Journal of the American Society of Nephrology 53

Cerebral Circulation: Humoral Regulation and Effects ofChronic Hypertension1

Frank M. Faraci,2 Gary L. Baumbach, and Donald D. Heistad

F.M. Faraci, G.L. Baumbach, D.D. Heistad, Departmentsof Internal Medicine, Pathology, and Pharmacology.The Cardiovascular Center and Veterans Administra-tion Medical Center, University of Iowa College ofMedicine. Iowa City, Iowa 52242

(J. Am. Soc. Nephrol. 1990;1:53-57)

ABSTRACTNew concepts have emerged in recent years con-cerning regulation of cerebral circulation. The pur-pose of this review is to summarize briefly several ofthese concepts. First, humoral mechanisms mayhave important effects on cerebral blood vesselsand blood flow to choroid plexus. Recent evidencesuggests that several vasoactive peptides may havemajor effects on fluid and ion balance in the brain

by altering blood flow to the choroid plexus andpossibly the production of cerebrospinal fluid. Sec-ond, chronic hypertension produces structural re-modeling and hypertrophy of cerebral blood vessels

and a shift in the relationship of cerebral blood flowto systemic blood pressure. Third, endothelium-de-pendent responses of cerebral arterioles to receptorand nonreceptor mediated agonists are impairedduring chronic hypertension. Alterations in endothe-hum-dependent responses of cerebral arterioles dur-ing chronic hypertension appears to be due to re-lease of an endothelium-derived contracting factor.

Key Words: choroid plexus, autoregulation, endothelium-dependent responses, structural remodeling, vascular me-chanics

A major concept in cerebral vascular physiology

has been that circulating humorab stimuli havelittle effect on the cerebral circulation. The blood-

brain barrier limits the access of many circulatingsubstances to vascular smooth muscle, so that avariety of blood-borne vasoactive stimuli do not alter

I This paper derives from an invited lecture preSented at the 1989 AnnualMeeting of the American society of Nephrolo9y.

2 Correspondence to Frank M. Farad, Ph.D., Department of Internal Medicine.

The Cardiovascular Center, University of Iowa College of Medicine, Iowa City,

Iowa 52242.

1046-6673/0 10 1-0053$02.OO/OJournal of the American society of NephrologyCopyright C 1990 by the American Society of Nephroiogy

cerebral blood flow. The blood-brain barrier is a

structural barrier, with tightjunctions between endo-thelial cells, and an enzymatic barrier, as endotheliab

cells contain relatively high levels of monoamine ox-

idases (1).The concept that humoral stimuli are not impor-

tant in the cerebral circulation should be revised (2).

Blood-borne stimuli such as vasopressin and anglo-tensin may have major effects on specialized regionsof the brain, such as the circumventricular organsand the choroid plexus, which lack tight junctionsbetween endothelial cells (3). The choroid plexus has

fenestrated capillaries, so that the blood-barrier isabsent, but there are tightjunctions between epithe-

blab cells, which compose a bbood-cerebrospinab fluidbarrier (4).

The choroid plexus is the major site of formation

of cerebrospinal fluid, and blood flow to the choroldplexus may be an important determinant of produc-tion of cerebrospinal fluid (3, 4). Perfusion is sub-

stantiably higher in the choroid plexus than in thecerebrum (Figure 1). High levels of blood flow supportthe filtration and transport functions of the choroidplexus, and they are similar to those of the kidney.

Production of cerebrospinal fluid appears to require1) filtration of plasma out of the fenestrated capilbar-ies and into the interstitial space of the choroidplexus and 2) active transport of ions across theepithelial cells and into the cerebral ventricles (Figure2). Filtration of plasma probably is passive, and de-pendent on local hydrostatic forces (determined in

part by blood flow) as well as capillary permeabilityand surface area. After plasma is filtered into theinterstitial space, secretion of cerebrospinal fluid isan active mechanism involving ion transport (4).

Vasopressin, angiotensin II, and endothelin have avariety of vascular and epitheliab effects in the kid-

ney (5- 1 2). Our studies suggest that these peptidesalso have important effects on the choroid plexus.Blood vessels of the choroid plexus are particularly

sensitive to circulating vasopressin. Increases inplasma concentrations of vasopressin to levels ob-served under physiological and pathophysiobogicalconditions reduce blood flow to the choroid plexus by

more than 50% and decrease production of cerebro-spinal fluid by approximately one third (1 3, 1 4). Va-sopressin levels In the blood can reach very highlevels during hypoxia and intracranial hypterten-

sion. We have suggested that increases in circulatingvasopressin may decrease blood flow the choroidplexus and formation of cerebrospinal fluid under

600

300

Metabolic Filtration/Transport

Blood Flow, ml-min1.lOOg”

nfl-Heart Brain Muscle Choroid

Plexus

CerebrospinalFluid

Kidney

Arteriole

Cerebral Circulation

54 Volume I - Number I ‘ 1990

0

I

E

Figure 1 . Blood flow to several organs under resting con-ditions. Blood flow to choroid plexus and kidney, in whichfiltration and transport are major functions, is relatively high.In contrast, blood flow to the brain, heart, and muscle ismuch lower under basal conditions. Blood flow to thesetissues is regulated to a major extent through mechanismscoupled with tissue metabolism. These data were obtainedin conscious dogs (46).

these conditions ( 1 4). Thus, a major extrarenal effect

of vasopressin may be to attenuate Increases in in-

tracranial pressure and possibly the formation ofcerebral edema.

Blood vessels of the choroid plexus also are veryresponsive to angiotensin II and endothelin (Figure

2). Our recent studies suggest that blood vessels of

the choroid plexus are at least as responsive to anglo-tensin II and endothelin as is the renal circulation

( 1 5, 1 6). In contrast to some systems, the vascular

effect of angiotensin II on the choroid plexus does notappear to be modulated by atniopeptin (17).

These findings suggest that vasopressin, angloten-

sin II. and endothebin all may modulate production of

cerebrosplnal fluid and participate in humoral regu-latlon of fluid and Ion balance in the brain. To what

extent these peptldes modulate epitheliab function in

the choroid plexus is not known. A recent study has

demonstrated that atriopeptin decreases sodiumtransport in the choroid plexus in vitro (18).

EFFECTS OF CHRONIC HYPERTENSION

Autoregulation of Cerebral Blood FlowA well-established concept regarding effects of

chronic hypertension on the cerebral circulation is

that the autoregulatory “plateau” of cerebral blood

flow shifts to a higher range of arterial pressure.

Thus, cerebral blood flow is normal in patients with

chronic hypertension (19) and In experimental

models of chronic hypertension (20-23), despite 1ev-

cbs of arterial pressure that would be expected to

produce passive vasodibatation and “breakthrough”of autoregubation in normotensive individuals. Fur-

thermore, reductions In cerebral blood flow during

Figure 2. Schematic of epithelium and a fenestrated cap-illary in the choroid plexus. Secretion of cerebrospinal fluid

is dependent on 1) plasma filtration through choroidal cap-illaries, which is regulated in part by the level of blood flow,

and 2) active ion transport, which establishes and maintainsan ionic gradient for the movement of water into the ventri-des. Arterioles of the choroid plexus are very responsive tovasopressin, angiotensin II, and endothelin. It is not knownwhether epithelial cells of the choroid plexus are also sen-sitive to these peptides.

acute hypotension occur at higher levels of arterialpressure in hypertensive than in normotensive ba-boons (2 1 ) and rats (20). During chronic hyperten-sion, therefore, cerebral vasoconstriction is en-

hanced during acute increases in arterial pressure,and cerebral vasodilatation is impaired during acute

reductions in pressure.Alterations In autoregulation presumably are re-

bated in large part to structural changes of the vesselwall during hypertension. Cerebral vessels In span-

taneously hypertensive rats (SHR) (20,24) and stroke-prone spontaneously hypertensive rats (SHRSP)

(25,26) undergo hypertrophy, which encroaches onthe vascular lumen and augments responses to con-strictor stimuli (27,28). Hypertrophy of large cerebral

arteries is associated with a reduction in distensibib-

ity (24,29,30). It is likely. therefore, that alterations

of autoregubatory responses are related to hypertro-phy of cerebral vessels and to a reduction in disten-

sibibity of barge cerebral arteries.

In addition to enhancing autoregubatory responsesto acute hypertension, structural changes duringchronic hypertension probably play a role in impair-ing autoregulatory responses to acute hypotension.

Encroachment on the lumen by vascular hypertro-phy and reduced distensibility of the vessel wallwould be expected to impair dilatation during reduc-

tions in pressure. Thus, one might postulate that thecontribution of structural changes to alterations in

autoregulation of cerebral blood flow might be similarat both ends of the autoregulatory curve. If this hy-pothesis were correct, the degree of impairment at

the lower end of the autoregubatory curve would be

CBF (S of Control)

200H��px��3 &hl*’

WKY

SIIR

Autoregulatlon MInImal Resistance

CVR (mmHglml p.r mm . 100g�)

1.0S�dxxh�’.� xl

0.5

�300 WKY SHRSP100 200

Mssn Artidal Prsssurs (mmHQ)

Faraci et al

Journal of the American Society of Nephrology 55

Figure 3. Effects of chronic hypertension on autoregulationof cerebral blood flow (left panel) and minimal cerebralvascular resistance (right panel). Left Panel: Autoregulationof cerebral blood flow is shifted to the right in spontaneouslyhypertensive rats (SHR) relative to normotensive WistarKyoto rats (WKY) (20). The magnitude of the shift is greateratthe upperthan the lower end ofthe curve, which suggeststhat enhancement of autoregulatory constriction in SHR isgreater than impairment of autoregulatory dilatation. Theautoregulatory curves were redrawn from Figure 2 in refer-ence 20. Right Panel: During bicuculline-induced seizures,which produce maximal dilatation of cerebral blood yes-sels, cerebral vascular resistance is greater in stroke-pronespontaneously hypertensive rats (SHRSP) than in WKY (33).Thus, minimal cerebral vascular resistance is increased inSHRSP.

similar to the degree of enhancement at the upper

end of the curve. In spontaneously hypertensive rats,however, the autoregulatory range of cerebral blood

flow is extended by 50 mm Hg at the upper end ofthe curve, whereas the lower end of the curve Isdiminished by only 30 mm Hg (20) (Figure 3, leftpanel). This finding suggests that, during chronic

hypertension, the degree of enhancement of autoreg-ulatory constriction may be greater than the degreeof impairment of autoregulatory dilatation. Thus, notonly is the autoregubatory range of cerebral blood

flow shifted to a higher bevel of arterial pressure, butthe range may be extended during chronic hyperten-slon.

Extension of the autoregubatory range duringchronic hypertension may be rebated to differential

changes in distensibility of barge and small cerebralblood vessels. In a recent study, we found that, incontrast to large cerebral arteries, which become less

distensible during chronic hypertension (24,29,30),distensibility of cerebral arterioles is increased instroke-prone spontaneously hypertensive rats, de-

spite significant hypertrophy of the vessel wall (26).We speculate that the Increase In distensibility of

arterioles may tend to counteract encroachment onthe lumen by hypertrophy of the wall, thus attenuat-Ing impairment of vasodibatation during acute hypo-

tension and other vasodibator stimuli. Increases inarteniobar distensibility during chronic hypertension,therefore, may contribute to a relative preservation

of autoregulatory dilatation, which in turn may help

to protect the cerebral circulation during severe re-

ductions in arterial pressure. Furthermore, becausedistensibility of blood vessels is altered by activation

of smooth muscle (3 1 ,32), it is likely that the protec-tive effect of encroachment on the lumen duringvasoconstniction is preserved In the hypertrophiedvessel despite the increase in arteriolar distensibility.

Minimal Resistance

Another webb-established concept is that chronichypertension results in a reduction in maximal diba-tor capacity of cerebral blood vessels. We (33) and

others (34) have found that increases in cerebral

blood flow during seizure (Figure 3, right panel) orhypercapnia are less than SHR than in normotensive

Wistar Kyoto rats (WKY).The primary mechanism that has been proposed to

account for Impairment of dilatation by chronic hy-pertension is hypertrophy of the vessel wall withreduction of internal diameter by encroachment onthe vascular lumen (34,35). If reductions in internal

diameter resulted solely from encroachment by hy-pertrophy, external diameter of cerebral arterioles

would be expected to be similar In hypertensive andnormotensive animals. We recently measured exter-nab diameter of plal arterioles during maximal dila-tation in WKY and SHRSP (36). External, as well as

internal, diameter was significantly reduced inSHRSP (Figure 4). Therefore, another mechanism, in

addition to inward growth of the vessel wall on thevascular lumen, must be invoked to account for im-

pairment of maximal dilatation of cerebral arterioles

in chronic hypertension.

WKY SHRSP

Figure 4. Comparison of external diameter in maximallydilated pial arterioles of WKY and SHRSP. Internal diameterof pial arterioles was measured at a pial arteriolar pressureof 70 mm Hg. External diameter was calculated from meas-urements of internal diameter and cross-sectional area ofthe arteriolar wall. External, as well as internal, diameterwas significantly smaller in SHRSP than in WKY. Reduction inexternal diameter suggests that reduction of internal di-ameter in SHRSP results from remodeling of the arteriolarwall as well as from encroachment of the wall on the vas-cular lumen. Drawn to a scale of 375:1.

Cerebral Circulation

56 Volume I #{149}Number I ‘ 1990

We have proposed that, during chronic hyperten-sion, cerebral arterioles may undergo structural re-

modeling (36). The possibility of vascular remodeling

In hypertension is supported by the observation thatwall-to-lumen ratio of intestinal arterioles is in-creased in humans with chronic hypertension, evenwithout evidence of hypertrophy of the arteriobar wall

(37). The findings suggest that chronic hypertension

may produce remodeling of the wall of cerebral arte-

niobes, which reduces external diameter without re-ducing vascular distensibility. Based on this concept,maximal dilatation of cerebral arterioles is impairedby reductions in external diameter. as well as by

hypertrophy of the wall, with encroachment on the

vascular lumen.

Endothelium-dependent Responses

Endothebium modulates vascular tone through theproduction and release of endothelium-derived relax-ing and contracting factors, as well as prostacyclin

(38,39). During chronic hypertension, relaxation toendothelium-dependent agonists Is impaired in the

thoracic aorta and carotid artery of SHR tn vitro

(40,41).

We have examined responses of cerebral arteriolesto endothebium-dependent agonists In vivo. InSHRSP, vasodilator responses to acetylchobine, aden-osine 5’-dlphosphate (ADP), and bradykinin are im-paired compared with responses of normotensiveWKY (42-44). Dilator responses to the calcium iono-

phone A23187, which releases endothelium-derivedrelaxing factor by a non-receptor mediated mecha-

nism, are also impaired in SHRSP (45). Altered re-

sponses of cerebral arterioles appear to be selective

for agonists that act through the endothelium be-cause dilatation to adenosine, nitric oxide, and nitro-

glycerin, which act directly on vascular muscle, isnot impaired In SHRSP (42-44).

Responses of the aorta to endothellum-dependent

agonists are impaired in SHR In part because, inaddition to releasing a relaxing factor, endothebiumalso releases a contracting factor (4 1 ). This contract-

ing factor appears to be a cycbooxygenase product. or

perhaps an oxygen-derived radical that is generatedby the cycbooxygenase pathway.

Indomethacin potentiates dilatation of cerebral ar-teniobes to ADP and converts responses to serotoninfrom moderate constriction to moderate dilatation in

SHRSP (43). Indomethacin has no effect on responsesof cerebral arterioles in WKY. These findings suggestthat cerebral arterioles of SHRSP release a contract-ing factor in response to ADP and serotonin. Thiscontracting factor contributes to decreased endothe-hum-dependent dilator responses of cerebral vesselsduring chronic hypertension.

Intuitively, it seems reasonable that hypertensionpredisposes to cerebral hemorrhage, but it is some-

what paradoxical that hypertension predisposes tocerebral ischemia and infarction. Impairment of en-

dothelium-dependent responses may contribute to

this predisposition. We have speculated that. when

platelets aggregate and release their vasoactive prod-ucts (serotonin, ADP, and thromboxane), an endothe-hum-derived contracting factor is released from cer-ebrab arterioles (43). Thus, platelets may initiate acerebral vasoconstrictor response in the presence ofchronic hypertension, in contrast to cerebral vaso-dilatation during normotension, and thereby produce

cerebral ischemia and perhaps stroke.

ACKNOWLEDGMENTS

Original studies were supported by a Medical Investigatorship andfunds from the Veterans Administration, by funds from the NationalInstitutes of Health grants HL-38901 , NS-24621 . HL- 16066, HL-14388. HL-14230, and HL-22149. and by an Established Investi-

gatorship of the American Heart Association.

REFERENCES

1 . Heistad DD. Kontos HA. Cerebral circulation. In: She-pard JT, Abboud FM, ed. Handbook of Physiology.section 2: The Cardiovascular System, Vol. III, Peniph-eral Circulation and Organ Blood Flow, Part 1 . Babti-more: The Williams and Wilkins Company: 1983:137-182.

2. Farad FM, Heistad DD: Regulation of large cerebralarteries and cerebral microvascular pressure. Circ Res1990:66:8-17.

3. Davson H, Welch K, Segab MB: The Physiology andPathophysiology of the Cerebrospinal Fluid. New York:Churchhill Livlngstone; 1987.

4. Johanson CE. Potential for pharmacological manlp-ulatlon of the blood-cerebrospinab fluid barrier. In:Neuwelt E, ed. Implications of the Blood-Brain Barrierand Its Manipulation, Vol. 1 . New York: Plenum Press;1989:223-260.

5. Hofbauer KG, Criscione L, Neisius D, Sonnen-burg C, Wood JM. The role of peptide hormones Inthe control of renal blood flow. In: Nobin A, Owman C.Anneklo-Nobin E, ed. Neuronal Messengers in VascularFunction. Amsterdam: Elsevier; 1987:271-291.

6. Cowley AW, Liard JF, Ausielbo DA. VasopressinCellular and Integrative Functions. New York: Raven;1988.

7. Chou SY, Porush JG, Faubert PF: Renal medullarycirculation: Hormonal control. Kidney Int 1990:37:1-13.

8. KIng AJ, Brenner BM, Anderson 5: Endothelln: Apotent renal and systemic vasoconstnictor peptide. AmJ Physiol 1989:256:F1051-F1O58.

9. Kon V. Yoshioka T, Fogo A, Ichikawa I: Glomer-ular actions of endothelin in vivo. J Clin Invest1989:83:1762-1767.

10. Loutzenhiser R, Epstein M, Hayashi K, HortonC: Direct visualization of effects of endothelin on therenal microvasculature. Am J Physiol 1 990:258:F6 1-F68.

1 1 . Simonson MS, Dunn MJ: Endothelin pathways oftransmembrane signaling. Hypertension 1 990; 15(Suppl):I-5-I- 12.

1 2. Zeideb ML, Brady HR. Kone BC, Gullans SR.Brenner BM: Endothelin, a peptide inhibitor of Na+-K+-ATPase in intact renal tubular epithelial cells. Am

Faraci et al

Journal of the American Society of Nephrology 57

J Physiol l989;257:Cl 101-Cl 107.

13. Farad FM, Mayhan WG, Farrell WJ, Heistad DD:Humoral regulation of blood flow to the choroid plexus:Role of arginine vasopressin. Clrc Res 1988;63:373-379.

14. Farad FM, Mayhan WG, Heistad DD: Effects ofvasopressin on production of cerebrospinal fluid: Pos-sible role of vasopressin (V1) receptors. Am J Physiol1 990;258:R94-R98.

1 5. Maktabi M, Heistad DD, Farad FM: Effects ofangiotensin II on blood flow to the choroid plexus. AmJ Physiol 1990;258:H414-H4l8.

16. Kadel KA, Heistad DD, Faraci FM: Effects of en-dothelin on blood vessels of the brain and choroidplexus. Brain Res (In press).

1 7. Schalk KA, Williams JL, Heistad DD: Effects ofatriopeptin on blood flow to cerebrum and choroldplexus. Am J Physiol 1989;257:R1365-Rl369.

18. Johanson CE, Sweeney SM, Parmelee JT, Ep-stein MH: Cotransport of sodium and chloride by theadult mammalian choroid plexus. Am J Physlol1990;258:C2l l-C2l6.

19. Strandgaard 5, Olesen J, Skinhoj E, Lassen NA:Autoregulation of brain circulation in severe arterialhypertension. Br Med J 1973;1:507-510.

20. Harper SL, Bohlen HG: Microvascular adaptation Inthe cerebral cortex of adult spontaneously hyperten-sive rats. Hypertension 1 984;6:408-4 19.

2 1 . Jones JV, Fitch W, MacKenzie ET, Strandgaard5, Harper AM: Lower limit of cerebral blood flowautoregulation in experimental renovascular hyper-tension in the baboon. Circ Res 1976;39:555-557.

22. Strandgaard 5, Jones JV, MacKenzie ET, HarperAM: Upper limit of cerebral blood flow autoregulationin experimental renovascular hypertension in the ba-boon. Circ Res 1975:37:164-167.

23. Strandgaard 5, MacKenzie ET, Sengupte D, Ro-wan JO, Lassen NA, Harper AM: Upper limit ofautoregulation of cerebral blood flow in the baboon.Circ Res 1974:34:435-440.

24. Brayden JE, Halpern W, Brann LR: Biochemicaland mechanical properties of resistance arteries fromnormotensive and hypertensive rats. Hypertension1983:5:17-25.

25. Hart MN, Heistad DD, Brody MJ: Effect of chronichypertension and sympathetic denervation on wall/lumen ratio of cerebral vessels. Hypertension 1980:2:4 19-423.

26. Baumbach GL, Dobrin PB, Hart MN, Heistad DD:Mechanics of cerebral arterioles in hypertensive rats.Circ Res 1988:62:56-64.

27. Folkow B: The haemodynamic consequences of adap-tive structural changes of the resistance vessels Inhypertension. Cbin Sd (Land) 1 97 1 ;4 1 : 1 -12.

28. Mulvany MJ, Hansen PK, Aalkjaer C: Direct evi-dence that the greater contractility of resistance yes-sels in spontaneously hypertensive rats Is associatedwith a narrowed lumen. CIrc Res 1978:43:854-863.

29. Winquist RJ, Bohr DF: Structural and functional

changes in cerebral arteries from spontaneously hy-pertensive rats. Hypertension 1983:5:292-297.

30. Toda N, Okunishi H, Miyazaki M: Length-passivetension relationships In cerebral and peripheral arter-ies isolated from spontaneously hypertensive and nor-motensive rats. Jpn Circ J 1982:46:1088-1094.

3 1 . Cox RH: Effects of norepinephnlne on mechanics ofarteries in vitro. Am J Physiol 1976:231:420-425.

32. Dobrin PB, Rovick AA: Influence of vascular smoothmuscle on contractile mechanics and elasticity of an-tenies. Am J Physiol 1969:217:1644-1651.

33. Sadoshima 5, Busija DW, Heistad DD: Mecha-nisms of protection against stroke in stroke-prone rats.Am J Physiol 1 983;244:H406-H4 12.

34. Johansson BB, Nilsson B: Cerebral vasomotor re-activity in normotensive and spontaneously hyperten-sive rats. Stroke 1979:10:572-576.

35. Folkow B, Hallback M, Lundgren Y, Weiss L:Background of increased flow resistance and vascularreactivity in spontaneously hypertensive rats. ActaPhysiol Scand 1970:80:93-106.

36. Baumbach GL, Heistad DD: Remodeling of cerebralarterioles in chronic hypertension. Hypertension1989:13:968-972.

37. Short DS, Thomson AD: The arteries of the smallintestine In systemic hypertension. J Pathol Bacterial1959:78:321-334.

38. Vanhoutte PM. Relaxing and contracting factors.Clifton: Humana Press: 1988.

39. Lee TJF: Cholinergic mechanisms in the large catcerebral artery. Circ Res 1982:50:870-879.

40. Luscher TF, Diederich D, Weber E, VanhouttePM, Buhler FR: Endothelium-dependent responsesin carotid and renal arteries of normotensive and hy-pertensive rats. Hypertension 1 988; 11:573-578.

4 1 . Luscher TF, Vanhoutte PM: Endothelium-depend-ent responses to platelets and serotonin in sponta-neously hypertensive rats. Hypertension 1 986:8(SupplII):II-55-II-60.

42. Mayhan WG, Faraci FM, Heistad DD: Impairmentof endothelium-dependent responses of cerebral arte-rioles in chronic hypertension. Am J Physlol 1987;253:H 1 435-H 1440.

43. Mayhan WG, Farad FM, Heistad DD: Responsesof cerebral arterioles in adenosine 5’-diphosphate. se-rotonin, and the thromboxane analogue U-466 1 9 dur-Ing chronic hypertension. Hypertension 1988; 12:556-561.

44. Yang ST. Mayhan WG, Heistad DD: Responses ofplal arterioles to bradykinin. nitric oxide. and nitro-glycerin during chronic hypertension. FASEB (Fed AmSoc Exp Blob) J 1 989;3:A846(Abstract).

45. Yang ST. Mayhan WG, Heistad DD: Mechanismsof impaired endothelium-dependent responses of cer-ebral arterioles during chronic hypertension. FASEB(Fed Am Soc Exp Blob) J l990;4:A556(Abstract).

46. Farad FM, Chiblan WM, Williams JK, HelstadDD: Effects of reflex stimuli on blood flow to theadrenal medulla. Am J Physiol 1989:257:H590-H596.