Hormonal and metabolic responses to intracarotid

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on growth hormone and prolactin response to arginine in man. Comparison with somatostatin. Lancet, i: 353-356. SCHALLY, A. V . , W-Y. HUANG,R. C. C . CHANG,A. ARIMURA, T, W. REDDING,R. P. MHLI~AR, M. W. HUNKAPILLAR, and E. E. HOOD. 1980. Isolation and stmcture of pro-somatostatin: a putative somatostatin precursor from pig hypothalamus. Proc. Natl. Acad. Sci. U.S.A.7'1: 4489-493. SEAL,A . , T. YAMADA,W. DEBAS, J . MBLI,INSHEAD, B. OSADCHEY, G. A ~ N T Eand , J. WAISH. 1982. Sonnatostatin-14 and -28: clearance and potency on gastric function in dogs. Am. 9. Physiol. 243: G97-G102. SRIKANT. C. B ., and Y. C. PATEI,.1981 . Receptor binding of somatostatin-28 is tissue specific. Nature (London), 294: 259-260. 1985. Somatostatin receptors in the rat adrenal cortex: characterization and comparison with brain and pituitary receptors. Endocrinology (Baltimore). 116: 1717- 1723.

Serswn, C., J. P. ESTEVE,N. VAYSSE,L. PRADAYROL, and A. RIBET. 1980. Somatostatin 28: effects on exocrine pancreatic secretion in conscious dogs. Gastroenterology, 79: 720-724. V ~ ~ s sN., e , J.'A. CHAYVIAI-LE, L. PRADAYWOI,, J. P. ESTEVE,C. SUSINH, J. LAPUELI-E, F. DESCOS, and A. RIBET.1981. Somatostatin 28: comparison with somatostatin 14 for plasma kinetics and lowdose effects on the exocrine pancreas in dogs. Gastroenterology, $1: 700-706. VHZI,E., T. HORVATM, and G. T. SQMOGYI.8984. Evidence that somatostatin releases endogenous substance(s) responsible for its presynaptic inhibitory effect on rat vas deferens and guinea pig ileum. Neuroendocninology,29: 14%-148. YAU,W. M . , P. F. LINGLE,andM. L. YOUTHEIR. 1983. Modulationof cholinergic neurotransmitter release from myenteric plexus by somatostatin. Peptides (NY), 4: 49-53.

Hormonal and metabolic responses to intracarotid and intrajugular infusion of P-endorphin in normal dogs1 K. MI. A. EL-TAYEB, C. J. T. GAUTHHER, P. &. BWUBAKER, H. L. A . LICKLEY, AND M.

VRAPIIC~

Departments qf Physiology, Surgery, and Medic.inr, Worncw's College Hospitul carad Uraiversr'bjioj Torsnro, Toronto, Orat., Ccrmsl'a

Received June 10. 1 9 8 EL-TAYEB, K. M. A., C. J. T. GAUTHIER, P. L. BRUBAKER, H. L. A. L I C ~ L E and Y , M. VKANPC. 1986. Worn~onaland metabolic responses to htracxotid and intrajugular inhsicsn of 6-endolphin in nonna%dogs. Can. J. Physiol. Pi~mnacol.64: 306-3 10. The hormonal and metabolic responses of P-endorphin infused cephalad into the carotid artery, or via the jugulx vein, were examined in BO normal dogs. The intracarotid administration of P-endorphin resulted in significant increases in plasma glucagon, adrenocorticotropin, and cortisol levels. Hepatic glucose production increased only transiently and there was no significant change in glucose disappearance or plasma glucose concentrations. Infusion of p-endorphin in the jugular vein gave rise tcs significant increases in glucagon and cortisol levels and to a transient increase in plasma epinephrine. Although no significant changes in glucose kinetics could be demonstrated, there was a slight transient decrease in plasma glucosc concentrations. In conclusion, both intracarotid and intrlrjugular infusions of @-endorphinstimulated glucago~lsecretion independent af circulating catecholamines, and increased cortisol release. probably through activation of the pituitary-adrenocortical axis. EL-TAYEB, K. ha. A . , C. J . T. GAUTH~ER, P. L. BRUBAKER, H. L. A. LICKLEY et M. VKANIC.1986. Wonnonal and metabolic responses to htracarotid md intmjuplaa- infusion of P-endoqhin in normal dogs. Can. J . Physiol. Phmaco!. 64:306-3 10. On a examink chez 10 chiens nomaux, les rdponses hom~onaleset rn6taboliques de %aP-endorphine perfuskc en direction cCphalique dans l'artkre camtide ou via la veine jugulaire. E'adrninistration intracarotidienne de la 9-endcsrphine resulte en des augmentations des taux de glucagon, de corticotrepBmine et de cortisol plasmatiques. La production de glucose hCpatiquc n'augmenta que trarasitoirernent ct on w'observa pas de variation significative de la dispasiticsn de glucose ou des concentrations de glucose plasmatique. La perfusion de @-endorphinedans %aveine jugulaire provoq~aades augmentations significatives des taux de cortisol et de glucagon et une augmentation transitoire d'kpinkphrine plasmatique. Bielr qu'on n'ait pu dkmontrer de variations significatives de la cinktique dln glucose, il n9y avait qu'une @ere diminution transitoire des concentrations de g8ucose plasmatique. En conclusion, les perfusions intracarotidieinaes et intrajugulaires de P-endorphine stima~ul&rent la sdcrktion de glucagon indkpendante des catCcholarnine4:circulantes et aug~raenterentla libkratic~ndc cortisol, probablemernt par l'activation des axes kypophysaires-~oHticos&1nr6naux. ['Traduitpar Ie journal]

Introduction Several studies have investigated the role of the endogenous opiates in glucose metabolism. Both in viva and in vilan, pand have been found to release of and glucagon tKeid a''d Yen 1981; 'PP et a'* 1980;Ipp et al+ 1978). lnuavenous administration of large doses ' ~ k a ~ ~ c ~by r tgrants e d from the Medical Research Council of Canada, Hospital ReCanadian Diabetes L4ssociation, The Women,s search Fund, and the Banting and Best Diabetes Centrc. ' ~ ~ tot wholn h ~ all~coflesp~ndencemay be sent at the following address: Departlraent of Physiology, Room 3358, Medical Sciences Building, University of Toronto, Toronto, Ont., Canada M5S 1A8.

of morphine or central administration of either morphine or fl-endorphin results in hyperglycemia. This was suggested to be mediated by an increase in plasma catecholan-aincs(for review see Giuglians 1984). In the present we have investigated the hormonal and nletabolic responses to infusion of P-endorphin in normal conscious dogs. To determine whether B-endorphin exens its effects by &ing directly on peripheral tissues and (or) indirectly via the central nervous system, we have studied the effects of @-endorphininfusion given either into the jugular vein or into the c ~ o t i dartery directed cephalad. It has been suggested that opioid peptides can cross the blood-brain b m i e r (Rapoport -8et a]. 1980), although another study has hiled to confirm this

NOTES

A


Sal~ne

@-Endorphin

Recovery

*:4

€3 P-Endorphin

Plasma P-Endorphin

b:4

Recovery

2000

(pglmi 1

FIG. I . Plasma levels of @-endorphinduring (A) an intracarotid infusion of P-endorphin (0.06 pg-kg-l.min-l),and (B) an intrajugular infusion of P-endorphin (0.06 pg-kg-B.min-lj. Vertical bars represent SEM. Significant increases are indicated in the text.

(Houghten et al. 1980). However, opioid peptides given into the carotid artery would certainly reach the circu~-nventricular organs (Wellens et al. 1975) which lack a blood-brain barrier (Pardridge 198 1) . Materials and methods Experiments were performed on 10 normal conscious mongrel dogs weighing 17-25 kg. The animals were offered daily a diet of 200 g hrina dug chow and %MIg beef chunks (Womar Pet Supplies, Toronto, Canada). At least 3 days prior to each experiment, polyvinyl cannulas were inserted under general anaesthesia. For sampling purposes, a cannula was introduced into the saphenous vein and advanced until the tip was just below the hepatic vein. T h e e infusion catheters were placed into the external jugular vein. In five of the dogs, an additional infusion catheter was inserted in the common carotid artery with the tip advanced cephalad into the internal carotid artery. The carotid artery was ligated distally. The position of this cannula was checked by x-ray

fluoroscopy usfng a radiopaque chemical (Hypaque W, Winthrop Laboratories, Aurora, Ontario) to ensure that infused materials would be delivered into the blood supplying the brain. Animals were fasted for 14- 16 h before each study, which commenced at 08146)-0900 h. The first protocol (five dogs) included ( a ) a 140-min tracer equil~bration and intracarotid saline infusion control period; (br) a 90-min infusion of P-endorphin (0.06 pg.kg-' -wmir~-') into the carotid cannula. and ( c ) a 60-nlin recovery period. The second protocol (five dogs) was identical except that saline and P-endorphin (0.06 pg-kg-' emin ') were infused into the jugular vein. Synthetic human @-endorphin(donated by National Institute of Mental Health. Rockville LMD, U.S.A.) was dissolved in saline immediately before use. Glucose concentration and kinetics, plasma irnmunoreactive insulin (IRI), glucagon (IRG). free fatty acids (FFA). catecholamines, and cortisol were determined as previously described (Wasserman et al. 1984). Adrenocorticotroopin (ACTH) was measured by radioimmunoassay (Orth 1979), using antibody R1543 (kindly supplied by Dr. D.

CAN. J. PHYSEOI,. PHARMACOL. VOE. 4 4 , 1086

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I

PIPZW AloresplnwRrh (pglml) eso


I

P188fiX~ ACTH (~~Irnl)

Plasma Cortisol Plasma Cor two1

(p~ldl) I

(ll~ldl)

Plasm Glucose (rngldi)

Glucoao Production (m~lkg)-mist)

35,

Glucose Dlsspoesrance (mglkg m ~ n )

*

2 5 .

2 0-

I

I

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FIG.2. Homc~naland metabolic responses to ineracarotid infusion of f3-endorphin (0.06 py.kg-'-ra~in-')in five normal dogs. N. Orth, Vmderbilt University, Nashville, TN). ACTH standard was donated by the National Pituitary Agency (Bethesda, MD). The range of normal canine basal values for ACTH has been reported as 10-40 pg/mL (Wood et al. 1982). P-Endorphian QP-E) levels were determined by radioimunoassay (Bennett et al. 1980) after an initial plasma extraction step (Orth 1979), using the antibody p-cndo-I1 (a generous gift of Brs. R. Benoit and N. Ling. Salk Institute, La Jolla, CA). The range of normal canine basal @-endorphinvalucs has been reported as 19-36 pg/ml (Levin et al. 198 1). Statistical significance was evaluated by unpaired Studerie's t-test and two-way analysis of variance (Winer 197%).

Results Hc~rmceraaband m~tabolicrusps~nsesto intr6rcarolkd P-endorpBzira irefision Figure l A shows that the infusion of P-endorphin in the internal carotid artery increased plasma P-endorphin levels from 48 t 8 to 2523 1 693 pg/mL ( P < 0.05), which then declined to 245 2 46 pg/mL ( P < 0.02) by the end of the recovery period.

FIG.3. Hormonal and metabolic responses to intrajaagular infusion of @-endorphin(0.06 pg-kg -man ') in five nomxal dogs.

'

As shown in Fig. 2, administration of P-E in the internal carotid artery did not cause any significant change in plasma epinephrine, norepinephrine, or insulin levels from basal values (132 k 37 pg/mL, 284 + 63 pg/rnL, and 13 + 2 yU/n.aL. respectively). Plasma ACTH increased from 3 1 + 8 to 129 -t- 4 1 pg/mL (P< 0.05) 30 min after the start of P-endorphin infusion and significant increases in plasma cortiso1 were also detected (basal, 1.7 9 0.2 pg/dL; F = 17, P < 0.005). Plasma glucagc~n increased significantly during the infusion period (basal value, 204 3- 28 pg/mL; F = 94, P < 0.005) and remained elevated during the recovery period ( F = 20 I , P < 0.005). Despite the increase in glucagesn, plasma glucose levels remained unchanged (basal value, 103 9 3 mg/dL; Fig. 2 ) . Hepatic glucose production (Ra), however, increased transiently after 10 min of endorphin infusion (basal value, 2.8 f 0.2 mg-kg-'omin'; P < 0.05).The glucose disappearance rate (PZd) also increased slightly, beat not sigalifisantly, from basaI (2.8 k 0.3 mg-kg-bin'). Thus, as glucose balance (Ra-Rd) did not

309

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change significantly, plasma glucose levels remained constant. Average basal plasma FFA levels were 697 k 127 pequiv./L and did not change significantly in response to intracarotid infusion of (3-endorphin (data not shown). Horrnorzal and metabolic rs,~ponsesto intrajugulur (3-sndorphirz infusion The infusion of P-endorphin into the jugular vein (Fig. 1B) increased plasma P-E from 43 + 7 to 3550 + 596 pg/mL ( P < 0.01). When compared with intracarotid infusion, the P-E levels rose both Inore quickly (B < 0.02 after 30 min of infusion) and to higher levels during intrajugular infusion (P < 0.05, area under the curve). Plasma P-E declined to 35 l k 105 pg/mL (P < 0.05) by the end of the recovery period. Infusion of P-E produced only a small transient increase in plasma epinephrine (basal value, 61 k 18 pg/mL; P < 0.05, after 20 rnin of P-endorphin infusion), without significantly affecting norepinephrine or IRI levels (basal values, 188 + 29 pg/mL and 1 1 5 2 pAJlmL, respectively). Plasma ACTH increased fourfold from 11 L- 5 to 47 +- 13 pg/mL 38 rnin after endorphin infusion; however, this increase was not significant. There was also a small increase in plasma cortisol (basal, 2.8 5 8.5 pg/dL; F = 12, P < 0.085).IRG levels rose significantly during the infusion period (basal, 163 ? 49 pg/mL; F = 24, P < 0.085) and remained high during the recovery period ( F = 18, P < 0.005). Despite the increase in glucagon, there were small transient decreases in both plasma glucose (basal, 88 + 3 mg/dL; P < 0.01) and hepatic glucose production (basal, 3.0 + 0.2 mge kg-Ismin-*; P = NS). Glucose disappearance did not change significanlty (basal, 3.1 + 0.2 mgskg-' emin-'). Average basal plasma I T A levels were 952 + 92 and did not change significantly (data not shown).

Discussion Infusion of P-endorphin stimulated glucagon release; hourever, the overall glucagon responses to infusion of P-endorphin via the carotid artery or the jugula- vein were not different as assessed by integrated areas during the infusion period (5055 + 112'7 p g - m i n - m ~ - l for intracarotid and 4325 zz! 2650 pg-min.m~-' for intrajugular routes of administration). It appears that these increases in glucagon were not mediated by circulating catecholamines, as plasma concentrations of epinephrine and norepinephrine were essentially unchanged. Intracerebroventricular administration of P-endorphin has been reported to stimulate the release of both epinephrine and norepinephrine (Van Loon and Appel i 98 1); however, our intracarotid infusion of P-endorphin did not alter plasma catecholamine levels. P-Endorphin infusion, at the concentration used in this study, had no effect on insulin levels. Although some investigators have reported increased insulin levels in response to Pendorphin (Reid and Yen 1981; Ipp et al. 1978), others have noted that the effects of opioids on insulin secretion are variable and depend largely on the opioid, as well as on the glucose concentration, the route of administration, and whether the opate is given as a bolus or infusion (for review see Giugliano 1984). Despite the elevated IRG levels, plasma glucose was not increased by eithcr P-endorphin infusion. In addition, hepatic glucose production increased only slightly during the intracarotid infusion, and not at all during infusion of P-endorphin in the jugular vein. It appears that P-endorphin interacts with the effects of other hc~moneson hepatic glucose production because B-endorphin decreases hepatic glucose production in dogs

when insulin and glucagon are clamped at basal Bevels (Radosevich et al. 5984) and, in addition, diminishes the stimulatsry action of epinepkrine on hepatic glucose production (El-Tayeb et al. 1985). Cortisol release was stimulated by P-endorphin infusion, independent of the route of administration, and the ACTH and cortisol responses to the two routes of infusion were not significantly different. These results are consistent with the stimulatory action of the opioids on the pituitary-adrenal axis (Haracz et al. 1981). P-Endorphin has been reported to increase glycerol production in isolated rabbit adipocytes (Schwandt et al. 1981). In this study, however, we could not detect a lipslytic activity of P-endorphin in the dog, as assessed by measurements of free fatty acid concentrations. The lack of significant differences between the hormonal and metabolic responses to the two routes of P-endorphin administration occurred despite the lower plasma 9-endorphin levels reached during the intracarstid infusion. Thus, it is possible that near maximal effects of (3-endorphin were achieved already at the lower concentrations of P-endorphin observed during the intracarotid infusion. The difference in plasma P-endorphin levels between the two routes of administration suggests a possible uptake and (or) degradation of P-endorphin by regions of the central nervous system perfused by the internal carotid artery. We could not quantitate the rate of such an uptake in this study, however, because the half-life of p-endorphin in the dog is not known and because of infrequent sampling periods. It is not clear whether P-endorphin crosses the blood-brain barrier, as data both supporting (Rapoport et al. 1980) and opposing (Houghten et al. 1980) this have been reported. p-endorphin rnay also enter the brain through the circumventricular organs, however, which lack such a barrier (Pardridge 1981). We have no direct evidence to indicate which: if any, effects, of 9endorphin were centrally mediated in the present study, since the opioid peptide was not administered directly into the intracerebroventricular system. In conclusion, infusion of P-endorphin was shown to stimulate glucagon secretion in the dog. This was independent of the route of administration, as equivalent responses were seen with both the intracarotid and intrajugular infusion of P-endorphin. This effect was also independent of changes in plasma catecholamines. It appears that p-endorphin also increases corticol secretion indirectly through stimulation of ACTH release.

Acknswledgemenmts We are indebted to N. Kovacevic, D. Bilinski, and E. Cook for their excellent assistance and to L. Payne for her help in the preparation of the manuscript. K. M. A. El-Tayeb is a doctoral student sponsored by the University of Gezira, Sudan; C. J. T . Gauthier is a Medical Research Council postdoctoral Fellow, and P. L. Brubaker is a Juvenile Diabetes Foundation postdoctoral Fellow. BENNETT, H. P. J., C . A. BKOWNE, and S. SOLOMON. 1984). Purification of two major forms sf rat pituitary corticotropin using only reversed-phase liquid chroanatography. Biocheanistry, 20: 4530-4538. EL-TAYEB, K . M. A . , P. %. BRUBAKER, M. VRANIC,and H. L. A. LICKLEY. 1985. Beta-endorphin modulation of the glucoregulatory effects of repeated epinephrine infusion in normal dogs. Diabetes, 34: 1293-1300. GIUGLIANO, D. 1984. Morphine, opioid peptides , and pancreatic islet function. Diabetes Care, 7: 92-98. MAKACZ, J . E., A. S. BI,(POM. R. I. H. WANC,and L. -F. TSENC;. 1981.


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Effect of intraventriculx p-endorphin and morphine on hypothalamic - pituitary - adrenal activity and release of pituitary Pendorphin. Neuroendocrinology ,33: 170- 175. HOUGHTEN, R. A., R. W. SWANN, and C. H. Ln. 1980. 63-Endorphin: stability, clearance behaviour, and entry into the central nervous system after intravenous injection of the tritiated peptide in rats and rabbits. Roc. Natl. Acad. Sci. U.S.A. 77: 4588-4591. IPP, E e , R. DOBBS,and W. H. UNGER.1978. Morphine and Pendorphin influence the secretion of the endocrine pancreas, Nature (London), 276: 190- I 9 1. IPP, E., V. SCHBJSDZHARRA?, V. HARRIS,and R. H . UNGER.1980. Morphine-induced hyprglycemia: role of insulin and glucagon. Endocrinology (Baltimore), 107: 46 1-463. LEVIN,E. W., B. SHARP,N. V. MEYER,and H. E. CARLSON. 1981. Naloxone and morphine release beta-endorphin immunoreactivity in dog plasma but not from incubated rat pituitaries. 63rd Annual Meeting of the Endocrine Society. p. 180. (Abstr. 390.) ORTH, D. N. 1979. Adrenocorticotropic homone QACTH). In Methods of hormone radioimmunoassay . Edited by B . M . Jaffe and H. W. B e h a n . Academic Press. New York. pp. 245-284. BARDRIDGE. W. M. 198I . Transport of nutrients and hormones though the blood-brain barrier. Diaktologia, 20: 246-254. R A ~ S E V I CP.HM., , P. E. WILLIAMS, J. R. MCRAE.W. W. LACY,D. N. QRTH,and N. N. ABUMRAD. 1984. 63-Endorphin inhibits glucose production in the conscious dog. J. Clin. Invest. 73: 1237- 1241.

W A ~ P B RS. T , I.: W. A. #LEE, K. D. PETTIGREW, and M. OHNO. 1980. Entry of opioid peptides into the central nervous system. Science (Washington, DC) ,207: 84-86. REID, R. L., and S. S. C. YEN. 1981. (%Endorphin stimulates the secretion of insulin and glucagon in humans. J. Clin. Endocrinol. Metab. 52: 592-594. SCHWANDT, P., W. RICHTER,and J. S. MORLEY. 1981. S-Liptropin contains two lipolytic sequences. Neuropeptides. 1:2 L 1-2 16. VANLOON,G . R.. and N. M. APPEL. 1981. P-Endorphin-induced hyperglycetnia is mediated by increased central sympathetic outflow to adrenal medulla. Brain Res . 204: 236-24 1. WASSERMAN, D. H., H. L. A. LICKEEY,and M. VRANIC.1984. Interactions between glucagon and other counterregulatory hormones during nomoglycemic and hypoglycemic exercise. I. Clin. Invest. 74: 1404-1413. WELLENS.D. L. F., L. J. M. R. WOUTERS,R. J. J. DE WEESE,P. BEIRNAERT, and R. S . WEWEMAW. 1975. The cerebral blood distribution in dogs and cats. An anatomical and functional study. Brain Wes. 86: 429-438, WINER,B. J. 1971. Statistical principles in experimental design. McGraw-Hill, New York. WOOD,C. E., I. SHINSAKO, and M. F. DAEI~MAN. 1982. Comparison of canine corticosteroid responses to mean and phasic increases in ACTH. Am. J. Physicsl. 242: E103-E108.

Effect of nifedipine on calcium-induced contractions to potassium in the aorta and mesenteric arteries of spontaneously hypertensive and normotensive rats M. S. KANNAN'AND A . E. SEBP Degartrneatt of Neurosciences, Wealth Sciences Centre, Mc=M~ss.ter Lrrziversity. 1200Main St. W . ,Harnilto~a,Ont., Canada LWS 3Z-5 AND

B. J .

CRANKSHAW

Department of Obstetrics and Gynecology, Health Sciences Centre, McMuster LIniversiby, 6200 Main St. W . ,Hamilton, Onb., Canada U S 32.5

Received June 7. 1985 KANNAN, M. S., A. E. SEIP,and D. I. CRANKSHAW. 1986. Effect of nifedipine on calcium-induced contractions to potassium in the aorta and mesenteric arteries of spontaneously hypertensive and normotensive rats. Can. J. Physiol. Pharmacol. 64: 310-314. Graded contractions to cumulative additions of calciurn in the presence of KC1 were obtained in strips of aorta and mesenteric arteries of nomotensive (WKY) and spontaneously hypertensive (SHR) rats. In calcium-free medium, a maximally effective concentration of KC1 produced a response that was larger in the mesenteric arterfes (43-51% of cc~ntrol)than in the aorta (12-14% of control). The calcium channel blocker nifedipine (NFD, up to M ) did not significantly alter these calciuminsensitive responses. The Cap-induced responses were inhibited by NFD, in a concentration-depcmmdentfashion, in both vessel types of WKY and SHW rats. The aortic responses were more sensitive to inhibition by NFD than the responses of rnesenteric arteries. Moreover, the aortic responses of WKY were inhibited to a greater extent than those of the SHR. The results suggest: ( a ) a differential calcium dependence of contractions to KC1 in the vessels studied; (h) that aortic responses are dependent on NFD-sensitive voltage-sensitive &'a" channels to a greater extent than the responses of mesentei-ic arteries; and ( c ) that hypertension results in a decreased sensitivity of the aorta Ca" channels to NFD. 1986. Effect of nifedipinc on calcium-induced contractions to potassiurrl in the KANNAN. M. S., A. E. SEIPet D. J. CRANKSHAW. aorta and rnesenteric arteries of spontaneously hypertensive and nomotensive rats. Can. J . Physiol . Pharmacol . 64: 380-314. On a obtenu des contractions gradukes pour des additions cumulatives de calcium en prksence dc KC], dam des bandes d'aortes et d'artkres m6sentCriques de rats nonnotensifs QWKY)et spontar16rnent hypertensifs (SHR). Dans un milieu sans calcium, une concentration maximalement efficace de KC1 provoqua une reponse qui fut plus forte dms les artkres mesentkriques (43-5 1V6 de la rkponse t h o i n ) que dans l'aorte (12-14% de la reponse tkmoin). L e laloqueur de canaux calcllques nifkdipine (NFD, jusqu'a ' ~ u t h s to r whom all correspondence may be addressed.