in In contrast, a widc variety of studies as rethe Nornzovolernic Animal viewed recently by Regoli et al. ( 1974) and by Four animals (3.0 t 0.4 kg) were infused Davis et al. (1974) have shown that [Sar1, intravenously with [Sar1, Ala8]-angiotensin 11 Alay-angiotensin TI competitively antagoilizes (10 pg/min) for 15 min. Furosemide was not angiotensin I1 and that the drug has no other administered to these animaIs. Infusion of the known biological activity. Furthermore the antagonist caused superior mesenteric arterial effects of the antagonist are readily reversible I ~ r O l B m l d l

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and cessation of an infusion of the drug results in rapid recovery of vascular conductancc. These propcrties of [Sar1, Alaq-angiotensin I1 made it an ideal choice to define more clearly the role c~fendogenous angiotensin both in the mechanism of the intestinal vasoconstriction and in the support of arterial pressure following furosemide-induced volume depletion in the pentobarbital anes thetized animal. Infusion of the antagonist abolished the intestinal vasoconstriction in hypophysectomized animals (groups 2 and 3 ) but it had little effect in animals in which the pituitary gland remained intact (group 4 ) . Although it has not been proven that the effects of hypophysectomy are due solely to removal of the vasopressin system, vasopressin is released following only small decreases in blood volume (Share 1967; Cousineau et al. 1973; Claybaugh and Share 1973) and there seems no need to postulate a role for some other unidentified hypoghyseal substance. The results suggest that the reninangiotensin system and the vasopressin system are overlapping mechanisms which constrict the intestinal resistance in response to furosemide. In the absence of one control system, the other compensates to maintain the response. Infusion of [Sar1, Ala8]-amgiotensin I1 in hypophysectomized animals abolished the intestinal vasoconstriction even when the intestinal innervation and adrenal glands remained intact (group 3 ) indicating that the sympatho-adrenal system played little role in the response. This finding was not unexpected since it is well known that 'escape' occurs in the intestinal resistance vessels in response to stimulation of the intestinal nerves or to infusions of noradrenaline (Folkow et al. 1964; Dresel and Wallentin 1966) and that infusions of adrenaline dilate the intestine (Ross 1967; Greenway and Lawson 1968). It could be argued that the effects of [Sar1, Alas]-angiotensin I1 are in part due to antagonism of the adrenergic potentiating effect of circulating angiotensin 11. Exogenous angiotensin 11 potentiates the vasoconstrictor response of the hindgaw resistance vessels to sympathetic nerve stiinulation and this effect of angiotensin II is antagonized by [Sar1, Alas]angiotensin 11 (Zimmerman 1973). However in two animals, infusions of angiotensin I1 (Hypertensin, Ciba) and (or) [Sar1, Alaq-

angiotensin 11 did not alter either the initial peak phase or the steady-state phase of the response of the intestinal resistance vessels to stimulation of the intestinal nerves (unpublished observations). Thus the effects of [Sari, Alas]-angiotensin I1 on the intestinal resistance vessels appear to be best explained by its ability to antagonize the direct effect of angiotensin 11 rather than its indirect adrenergic potentiating effect. 'The observation that [Sar1, Alay-angiotensin 11 increased superior mesenterie arterial conductance slightly above control values in groups 2 and 3 suggested that circulating angiotensin I1 might play a role in the control of the intestinal resistance vessels in the norrnovolemic anesthetized animal. This possibility was supported by the finding that the antagonist caused a small increase in superior mesenteric arterial conductance in four animals not subjected to volume depletion. Further experiments would be required however, to confirm these findings and to determine if such a role for angiotensin exists in the unanesthetizcd animal. The initial values (prefurosemide) for superior mesentcric arterial flow and conductance were significantly higher in those animals subjected to intestinal denervation and adrenalectomy (groups 2 and 4 ) than in those animals with intact innervation and adrenal glands (groups 1 and 3 ) . This could suggest that the nerves and(or) adrerlals play an important role in maintaining tone of the intestinal resistance vessels in the normovolemic animal. However flow and conductance values even when expressed on a body weight basis vary widely froma one animal to the next and it is difficult to place much significance on these differences between various groups of animals when the number of animals in any one group is snlall. Furthermore, when control values from previous studies (McNeill et al. 1970; McWeill 19743) are compared with the present study there is no consistent relationship between superior mesenterie arterial flow and conductance values and the presence and absence of the intestinal nerves and adrenals. In any case the intestinal nerves and adrenals did not appear to play an important role in the intestinal vasoconstrictor response to furoscmide since the vasoconstrictor response was

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similar in all groups of animals studied and [Sar1, Alas]-angiotensin I1 abolished the response in hypophyscctomized animals even in the presence of the intestinal nerves and adrenal glands. The observation that arterial pressure fell significantly when [Sar1, Alaq-angiotensin I1 was infused in hypophysectomized animals but not in animals in which the pituitary gland remained intact is of particular intercst and suggests that both the renin-angiotensin and vasopressin systems are important compensatory control mechanisms maintaining arterial pressure in the face of a decreasing blood volume. Renin has been shown to be released following volume dcplction induced by hemorrhage (Scornik and Paladlni 1964; Hodge et al. 1966; Claybaugh and Sharc 1973) or by furosemide (Meyer et al. 1968; Vander and Carlson 1969; Wosenthal et al. 1968). Although the possibility of vasopressin release in response to furosemide administration does not appear to have been studied, vasopressin is released following even small blood losses (Beleslin et (11. 1967; Share 1967; Cousineau et al. 1973; Claybaugh and Share 1973). These findings are consistent with our results implicating both systems in the support of arteriaI pressure follow~ing volume depletion. -Phe support of arterial pressure by these endogenous peptides would appear to be in part due to vasoconstriction of the intestinal resistance vessels. However, the large fall in arteriaI pressure suggests that other vascular beds may also be constricted by these peptides. Both the intestinal resistance vesseIs and skeletal muscle resistance vessels are highly sensitive to angiotensin IT and vasopressin (Cohen et al. 1970; Schmid et al. 1974). Tt has also bee11 show11 that the resistance vessels of the hindlimb preparation constrict in response to furosemide-induced volume depletion (Ludens et al. 1970) and that the vasoconstriction is abolished by hypophysectomy (Willis et al. 1971 ) suggesting that vasopressin may also constrict skeletal muscle resistance vessels. Acknowledgments We are grateful to the Saskatchewan Heart Foundation and to Our Lady of the Prairies Foundation for grants in support of this work and to the Norwich Pharmacal. Co, for a gener-

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BLLESLIN,D., BISSC'I',G. W.. A ~ L D ~J.,R and , POLAK, K. L. 1957. The release of vasopressin without oxytocin in response to hemorrhage. Proc. K. Soc. laondon,Ser. H, 166, 443. CI.AYBAUGH, J. K., and SHARE,L. 1973. Vasopressin, renin and cardiovascular responses to continuous slow hemorrhage. Am. J. Physiol. 224, 5 19-523. COIILN, M. M., SITAR,D. S., MCNEILL,J. R., and GKLENWAY. C. V. 1978. Vasopressin and angiotensin on resistance vessels of spleen, intestine, and liver. Am. J. Physiol. 218, 1784. COUSINEAU, D., GAGNON, D. J., and SIROIS,P. 1973. Changes in plasma levels of vasopressin and renin in response to hemorrhage in clogs. Br. J . Pharmacol. 47, 3 15-324. DAVIS,J. O., FREEMAN, K. H., JOHNSON,J. A., and SPIELMAN, W. S. 1974. Agents which block the action of the renin-angiotensin system. Circ. Res. 34,279-285. DRTSEI., P. E., and W A L L , ~ N ~ 'I.I N1966. , Effects of sympathetic vasoconstrictor fibres, noradrelmaline and vasopressin on the intestinal vascular resistance during constant blood flow or blood pressure. Acta Physiol. Scand. 66, 427-436. ENGI:L, S. L.. SCKAEFFER,T . R., GOLD, B. I., and RIJBIN,B. 1972. Inhibition of pressor effects of angiotensin I and augmentation of depressor effects of bradykinin by synthetic peptides. Proc. Soc. Exp. Biol. Med. 140, 240-244. ERRINCTON, M. L., and KOCHAE SILVA,M., JR. 1974. On the role of vasopressin and angiotensin in the development of irreversible haemorrhagic shock. J. Physiol. 242, 119-141. FOLKOW, B., LEWIS,D. H., LUNDGREN, E., MELI~ANDER, S.,and WALLENTIN, I. 1964. The effect of graded vasoconstrictor fibre stimulation on the intestinal resistance and capacitance vessels. Acta Physiol. Scand. 61,445-457. GINSBURG.M., and HELLER,H. 1953. Antidiuretic activity in blood obtained from various parts of the cardiovascular system. J. Endocrinol. 9, 274282. GREENWAY, C. V., and LAWSON,A. E. 1968. Effect of adrenaline and propranolol on the superior mesenteric artery blood flow. Can. J. Physiol. Pharmacol. 46,906-908. HODGF?, R. L., LOWE,K.D., and VANE,J. R. 1966. The effects of alteration of blood-volume on the concentration of circulating angiotensin in anesthetized dogs. 3 . Physiol. 185, 61 3. I I u ~ m s J. , H., HL:,ITZ,D . C., BRODY,M. J., and WILH. E. 1970. Differential effect of furoLIAMSON, semide on renal and limb blood flows ilrl the conscious dog. J. Pharmacol. Exp. Ther. 171, 300-306. MCNFILI,,J. R. 1972. Role of vasopressin and angiotensin in response of splanchnic resistance vessels to hemorrhage. Irz The fundamental mechanisms of shock. Edited by L. B. Hinshaw and B. G. Cox. Plenum Publishing Csrp., New York, N.Y.


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Elastic properties of lung parenchyma: the effect of pressure--volume hysteresis on the behavior of large blood vessels.

Effect of acute volume depletion on blood pressure, plasma renin activity and plasma aldosterone concentration in hypertensive subjects.

Effect of Sar1-ala8-angiotensin II on blood pressure and renin in Bartter's syndrome, before and after treatment with prostaglandin synthetase inhibitors.

Reduction of collagen biosynthesis in blood vessels and other tissues by reserpine and hypophysectomy.

Intestinal Na+ loss and volume depletion in JAK3-deficient mice.

Effect of increased intra-abdominal pressure on mesenteric arterial and intestinal mucosal blood flow.

The effect of resistance exercise on fitness, blood pressure, and blood lipid of hypertensive middle-aged men.

Effect of blockade of angiotensin II on blood pressure, renin and aldosterone in cirrhosis.

Effect of an angiotensin antagonist, Sar1-Ala8-angiotensin II on physiological thirst.

Definitions and characteristics of salt-sensitivity and resistance of blood pressure: should the diagnosis depend on diastolic blood pressure?

Blood volume and blood pressure in infants with respiratory distress.

Acute effect of hypophysectomy on the natriuresis following saline infusion in dogs.

Cerebral blood volume and oxygen supply uniformly increase following various intrathoracic pressure strains.

Arterial pressure variations as parameters of brain perfusion in response to central blood volume depletion and repletion.

The course of arterial pressure and the effect of Sar1-Thr8-angiotensin II in a new model of two-kidney hypertension in conscious dogs.

Effects of alpha,beta-methylene ATP on resistance and capacitance blood vessels of the cat intestinal circulation; a comparison with other vasoconstrictor agents and sympathetic nerve stimulation.

Effect of hypophysectomy on rat preadipocyte replication and differentiation.

Effect of hypophysectomy and insulin on lipogenesis in cockerels.

The effect of acute vs chronic magnesium supplementation on exercise and recovery on resistance exercise, blood pressure and total peripheral resistance on normotensive adults.

[The effect of acetazolamide-induced, endogenous volume stress of the cerebrospinal system on intracranial pressure. Diamox--effect on intracranial pressure].

Effect of Buddhist meditation on serum cortisol and total protein levels, blood pressure, pulse rate, lung volume and reaction time.

The effect of hypophysectomy on the uterine response to estradiol.

Effect of chymotrypsin on rat blood pressure.

The effect of dietary sodium intake on the blood pressure and cardiac output responses to angiotensin II in unanaesthetized rats.