Pathogenesis of Organic Changes in Chronic Hypertension and Hemodynamic Effects of Antihypertensive Agents Senior Mrtlical Investigator, Veternns Administ,ration Hospital; Associ:lte l'rofcssor of Xlcdicine. Georgetown IJniversity School of Medicine, Washington? I). (1. T FII~~ characterist,ic hemodynamic abuor- mality in hypcrtcnsion is t,he increase of t otjal peripheral vascular rcsistnnw. All ot hei possible factors such as cardiac output, Wtal blood volun~e and blood viscosity aw normal ill uucomplicated essent in1 hypertension, but, when unduly c>lc:cated might produce a rise of blood pwssurc~. Except in w-0 instances, as in patients with pheochromocyt oma, the cause of t,he vascular constri&on is unkuo~u. Ikspik the present ignorance concerning the etiology of chronic hypertension, there is wn- sidwablc evidence to suggest that thr> pntho- genesis of organic complicut ions is conncctc~d directly to the elevation of arterial pressure. The charactwistic pathologic lesion is hyper- plusia of the intima of the arterioles. It was considered previously that this chuuge, as a primary process, produced t)he incrcawd periph- eral resist awe, resulting in hypcrtcnsion, the impression having been gained from autopsy examiuation of patients dying in the ad\,anccd stages of the disease. It, is knowr that. proliferation and fibrosis of the artcbrial intima are not, found early in the course of benign essential hypc~rtcllsion. Biop- sies of mnsclt~ and also of kidney as well as autopsies in yr~ung hyptrtcwsives dying of other causes fail to reveal structural changes in the iutima of the arterioles. hrtcriolos~lerosis, thcwforc:, is a late development. In the wrlJ7 stages, the constrictioil is functional -a narrowing due to smooth muscle coii- traction. `I'his functional constriction oftcw can be swn ill the optic fundi of patients with significant hypertension of relatively short du- ration. More interesting, the spasm may sub- side when the blood pressure is reduced. Byron1 has shown this rcvcrsal to occur in the mc- ningenl arterioles of hypcrtcnsive rat s.l lklnxn- tion of arteriolar spasnl has beeu seeu iu t hc optic fundi in patients with short-lived hyper- tension such as acute nephritis or toxemia of pregnancy when the blood pressure uxs reduced with antihypertwlsivr agents or following re- covcrp from thr acute hypcrtcnsivt, state. Reversal of fundic arteriolar spnsnt may also occur in young adults with c~liroiiic: wsent ial hypwtension aftcar their blood ptwsurw harye been wntrolled at normotensi\~c~ levels with antihypertensivc agents. Since the sclerosis of arterioles follows that hypertension by sontc years, it seems possibk that ihe condition is produced by the hypcr- tension per se or by the associntcld arteriolar spasm. Evidence supporting this collwpt has been supplied by Wilson and Hyronl.l They induwd hypertens;iolL ill the rat, by cottstrictiltg one renal art cry with a part iully occludiltg clamp. As a result, distal to the clamp thr>rr occurred not only reduction of blood flow l)llt also of blood pwssure. A sevcw hyprrt ension, howc\w, developed in the remail&v of the animal, including t hc artwinl branches of t hfx opposite kiditry. In the animals who died of sevcrc hypertensioll, typical :Li'tcl'ioloscleiot ita and artcriolonecrotic lwions w'crc foulld in t hc vessels of the opposife or high-pressure kidney, whereas in the low-pwssuw kidney distal to t'hr clamp thv arterioles appeared quite ilornlnl. Some iitstanccs of hypertension associatrd with narrowing of a renal artery in man suggrst that human arterioles react similarly. lcor es- ample, in patients with hypertension sccol~l- ary to partial thrombosis or other forms of iiarro~ving of one renal artery, intimnl prolifer- ation of arterioles is found in the opposite kid- ney but seldom in the invol\yed kidney. Bland 295 described an unusual instance of hypertension apparently due to thrombosis of a main branch of one renal artery. Approximately one-half of the kidney was supplied with low blood flow and pressure, the other with blood under high pressure. Histologic examination revealed hy- perplastic arterioles on the hypertensive side and nornlal-:l.ppc,arirlg arterioles on the hypo- t,enxive side. Since the hypotensive side was not infarct,ed, it must have received some Mood supply even though this was limited. Thus, if there were any unknown circulating or neurogenic toxic suhst ancc acting on art eriolai walls to damage them one would expect this fact,or to act on hot h portions of the kidney. Indeed, since the side distal to the thromhosed artery was the seat of the disorder, one would expect, the arterioles to be, if anything, more diseased in that portion. There is tvidencc to suggest thai arteriola~ smooth muscle, like the smooth muscle of the ureter or gastrointestinal tract, reacts to st ret thing by further contract ion. iLIany years ago, Bnylis made this proposal, and more re- cently l~olkow and others have show11 that in vessels entirely freed of neurogenic or humoral influences elevation of pressure produce vascu- lar constrict ion, while reduction of pressure juduces peripheral vascular relaxation.' Teleo- logically, this intrinsic response of vascular smooth muscle provides a second line of dc- fense in case of exhaustion or failure of the moderator (carotid sinus and aortic arch) reflexes. It also is irnportallt to note ill this connection that the moderator reflexes ill hy- pertensive individuals are set at a higher level. In addition, it is apparent that the constriction of smooth rnusolc to pressure provides a mcch- anism for the continuation of increased periph- eral resistance even aft'er the initiating cause of the hypertension has heen removed. This may explain why hypertension sometimes fails to regress following removal of a phcochromocy- toma, or a unilaterally diseased kidney, or following delivery in toxemia of pregnancy. Another important factor in the perpetual ion of some hypertensions is the development of nephrosclerosis. Many of the incapacitating or fatal compli- cations of hypertension are caused by the frequency of atherosclerosis of large arteries particularly in the cercl~ral tl~~tl coronary l~lood vessels. The hvpertcnsi\-e patirwt is more prolw to de\:clop atherosclerosis t ha11 the normal ill- dividual. The incidence of myocardial illfnrc- tion has been found to 1~ four to five times higher in hypertensi\-e males t ban ill the gel)- era1 population and t\\wlty timw higher ilt hyperteljsive thaII iu normotensi\-e females." It is ~~~11 recognized also that the incidence of cerehrovnscular ath~~l,osc,l(,rosis and thromt)osis is u~~uswally high ill the hyprrtcwi\.c popula- tion. Some factor mwt 1~ prweiit ill the hyper- tensives which accelerates the atherosclerotic process. This acccleratioll m:~y he due to the high pressure existing in the arterial tree or to some other unki~~wi~ fact or present in hyper- tensi\-f> patients. 111 deriding hf~twwii these two possihilit ies, it is pertiiwit to refer to t tie changes that may occur ill the pulmolrary arteries following loiig-stnuding alit1 persistent pulmonary hypertension. l'uln~~nary hq'perte~~- sion of long duratioil is fornld in certaiu forms of congenital heart discasc, sucah ;~h iI1 patent ductus artcriosis with right-to-left Aunt or ill largfa iiitcrveiltric~rilar 5ept:d defects iii which the paticut s oc~casionnlly survive to adult life. The lc\rel of pulmonary presslw iti yuch illdi- viduals is se\-era1 fold higher thnu ih normal for that system. At autopsy, it is cotn1no11 to filld in such patients extensive at herosclrtwsi:: of the pulmonary rather t hall the systemic art wial system. It is evident that if the acceleration of atherosclerosis were due to some circulating or neurogenic noxious factor it should affect twth sides of the circulation. It would not q>:tre the systemic circulation in pulu~onary hyperteiisioil and the pulmonary circulation in systemic hypertension. The fact that the athc~~osc~lerosis is limited in each case to the are;ls of elc\.:lted pressure suggests strongly that the hypertell- sioll is the aggravating factor. Thwe ohserva- tions are not cited to imply that hypcrtclwiolj ORC;AKIC CHAS(;I~:S IN CHROSIC HYI'ERTEXSIO?; 297 causes atherosclwosis hut rat,hcJr to iudicat e that the hydraulic ctiect of an inrreascd pres- sure head clxisting \vit hin the arterial tree hastens and intensifies thtl process of lipid deposition. It has been rccogniacd for many years that the left ventricle responds immedintc~ly to an increased peripheral resistance by dilation and somewhat later by hypertrophy. ?`he dilatation is puwly a mechanical response conditiowd by the contractile propcrtiw of cardiac muscle. If the peripheral wsistancc is elevated, the vets- trick fails to empty as completely as it had previously. As a result, the volume of residual l~lood illcreases ilr the \rent riclc producing fur- thcr stretching of the mywardial fillers. Ac- corditg to Starling's law, cardiac output is proportional to diastolic fiber length; the greater the stretch the greater the suhscqucnt contractiotl. As :L result, thr output is restored to twrmal despite the c>lcvatcd uortic' prwsure. It should be uotcd, however, that in order to maintail a normal output the contraction of thv heart muscle is illcreased; this recluires a greater expendit we of euergy (increased work). As with any muscle auhjrc'ted to prolonged work demands, the fibers hypcrtrophy and t hc \~etitricular wa!! thiclwns. Evcwtually, if the hypertension l~~~n~~es morc~ severe, or if the ~~lood supply to the myo- c~ardium hewmw wmpromised by athcrosclc- rosis of t h(> corouary arteries, or if tht tnyocar- dial musculat we 11c~~~mt:s diseased t hrough other causes, a point is reached in which fur- ther diastolic stretching leads to less efiecti\-e rather than more effwti\-c: contractioil. I1 was demonstrated by Starling and later amplilied by Sarnofl' that there are limits to the cornpctr- satorp powers of cwdiac muscle. In every nlyocardium there is a critical point at which further stretching of the fibers leads to less effc~ctive contraction and the cardiac output falls. Once this point is passed, additional in- creases in arterial pressure evoke progressively poorer cant rwtions with a conrequent rapid derlinc in output. Tf the heart is damaged from other wuses such as coronary artery disease or myocnrdial filxosis, this csriticsl point occurs at lower aortic prwsurw t hail in ai1 uirdamagc:d heart. It is logical to assume that the left I-c~~rtriclv will fail first and that pulmonary edema will result ; and indeed this is often i he caw. At first , there will he only dyspnea OII exert ion, then paroxysmal nwturual dyspnea and finally per- sisteut chronic puln~ot~at~y edema or houis of acute pulmonary edema recluiring emergency t herupy. It is possil)lc, howvor, for right \-cntriculat failure to occur and even predominate with th(b appearance of peripheral edema, high WINJUS pressure aud an enlarged liver. The reasons for this are not wmplvtt~ly uildrwtood, but 1 hew are several possil)lr tq~lauations which plot)- ably operate in concert to product i hc> right wntricular failure. 1+&t, it .should 1~ rwallr~d that the myorardial musculnturc is :I syncytium involving 110th ventricles. I)arnagc~ to thv major or left ventricle wn compromise the tveakcr or right vrntrirlr, although the reverse seldom occurs. Second, t hc rcduct ion of left vw t ricular output lowers the driving force that kwps t hc hlood circulating atid results in a tcildclicy fot blood to collect on the venous side of the cGc:w lution. Third, reduction of uricrial prwsuw secondary to thr fall of cardiac output st imw latw the aortic and wrotid sinus nerws to produce pwiphcral \-asoc~oiistric:tion involving postarteriolnr as well a6 nrtcriolar small vcwt:ls. By this meails. much of the Mood normally distributed in the small \-rswls is shunted illto the central venous system whew it tends to accumulate twxuw of the inc+fc&\.v wrdisc output. I~inally, thrb disordered circwlatioll stimulates secondary wactions, possibly itl- voicing aldosteronr srcrctiou. This may com- promise salt aird water escrction in the kidney, t,hus favoring salt, rctent ion and &ma. It. seems probable, as poiilted out a nurntwt of years ago on the seclucncc of events followitlg severe myocardial infarction, that the body has only a limited numlw of response: patterns t 0 stress. Indeed, most important for survi\xl of the species are the react ions folio\\-iilg humor- rhage; the wounded animal must fight or flw if hc is t,o survive and propagate. Aft pr hrbmor- rhage, as the cardiac output falls, the huro- receptors are stimulatcvl to constrict small peripheral vessels of all types in order to shunt, blood into thts central circulnt ion. _At, the same time, the heart rate increases. 111 the healthy individual subjected to blood loss, these reac- tions are ad\rantugeous, but with a low output, as in heart failure they only add to the burdens of an already overworked myocardium. In additioit, the reduction of cardiac output OI possibly of arterial blood \-olumc following hemorrhage or low out put heart failure stimu- latcs renal salt and wutr~r reteution with result iug expansiou of the extracellular fluid uud plasma volumes. Within 48 hours following blood loss there dcwlops a considcrnble expan- sion of plasma volume due to this mechanism. Vnfortunatrly, the body does not. srrm to diffcwnt iat e bet,w:en a reduction of cardiac output due to blood loss and a reduction due to cardiac failure. The reaction which is so help- ful to the rapid rwtoration of blood wlumo following hemorrhage only adds to the burdens of the failing heart producing edema and fur- ther ~w~ous congestion. The salt and water retention mechuilism rrst ores blood volume a,nd cardiac output in the healthy hrart, thereby shutting off the stimulus to further salt reten- tion. Iu the failing heart, however, as these burdens further reduw the cardiac output, the st imulun to salt and water retention increases, therclby setting up a vicious cycle,. ()TIIER COMPLI(`1TIOSS Dissecting aueuryxil of the aorta which occurs almost exclusively in hypertensi\-e pa- tients may also be a dirwt consequence of the elevated prc'ssure. The aorta, heiug made up primarily of elastic tissue rather than smooth rnusclr, dilates in the prewncc of hypertension. It) SF`PI~S possible that the distention and stretching of t,he aort ic wall may compromise the patency of the capillarirs feeding the media and thus lead to medial nrcrosis. The resultant, weakwss of the aortic NAP favors traring or splitting iu the presence of a constantly in- creased distrndiug prtssure or in a moment of est remr hyperteltsive overshoot. Very littlr is known about) the mcchunism of cerebral hrmor- rhagc. It is recognized, however, that hyperteu- sion contributes to escessivc hlerding duriug brain surgery. These considrratious xs to the pathogrltcsis of the various organic: cwmplirat ious of hyper- tension arr of more than academic illtcrwt. If it, is true that the elcvatrd prrssuw produces orgattic damage, then wductiou of blood pres- sure in thr cad!/ stagrs of the disww would retard or prevent the clcvrlopment of orgaiii(~ damage. The argumcttt that effwtivv aut ihy- pcrtcnsive therapy should be reset,\-4 only for thr advanced pat icnts who already havtx severe organic damaga lxcomes illogical when \,iewtl in the light of the basic ronsiderai ions. The basic mechanisms by which nrtvrial prossuw may 1~ wduced are: (1) by decreasilig cardiac oulput alld (2) by rvduciltg tot al periph- eral resistance. JIost of thr ageiits uwd toclay probably act, 011 both mrchaltisms. The hemodynamic~ effects of the ganglion- blocking drugs can br demowt rated most clearly by substituting a mc&a~ticul pump for the left) vcwtricl(~.:3 In an atrwthvtizcvl dog, blood is tlivcrtcd as it rllters thv Ivft atrium into a rcwrvoir and then is pumped back illto the allima via a 7' tube iIt the dcscrltdiug thoracic aorta. When hes:lriietholliultt is in- jected intraveuously, there is first a fall in arterial pressure, indicating clearly :L decrease in peripheral vascular resist alIce, siuce I he pump is maiiitaii~ctl at 3 cwiistant output . There SOOII follows, howr\-cr, a dwrcwc in cciitral venous pressure, pulmoiiary arterial pressure and a transient dwrease in the \olunw of blood returned from thr right heart through the pulmonary ciroulatiolt to the rcwrwir. :1s a result of the temporary disparity brtwwt the output of the right heart aud i hr pump's constant flow, the rcscrvoir is depleicd of sev- era1 hul&c:d milliliters of blood. Thus, t hc \as- cular volume or capacity of the dog miist have increased sufficiently to accommodate t hv amount of blood transfrrred from i hr rrsrrvoir t,o the animal. Since this amount is too great to be explained on the basis of artcriolar dilation alo1w, it is apparent, that thv posturteriolar vessels must' have dilated as \vcll. ORGANIC CHAXGES IN CHRONIC HYl'b:RTESSION 29!) In the intact animal or humnn,4 the sequence of events appears to be as follows: As sympa- thetic vasoconstrictor discharges are inhibited by the blocking agent, some nrteriolar dilation occurs which is followed cluickly by postarterio- lar (capillary and venular) relaxation and pool- ing of blood in these small vessels. As a result, right heart, filling pressure declinrs due to lack of adequate wnous ret urn, and the cardiac output falls. Thus, there is produced a further fall in arterial prcssurc. Since arteriolur relaxa- tion and reduced cardiac output are presellt, the cnlculntcd total peripheral rcsistanw rcla- tive to the cardiac output shows no significant change. In the presetIce of congestive heart failure, howwr, the cardiac output risw rather than falls after gauglioll-blocking agents. This para- doxical respowc results from the combined bcnt+icial effects of arteriolar reluxat ion (de- creased aortic prwsurc head reducing the work load) and pooling of blood volume peripherally (rclicf of central venous congcstioii). The vffwts of the inhibition of the sympa- t het its arc aggravated when the patient, assumes t,he erect, posit ion (failure of compensa- tory reflex vasoronstric:tioll) and are countcr- a&d when he assumes the head down posit ion, since gravity facilitates venous return. Sirni- Iarly, blood loss cannot be compcwsatc>d for by ~asoconstrictiol1, and severe hypotension can result from only modcratc depletions of total blood volun~e.3 With continued inhibition of the sympatheiics, however, some homeostasis seems to return in time. This so-called "autono- mous tone" of the muscular blood vessels probably is due to the intrinsic property of smooth rnuselc to contract under stretch and to relax after the stretching force has been removed. Kormally, the sympathetic reflexes rat her t han autonomous tone provide the quick adjustments required for circulatory homeos- tasis during changes of body position. When the sympathet its no longer function effectively, as after surgical sympathect omy or ganglion- blocking drugs, the autonomous tone mecha- nism probably comes into play as a second line of defense. When the sympathetic tone is released, following ganglion-blocking agents there is also some redistribution of blood flow to thv various areas of the body." Renal blood flow is wduced at, first, but, due to the ron~arkablc nutotlomy of t hc renal \wculat urc, adjustmenth WV made promptly to restore blood flo\v to control levels. Essenti:dly, the same adjustment oc(ws in the brain. The hepat ic-port al blood flon- decreastrs whcrcas the flows of the calf :uld forearm iilcwnse immediately. In the hailds and feet, however, if there has bwn ~~;woco~~- strict ion by, e.g., placing the subject in a cold room, the increase in blood flo\v is approxi- mately tc~~lfold. The other c#cc:t s of g:uuJionic blockade are related to inhibitc~d i ransnlissiou of nervous impulsw through all autonomic ganglia, purasylnp:lthc~tic ad \vell as sympa- thrtic. Since it is our belief that low sotlium t1ic.t s and saluretic agents such as chlorothiaxid~~ pro- duce similar hvmody~wnic effects, they will tw discussed ul~dcr the sanw heading. 1'11~ COII- sidrrations arc limited to the c4fec.t s of diets, such as the rice diet, which are rcsi ricted to 200 mg. of sodium per day or less. It .~hould bc mentioned that diets more liberal in sodi~lnl content do not produce a degree of salt deple- tion necessary to induce a reduct ioii of blood pressure. Salt depletion can be accomplished more efirctively and quickly with a suluwtic: agc~~t, such as chlorot hixzidc, than with a sodiuu-rcl- strict ed diet. If a noiwdvmat ous, hypert eilsivc patient is given orally 1 .O to 1.5 Gnl. of cshloro- thiazide per day, there will occur a prompi diuresis of sodium :uld chloride, :uld, to a lesser extent, potassiuni.5 During the first 48 to 72 hours, approximately `) -50 to 350 rnl'q. of so- dium and chloride arc lost from body stores, i.e., over and above the daily intake. If the chloro- t hiazide is maintained bc~yond this period, the depletion of body stores of salt lc\,els OH' s11d the patient comes into balance with his illtake. However, he does not regain the original losses. If the salt iugestion is increased, the extra amount is excreted unless the intake is pushed to excessive levels (approximately 25 Gm. pcl day). The excreted salt appears to be derived primarily from the total extracellular fluid space. The patient characteristically loses I to 2 kilos of body weight and I io 2 I,. of extra- cellular fluid as measured by thiocyxnate, radiosodium or radiosulfate dilution spaces. The serum concentrations of sodium and chlo- ride do not change significantly indicating that the elimination of extracellular salt and \vater is proportionate. The serum concentration of pot,assium usually falls slightly, but this reduc- tion frequently is progressive unless potassium supplements are adrninirtercd. Included ill the extracellular fluid space is the plasma volume whirh is reduced by about 15 per cent from its original level. All of these effect,s occur approximately within the first 48 hours, during which time the blood pressure also falls. Thf~ reduction in plasma volume and exlrac~ellular fluid space usually is maintained for periods of at least one month with the con- tinued administration of rhlorothiazide in the dosage of 500 mg. twice daily. The hemody- namic import ante of the plasma volume deple- tion is indicated by the fact that restoration of plasma volume loss alone, without, added salt, as by infusion of 300 ml. of (i per cent dextran in glucose and water, usually ret urns the blood pressure t 0 the previous or pretreatment level. Normotensive, l~oJlf:tlrJ~~ntous individuals also exhibit a similar saluret ic response and reduction of extrarcllular fluid and plasma volurncs. However, unlike the hypertensive paCents, there is no reduction of basal blood pressure. Xerertheless, altered vascular reac- t,ivit,y in that the drgree of blood pressure elevation following infusioits of pressor agents such as norepinephrinr usually is reduced and t,he hypot ensive response to depressor agents is increased. This altered vascular responsive- ness can be reversed by restoring the plasma volume with salt -free dext ran. Several important considerations ernerge from t.hese observations. Ii'irst, there is a labile pool of extracellular fluid and plasma volume which can hr eliminated eithrr by effective salurctic agents or by se\,crcly restricted salt, intake. Parenteral merrurials also produce a de- pletion of plasma volume with an alteration in vascular reactivity. Second, the reduction of plasma volume alt.ers vascular reactivity in hot h the normo- tensivc and hypertensive individual but IX'- tlucc~ basal blood pressure only iii the hy-perteir- sivc. Our expericllre indicates that indi\Gluals with basal diastolic blood pressures in the rcgioll of 90 mm. Hg or abo\~e rfwt to rhloro- thiazide with a fall of basal blood pressure, whereas those nith diastolic lcvrls of 83 or lower are llot responsive. Sillre the fall of blood pressure may occur eveii iii patients n-it h only mild elevations of diastolic blood pressure3 it, is concluded that a basic diff(:relIce exists between mildly hypertcnsi~~e and nornlotelAvc% indiyiduuls. We have int erprrted our results to indicate that in all hypertensivea, including those with only modcratr elevations, a press01 mechauism or stimulus of some type is opera- tive. Chlorothiazide reduces the blood pressure in such a group by decreasing the vasrular reactivity to this stirnulux. A third irnplicat ioll is that the studies she\\ an important relationship bet wee11 total blood volume and vascular reaci ivity. It is probable that when the venous system is well filled a stimulus to vascular contraction produces a greater vc~~ous return to the heart t hall when I he venous system is poorly filled. Acc*ording to C'roslcy and also Dunstall, the cardiac output in hypertensive patients is reduced by chloro- thiaxide. It is a general property of muscle cells that the greater the initial tension the grrnter the contractioll. Thus, oi her things bring ecld, a decrease in blood volume would reduce XXS- cular tone. This rrduct ion of vascular tone does not occur following hemorrhage, because: the baroreceptor reflexes init iatc sympathetic vase- cons1 rictioli, alld thr tot al blood \.olume is restored rapidly through hemodilutioll. I;ollon-- ing rhlorot hiazide, however, these compensu- tory reactions are not prominent. There is no tachycardia or other evidences of rompensatory varoronstrirtion in the hypertensi\~e as COII- t,rastrd to the normotensi\~e subjrrt after rhlor- thiazide. Icinnlly, the studies of salt restrict iolt and saluretic agents provide no cvidencc that so- dium plays an importalrt rtiologic role ill hypertension. The cfkrt of sodium seems to be secondary rat her t ban primary, permissive rather than causative. The admillistrat ion of an c.r-crss~z~ amount of salt does not elevate the blood pressure of ~~o~~ed~~~~~ato~~s l~(~rrn~)tel~sj~~~~ or hypertensive subjects. 11, appears that, a ckplrtion~ of sodimn ion induced either by diet, or by potent salurct ic: agents reduces blood pressure in hypertcnsivc patients. However, the h~~(-)tel~siol~ occurs priil~aril~ because the saftZ loss is associated with a reduction of plasma volume. The unimportance of the sodium ion per se is indicated by the fact that the blood pressure can be rest orcd simply by replenish- ing the plasma volume with s&free dextrw solutions. The role (of salt, thewfortt, appears to be prrmissiw. Its presence is required to main- tain a normal espunhion of plasma volume. This expansion pwnits ~~ormal vascular reac- tivity to the unli~~n~n prcssor mech:mism operative in ~l~pertellsiol~. Salt loss and result- ing plasma volume dcplet ion reduce this wscu- lar reactivity. Hydralnzine or Aprtsoline produce hcmody- namic effects which are unique among the an- t ihypert ensive agents. I'yrogcnic xubst antes produce similar hemodynamic changes, but) hydralazine does not induce fever. Either hy- dralnxine or pyrogeuic subst~nrices produce a marked decrease it l total peripheral vascular resistance while at tht-b same time approximately doubling the cardiac output .@ The heart rate also ncwlernt es. Itenal, splunchnic, cerebral and cortmary I)lood flows iuwease, whereas flow remains essentinlly ~ill(~h:Lt~~e(l in the extremi- ties. Teleologic;~lly, tht> iucrwsed circulatory rate, particularly through the kidneys, heart and liver, aids in the rapid dttoxification ant1 elim- ination of noxious protlwts associated with fr+rile infections und with the l~~obilizatioll of body defenses. This wprwents anot her react ion pattern of the body ust~ful for survival of the specks which is advnntageous in the t rcat mcwt of hypcrtcnsiw patients. The increase in cardiac out put coll~lter~~~ct~ the rnarkcd nrtcriolar relnxat iou induced by hydralazine, so that the percentage of fall in systolic pressure is lwt a:: great as the fall in diastolic. Therefore, when hydralazine is ad- ministered aloue, the most ~i~ili~catlt reduc- tions occur in the diastolic pressure. Homc~er, it is readily sew that if the Venous return to the heart is impaired by the addition of gan- glion-blocking agents or chlorothinzide the cardiac output cannot increase effectively, and the peripheral dilating effects of hydralazine then become r&t iveiy unopposc~1. I*`or this reason, h~~~ralazijle is far more t+I'ect ive when used in combinatiolr with other drugs which reduce cardiac output, particukwly chlorot hia- zide. The t achyenrdia and palpitai ion produced by h~~dralazil~(, somet imw is dist url~i~g to I ht: patient. If this is troublrsomr~, Ilauwolfia, which produces some brndycardia :md also dully apprehension, provides a wart hwhilo cwmter- agent). Jn high dosngc~s, hydralaziw may pro- duce a syndrome in(listiilgtlishai,ir from dis- seminated lupus t,i,~tht~rllatoxus. This does not. occur, however, when dosages are maintained below 200 mg. per day. Whell propcbrlg admiw- istered, hydralazine is an cxt mncty nscful ant ihypertetisivc agtw t . Lit t.le is knows about the hemodynamic: effects of RnttzudJn wrpcvttina. When injwt,ed parenterally in nuimals, reserpine, the active alkaloid of l~a~~~~(~l~~~, products a wnt ral de- pressmu of sympathetic \~usocollu~i.ict.or re- flexes. When given orally in man: it is doubtful that the drug reduces basal blood pressure. It. appears mow likely 1 hat, following I~auwolfia, thrb pstient becomes It~ss emot ionalfy reactive, :md as a result t hc tratrsient elevations of blood pressure caused by ftw and apprehcwsio~~ be- come less fryuel~t :uld .sewrt". Since these elwnt ions often occur as t hc result of subcon- srious or conscious fears associated with bhe visit to thr doctor's oftiw, I~:~I~~~-(~lfi~~ n-ray givci a false overestimation of ant ihypertc~lwivr! po- tency wheu c~\~aluatetl uudcr swh cwltlif ions. When evnluat rd uudrr more critical cwltlit ions, not ably in hospit alizcd patients, t htt drug in customary dos:~ge has litt-le if :urg ant ihyper- tensiw: cffrrt on busal blood pressure. The considwat ioils of Rauwoltia are 11ot meant to imply that thr drug :uitl its actjive alkaloid reserpinc hnvth no place in t hta twat- mcnt of hypertensive patients. By I he pawn- teral route itt dosages of 2 to 3 mg., rewrpine is an active ant ihypertensive drug. 12~ the oral route in far sm:Gr dosages, it map be a weful adjunct, in the total management of the pa- tient. l'sychic factors arc important,; certain emotions, particularly fear (but, probably not, anger unassociat,ed with fear) and anxiety, tend to oppose the antihypertensive effectiveness of most blood pressure-reducing drugs. Itraerpine is a particularly useful sedative in such patients. It should be mentioned, however, that the drug also is potentially harmful, since serious and long-lasting mcnt al depressions as well as ot he1 disturbing side effects call occur following prolonged use. Therefore, it is safer to admin- ister other sedative drugs, such as the bnrbit- urat es or meprobamatc:, whenever these will provide the desired psychic effects. In regard to the so-called nonsedative, aut ihypertensive al- kaloids of Rauwolfia, such as res~imlamine, when given orally in the advised dosages, this author has merely found a placebo-like action. The 17~ratncrn al/iaioicl's stimulate still an- other type of hemodynamic reaction pattern used by the body for survival. This occurs whw1 blood loss poses limitations for violent, activity or when fear and other forms of psychic shock become overwhehning in the face of a ehallelige which cannot be met, either by de- fense or flight. In this situation, a sudden vasodilation occurs with a rnarkcd fall of blood pressure, the heart rate slows and the pulse becomes almost] imperceptible; a deathly pallor ensues and consciousness is lost as the individ- ual falls to the ground in a faint. This reaction is a promitreni protective device of cold-blooded animals who affect all the appearances of death when caught, ilr a position that, permits no successful escape. In man, the residual of this reaction is called vagovagal syncope. The efferent arm of the reflex response as mentioned above trawls out over the vagus nerve to produce bradycardia and over un- kuown pathivays to produce peripheral vasodi- lation. The afferent arm may originate as fol- lows: in the cortex under the impact of some intense emotional shock, in the carotid sinus or in afferent vagal nerve endings distributed to t)he lungs and myocardium. The Verat.rum alkaloids stimulate t hew afferent) nerve endings and so init iate a reflex uasodilat ion and brady- cardia. Syncope, however, rarely occurs, but, nausea and vomiting, due to stimulation of t,hc emetic center, is common. Thus, the drug does not entirely reproduce the pict urc of \ragovag:d syncope. Of all known antihypertensi\,c agcallts, the hemodynumic responses produced by the \`er- atrum alkaloids are t hr most physiologic. The cardiac out put, remains utlchnngcd while the total peripheral resista1w fnll~.~ Blood flowing lo \-arious body areas may flwtuate initially but' soon reverts to the pretreat melit Iv\-(11. There is no interference with postural :uld othw homeostatic r&:x adjust mrljts. IYnfor( unatc~ly, Veratrum has bwn less sat isfactory t ban other agents in long-term therapy for the fol- lowing reasons: (I) a narrow spread lwtwcw the hypotcnsivc :uld the cmctic~ dose and (2) t hc dwelopement of tolrrallcc to thr alltihyprr- tensivc rffwt. Considerable progress has bwn made in t hcl control of hypertension during the past 10 years and further advances arc to be expected in 1 he fut we. Careful study of the mwhanisms by which blood pressure can be reduced may continue to shed more light 011 the hypertrnsi\.e process. 1. I~YROM. F. 13.: The pathogrnesis of lrypertcnsivc enreph:tlopathy and its relation to the malign:~nt phase of hyl)ertension. I~:uwet 2: 201, 1954. 2. FOLKOW, H. : IIlt l'LLV~~C11~:1I. ,,l'l?SS,l~l? :tS :1 f:LCtOr regulating the tone of the sm:rll veswls. Acta. physiol ticandirmv. 17: 280: 1010. 3. E'REIS, P:. I)., AND I~OSS, J. <:.: The symprthrtic nervo~w system, the V:LSCII~:II. volume and t hr venolw return in relation to cnrtliov:tscrtl:tr intc- gration. Am. J. Med. "2; 175, 1057. 4. --,--, I'ARTESOPE, 15. r\., ~IIM;INS, T. F.. ~~EI.I,EI., Il. T., SPHSAP~;R. H. I%`., nrn JO~ISSON, It. I,. : The hemodynnmic effecth of hypotenrivc d~~tys in man. III. Hes:~metllollirnn. J. Clin. Invest. SP: 1285, 1053. 5. --: The treatment of h>-pcr.t rnsiorl \I ith chloro- thiazidc. Angiology. In Press. 6. --, IbPE: J. C., HIC+GINS, T. F., FINNb:RW, F. A., JH., JCIcl,l,r:y, II. T., ANI) ~`.\RTIC:NOP~:, I+:. A.: The hcmodymlmic effects of h>.potensiw drllgh in man. IV. 1-h~d~:~zi~~ophtlI:rl:tzjlrr. Circulation 8: 199, 195:s. 7. --, STaNTON, J. I~., C~-I.B~TSON, J. &`., LITTER, J., HALIWRIS, 31. H., I