Brief Review

The Role of Calcium in Genetic HypertensionKAI LAU AND BONNIE EBY

T HE importance of the calcium ion in musclecontractility and in the optimal functions ofthe cardiovascular and neurological systems

has been recognized since the time of Ringer. A hugebody of research data has been generated investigatingvarious facets of the control of blood pressure, includ-ing the role of calcium in the biochemistry and physiol-ogy of contractile proteins. Interests have been re-newed over the past decade on the role of calcium ingenetic hypertension at the molecular as well as theorgan or whole organism level. Many recent observa-tions on this subject in humans with essential hyperten-sion and in the rat model of spontaneous hypertensionare of potential scientific and clinical interest. Thisreview is an attempt to critically analyze the pertinentavailable data with the following objectives in mind:

1. To present the evidence for and against the role of calciumdeficiency in genetic hypertension

2. To integrate the information on this subject under a workinghypothesis

3. T& define the important issues that need to be resolved4. To suggest some areas and approaches of research that may

fill in the gaps of our knowledge of the potential role ofcalcium in the pathogenesis of genetic hypertension

Evidence of Calcium Deficiency inGenetic Hypertension

Recent clinical1"14 and animal studies15"26 suggest arole of calcium deficiency in genetic hypertension. Asthe following list shows, the data can be grouped intosix categories, which will be reviewed and discussed:

I. Hypercalciuriaa. Hypertensive subjects1"3

b. Spontaneously hypertensive rats (SHR)15-24- 26

From the Division of Ncphrology. Department of Medicine, MichaelReese Hospital and Medical Center, and the Pntzker School of Medi-cine, University of Chicago, Chicago, Illinois.

Address for reprints: Kai Lau, M.D., Division of Nephrology, Mi-chael Reese Hospital and Medical Center, Lake Shore Drive at 31stStreet, Chicago, Illinois 60616.

Supported in part by National Institutes of Health Grant RO1AM33507 and by American Heart Association Grant 841296 during Dr.Lau's tenure as the recipient of an NIH RCDA #KO4 AM01255.

2. Reduced serum ionized calcium levelsa. Hypertensive subjects4-27

b. SHR15"18

3. Increased serum parathyroid hormone (PTH) levelsa. Hypertensive subjects'-3

b. SHR1518

4. Decreased intestinal calcium absorptiona. SHR19

5. Low calcium intake associated with higher blood pressurea. Humans5""b. Animals20"23

6. Oral calcium loading associated with reduced blood pressurea. Humans12"14

b. SHR and other animal models15- v~1(>

The presumed evidence falls into two broader cate-gories: calcium deficiency and the inverse relationshipbetween calcium intake and blood pressure; however,a cause and effect relationship cannot be establishedfrom inferences using indirect and often imprecise in-dices of calcium balance'"3-15~19 or from the mere asso-ciation between reduced calcium intake (based on dietrecall) and higher blood pressure.5"" For example, in astudy that directly measured external calcium balance,the adult SHR were found to retain more calcium thantheir normotensive controls, the Wistar-Kyoto rats(WKY).26 Because many confounding variables arenot excluded in epidemiological studies, interpretationis difficult, as is exemplified by analyses of the firstNational Health and Nutrition Examination Survey(1971-1973) data by two independent groups of inves-tigators,8-28 which drew different conclusions.

Hypercalciuria

Hypercalciuria has been demonstrated in humanswith essential hypertension1"3 and in adult SHR, ascompared with their controls, the WKY.15-24-26 Not allforms of hypercalciuria are indicative of a calciumdeficiency. In these studies, the role of hypercalce-mia,2 the nonfasted status,1 and the higher sodiumintake present only in hypertensive subjects3-N werenever excluded as possible causes or contributing fac-tors. At least in the SHR, the hypercalciuria was foundto be absorptive and entirely dependent on food orcalcium intake. When standard clearance techniques

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were used, no detectable renal calcium leak could bedemonstrated after an overnight fast either in the para-thyroid intact state or after parathyroidectomy.26 Had itnot been for the reduced sodium excretion rate, thelower calcium clearance rate in the SHR would implyenhanced renal calcium reabsorption, not tubular wast-age. Furthermore, when directly measured, calciumbalance and skeletal calcium deposits were found to beincreased in the SHR.26

Reduced Serum Ionized Calcium LevelsSerum ionized calcium levels have been found to be

reduced in hypertensive subjects4-27 and SHR.5"18 It isunclear if these data truly reflect total body calciumeconomy because these studies did not exclude the roleof respiratory alkalosis,4-15~18-27 fasting versus feed-ing,16"18 and differences in extracellular fluid volumestatus.4' IJ~18-" For example, while total serum calciumconcentration was not different from that in controls,serum phosphorus levels were reduced in the hyperten-sive patients, which is consistent with the interpreta-tion of acute hyperventilation. The role of feeding isbest illustrated by the increased serum ionized calciumlevels found in the SHR when they were bled at mid-night,26 shortly after a heavy calcium intake, since therats are nocturnal animals.

Increased Serum Parathyroid Hormone LevelsSerum immunoreactive PTH levels have been re-

ported to be increased in hypertensive subjects'-3 andrats,13- " but the specificity and reliability of these find-ings referable to calcium homeostasis will remain un-certain unless and until the role of volume expansionand the status of magnesium balance are also defined.For example, when 24-hour urinary cyclic AMP excre-tion was evaluated, the SHR actually had decreasedrates of excretion.26 In general, the literature is repletewith observations in which ionized calcium and PTHlevels could not be used to accurately predict calciumbalance. Despite calcium deficits from increased re-sorption, increased serum ionized calcium and de-creased PTH concentrations generally are seen, forexample, in PO4 depletion30-31 and immobilization.32

Decreased Intestinal Calcium AbsorptionDecreased calcium absorption was recently de-

scribed, based on recirculation perfusion studiesacross small intestinal segments of the anesthetizedSHR or on experiments using isolated, everted duode-nal sacs.19 Extrapolated to the entire intestine, theseresults would predict calcium malabsorption but clear-ly do not prove the presence of calcium deficiency.Conversely, virtually opposite results have been re-ported using essentially the same two techniques.33

This gross discrepancy in results has remained unex-plained. Furthermore, in the natural, conscious phys-iological state, overall net calcium absorption alongthe entire intestine, as determined by balance studies26

or by the excretion of orally administered ^Ca,34 hasbeen found to be increased in the SHR. In situ duode-

nal 43Ca uptake in conscious SHR was also found to begreater than that found in the control WKY.26 The bulkof the experimental findings is therefore incompatiblewith the notion of calcium malabsorption in the SHR.In the prehypertensive SHR, a similar hyperabsorp-tive phenomenon has been suggested by preliminarystudies.33

Low Calcium Intake and Higher Blood PressureSeveral laboratories have noted higher blood pres-

sure in normotensive20"22 and hypertensive rats23 duringlong-term dietary calcium deprivation. There are,however, problems with the interpretation of thesedata. In addition to the obvious inference that calciumdeficiency may lead to hypertension, there are otherunexcluded factors, such as marked weight loss,growth retardation, severe secondary hyperparathy-roidism, and magnesium depletion, which invariablyaccompanied long-term calcium deficiency. The PTHand magnesium depletion are well-known variables ofvascular resistance and systemic blood pressure.3*~41

Indeed, preliminary observations with mild calciumrestriction within the physiological range failed toshow an elevation in blood pressure despite 50% re-duction in calcium balance as long as normal growthwas maintained.33

Oral Calcium Loading and Reduced Blood PressureThe sixth line of evidence is the association ob-

served by several epidemiological surveys between re-duced intake of dairy products and higher blood pres-sure, though the latter was generally within the normalrange.7"" All these studies are open to the followingcriticisms. First, the method of dietary recall by ques-tionnaires is obviously fraught with problems of accu-racy and reliability. Second, factors that influencepreference or avoidance of dairy products may inde-pendently affect blood pressure. Conceivably, the con-scious reduction in milk and cheese consumption, forexample, was the consequence of obesity, which waspresent in one study10 and which is known to be corre-lated with higher blood pressure. Third, differences inother nutrients and ions like potassium10 could not beeliminated in these population studies, which couldaffect blood pressure independently of calcium. It iswell known that potassium supplement is natriureticand antihypertensive42-43 and that potassium deficiencyhas the"opposite effects.44

Fourth, "soft" water is not necessarily lower in cal-cium alone. If magnesium and potassium were similar-ly affected, a relative deficiency of these other ions isjust as likely to contribute to the higher blood pres-sure38-39 as is calcium deficiency.5-6 Fifth, and mostcrucial of all, epidemiological surveys can at best es-tablish an association. Even if the other reservationscould be removed, a causal role has yet to be proven.

Finally, and perhaps theoretically the strongest sup-port for the postulate of calcium deficiency in genetichypertension, oral calcium loading has been found tobe associated with a decline in blood pressure in hu-

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mans2"14 and animals.1523"26 Long-term administrationof a diet containing threefold to 10-fold the normalamount of calcium was accompanied by a slight butsignificant reduction in blood pressure as comparedwith that in controls that were matched for age, sex,strain, and species. 12"l3iB"26i43t46 Doubts were raised,however, by the findings that long-term intraperitonealcalcium injections, which achieved a comparable mag-nitude of hypercalcemia, could not reproduce theseresults.26

Perhaps more importantly, when the reduction inPO4 balance that accompanied oral calcium loadingwas prevented, the antihypertensive effect was alsoabolished,47 which suggests that reduced PO4 balancerather than increased calcium balance is the mediator.Direct and unequivocal effects of PO4 deficiency onvascular resistance have recently received additionalsupport.4* Nonetheless, preliminary clinical trials sug-gested an overall 6.5 mm Hg fall in standing systolicblood pressure in about 30 hypertensive patients treat-ed for 8 weeks with 1 g of calcium supplement, whichis arguably a nonpharmacological dose.1449 Even ifthese effects proved to be statistically significant andextended to diastolic blood pressure, whether they aremediated by the mechanism of augmenting calciumbalance would remain an issue. Actually, a small andinitial natriuresis would have been missed without se-rial sodium balance data in the early phase of calciumsupplementation, as was observed during the firstweek of instituting dietary calcium supplement.26 Inaddition, a small reduction in PO4 balance would notbe detectable by merely measuring outpatient serumand urine PO4 at 2- to 4-week intervals, unless PO4

intake and output (in the stool and urine) were quanti-fied. Conceivably, long-term changes in PTH levelsmay produce effects on blood pressure that are verydifferent from that of the acute vasodilation and hypo-tension.50

It should be noted that preliminary findings suggestthat other maneuvers that increased calcium balancewithout reducing PO4 balance, as was produced by theadministration of 1,25 dihydroxy-vitamin D3

51 or mag-nesium supplements,52 failed to attenuate the severityof hypertension in the SHR or reduce the blood pres-sure in the WKY rats.35 Initial trials in hypertensivesubjects also failed to document any antihypertensiveeffects with 1,25 dihydroxy-vitamin D3 administra-tion."

Taken together, the available clinical and experi-mental data do not at present justify the conclusion thatgenetic hypertension is characterized by deficits in cal-cium. Until this conclusion is firmly established, itwould be premature, in our opinion, to base therapeu-tic decisions on such incomplete and equivocal find-ings. Furthermore, an equally impressive if not moresolid body of evidence has been accumulated, whichoffers a cogent argument for the role of calcium excessin the genesis or the maintenance (or both) of thehypertensive state, and will be summarized in the suc-ceeding pages.

Evidence of the Calcium Excess in HypertensionObservations implicating a role of calcium excess in

hypertension can be divided into the following sixcategories:1. Vasoconstrictive and hypertensive effects of acute hypercal-

cemia have been produced by calcium injections.40-54"56

2. Chronic hypercalcemia from vitamin D overdose or hyper-parathyroidism, or both, has been associated with hyperten-sion.2' 37'40-41

3. Decreased contractility of vascular smooth muscle by cal-cium-channel antagonists and other vasodilators has beenassociated with reduced cytoplasmic free calcium or with45Ca fluxes predictive of such a reduction.57"67

4. Increased cytosolic free calcium has been observed in theplatelets of hypertensive men and lymphocytes of SHR.68 'w

5. Increased intracellular calcium content of adipocytes hasbeen found in hypertensive patients and SHR.70"72

6. Increased calcium balance has been found in SHR.26'34'35

Vasoconstrictive and Hypertensive Effects ofAcute Hypercalcemia

Current concepts suggest that the final commonpathway for the control of vascular reactivity and, ulti-mately, peripheral vascular resistance lies at the levelof the vascular smooth muscle cell.73"79 Contraction ofthe smooth muscle cell depends on the interaction,attachment, and cycling of cross bridges between theactin and myosin filaments, the contractile proteins.The mechanical process is therefore initiated by a risein cytosolic free calcium concentration.73"79 Thus, re-gardless of the precise pathogenetic factors mediatingthe hypertension, be they neural, humoral, cardiac,metabolic, myogenic, or any combination thereof, acommon denominator at the cellular level is an alter-ation in free calcium concentration in the musclecells.56-74"79

Increases in extracellular fluid calcium concentra-tion (e.g., acute hypercalcemia as produced by intra-venous calcium administration) have been found onnumerous occasions to be associated with systemichypertension and increased peripheral vascular resis-tance,40- M-55 which is consistent with the prediction bythe current concepts. These vasoconstrictive effectscan be attributed to increased contractility of vascularsmooth muscle in response to presumably elevatedcytoplasmic calcium concentrations.73- 74- 77-79 Indi-rect8**-85 j , ^ direct 45£a flux measurements57"64 inresponse to high potassium depolarization,57-80-8I nor-epinephrine stimulation,54'8a 8I•M-85 and their blockageby lanthanum82"85 or calcium channel antago-nists57"64- " • u - " have firmly established the roleof increased cytosolic free calcium in mediatingthe excitation-contraction coupling of myocytes inisolated venous or intact vascular beds, regardlessof whether the increment is derived from extra-cellular60- 62'63- "•80-M or intracellular calciumpools_6i.M, 63,78. si, g*. 8«-9o j n contrast, many vasodila-

tory and antihypertensive agents were found to exerttheir effects by interference with the calcium-depen-dent mechanisms or by a reduction in cytoplasmic ion-ic calcium concentration.9192

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Chronic HypercalcemiaThe clinical literature is also replete with instances

of hypertension in sustained hypercalcemic states,caused by vitamin D overdose or hyperparathyroid-ism.37-40 4I A positive correlation between serum cal-cium levels and systolic, as well'as diastolic, bloodpressure was also recently reported in a large seriesinvolving Belgian army recruits.2

Decreased Contractility of Vascular Smooth MuscleDecreased contractility of vascular smooth muscle

in response to a variety of vasodilatory and antihyper-tensive agents, such as adenosine,65 92 /3-adrenergicblocking agents,92 hydralazine90 and calcium channelantagonists,57"63-" generally is associated with a reduc-tion in cytoplasmic free calcium, if measured direct-ly65-66 or with alterations in 45Ca fluxes that wouldpredict such a reduction. On the other hand, the in-creased vascular reactivity observed in SHR,67- 93~% hasbeen attributed to the membrane leakiness to calcium,similar to that for sodium, potassium, and chlo-ride,97 •98 although, as will be discussed, the evidencefor defective membrane calcium regulation is largelyindirect.

Increased Cytosolic Free CalciumMeasurements of peripheral blood elements such as

platelets in hypertensive patients68 and lymphocytes inSHR,69 using fluorescence signals of quin 2, a calciumchelating dye, have also revealed increased intracellu-lar free calcium concentration. More importantly, pa-tients with borderline hypertension were found to havemildly elevated calcium levels, which were intermedi-ate in value between the normotensive and the franklyhypertensive subjects.68 Furthermore, long-term treat-ment of the hypertension with thiazide diuretics and (3-adrenergic blocking agents was found to restore thecytosolic free calcium to normal.68 These investigatorsalso obtained a significant correlation between bloodpressure and platelet intracellular calcium concentra-tion. These results confirmed but extended the ob-served association between reduced force generationby adenosine in ferret portal vein strips and the reducedcytoplasmic free calcium concentration, as determinedby aqueorin, a bioluminescent protein.65 They also cor-roborated the calcium flux data across coronary arter-ies in adenosine-treated dogs67 and reinforced the re-sults of calcium uptake in adenosine-treated intact andcultured vascular smooth muscle cells.66

Increased Intracellular Calcium Content of AdipocytesKinetic studies using 45Ca fluxes suggested that the

two slowly exchanging intracellular calcium pools inadipocytes are enlarged in SHR,70 regardless of wheth-er the animals had previously been adrenalectomized71

or rendered normotensive by peripheral immunosym-pafhectomy.70 Similar results have also been reportedin the adipose tissue of hypertensive patients by thislaboratory.72 These findings are further indications thatthe derangements in calcium metabolism in genetichypertension tend to be characterized by intracellular

calcium excess rather than deficiency. Since the SHRsubjected to sympathectomy had maintained normalblood pressure from the fourth through the ninth week(the time of study), the increased intracellular calciumpools were unlikely to be the consequence of hyperten-sion. In this connection, the persistence of the hyper-calciuria in hydralazine-treated adult SHR reinforcedthe concept that disturbances in calcium metabolism ingenetic hypertension are not secondary to untreatedhypertension.26

Increased Calcium BalanceAs was mentioned earlier, when complete external

calcium balance was measured directly, the adult SHRwere found to retain more calcium than were the con-trol WKY.26 This finding was true for both sexes andclearly attributable to intestinal hyperabsorption of cal-cium.26 Skeletal calcium accumulation was also in-creased in the hypertensive animal.26 Preliminary stud-ies in 3'/2-week-old normotensive SHR also revealedsimilar balance results,35 which indicates that thesechanges precede the onset of hypertension and thatthey may conceivably play a role in the subsequentelevation of blood pressure. Absorption of45Ca in theconscious intact animal, as measured by urinary recov-ery, was also increased in the SHR34 which supportsour group's findings.35

Calcium deposition in bone has also been shown tobe higher in SHR,26 as have the calcium contents in thetail artery99 and aorta of hypertensive rats.100-l01 Thus,the weight of the presently available evidence on theissue of disturbances in calcium metabolism favors theview that intracellular calcium is abnormally elevatedin the hypertensive state, at least in tissues studied thusfar. At least three possible and not necessarily mutual-ly exclusive explanations may partly reconcile the ap-parent paradox between parenteral and oral calciumloading, on the one hand, and the conflicting resultsobtained using different indices of calcium balance andmetabolism, on the other hand: 1) generalized mem-brane defects in calcium regulation, 2) role of PTH,and 3) membrane stabilizing effect of high calciumlevels.

Membrane Defects in Calcium RegulationThe observations of reduced serum ionized calcium

and elevated PTH levels by some though not all inves-tigators are not necessarily incompatible with intracel-lular calcium excess if one accepts the hypothesis of amembrane defect in calcium regulation in genetic hy-pertension. In the most simplistic scheme, too muchcalcium is distributed inside the cytosol as free ioniccalcium owing to a combination of increased leakinessacross the plasma membrane, decreased effectivenessof the extrusion mechanism(s) (or incomplete compen-sation by the calcium-dependent ATPase), reduced ca-pacity for buffering cytosolic calcium, or increasedcalcium release by intracellular organelles, such as themitochondria, endoplasmic reticulum, or sarcoplasmicreticulum. This hypothesis does not address or dependon the issue of whether the derangements in calcium

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transport are causes for or effects of the hypertension,if they are related at all. Emerging evidence tends toargue against the second possibility, however, sincemany of these changes predate the onset of hyperten-sion.26' "• 70The direct observations consistent with thismembrane hypothesis are tabulated in the followinglist and will be briefly summarized.

1. Duodenal epithelium: increased calcium absorption2633"35

2. Renal epithelium: increased calcium reabsorption26-33-102

3. Lymphocytes of SHR and platelets of men with essentialhypertension: increased cytosolic free calcium6869

4. Red blood cellsa. Increased passive influx and permeability103

b. Decreased ATP-dependent calcium extrusion103

c. Decreased 45Ca binding to inner membrane103- 104

5. Adipocytesa. Decreased endoplasmic reticular 45Ca uptake105

b. Increased mitochondrial 45Ca uptake105

c. Increased intracellular fluid calcium pool70"72

6. Arteriesa. Increased 45Ca uptake (aortic strip)101

b. Increased calcium accumulation in tail artery and aor-ta99- 101

7. Vascular smooth musclea. Decreased microsomal 45Ca uptake101- 105~107

b. Increased sarcolcmmal 45Ca influx108- l09

c. Decreased binding of 45Ca to inner membrane110- ' "d. Increased calcium-dependent ATPase in microsome107

8. Cardiac myocytea. Decreased sarcoplasmic reticulum 45Ca uptake1"b. Decreased microsomal 45Ca uptake106

Despite conflicting data,19 duodenal calcium trans-port in situ26 and in vitro33 has been found to be in-creased, which corroborates the net calcium absorp-tion results reported by balance studies.26-34 Tubularcalcium reabsorption was found to be increased,26 adifference that recently was demonstrated to be inde-pendent of PTH levels, changes in ultrafilterable cal-cium levels, and sodium and calcium excretionrates.34-102 Cytosolic free Ca calcium has been shownto be increased in platelets of hypertensive men68 andlymphocytes of SHR,69 as previously mentioned.

Disturbances in calcium fluxes and permeabilityhave been reported in a variety of plasma membranesof the SHR, including erythrocytes, adipocytes, andmyocytes. For instance, passive influx of 45Ca acrossATP-depleted erythrocytes was found to be abnormal-ly increased as early as 3 weeks of age in SHR.'03

Decreases in ATP-dependent calcium extrusion, asreflected by lanthanum-sensitive, calcium-dependentATP hydrolysis, also was observed, which is consis-tent with reduced calcium pump activity.l03 Binding of45Ca to inner surface of plasma membrane was reducedin erythrocytes of SHR103 and hypertensive subjects.104

Together, these data suggest that if there were nocounter-regulatory mechanisms, cytosolic calcium inthese tissues ought to be increased in genetic hyperten-sion, as was found in platelets68 and lymphocytes,69

which, as far as we know, are the only tissues directlystudied thus far.

As previously mentioned, the intracellular calcium

pool in adipocytes of SHR and hypertensive man hasbeen found to be enlarged70"72 and was associated withreduced endoplasmic reticulum 45Ca uptake.105 Totalcalcium content was found to be increased in the tailarteries and aorta of hypertensive rats,99-l01 and short-term flux studies also demonstrated an increased rateof 45Ca uptake, which was presumably caused by in-creased passive leakage.101 In vascular smooth musclemembrane vesicles preparations, similar decreases in45Ca uptake by the microsomal fraction101-105-107 and bythe inner surface of plasma membrane110-'" have beendocumented in the SHR and have been associated withincreased influx across the sarcolemma.108-109 The lat-ter could also be substantiated in 3-week-old SHR be-fore any demonstrable hypertension was apparent.108

Decreases in 45Ca uptake by sarcoplasmic reticu-lum1" and by the microsomes106 have been reported inthe cardiac muscle cells of the SHR. One, though notthe only, inference of these findings is decreased se-questration of calcium by' intracellular buffers and,presumably, a consequent increase in cytosolic cal-cium. To the best of our knowledge, direct measure-ments in the vascular smooth or cardiac muscle withcardiac-selective microelectrodes orquin 2, or both, tocompare the SHR and normotensive control have notbeen published. If confirmed, these changes clearlycould provide a cellular basis for increased musclecontractility, vascular reactivity, and resistance ulti-mately leading to systemic hypertension.

While the present state of our knowledge is frag-mentary and at times conflicting or even confusing,there appears to be a consensus that fundamental de-fects exist in calcium homeostasis in the SHR and,probably, in human essential hypertension. The basicabnormalities have yet to be defined, and a lot moreinformation is needed at the cellular and organ levelbefore one can objectively and adequately address thecontroversial issue of calcium supplementation in es-sential hypertension, its scientific rationale, if any, andits potential therapeutic benefits.

Role of Parathyroid Hormone in HypertensionThe second possible explanation for the apparent

paradox in the effects on pressure between oral andparenteral calcium loading is the role of changes inPTH levels, as the following list briefly enumerates.

I. Excess PTHa. Primary hyperparathyroidism is often associated with hy-pertension in humans that resolved following surgical re-

pairs3 7 . 4 0 . 4 1 . 112

b. Long-term PTH administration has been shown to in-crease arterial blood pressure in humans and rats."3- " 4

2. Parathyroidectomy was found to attenuate hypertension,which reappeared following parathyroid gland autotrans-plantation.3*- 115-"8

3. PTH has been shown to act as an endogenous calcium iono-phore across vascular and other tissues."5- n9"123

It should be quickly stated that the effects of short-term5o..i4. i24-,27 a n d iong. term PTH" 3 " 4 administra-tion are probably very different. In the short term, PTHor its biologically active fragments have been found to

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produce a marked but transient vasodilation, and thehypotensive effects last only a few minutes.50-"4- 124~127

Much as the biochemical mechanism is poorly de-fined, the physiological relevance of this short-livedeffect in the clinical setting is obscure. In contrast,long-term administration of PTH to humans"3 andrats"4 was reportedly associated with sustained hyper-tension. This finding constitutes the first line of evi-dence suggesting that PTH plays a role in hyperten-sion. In these situations, relative hypercalcemia wasinvariably present. Therefore, the separate effects ofexcess PTH and elevated serum calcium concentrationcould not be differentiated, as was often the casewith primary hyperparathyroidism in clinical set-t ings. 3 7 4 0 4 1" 2 Primary hyperparathyroidism, occur-ring either in nature or in experiments, cannot beequated to a mere increase in serum PTH and serumcalcium, since many other metabolic derangements areknown to coexist, including changes in metabolism ofcalcium, PO4, magnesium, and vitamin D. Neverthe-less, it is generally true that the combination of PTHexcess and hypercalcemia is accompanied by hyper-tension. Resolution of the hypertension has indeedbeen reported following surgical parathyroidectomy,although the precise mechanism was not defined inthese clinical cases.3740

Parathyroidectomy has been found to attenuate themagnitude of hypertension in S H R 3 6 " 5 " 8 and indeoxycorticosterone acetate-salt treated ra t s . " 6 " 7

However, the role of the concomitant hypocalcemia,as a result of the long-term absence of PTH,3*-"5""7 orthat of oral calcium loading"8 could not be dissociated.In the rats, retarded growth invariably follows para-thyroidectomy,36 which per se could modify the hyper-tension. Nevertheless, the combination of PTH defi-ciency and hypocalcemia appears to be frequentlyassociated with hypotension, which is the oppositepicture of the pressure and biochemical changes seenin primary hyperparathyroidism and discussed above.When the parathyroid gland was autotransplanted backto the SHR that had undergone parathyroidectomy,elevated systolic blood pressure indeed reappeared.36

In a variety of tissues, including rat aorta,"9 cardiaccells,"9 erythrocytes,120 and renal tubular cells,121 m

intracellular calcium uptake by isotopic or quin 2 tech-niques has been found to be elevated by PTH, as if thehormone acted as a natural or endogenous calciumionophore123 with calcium and cyclic AMP serving asthe two intracellular secondary messengers. If a short-term rise in cytoplasmic calcium is the ultimate triggerto initiate contraction,56-73~76-78-94 then the increasedinflux of calcium facilitated by PTH should enhancevascular tone and reactivity, which would increaseresistance and blood pressure.

The accentuation by long-term PTH administrationof the hypertension induced by deoxycorticosteroneacetate and salt administration,"4 the blunted vascularreactivity,"7 and the reduced calcium content afterparathyroidectomy"5 are all consistent with thehypothesis that PTH exerts an ionophoretic and there-fore a permissive effect on the vasoconstrictive and

hypertensive action of extracellular fluid calcium.123

According to this postulate, increased calcium entryalone ought to enhance smooth muscle contractilityand increase the blood pressure; PTH facilitates cal-cium influx and potentiates the effect of hypercalcemiaas in clinical and experimental hyperparathyroidism.The absence of PTH, coupled with hypocalcemia,would produce the opposite effects. When endogenousPTH is suppressed by oral calcium loading, two oppos-ing effects are at play; functional hypoparathyroidismtends to diminish and mild hypercalcemia tends toenhance muscle contractility. According to this pos-tulate, the net effect favors an attenuated vascular reac-tivity, expressed as a reduction in blood pressure, aswas found in many clinical12"14 and animal stud-ies.15-23"26 This concept is further supported by thehypotensive effect of oral magnesium loading (0.96%vs the normal 0.21% magnesium diet), which is simi-lar to that of calcium loading in deoxycorticosteroneacetate hypertension.36 It must be emphasized that notall studies evaluating the effects of magnesium loadingproduced these findings,38-128 and even if confirmed,the mechanism may lie in membrane competitionbetween calcium and magnesium," rather than PTHsuppression.

On the other hand, acute hypercalcemia resultingfrom intravenous calcium infusion elevates systemicarterial blood pressure, presumably because the netbalance of the two opposite actions is tilted in favor ofhypercalcemia. Although much of the published litera-ture could be accommodated by this interpretation, notevery piece of conflicting data could be so resolved.For example, it remains to be explained why in para-thyroidectomized SHR, an antihypertensive effect oforal calcium loading was still evident, when comparedwith identically treated rats fed a normal calciumdiet.47 Furthermore, this hypothesis would not explainthe absence of a blood pressure difference betweenintact and parathyroidectomized rats fed the same nor-mal calcium diet" or the lack of a hypotensive effectwith magnesium supplementation in intact SHR thatdemonstrated augmented calcium absorption and cal-cium balance.35 Clearly, if PTH modulates the rate oftransmembrane calcium fluxes and if the final signal tovascular smooth muscle contraction is a transient risein cytosolic free calcium, this hypothesis can only betested directly by applying a calcium-selective micro-electrode to accessible vascular tissues. Alternatively,changes in PO4 balance and extracellular fluid volumestatus may indeed play a role in the antihypertensiveeffects of oral calcium loading. The role of alterationsof PO4, sodium, and possibly magnesium balance mustbe specifically and appropriately evaluated in futureclinical and animal trials to study the mechanismwhereby oral calcium supplements, unique among allattempted maneuvers that promote greater calcium re-tention, produce an antihypertensive effect.

Dual Effects of CalciumThe third possibility that could resolve much of the

existing controversy is the concept that the calcium ion

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exerts more than one biochemical effect on vascularreactivity. For example, more than 2 decades agoBohr5* suggested that the "membrane excitation" ofrabbit aorta, corresponding to the fast component ofcontractile responses to epinephrine, may actually bereduced by a medium high in calcium (>3 mM),whereas the "coupling" process, corresponding to theslow component of the force development, is depen-dent on an optimal concentration of calcium in themedium (around 1.0 mM). Bohr termed the reductionin force development the membrane stabilization ef-fect of calcium. The thesis gained further support insubsequent experiments by Webb and Bohr,77-*• whichcompared the relaxing effects of calcium and potas-sium in helical strips of rat tail artery after norepineph-rine stimulation. The membrane stabilization effects ofthese two ions were attenuated by ouabain, reducedtemperature, and media low in sodium and potassiumconcentrations, which is consistent with either stimu-lation of the Na, K-ATPase or reduction in ion conduc-tance. In this context, it is conceivable that calciumsupplementation may exert a similar membrane stabili-zation effect.

These results must be interpreted with caution, how-ever, since these levels of hypercalcemia (3-20 mM ofionized calcium) are rarely experienced in pathophys-iological conditions that are compatible with life. Infact, in a medium with a calcium level below 4.0 mM,contraction was directly related to calcium concentra-tions.77 In the original experiments, within the first 10minutes of withdrawing calcium from the bathing solu-tion, the fast component of the force contractile re-sponse was reduced before it registered a 15% in-crease.5* In addition, the vascular strip preparation hadto be previously stimulated by epinephrine5* or norepi-nephrine.77 Finally, the calcium concentration in themedium was always increased in stepwise fashion, sothat without an appropriate time control lasting a fullhour between two maneuvers, it is not clear whetherthe reduced contraction observed was necessarily as-sociated with the further increment in calcium concen-tration.

All these reservations must be borne in mind whenextrapolating their results to the interpretation of dataconcerning the role of calcium in hypertension. Al-though potentially interesting, it is uncertain that theseexperiments are clinically relevant when other manip-ulations achieving similar degrees of hypercalcemiafailed to reduce the blood pressure. Again, intracellu-lar free calcium measurement in response to all thesemaneuvers would be invaluable to assess this theoreti-cal explanation.

ConclusionsMore research clearly is needed to define the direc-

tion and nature of disturbances in calcium metabolismin genetic hypertension. Based on analyses of theavailable literature, we favor the view that cytosolicfree calcium concentrations are abnormally increased,regardless of what extracellular fluid biochemical indi-ces would suggest. The underlying mechanism is not

defined but, hypothetically, is most likely related to ageneralized defect in membrane calcium regulation105

that is genetically transmitted rather than acquired as aconsequence of the hypertension. The precise relation,if any, of altered membrane permeabilities to otherions,129 in particular sodium,130"135 is not clear.

As shown in Figure 1, a plausible working hy-pothesis could integrate the concepts of Dahl,133 deWardener and MacGregor,134 Bianchi and co-work-erS)i36-iw Blaustein and Hamlyn,130 and oth-ers.120135139140 This model suggests that, in genetichypertension, the renal tubule is abnormally sodiumretentive before the onset of hypertension,136"140 whichexpands the intrathoracic blood volume134 and ulti-mately increases cellular sodium content.131 If thispathophysiological sequence of events is proved cor-rect, then circulating inhibitors for Na, K-ATPasewould be increased and sodium transport would bereduced.130-'34'35 The sodium pump inhibition maypartially offset the intrinsic renal defect in sodium re-tention, but across a variety of vascular tissues, intra-cellular sodium content would increase, norepineph-rine release would be enhanced while reuptake wouldbe reduced.130 An additional cellular mechanism in-volves the reduced transcellular sodium gradient(caused by increased cytosolic sodium) and a reducedcalcium extrusion by the Na-Ca exchange mechanism.Such a formulation would provide a theoretical basisfor some of the intracellular and membrane calciumabnormalities in SHR. Presently, however, the exis-tence and the role of this exchange mechanism in vas-cular smooth muscle cell are poorly documented141"144

and have been seriously questioned.78-98

Dvfeotfre mernpfana

|ECFvolum«T

PreeeureNatriuraete

\

\\i

i Na-Ca exchange

T CytoeotoCa1*

Other meonanlamaCardovaacutarHumoral (e 5., PTH)

NeuroQanfc

t Myocyte tone, oortrectfcy,andraactMTy

T Vaacutarnahtiiiii

t Blood preeeixe

T CatturiaA 9 * i m [ C t « ( ]A Serum PTH

FIGURE 1. A hypothetical model for genetic hypertension.ECF = extracellular fluid; ANF = atrial natriuretic factor;PTH = parathyroid hormone.

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This model is intended to accommodate the role ofmany potential and well-established factors, other thancalcium, in the pathogenesis of genetic hypertension.Clearly, the challenge to basic and clinical investiga-tors alike is a better in vitro and in vivo understandingof the chronology of, mechanisms for, and relation-ships between the abnormalities in membrane regula-tion of the various ions. To achieve this, we needstudies employing newer tools such as calcium-sensi-tive dyes, ion-selective microelectrodes, better tissueculture techniques for vascular smooth muscle cells,and more sophisticated approaches in protein bio-chemistry and molecular biology. Until additional in-formation derived from these sources is made avail-able, the role of calcium in the pathogenesis ormaintenance of hypertension will remain incompletelyunderstood.

AcknowledgmentThe authors thank Lorraine Butler for her secretarial support.

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