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Venous function in hypertension
TIPS - January, 1980
depression of salt and water intake sufficient to reduce their balance, whether or not any particular compound increases or reduces the daily output of salt and water. Can their effect be on an osmoregulatory mechanism more or less sensitive to fine changes in salt concentration, or on the thirst-antidiuretic axis that would relate more directly to water intake and excretion? What else? Well, Guyton’s experiments in dogs would seem to indicate that extracellular sodium concentration was regulated more by combined thirst and antidiuretic hormone release than by, say, aldosterone. This is that infinire gain feature of the arterial blood pressure control system again. Thus. if sodium intake was reduced as by diet or drug, decreased thirst and/or decreased ADH release would be required to sustain an appropriate osmotic concentration of salt in a lesser volume of body fluids. Recapitulated, this reduced salt and water balance would diminish extracellular fluid volume, hence lower blood pressure. In our experiments, both salt and water intake were reduced by the chemicals whether they did or did not have the sulfamoyl group required for saluretic activity. Since volume was reduced concomitant with salt deficit induced by the drugs, it seemed tenable that unless increased vasoconstrictor activity were overriding, hypertensive blood pressure should be reduced. It was. Whereas the frequency of cfferent neuronal outflow to the vessels is reported to be increased by the thiarides, the effectiveness of that greater frequency is reduced. Moreover, it has been know,n for many years that the thiazides reduce the responsiveness of arterioles to the vasoconstrictor activity of norepinephrine and angiotensin, and so does salt depletion. Conversely, salt restriction enhanced the adrenal (aldosterone) responsiveness. It follows that the vasodilatory effect of compounds that obtund adretnergic modulation of tonus or which inhibit angiotensin induced vasoconstriction is enhanced by salt depletion. The aldosterone response to angiotensin 11 in patients in whom the renin-angiotensin system was activated by change in posture or by salt restriction was inhibited by saralasin and by teprotide. From theory to therapy the physiological interactions 1 have recited are fascinating to us. We rather think it is
121
worth looking at the effects of these compounds on some of the functions of the paraventricular areas of the brain, but you can do that work too, if you like. I think we know that it is the sodium in our diet that needs to be incriminated to the extent that its balance is covered by chloride. What else? I think we know that a genetic predisposition to hypertension is the unfortunate balance of those same many factors that cause most of us to be normotensive when they are set more appropriately. In a way, though, hypertension may be thought of as a life-saving measure intended somehow to carry those of us so afflicted, usually males, through our most. productive, most creative years. but at some cost with respect to duration of life expectancy. This compromise between an effective life now and a
2. Kempner. U 3. Bever. li H. 410-520. h. Bqer. K. H. Fher 98.97-i 5.
(I‘MI
(19:‘)
J 44ed .I. N-S-Ptwpwr Hw/ Wed 20.
:lm
(IYS.ll .4rch In’ I’
Phurmuwd,,,
6. Hollandcr, W and \hilkms. R. H’. (195-b Bosron Med. Q. #.69-15. Tobian, L.. Janeirk. J . Fokcr. J and Ferrelra. D (1%:) Am. J Phvrrol IO?. 905-908. Rubm. A. A., %tto*iu. 1.. and Hauv.~. I f 1963) J. Pharmuco!. hp. 771~7 la. &%!I Gu~lon. A. C.. t&man. T (; . Coule). 4 W.. Scheel. K. # , Uanning, R P and Norman. R A (iY72) 4nr / Clr,l ?Z. SW-S9Q 10a. H’dron. I. 51. and Fret\. E. 0 119%)(ircularron20. 1028-1036. lob. Murphy. R. I. F 119X)) J (‘lm lnirrr 29. 912-917. IOc. Hatkmi. D V . Fracb. H H Harch. t T and Gurman. 4 H (19SO) .4m 1. 44ej. 9. 431-w.
sooner death then does not have to be
that way, today. Today, the combined use of drugs that moderate both electrolyte autonomic balance and appropriately can go a long way toward sustaining and prolonging a useful life. Even so, we have a lot to do before we have consummated the basis for discovery and development of what may be tomorrow’s useful, rational, therapy. Reading list I. Pickering,
G.
(1972)
.4tn.
J.
Wed
52.
570-583.
Venous function in hypertension* Stan Greenberg? Vascular Smoorh Muscle Laboratory, Deparrmenr o;. Phurmu‘olo.~k. L’mwrsrr\ or’ S
Introduction
The finding of an enhanced reacrivi:y of arterial smooth muscle in experimental and human hypertension has generated the idea that alterations in vasl:ular smooth muscle function contribute to the pathogenesis of hypertension. The direct involvement of arterial vascular smooth muscle derangements in the *Supported in part by USPHS grams HL-22216 and HLOOIZR. t Dr Greenberg is a recipient of a Research Career Development Award 7-KO4HL-00128 from the Hypertension Branch of rhe Narwxil Herrc. I ung and Blood Inwwe.
maintenance of the hypertensive stare is not really disputed. However. a conflict revokes
around rhe quesrion of whsrher
smooth muscle abnormalitles precede (and [hereby mediate) or follow (result from) the increased intra\ ascular pressure of hypertension. or
not
arterial
Moreover.
rhe
mechanism
of
rhe
increased arterial resistance of hypertension is also uncertain. Venous smooth
muscle function and s:ructure is altered in hypertension. In addition, venous distensibility is impaired in canine and human hypertension. Since large veins do not ‘see’ the increased intravascular
TIPS - January, 1980
122 pressure of the hypertension, altered venous smooth muscle function must reflect intrinsic defects in the smooth muscle cell of the hypertensive animal. Thus, veins provide a model for the study of char pes 6n rhe vasculature of the hypertewve amimul. uncomplicated by the effects of an increased intravascular pressure. In addition, aiterations in venous smooth muscle tone or compliance could modulate or aggr-;lvate the hypertensive process by a&ring post/pre-capillary resistance ratio thereby increasing the arteriolar resistance IO flow. This review will evaluate the potential contribution of alterations in the function of veins and arteries tD the pathogenesis of hypertension. Structural and fuoctional changes in vnsrular smooth muscle io hypertension The pressor responses of intact animals or perfused vascular beds to vasoactive stimuli are enhanced in hypertensive animals and man. Many factors can influence the responses of vascular smooth muscle to vasoactive stimuli [Table I). The effects of vascular geometry. increased vascular pressure and intrinsic changes in the vascular smooth muscle cell itself, appear to be the subject of much controversy. TABLE I. Facrors affecting funa~on ID hypmension.
rmoorh
muscle
1. Vascular geometry, medial hvpertrophy. warerlogging. 2. Long-term effects o!i increased intravascular pressure. 3. Circulating humord facnor - prostaplandius, steroids. renin. 4. Long-1m0 effecrs of diswrbed neurotransmiuion. 5. Intrinsic production of hvmoral factors within the vaxular smooth mmsclecell. 6. AlterVions in receptor-transduction mechani§mr 7 Properties of etastic and cc;Jagenous demencs in the vascular IWAIL 6. Inwin.%~ malfunrtion in the w.scular smooth muscle cell.
Folkow and co-workers’ have presented evidence indicating that most, if not all, of the increased vascular resistance and reactivity in experimental and human essential lrypenenslon is caused by an increased vascular wall thickness. Concentration-response curves of renal and spontaneously hypertensive rats (SHR) to norepinephrine differ from those of the normotensivc animals in the same manner as did calculated concentration response curves of a mathe-
matical model with normal wall thickness, in which it was assumed that medial waI1 thickness was increased by approximat4y 30% and the increase in widl thickness had encroached on the lumen wheq the smooth muscle was completely relaxed to maximal dilation. Si:nilar co:lclusions were obtained from thr: studies of Conwati who observed that maximal dilation of the human foiearm vasculature with acetylcholine resulted ia a greater residual resistance in the forearm of hypertensive man than normotems;ve man. It was suggested that structural vascular changes might be responsible for the increased vascular reiistancc and vascu!ar reactivity of hypertensive man. Tobian and coworkers? suggested that the increased wall/lumen ratio and enhanced vascular reactivity was due in large measure to the increased sodium and water in the vascular wall, i.e. ‘water-lo&ng.’ However, water-logging does not occur, at least in the rat, until late in the hypertensive process. Other investigators demonstrated that the increased vascular reactivity and perhaps, permeability, of arterial smooth muscle strips occurs prior to, and early in. respectively the development of hypertension. However, a reduction in pressure is a sufficient stimulus to alter vascular reactivity in normotensive animals. Therefore, the intervention used to assess the importance of functional versus structural and pressure influences of vascular smooth muscle function in hypertension, may directly affect the smooth muscle function. This possibility has also been suggested by the recent experiments of Bevan and co-workers’. Employing rings of rabbit ear and saphenous artery in vitro, these investigators demonstrated that an increased intravascular pressure of aortic coarctation is associated with an increased tension developm.ent which was direcqly correlated with the rise in arterial pressure. Thus intrinsilc changes in vascular smooth muscle function may be masked or modified by the hypertension itself. This conclusion is supported by the experiments of Freidman and co-workers5 and Bohl4. The orly profound vascular changes that occur in experimental hypertension are seen in vessels larger than 100 microns in external diameter. The smaller arterioles and resistance vessels do not appear to be affected to any significant extent, The Freidman group believes that this indicates that a primary change occurs in the small resist-
ante vessels; these vessels constrict and increase the pressure upstream, thereby increasing upstream w.111stress and producing the structural changes which occur in hypertension. The intraluminal pressure downstream does nor increase because these vessels are constricted, hence their structure is not altered. These studies would seem to indicate that the changes in vascular reactivity and electrolyte metabolism in vessels larger than lOUp, O.D., are secondary to the increased intravascular pressure. Veins are not exposed to the increased intravascular pressure of hypertension. Veins are blood vessels with properties similar to arterial smooth muscle. If intrinsic changes in vascular function occur prior to the development of hypertension, then it is possible that these will be reflected in altered venous smooth muscle function, as well. Since veins are not subjected to the high blood pressure of hyfirtension then a study of venous smooth muscle function du in8 the development of hypertension should provide information on the qualitative aspects of vascular dysfunction of the hypertensive process, uncomplicated by modifications secondary to structural and pressure influences. Venous capacitalace, coatr8ctitity and hypertension There is now direct evidence to suggest that altered venous function is present in animals and man with essential hypertension. Some indirect evidence seems to suggest that a decreased venous distensibility in patients with renal hypertension may account for the increased cardiac output noted in these patients. Plethysmographic data suggest that vascular distensibility is decreased in the digits and forearm of patients with essential hypertension’. Since approximately tw&hirds of systemic blood volume is normally contained in veins, the decreased digital and forearm vascular capacity suggests that the veins are participating in the decreased vascular distensibility of essential hypertension. Frohlich and co-workers’ found decreased total and peripheral blood volumes and increased cardiopulmonary blood volume in patients with renal hypertension. In the absence of overt heart failure, the distribution of blood between the systemic and cardiopulmonary segments of the circulation reflects the di:stensibility of the peripheral and pulmonary capacitance beds. The shift of blood volume could reflect
TIPS - Jonuury. I980 a decreased systemic venous capacity ar
a consequence of a decrease in venous distensibility or veno-constriction. Despite the implications of disturbances in venous smooth muscle function in the hypertensive state, a paucity of literature exists in which venous function has been directly studied. Floyer and Richardson’, measured blood volume, arterial pressure and sodium excretion in parabiotlc normofensive and hypertensive rat;. They obtained indirect evidence for a decreased venous capacity and increased capillary pressure in renal hypertension. These investigators postu
lated that the decreased venous capacity initiates the rise in cardiac output and thereby increases arterial pressure, as a consequence of the whole body autoregulatory response. Venous responses of hypertensive man 10 angiotensin II amide were reduced but forearm vascular distensibility was normal. When venomotor tone of small digital veins and venules are evaluated with the technique of rheoplethysmography, the pressure-volume curve of the digital veins is shifted toward the pressure axis in hypertensive patients. This finding
suggests a decreased venous compliance in hypertension. Small veins and venules may participate in the overall increase in
total peripheral resistance in hypertension. Overbeck* evaluated changes in venous compliance and resistance in the early phase of experimental hypertension produced by wrapping kidneys with cellophane (perinephritic hypertension). compliance was Reduced venous observed in the femoral vein, but not in the jugular vein, from perinephritic hypertensive dogs. A decreased venous compliance was also evident in renal hypertensive dogs. Decreases in mesente;ic venous compliance and an increase in venous smooth muscle water and electrolyte content of veins from hyper-
tensive dogs and rats also occur. These were the first reports of measurable differences in eleclrolyte contents of veins in hypertension. Direct evidence of decreased venous smooth muscle compliance in hypertension has now been obtained by several groups of investigators. The first direct evidence that veins are not spared functional changes in experimental hypertension was presented simultaneously by Greenberg and Bohr” and Bevan and co-workers’. Evidence was presented which demonstrated that veins from genetically hypertensive rats developed more tension to vasoactive
123
stimuli, were more sensitive to prostaglandins AI and B2. and were less extensible (stiffer) than veins from an inbred strain of normotensive Wistar rat. Similarly, veins from rabbits with aortic coarctation were more sensitive ro catecholamines than were veins from notmotensive ratd>its. Veins from SHR are less sensitive to the relaxant effects of vasodilator agents. Ramanathan and Shibala’! also demonstrated a decrease in cyclic AMP in portal veins from spontaneously hypertensive rats. The level of cyclic AMP was apparently related in some manner to the blood pressure since cross-breeding of normotensive and hypertensive rats resulted in a level of cyclic nucleotide (hat was intermediate to that of the two groups, similar to the blood pressure. A decrease in cyclic AMP may explain the inability of the portal vein from spontaneously hypertensive rats to relax, but may serve another function as uell (see below). The studies cited above, clearly demonstrate that venous smooth muscle function is impaired in hypertension. These changes must be intrinsic to the smooth muscle of the vasculature and not secondary to the effects of high blood pressure since the veins are not exposed to the increased intravascular pressure of hypertension. However, little is known concerning the relationship of these changes to the development of hypertension. There is a pauciry of studies concerning the mechanism of the altered venous smooth muscle function in hypertension. Finally. little thought has been given to the potential significance of the changes in venous function in hypertension. other than to their posfu the increased sible relationship cardiac output of the labile hypertensive. Relationship of obberant vascular fuactioa to the developmeat of hypertension
Frohlich and co-workers. and Lais and Brady’? employing measurement of pressor responses in conscious animals and perfused hind limbs in anesthetized animals have demonstrated that enhanced vascular smooth muscle function Imayprecede the development of hypcrtension in the Okamoto-Aoki strain of SHR. Shibata and co-workers” and Bohr and co-workers* employing isolated vascular smooth muscle, in vitro.
intraluminal pressure ol hyper:ension. Bevan and co-workers’ demonstrated that venous smooth muscle from rabbits with aortic coarctarion hypertension demonstrated a s!lghtly enhanced tensitiviry to norepinephrme. This sensitibit! was apparently reiated !o fhe hspertension since as carotid pressure increased, sensitivity of the veins to norepinephrine increased. Since veins are not expo>ed to the increased intravascular pres,ure of the hypertension this change necessarily reflects an intrinsic change in the vascular smooth muscle cells or a response of the veins to a circulating humoral agent secondary to the hypertensive stimulus. These investigators did nor examine the time course of the changes in venous function in relation to the development of the hypertencion. Overbeck and co-workers+ employiag measurements of vascular comphance and electrolyte and water contents of mesenteric and muscle beins in animals with aortic coarctarion and renal hypertension, have provided evidence Hhich suggest that water-logging and enhanced permeability of venous smooth muscle fo electrolytes may occur early in rhe hypertensive process. Biochemical changes in mucopol?saccbnrides and proteins in veins and arteries in experimental hypertension
The arteriolar wall undergoer hyperand human trophy in experimental essential hypertension. The arterial and arteriolar wall contains extra uarer. sodium and calcium ion, and exhibits an increase in wall to lumen ;z+tio. sirh :: resultant encroachment of the medIal smooth muscle intc the lumerl. These changes promote a narro\ting oi the of rhs lumen, a hyperresponsiveness vasculature, ins&eased pressure and J stimulus to the hgpenrophic process. II has long been known that hrgh sodium in the diet promares hypertension in susceptible animal models and in man.
Sodium is bound to cell membranes h!, (Lurrrnrlb mucopolysaccharides acid termed glgcoprorcin:, or glycosaminoglycans). In an artrmpr lo e\aluatr whether the binding sites for sodium Ion were changed in deso~)cor~l~ostsronerats. hypertensi\.c (DOCAb-sodium Crane evaluated the uptake of [“Slsulfate by the vasculature of DOCA-
hypertensive
rats as an
indicator
of
>)Ilmucopol\>accharrde have provided evidence that impairment membrane of vascular contractility and altered thesis. Mesemeric arteries from DOCAnon-physiologic hypertensive rats demonstrated a sevenresponsiveness to cations may also precede the increased fold incrcahc in [“S]-SO, incorporarion
TIPS - January, 1980
124
and utilization compared with corresponding controls. Some suggestive evidence for a renal factor controlling this process is that a 28% decrease in [“SlSO, is evident lfter unilateral nephrec10my. The dst.a demonstrated that a disproportionate increase in Cell metibr;me mucopolysaccharide relative to the pressure rise may occur in the vascula-
ture of hypertensive rats. In an attempt to explain the mechanism of the altered mucopolysaccharide turnover. Hollander and co-workers incubated canine aortic tissue with precursors of cell protein and lipid synthesis. These investigators found that norepinephrine and epinephrine inhibited the synthesis of acid mucopolysaccharides and lipids, whereas angiotensin II was devoid of any effect on these processes. The investigators con-
cluded that the binding of the caiecholamines to the tissues produced the inhibition of giycoprotein and lipid syn-
and co-workers’0 thesis. Greenberg demonstrated that clonidlinr, an L)ympathomimetic antihccrtensive drug, ‘,Mb.:rs glucosamine incorporation into vent ‘s smooth muscle. and promotes the reversal of the hypertrophy of venous smooth muscle. It is doubtful, t- iwever, that alteration itn the Oinding ~j norepinephrine to the arterial and venous smooth muscle wall alone can result in an increase in mucopolysacchar .3e synthesis, sodium binding
and perhaps a hyperresponsiveness to vasoactive pressor agents. 1ndi:ect evidence that the increased mucopol:!saccharide content or incorporation of sulfate into the vascufature animals of hypertensive reflected enhanced synthesis of these glycoproteins. was presented by the studies of Yamow I and Go-workers who measured [‘Hjlysiue into incorporation noncollagencus proteins of the vasculature of (8 week) SHR before and during antihypertensive therapy. ‘The authors provide evidence for an increased blood ve?jSelsynthesis Of proteins in arteries ‘of young SHR. Thrs effect was abolished by sympathectomy, in the absenc:e of an increased sympathetic activity. These data demonstrate a noradrenergic control of vascular smooth musclehypertrophy in hypertension. The above experiments Considered together, suggest that catecholamilnes may modulae protein and membrane &Opro:ein synthesis, which in turn a&s sodium and
calcium binding, and modulates the vascular responsiveness to tnorepinephrine itself. In hypertension, the feed-
back mechanisms or the synthetic mechanism for cellular protein synthesis
may be kIltered. Despite the documentation of changes irt arteriril smoorh muscle protein and glycoprotein synthesis in arterial smooth muscle from hypertensive animals, the qkrestion could not be resolved whether or not the changes were casual to or resulted from the elevated intmvascular pressure qf hypertension. This question
was resolved by the studies of Greenberg and co-workers” which demonstrated changes In venous smooth muscle wall biochemistry and structure. Panamanil’ examined the H,O, sodium and potassium I:omposition of arteries and veins in rats with aortic coarctation hypertension. The results demonstrated that veins, independent of pressure changes, accumulated more electrolytes per mg of tissue when obtained from hypertensive rats. These findings must now be reevaluated in terms of the increased muscle mass of the hypertrophied cell. Furthermore, the alterations in calcium and magnesium reported by these investigators may reflect an increased binding to membrane mucopotysaccharides and perhaps glycoproteins in the vein wall. Simon and Ahman” investigated the biochemical basis of the decreased compliance of the veins obtained from Wistar-Kyoto (WKY) and SHR. These investigators fourd a decreased collagen and increased hexosamine content of the veins obtained from the SHfi. They concluded that the decreased collagen reflected the decreased extensibility of the veins. The findtngs of the increased hexosamine suggested enhanced mucopolysaccharide synthesis, in the veins obtained from SHR. when compared with blood vessels obtained from WKY. These findings confirmed the studies of Greenberg and co-workers” which demonstrated enhanced incorporation of [“Clglucosamine into the venous and pulmonary arterial smooth muscle of SHR. as well as histological evidence of venous and pulmonary arterial smooth muscle hypertrophy. Since the biochemical changes occur in the absence of an increase in intravascular pressure, it is possible that the cellular processes initiating the smooth muscle hypertrophy could be casual to the development of the hypertension. Stmcturd changes in veins in hypertension Hypertension in rats leads to increased synthesis and deposition
an of
collagen and non-collagenous protein. The synthesis of non-collagenous protein is associated with hypertrophy of the arterial and venous smooth muscle.
undergoes Arterial smooth muscle hyperplasia as well. Bevan and coworkers evaluated cellular hyperplasias of blood vessels above and below the
ligature of rabbits with aortic coarctation hypertension. The authors provide evidence that an increased arterial pressure stimulates arterial smooth muscle hypcrplasia which is not present in the veins. Kaufman demonstrated that hyperplasia does occur in veins which undergo hypertrophy secondary to increased venous pressure. However, the incidence of mitoses (1: 1000-l : 10,000 cells) suggested to the authors that hypertrophy does not depend on the presence of subfsequent hyperplasia. Similar findings were made by Crane and Dutta who demonstrated increased DNA synthesis in the nuclei of arterial and arteriolar smooth muscle but not in the veins. The first evidence of venous hypertrophy was demonstrated by Greenberg and co-workers lo. IEmploying SHR these investigators demolnstrated that, in the absence of increased venous pressure, pulmonary arteries, inferior venae cavae and portal veins of SHR were found to have thicker walls and more smooth muscle in comparison to corresponding vessels obtained from normotensive WKY rats. The ability of the vessels from SHR to ta.ke up periodic-acidSchiff stain, indicative of increased synthesis, was mucopolysaccharide greater than that in the vessels obtained from WKY. Electron microscopic studies demonstrated a hypertrophic smooth muscle ceil approximately twice the diameter of that found in the veins of the WKY. Associated with the hypertrophy was an increase in the size and number of Golgi organelles indicative of increased protein synthesis. In addition, disproportionately enlarged nucleoli in nuclei of hypertrmophic veins and pulmonary artery from SHR indicated that DNA-directed RNA synthesis was enhanced in the low pressure vessels of SHR. [ “C]glucosamine. a precursor for membrane and cellular glycoproteins was found to he accumulated to a greater degree in portal veins, venae cavae and pulmonary arteries obtained from SHR when compared with WKY. [“Cjthymidine. an index of DNA-synthesis, was not significantly d,ifferent in
TIPS - January, I980 veins and pulmonary artery obtained from SHR when compared with WKY. Previous studies demonstrated an increase in prostaglandin synthesis and a decrease in cyclic AMP in veins obtained from the SHR when compared with WKY. The protein content per gram of wet weight was also greater in veins and pulmonary artery obtained from SHR when compared with WKY. Data from these studies and those published elsewhere demonstrate that venae’cavae, portal veins and pulmonary arteries obtained from SHR show hypertrophy in the absence of an increase in corresponding vascular pressures. The hypertrophy is not the result of fixation artifact or contracture of muscle fibers since {I) the muscles were fixed in a solution containing nitroglycerin to completely relax the muscles, (2) the hypertrophy is accompanied.by an increase in the protein content of the blood vessels obtained from the SHR, and (3) the hypertrophy can be selectively reversed by antihypertensive drugs. These data clearly suggest that vascular smooth muscie hy~rtrophy can occur in the SHR in the absence of an increase in intravenous and intrapulmonary artery pressure. It is possible that the increased TABLE Il. Summary of changes in venous smooth muscle in hypertension. Veins effected 1. Portal vein. 2. Femoral vein. 3. Mesenteric vein. 4. Forearm vein.
5. Saphenous vein. 6. Vena cara. 7. ~lmon~y artery. 8. Vena venorum. Hypertensive models I. Human essentiai hypertension. 2 S~ntan~usly hypertensive rats. 3. Renal hypertensive rats. 4. DOCA-salt hypertenshe rats. 5. Aortic coarctation hypertension in rats and rabbits. 6. Perinephrjtic hypertension in dogs. 7. Renai hypertension in dogs. Lt. Hypertensive man. A Iterations 1. Enhanced contractility 2. Decreased extensibility and compliance. 3. Decreased sensitivity to vasodilators. 4. Enhanced reactivity to vasoconstrwor agertr. 5. Decreased cyclic AMP. 6. Decreased sensitivity to angiotensin Ii. 7. Enhanced prost~landin synthesis. 8. Hypertrophy. 9. increased membrane gllycoprotem synthesis. IO. Diminished prostacychn synthesis. 11.Enhanced pufmonary responses to sympathetic nerve stimuIatjon.
125
arterial pressure may liberate a stimulator of tell growth or a derepressor of an inhibitor of cell growth from the kidney or arterial side of the circulation. Alternatively, abberant changes within the vascuiar smooth muscle cell may result in the hypertrophic cell. DNA-directed RNA synthesisunder the control of cyclic AMP may be inhibited in SHR (Breckenridge, 1974). An enhanced synthesis of pro~taglandin~ may result in a diminIl~ion of cyclic AMP synthesis. removal of the inhibitory effect on cell growth, and enhanced cellular synthesis of proteins and mucopolysa~char~de~, such ar giucosamine containing glycocaminoglycans. Previous studies from our laboratory (Greenberg and Bohr, 1975; Greenberg, 1976) demonstrated an enhanced venous contractility in portal veins obtained from SHR when compared with WKY. Ahhough a multitude of defects are evident in the veins of SHR (Table II), a direct correlation between them and the entranced contractility was not forthcoming. The tinding of hypertrophy and associated changes in contractife proteins provides a theoretical framework, to explain the enhanced contractility of veins obtained from the SHR. Furthermore, the demonstration of pressureindependent hypertrophy indirectly suggests the possibility of venous or arterial smooth muscle hypertrophy initiating the development of hypertension. Summary The results described in thi% review clearly demonstrate that venous exteniibility, contractility and prostagiandi~ synthesis are aftered in veins from hypertensive animals and man. Similarly, venous smooth muscle compliance seems to be impaired in human essential and experimental animal hypertension. Decreased venous compliance and enhanced venous contractility may account for the transrent increase in cardiac output observed during the labile phase of hypertension. Alterations in venous contractility may reflect intrinsic changes in the vascular smooth muscle later in the hy~rtensive process. Alternatively, the veins may respond sooner to a circulating humora) stimulus which will subsequently modify arterial smooth muscle function, or to whrch the arteries are unresponsive. Therefore, the study of venous and arterial rinooth musde functioln during the development of the hypertensive process could well identify the site, and perhaps, stimulus for the
initial changes that occur in hypertension. Similarly, a study of venous and arterial smooth muscle function in hypertension can adequately define those changes intrinsic to the hisir blo& pressure and those secondary to the increased vascular pressure of the hypertension. Therefore, analysis of the tjpe. mechanism and sequence of v-lnous changes which occur in hypertension can provide insight into rational drug therapy to trest the cause, and not the symptoms, of hypertensive vascular disease. Reading list 1. Folkorc, B.
(1971) Urn. ‘kr. 41. I-J2. Conway. J. (I9661 Cwr. Rex 18. 190 3. Tobran. L . . Janacek. 1.. Tombuhan. %.. ani! Ferrerra,0. (JPhlfClm fnr-etr S , 1921. 4 Bevan. 1. A.. Beun. R 1). Chmg. P c Pegram. B L . Purdy. R. t_ .inJ Su c (19’5) C-w. Res 3’. 183. 5. Freidman. 5. Id.. Scott, G. H and Nakashrma, 41. t 1971) ilnat. RET 1-l. $29. 6. Bohr, D F. 119701 Fed. Pror- 33. 12’ 7. Frohlich. E. D Ulryzh. Xl . Taraz,. R C . Dustan. H. P. and Page. I. J-l 1196-r circulatron 35. 209.
depression of salt and water intake sufficient to reduce their balance, whether or not any particular compound increases or reduces the daily output of salt and water. Can their effect be on an osmoregulatory mechanism more or less sensitive to fine changes in salt concentration, or on the thirst-antidiuretic axis that would relate more directly to water intake and excretion? What else? Well, Guyton’s experiments in dogs would seem to indicate that extracellular sodium concentration was regulated more by combined thirst and antidiuretic hormone release than by, say, aldosterone. This is that infinire gain feature of the arterial blood pressure control system again. Thus. if sodium intake was reduced as by diet or drug, decreased thirst and/or decreased ADH release would be required to sustain an appropriate osmotic concentration of salt in a lesser volume of body fluids. Recapitulated, this reduced salt and water balance would diminish extracellular fluid volume, hence lower blood pressure. In our experiments, both salt and water intake were reduced by the chemicals whether they did or did not have the sulfamoyl group required for saluretic activity. Since volume was reduced concomitant with salt deficit induced by the drugs, it seemed tenable that unless increased vasoconstrictor activity were overriding, hypertensive blood pressure should be reduced. It was. Whereas the frequency of cfferent neuronal outflow to the vessels is reported to be increased by the thiarides, the effectiveness of that greater frequency is reduced. Moreover, it has been know,n for many years that the thiazides reduce the responsiveness of arterioles to the vasoconstrictor activity of norepinephrine and angiotensin, and so does salt depletion. Conversely, salt restriction enhanced the adrenal (aldosterone) responsiveness. It follows that the vasodilatory effect of compounds that obtund adretnergic modulation of tonus or which inhibit angiotensin induced vasoconstriction is enhanced by salt depletion. The aldosterone response to angiotensin 11 in patients in whom the renin-angiotensin system was activated by change in posture or by salt restriction was inhibited by saralasin and by teprotide. From theory to therapy the physiological interactions 1 have recited are fascinating to us. We rather think it is
121
worth looking at the effects of these compounds on some of the functions of the paraventricular areas of the brain, but you can do that work too, if you like. I think we know that it is the sodium in our diet that needs to be incriminated to the extent that its balance is covered by chloride. What else? I think we know that a genetic predisposition to hypertension is the unfortunate balance of those same many factors that cause most of us to be normotensive when they are set more appropriately. In a way, though, hypertension may be thought of as a life-saving measure intended somehow to carry those of us so afflicted, usually males, through our most. productive, most creative years. but at some cost with respect to duration of life expectancy. This compromise between an effective life now and a
2. Kempner. U 3. Bever. li H. 410-520. h. Bqer. K. H. Fher 98.97-i 5.
(I‘MI
(19:‘)
J 44ed .I. N-S-Ptwpwr Hw/ Wed 20.
:lm
(IYS.ll .4rch In’ I’
Phurmuwd,,,
6. Hollandcr, W and \hilkms. R. H’. (195-b Bosron Med. Q. #.69-15. Tobian, L.. Janeirk. J . Fokcr. J and Ferrelra. D (1%:) Am. J Phvrrol IO?. 905-908. Rubm. A. A., %tto*iu. 1.. and Hauv.~. I f 1963) J. Pharmuco!. hp. 771~7 la. &%!I Gu~lon. A. C.. t&man. T (; . Coule). 4 W.. Scheel. K. # , Uanning, R P and Norman. R A (iY72) 4nr / Clr,l ?Z. SW-S9Q 10a. H’dron. I. 51. and Fret\. E. 0 119%)(ircularron20. 1028-1036. lob. Murphy. R. I. F 119X)) J (‘lm lnirrr 29. 912-917. IOc. Hatkmi. D V . Fracb. H H Harch. t T and Gurman. 4 H (19SO) .4m 1. 44ej. 9. 431-w.
sooner death then does not have to be
that way, today. Today, the combined use of drugs that moderate both electrolyte autonomic balance and appropriately can go a long way toward sustaining and prolonging a useful life. Even so, we have a lot to do before we have consummated the basis for discovery and development of what may be tomorrow’s useful, rational, therapy. Reading list I. Pickering,
G.
(1972)
.4tn.
J.
Wed
52.
570-583.
Venous function in hypertension* Stan Greenberg? Vascular Smoorh Muscle Laboratory, Deparrmenr o;. Phurmu‘olo.~k. L’mwrsrr\ or’ S
Introduction
The finding of an enhanced reacrivi:y of arterial smooth muscle in experimental and human hypertension has generated the idea that alterations in vasl:ular smooth muscle function contribute to the pathogenesis of hypertension. The direct involvement of arterial vascular smooth muscle derangements in the *Supported in part by USPHS grams HL-22216 and HLOOIZR. t Dr Greenberg is a recipient of a Research Career Development Award 7-KO4HL-00128 from the Hypertension Branch of rhe Narwxil Herrc. I ung and Blood Inwwe.
maintenance of the hypertensive stare is not really disputed. However. a conflict revokes
around rhe quesrion of whsrher
smooth muscle abnormalitles precede (and [hereby mediate) or follow (result from) the increased intra\ ascular pressure of hypertension. or
not
arterial
Moreover.
rhe
mechanism
of
rhe
increased arterial resistance of hypertension is also uncertain. Venous smooth
muscle function and s:ructure is altered in hypertension. In addition, venous distensibility is impaired in canine and human hypertension. Since large veins do not ‘see’ the increased intravascular
TIPS - January, 1980
122 pressure of the hypertension, altered venous smooth muscle function must reflect intrinsic defects in the smooth muscle cell of the hypertensive animal. Thus, veins provide a model for the study of char pes 6n rhe vasculature of the hypertewve amimul. uncomplicated by the effects of an increased intravascular pressure. In addition, aiterations in venous smooth muscle tone or compliance could modulate or aggr-;lvate the hypertensive process by a&ring post/pre-capillary resistance ratio thereby increasing the arteriolar resistance IO flow. This review will evaluate the potential contribution of alterations in the function of veins and arteries tD the pathogenesis of hypertension. Structural and fuoctional changes in vnsrular smooth muscle io hypertension The pressor responses of intact animals or perfused vascular beds to vasoactive stimuli are enhanced in hypertensive animals and man. Many factors can influence the responses of vascular smooth muscle to vasoactive stimuli [Table I). The effects of vascular geometry. increased vascular pressure and intrinsic changes in the vascular smooth muscle cell itself, appear to be the subject of much controversy. TABLE I. Facrors affecting funa~on ID hypmension.
rmoorh
muscle
1. Vascular geometry, medial hvpertrophy. warerlogging. 2. Long-term effects o!i increased intravascular pressure. 3. Circulating humord facnor - prostaplandius, steroids. renin. 4. Long-1m0 effecrs of diswrbed neurotransmiuion. 5. Intrinsic production of hvmoral factors within the vaxular smooth mmsclecell. 6. AlterVions in receptor-transduction mechani§mr 7 Properties of etastic and cc;Jagenous demencs in the vascular IWAIL 6. Inwin.%~ malfunrtion in the w.scular smooth muscle cell.
Folkow and co-workers’ have presented evidence indicating that most, if not all, of the increased vascular resistance and reactivity in experimental and human essential lrypenenslon is caused by an increased vascular wall thickness. Concentration-response curves of renal and spontaneously hypertensive rats (SHR) to norepinephrine differ from those of the normotensivc animals in the same manner as did calculated concentration response curves of a mathe-
matical model with normal wall thickness, in which it was assumed that medial waI1 thickness was increased by approximat4y 30% and the increase in widl thickness had encroached on the lumen wheq the smooth muscle was completely relaxed to maximal dilation. Si:nilar co:lclusions were obtained from thr: studies of Conwati who observed that maximal dilation of the human foiearm vasculature with acetylcholine resulted ia a greater residual resistance in the forearm of hypertensive man than normotems;ve man. It was suggested that structural vascular changes might be responsible for the increased vascular reiistancc and vascu!ar reactivity of hypertensive man. Tobian and coworkers? suggested that the increased wall/lumen ratio and enhanced vascular reactivity was due in large measure to the increased sodium and water in the vascular wall, i.e. ‘water-lo&ng.’ However, water-logging does not occur, at least in the rat, until late in the hypertensive process. Other investigators demonstrated that the increased vascular reactivity and perhaps, permeability, of arterial smooth muscle strips occurs prior to, and early in. respectively the development of hypertension. However, a reduction in pressure is a sufficient stimulus to alter vascular reactivity in normotensive animals. Therefore, the intervention used to assess the importance of functional versus structural and pressure influences of vascular smooth muscle function in hypertension, may directly affect the smooth muscle function. This possibility has also been suggested by the recent experiments of Bevan and co-workers’. Employing rings of rabbit ear and saphenous artery in vitro, these investigators demonstrated that an increased intravascular pressure of aortic coarctation is associated with an increased tension developm.ent which was direcqly correlated with the rise in arterial pressure. Thus intrinsilc changes in vascular smooth muscle function may be masked or modified by the hypertension itself. This conclusion is supported by the experiments of Freidman and co-workers5 and Bohl4. The orly profound vascular changes that occur in experimental hypertension are seen in vessels larger than 100 microns in external diameter. The smaller arterioles and resistance vessels do not appear to be affected to any significant extent, The Freidman group believes that this indicates that a primary change occurs in the small resist-
ante vessels; these vessels constrict and increase the pressure upstream, thereby increasing upstream w.111stress and producing the structural changes which occur in hypertension. The intraluminal pressure downstream does nor increase because these vessels are constricted, hence their structure is not altered. These studies would seem to indicate that the changes in vascular reactivity and electrolyte metabolism in vessels larger than lOUp, O.D., are secondary to the increased intravascular pressure. Veins are not exposed to the increased intravascular pressure of hypertension. Veins are blood vessels with properties similar to arterial smooth muscle. If intrinsic changes in vascular function occur prior to the development of hypertension, then it is possible that these will be reflected in altered venous smooth muscle function, as well. Since veins are not subjected to the high blood pressure of hyfirtension then a study of venous smooth muscle function du in8 the development of hypertension should provide information on the qualitative aspects of vascular dysfunction of the hypertensive process, uncomplicated by modifications secondary to structural and pressure influences. Venous capacitalace, coatr8ctitity and hypertension There is now direct evidence to suggest that altered venous function is present in animals and man with essential hypertension. Some indirect evidence seems to suggest that a decreased venous distensibility in patients with renal hypertension may account for the increased cardiac output noted in these patients. Plethysmographic data suggest that vascular distensibility is decreased in the digits and forearm of patients with essential hypertension’. Since approximately tw&hirds of systemic blood volume is normally contained in veins, the decreased digital and forearm vascular capacity suggests that the veins are participating in the decreased vascular distensibility of essential hypertension. Frohlich and co-workers’ found decreased total and peripheral blood volumes and increased cardiopulmonary blood volume in patients with renal hypertension. In the absence of overt heart failure, the distribution of blood between the systemic and cardiopulmonary segments of the circulation reflects the di:stensibility of the peripheral and pulmonary capacitance beds. The shift of blood volume could reflect
TIPS - Jonuury. I980 a decreased systemic venous capacity ar
a consequence of a decrease in venous distensibility or veno-constriction. Despite the implications of disturbances in venous smooth muscle function in the hypertensive state, a paucity of literature exists in which venous function has been directly studied. Floyer and Richardson’, measured blood volume, arterial pressure and sodium excretion in parabiotlc normofensive and hypertensive rat;. They obtained indirect evidence for a decreased venous capacity and increased capillary pressure in renal hypertension. These investigators postu
lated that the decreased venous capacity initiates the rise in cardiac output and thereby increases arterial pressure, as a consequence of the whole body autoregulatory response. Venous responses of hypertensive man 10 angiotensin II amide were reduced but forearm vascular distensibility was normal. When venomotor tone of small digital veins and venules are evaluated with the technique of rheoplethysmography, the pressure-volume curve of the digital veins is shifted toward the pressure axis in hypertensive patients. This finding
suggests a decreased venous compliance in hypertension. Small veins and venules may participate in the overall increase in
total peripheral resistance in hypertension. Overbeck* evaluated changes in venous compliance and resistance in the early phase of experimental hypertension produced by wrapping kidneys with cellophane (perinephritic hypertension). compliance was Reduced venous observed in the femoral vein, but not in the jugular vein, from perinephritic hypertensive dogs. A decreased venous compliance was also evident in renal hypertensive dogs. Decreases in mesente;ic venous compliance and an increase in venous smooth muscle water and electrolyte content of veins from hyper-
tensive dogs and rats also occur. These were the first reports of measurable differences in eleclrolyte contents of veins in hypertension. Direct evidence of decreased venous smooth muscle compliance in hypertension has now been obtained by several groups of investigators. The first direct evidence that veins are not spared functional changes in experimental hypertension was presented simultaneously by Greenberg and Bohr” and Bevan and co-workers’. Evidence was presented which demonstrated that veins from genetically hypertensive rats developed more tension to vasoactive
123
stimuli, were more sensitive to prostaglandins AI and B2. and were less extensible (stiffer) than veins from an inbred strain of normotensive Wistar rat. Similarly, veins from rabbits with aortic coarctation were more sensitive ro catecholamines than were veins from notmotensive ratd>its. Veins from SHR are less sensitive to the relaxant effects of vasodilator agents. Ramanathan and Shibala’! also demonstrated a decrease in cyclic AMP in portal veins from spontaneously hypertensive rats. The level of cyclic AMP was apparently related in some manner to the blood pressure since cross-breeding of normotensive and hypertensive rats resulted in a level of cyclic nucleotide (hat was intermediate to that of the two groups, similar to the blood pressure. A decrease in cyclic AMP may explain the inability of the portal vein from spontaneously hypertensive rats to relax, but may serve another function as uell (see below). The studies cited above, clearly demonstrate that venous smooth muscle function is impaired in hypertension. These changes must be intrinsic to the smooth muscle of the vasculature and not secondary to the effects of high blood pressure since the veins are not exposed to the increased intravascular pressure of hypertension. However, little is known concerning the relationship of these changes to the development of hypertension. There is a pauciry of studies concerning the mechanism of the altered venous smooth muscle function in hypertension. Finally. little thought has been given to the potential significance of the changes in venous function in hypertension. other than to their posfu the increased sible relationship cardiac output of the labile hypertensive. Relationship of obberant vascular fuactioa to the developmeat of hypertension
Frohlich and co-workers. and Lais and Brady’? employing measurement of pressor responses in conscious animals and perfused hind limbs in anesthetized animals have demonstrated that enhanced vascular smooth muscle function Imayprecede the development of hypcrtension in the Okamoto-Aoki strain of SHR. Shibata and co-workers” and Bohr and co-workers* employing isolated vascular smooth muscle, in vitro.
intraluminal pressure ol hyper:ension. Bevan and co-workers’ demonstrated that venous smooth muscle from rabbits with aortic coarctarion hypertension demonstrated a s!lghtly enhanced tensitiviry to norepinephrme. This sensitibit! was apparently reiated !o fhe hspertension since as carotid pressure increased, sensitivity of the veins to norepinephrine increased. Since veins are not expo>ed to the increased intravascular pres,ure of the hypertension this change necessarily reflects an intrinsic change in the vascular smooth muscle cells or a response of the veins to a circulating humoral agent secondary to the hypertensive stimulus. These investigators did nor examine the time course of the changes in venous function in relation to the development of the hypertencion. Overbeck and co-workers+ employiag measurements of vascular comphance and electrolyte and water contents of mesenteric and muscle beins in animals with aortic coarctarion and renal hypertension, have provided evidence Hhich suggest that water-logging and enhanced permeability of venous smooth muscle fo electrolytes may occur early in rhe hypertensive process. Biochemical changes in mucopol?saccbnrides and proteins in veins and arteries in experimental hypertension
The arteriolar wall undergoer hyperand human trophy in experimental essential hypertension. The arterial and arteriolar wall contains extra uarer. sodium and calcium ion, and exhibits an increase in wall to lumen ;z+tio. sirh :: resultant encroachment of the medIal smooth muscle intc the lumerl. These changes promote a narro\ting oi the of rhs lumen, a hyperresponsiveness vasculature, ins&eased pressure and J stimulus to the hgpenrophic process. II has long been known that hrgh sodium in the diet promares hypertension in susceptible animal models and in man.
Sodium is bound to cell membranes h!, (Lurrrnrlb mucopolysaccharides acid termed glgcoprorcin:, or glycosaminoglycans). In an artrmpr lo e\aluatr whether the binding sites for sodium Ion were changed in deso~)cor~l~ostsronerats. hypertensi\.c (DOCAb-sodium Crane evaluated the uptake of [“Slsulfate by the vasculature of DOCA-
hypertensive
rats as an
indicator
of
>)Ilmucopol\>accharrde have provided evidence that impairment membrane of vascular contractility and altered thesis. Mesemeric arteries from DOCAnon-physiologic hypertensive rats demonstrated a sevenresponsiveness to cations may also precede the increased fold incrcahc in [“S]-SO, incorporarion
TIPS - January, 1980
124
and utilization compared with corresponding controls. Some suggestive evidence for a renal factor controlling this process is that a 28% decrease in [“SlSO, is evident lfter unilateral nephrec10my. The dst.a demonstrated that a disproportionate increase in Cell metibr;me mucopolysaccharide relative to the pressure rise may occur in the vascula-
ture of hypertensive rats. In an attempt to explain the mechanism of the altered mucopolysaccharide turnover. Hollander and co-workers incubated canine aortic tissue with precursors of cell protein and lipid synthesis. These investigators found that norepinephrine and epinephrine inhibited the synthesis of acid mucopolysaccharides and lipids, whereas angiotensin II was devoid of any effect on these processes. The investigators con-
cluded that the binding of the caiecholamines to the tissues produced the inhibition of giycoprotein and lipid syn-
and co-workers’0 thesis. Greenberg demonstrated that clonidlinr, an L)ympathomimetic antihccrtensive drug, ‘,Mb.:rs glucosamine incorporation into vent ‘s smooth muscle. and promotes the reversal of the hypertrophy of venous smooth muscle. It is doubtful, t- iwever, that alteration itn the Oinding ~j norepinephrine to the arterial and venous smooth muscle wall alone can result in an increase in mucopolysacchar .3e synthesis, sodium binding
and perhaps a hyperresponsiveness to vasoactive pressor agents. 1ndi:ect evidence that the increased mucopol:!saccharide content or incorporation of sulfate into the vascufature animals of hypertensive reflected enhanced synthesis of these glycoproteins. was presented by the studies of Yamow I and Go-workers who measured [‘Hjlysiue into incorporation noncollagencus proteins of the vasculature of (8 week) SHR before and during antihypertensive therapy. ‘The authors provide evidence for an increased blood ve?jSelsynthesis Of proteins in arteries ‘of young SHR. Thrs effect was abolished by sympathectomy, in the absenc:e of an increased sympathetic activity. These data demonstrate a noradrenergic control of vascular smooth musclehypertrophy in hypertension. The above experiments Considered together, suggest that catecholamilnes may modulae protein and membrane &Opro:ein synthesis, which in turn a&s sodium and
calcium binding, and modulates the vascular responsiveness to tnorepinephrine itself. In hypertension, the feed-
back mechanisms or the synthetic mechanism for cellular protein synthesis
may be kIltered. Despite the documentation of changes irt arteriril smoorh muscle protein and glycoprotein synthesis in arterial smooth muscle from hypertensive animals, the qkrestion could not be resolved whether or not the changes were casual to or resulted from the elevated intmvascular pressure qf hypertension. This question
was resolved by the studies of Greenberg and co-workers” which demonstrated changes In venous smooth muscle wall biochemistry and structure. Panamanil’ examined the H,O, sodium and potassium I:omposition of arteries and veins in rats with aortic coarctation hypertension. The results demonstrated that veins, independent of pressure changes, accumulated more electrolytes per mg of tissue when obtained from hypertensive rats. These findings must now be reevaluated in terms of the increased muscle mass of the hypertrophied cell. Furthermore, the alterations in calcium and magnesium reported by these investigators may reflect an increased binding to membrane mucopotysaccharides and perhaps glycoproteins in the vein wall. Simon and Ahman” investigated the biochemical basis of the decreased compliance of the veins obtained from Wistar-Kyoto (WKY) and SHR. These investigators fourd a decreased collagen and increased hexosamine content of the veins obtained from the SHfi. They concluded that the decreased collagen reflected the decreased extensibility of the veins. The findtngs of the increased hexosamine suggested enhanced mucopolysaccharide synthesis, in the veins obtained from SHR. when compared with blood vessels obtained from WKY. These findings confirmed the studies of Greenberg and co-workers” which demonstrated enhanced incorporation of [“Clglucosamine into the venous and pulmonary arterial smooth muscle of SHR. as well as histological evidence of venous and pulmonary arterial smooth muscle hypertrophy. Since the biochemical changes occur in the absence of an increase in intravascular pressure, it is possible that the cellular processes initiating the smooth muscle hypertrophy could be casual to the development of the hypertension. Stmcturd changes in veins in hypertension Hypertension in rats leads to increased synthesis and deposition
an of
collagen and non-collagenous protein. The synthesis of non-collagenous protein is associated with hypertrophy of the arterial and venous smooth muscle.
undergoes Arterial smooth muscle hyperplasia as well. Bevan and coworkers evaluated cellular hyperplasias of blood vessels above and below the
ligature of rabbits with aortic coarctation hypertension. The authors provide evidence that an increased arterial pressure stimulates arterial smooth muscle hypcrplasia which is not present in the veins. Kaufman demonstrated that hyperplasia does occur in veins which undergo hypertrophy secondary to increased venous pressure. However, the incidence of mitoses (1: 1000-l : 10,000 cells) suggested to the authors that hypertrophy does not depend on the presence of subfsequent hyperplasia. Similar findings were made by Crane and Dutta who demonstrated increased DNA synthesis in the nuclei of arterial and arteriolar smooth muscle but not in the veins. The first evidence of venous hypertrophy was demonstrated by Greenberg and co-workers lo. IEmploying SHR these investigators demolnstrated that, in the absence of increased venous pressure, pulmonary arteries, inferior venae cavae and portal veins of SHR were found to have thicker walls and more smooth muscle in comparison to corresponding vessels obtained from normotensive WKY rats. The ability of the vessels from SHR to ta.ke up periodic-acidSchiff stain, indicative of increased synthesis, was mucopolysaccharide greater than that in the vessels obtained from WKY. Electron microscopic studies demonstrated a hypertrophic smooth muscle ceil approximately twice the diameter of that found in the veins of the WKY. Associated with the hypertrophy was an increase in the size and number of Golgi organelles indicative of increased protein synthesis. In addition, disproportionately enlarged nucleoli in nuclei of hypertrmophic veins and pulmonary artery from SHR indicated that DNA-directed RNA synthesis was enhanced in the low pressure vessels of SHR. [ “C]glucosamine. a precursor for membrane and cellular glycoproteins was found to he accumulated to a greater degree in portal veins, venae cavae and pulmonary arteries obtained from SHR when compared with WKY. [“Cjthymidine. an index of DNA-synthesis, was not significantly d,ifferent in
TIPS - January, I980 veins and pulmonary artery obtained from SHR when compared with WKY. Previous studies demonstrated an increase in prostaglandin synthesis and a decrease in cyclic AMP in veins obtained from the SHR when compared with WKY. The protein content per gram of wet weight was also greater in veins and pulmonary artery obtained from SHR when compared with WKY. Data from these studies and those published elsewhere demonstrate that venae’cavae, portal veins and pulmonary arteries obtained from SHR show hypertrophy in the absence of an increase in corresponding vascular pressures. The hypertrophy is not the result of fixation artifact or contracture of muscle fibers since {I) the muscles were fixed in a solution containing nitroglycerin to completely relax the muscles, (2) the hypertrophy is accompanied.by an increase in the protein content of the blood vessels obtained from the SHR, and (3) the hypertrophy can be selectively reversed by antihypertensive drugs. These data clearly suggest that vascular smooth muscie hy~rtrophy can occur in the SHR in the absence of an increase in intravenous and intrapulmonary artery pressure. It is possible that the increased TABLE Il. Summary of changes in venous smooth muscle in hypertension. Veins effected 1. Portal vein. 2. Femoral vein. 3. Mesenteric vein. 4. Forearm vein.
5. Saphenous vein. 6. Vena cara. 7. ~lmon~y artery. 8. Vena venorum. Hypertensive models I. Human essentiai hypertension. 2 S~ntan~usly hypertensive rats. 3. Renal hypertensive rats. 4. DOCA-salt hypertenshe rats. 5. Aortic coarctation hypertension in rats and rabbits. 6. Perinephrjtic hypertension in dogs. 7. Renai hypertension in dogs. Lt. Hypertensive man. A Iterations 1. Enhanced contractility 2. Decreased extensibility and compliance. 3. Decreased sensitivity to vasodilators. 4. Enhanced reactivity to vasoconstrwor agertr. 5. Decreased cyclic AMP. 6. Decreased sensitivity to angiotensin Ii. 7. Enhanced prost~landin synthesis. 8. Hypertrophy. 9. increased membrane gllycoprotem synthesis. IO. Diminished prostacychn synthesis. 11.Enhanced pufmonary responses to sympathetic nerve stimuIatjon.
125
arterial pressure may liberate a stimulator of tell growth or a derepressor of an inhibitor of cell growth from the kidney or arterial side of the circulation. Alternatively, abberant changes within the vascuiar smooth muscle cell may result in the hypertrophic cell. DNA-directed RNA synthesisunder the control of cyclic AMP may be inhibited in SHR (Breckenridge, 1974). An enhanced synthesis of pro~taglandin~ may result in a diminIl~ion of cyclic AMP synthesis. removal of the inhibitory effect on cell growth, and enhanced cellular synthesis of proteins and mucopolysa~char~de~, such ar giucosamine containing glycocaminoglycans. Previous studies from our laboratory (Greenberg and Bohr, 1975; Greenberg, 1976) demonstrated an enhanced venous contractility in portal veins obtained from SHR when compared with WKY. Ahhough a multitude of defects are evident in the veins of SHR (Table II), a direct correlation between them and the entranced contractility was not forthcoming. The tinding of hypertrophy and associated changes in contractife proteins provides a theoretical framework, to explain the enhanced contractility of veins obtained from the SHR. Furthermore, the demonstration of pressureindependent hypertrophy indirectly suggests the possibility of venous or arterial smooth muscle hypertrophy initiating the development of hypertension. Summary The results described in thi% review clearly demonstrate that venous exteniibility, contractility and prostagiandi~ synthesis are aftered in veins from hypertensive animals and man. Similarly, venous smooth muscle compliance seems to be impaired in human essential and experimental animal hypertension. Decreased venous compliance and enhanced venous contractility may account for the transrent increase in cardiac output observed during the labile phase of hypertension. Alterations in venous contractility may reflect intrinsic changes in the vascular smooth muscle later in the hy~rtensive process. Alternatively, the veins may respond sooner to a circulating humora) stimulus which will subsequently modify arterial smooth muscle function, or to whrch the arteries are unresponsive. Therefore, the study of venous and arterial rinooth musde functioln during the development of the hypertensive process could well identify the site, and perhaps, stimulus for the
initial changes that occur in hypertension. Similarly, a study of venous and arterial smooth muscle function in hypertension can adequately define those changes intrinsic to the hisir blo& pressure and those secondary to the increased vascular pressure of the hypertension. Therefore, analysis of the tjpe. mechanism and sequence of v-lnous changes which occur in hypertension can provide insight into rational drug therapy to trest the cause, and not the symptoms, of hypertensive vascular disease. Reading list 1. Folkorc, B.
(1971) Urn. ‘kr. 41. I-J2. Conway. J. (I9661 Cwr. Rex 18. 190 3. Tobran. L . . Janacek. 1.. Tombuhan. %.. ani! Ferrerra,0. (JPhlfClm fnr-etr S , 1921. 4 Bevan. 1. A.. Beun. R 1). Chmg. P c Pegram. B L . Purdy. R. t_ .inJ Su c (19’5) C-w. Res 3’. 183. 5. Freidman. 5. Id.. Scott, G. H and Nakashrma, 41. t 1971) ilnat. RET 1-l. $29. 6. Bohr, D F. 119701 Fed. Pror- 33. 12’ 7. Frohlich. E. D Ulryzh. Xl . Taraz,. R C . Dustan. H. P. and Page. I. J-l 1196-r circulatron 35. 209.