SystemicHypertensionin DiabetesMellitus JAMES V. FELICEllA,
MD and JAMES R. SOWERS, MD
Hypertension occurs more frequently in diabetics and markedly exacerbates the vascular morbidity and mortality resutting from this metabolic disorder. However, the etrology of hypertension In diabetics remains poorly understood. Like aging persons, dlabetics have increased systemic resistance and a
probable reduction In baroreceptor sensttivity. They also have an expanded total body sodiim pool and a tendency to lower levels of plasma renin activity. Some of these factors suggest that a subtle calcium deficiency could also be of etlologie Importance. (Am J Cardiol 1988;81:34H-40H)
he prevalence of hypertension in diabetics is increased twofold over its prevalence in the nondiabetic population. This hypertension plays a major role in potentiating the vascular morbidity and mortality that result from diabetes.l Despite this, little is really known of the underlying mechanisms that initiate and sustain hypertension in the diabetic population. Several lines of evidence, however, suggest that diabetes can be considered a model of premature aging because many of the disturbances in blood pressure regulation seen in diabetics are similar to those seen in the aged popu1ation.l There is an increased systemic resistance, as well as a probable reduction in baroreceptor sensitivity, features typical of elderly patients with hypertension.* This study reviews the available data concerning hypertension and diabetes, and explores the possible contributing etiologic role of a subtle calcium deficiency. The prevalence of hypertension is well documented to be increased in diabetics compared with nondiabetics. Krolewski et al2 studied the prevalence of hypertension in diabetics age 18 to 74 years who were followed up at the Joslin Clinic. They found that 26% of the men and 34% of the women were hypertensive, compared with 13.7 and 19.5% of age-matched nondiabetics. Two large British surveys2~3have reported a prevalence of hypertension in diabetes in the range of 40 to 5O%, even when hypertension is stringently defined as a pressure of 160/95 mm Hg. From the Departments of Medicine, Veterans Administration Medical Center, Phoenix, Arizona, and Allen Park, Michigan, University of Arizona and Wayne State University. Address for reprints: James V. Felicetta, MD, Chief, Medical Service, Veterans Administration Medical Center, 7th Street and Indian School, Phoenix, Arizona 85012. 34H
The risk of vascular disease posed by the coexistence of hypertension and diabetes is very great. Overall, the risk of cardiovascular death in diabetic persons is roughly doubled by the coexistence of hypertension.4,5 The Framingham Study also showed clearly that the coexistence of diabetes and hypertension compounds the risk for cardiovascular events.e-8 Diabetic patients with hypertension, for example, have a considerably higher frequency of transient ischemic attacks and strokes than normotensive diabetics.g-l* Hypertension also increases the risk of coronary artery disease12and peripheral arterial disease.13Although hypertension may either precede the onset of diabetes or develop during its course, the onset of renal disease is almost invariably accompanied by hypertension,14 with an accelerated decline in renal function.15v16Antihypertensive therapy has been clearly shown to be the single most important factor in retarding the progression of renal impairment in diabetes with nephropathy.17-I9 The pathophysiology of diabetic hypertension, however, remains very poorly understood. Studies to date have been quite limited in their focus, and no unifying concepts have emerged to allow a comprehensive understanding of the pathogenesis of hypertension in Type II diabetes. Aberrations in the metabolic and hemodynamic responses to dietary salt, however, are probably important in pathogenesis. Several studies have clearly shown an increase in exchangeable body sodium in diabetics, even in normotensive diabetics who are free of complications. 20-23In metabolically stable nonazotemic diabetics, exchangeable sodium is increased by an average of 10%. 22This increase occurs regardless of age, insulin dependence or independence, and the presence or absence of diabetic nephropathy. The mechanisms underlying this sodium retention are not
known, but an early renal defect or an altered distribution of extracellular fluid volume could play a role.22J3 Hyperglycemia plays a role in increasing extracellular fluid volume.ll This effect occurs because of an increased osmotic load under conditions of free accessto water. In diabetic rats, Malchoff et alz4recently reported that an increased intake of salt was secondary to the obligate polyphagia accompanying diabetes: together with a defect in salt excretion, this could lead to volume expansion. In streptozotocin-diabetic rats, Brenner’s group also recently reported that increased sodium reabsorption results from hyperglycemia-induced chronic volume expansion.25 Hyperinsulinemia, a feature of many Type II diabetics in the earlier years of the disease, also enhances renal tubular sodium absorption, which would again lead to relative volume expansion.26 However, the possible role of insulin in the etiology of diabetic hypertension is extremely poorly defined. For example, Sasaki and Bunagz7 reported that insulin therapy actually reversed hypertension in streptozotocin-diabetic rats: they claim insulin reverses hypothalamic depression, thereby correcting the enhanced sympathetic output in this model. Some recent work has suggested a possible role for hyperinsulinemia and associated insulin resistance in the pathophysiology of hypertension in diabetes. Ferrannini et a128recently reported measurements of insulin sensitivity, glucose turnover and whole-body glucose oxidation in a group of young, nonobese, nondiabetic volunteers with untreated essential hypertension. They found that during steady-state euglycemic hyperinsulinemia, achieved with an insulin clamp technique, total insulin-induced glucose uptake was markedly impaired in these subjects. Virtually all of the defect in overall glucose uptake could be attributed to reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis), suggesting a state of marked peripheral insulin resistance. The security of the insulin resistance correlated with the severity of the hypertension, suggesting an etiologic correlation between the 2. Because hypertension occurs more often with obesity, hyperinsulinemia could be a common factor in the hypertension associated with increased weight as well as the hypertension seen in many Type II diabetics. Low-plasma renin activity (PRA) may also accompany increases in total body sodium and extracellular fluid volume in diabetic humans, although a reduction in renin levels has not been consistently found.llJz PRA levels and aldosterone levels are both typically low in the presence of diabetic nephropathy.ll Christlieb et a12greported relatively normal levels of PRA in normotensive diabetics and in diabetics with hypertension but no nephropathy, although the mean renin activity in hypertensive diabetics was lower than the mean in normotensive diabetics. DeChatel et a130also reported a tendency to reduced renin levels in some, but not all, hypertensive diabetics. Christliebsl also reported suppression of PRA in the acutely diabetic alloxan-treated rat, suggesting that PRA can be low in diabetic models even in the absence of diabetic ne-
phropathy. Interestingly, some, but not all researchers believe that factors inhibiting renin secretion are associated with increased intracellular calcium levels in juxtaglomerular cells,32 consistent with a model that diabetic hypertension is associated with elevated cytosolic calcium. Katayama and Lee33 ascribed the lowrenin levels to insulin deficiency in a rat model. Alterations in resistance vessels develop early in the course of diabetes mellitus and may partly explain the exaggerated cardiovascular reactivity to pressor agents, such as angiotensin II and norepinephrine.20,22,31 A portion of the increased systemic vascular resistance characteristic of hypertension in diabetes may relate to salt-induced abnormalities in calcium transport, as discussed in greater detail later. These abnormalities in calcium transport result in increased intracellular levels of calcium and hence, greater tone in the smooth muscle cells in blood vessel walls.34 As in the elderly, these changes lead to increased peripheral resistance and a disproportionate increase in systolic, as opposed to diastolic, blood pressure. Alterations in baroreceptor sensitivity may also play a very important role in the pathogenesis of diabetic hypertension. There are 2 types of baroreceptors, the high-pressure arterial baroreceptors located in the carotid sinus and the aortic arch, and the low-pressure cardiopulmonary baroreceptors, located in the cardiac atria and the pulmonary parenchyma.35 The role of the arterial baroreceptors is to monitor blood pressure continuously and to modulate changes in pressure by central nervous system-mediated alteration in vagal tone and sympathetic tone. With an increase in arterial pressure, there should be an increase in vagal tone and a concomitant reduction in sympathetic tone, as reflected in lower spillover levels of plasma norepinephrine.36 A number of workers have already demonstrated decreased arterial baroreflex sensitivity, as measured by the change in interbeat interval per unit change in systolic pressure after injection of vasoconstrictor substances or after Valsalva, in nondiabetics with essential hypertension.37-41 Eckberg et a142recently demonstrated multiple disturbances in arterial baroreceptor sensitivity in normotensive Type I diabetics. They studied autonomic responses over a range of pharmacologically induced arterial pressure changes in 10 diabetics without autonomic neuropathy and in 12 age-matched nondiabetic controls. Sympathetic abnormalities in the diabetics included subnormal baseline norepinephrine levels, a virtual absence of changes in norepinephrine during changes of arterial pressure, and supranormal pressor responses to phenylephrine infusions. The hypersensitivity to pressers may be due to subnormal baroreflex buffering of blood pressure elevations. Parasympathetic abnormalities included subnormal baseline standard duration of RR intervals, and subnormal RR interval prolongations during elevations of arterial pressure. These data suggest that disturbances in highpressure baroreceptor function could play an important role in the pathogenesis of hypertension, as well as of orthostatic hypotension, in Type I diabetics. Comparable studies in Type II diabetics, or in hypertensive
diabetics of either type, have yet to be performed. If there are alterations in baroreceptor functions in diabetics analogous to those in the elderly,43 increased circadian variability of blood pressure would be expected. Low-pressure cardiopulmonary baroreceptors are activated by very modest reductions in cardiac filling pressure that are not sufficient to alter arterial blood pressure or heart rate. However, there is a significant increase in sympathetic outflow when low-pressure baroreceptors are activated, as evidenced by increases in forearm vascular resistance.35044-4g Accordingly, low-pressure baroreceptor sensitivity can be determined by measuring norepinephrine and vascular resistance responses to selective unloading of lowpressure baroreceptors, followed by testing of highpressure baroreceptors. An important central interaction between the arterial baroreceptors and the cardiopulmonary baroreceptors occurs-at least in the dog model-through vagal afferents. 5oThe inhibitory influence of cardiopulmonary baroreceptors may be heightened when the inhibitory influence from arterial baroreceptors is reduced, as in borderline essential hypertension.37-41 Exaggerated cardiopulmonary baroreceptor responses to orthostatic stress could contribute to the increased systemic vascular tone noted in the hypertension associated with diabetes. Relevant to the salt-sensitivity issue, extracellular sodium and calcium have been shown to affect baroreceptor sensitivity in animal models.51J2 Another critical area that has not been systemically examined in the pathogenesis of diabetic hypertension is a possible calcium deficiency, relative to salt intake. Such a calcium deficiency could paradoxically eventuate in a postulated increase in intracellular cytosolic calcium and thus result in increased vascular tone. Patients who are salt-sensitive may be more likely to have hypertension that responds favorably to calcium supplementation. Resnick et als3showed a correlation between the serum ionized calcium level and PRA, with low-renin hypertensive patients tending to have low levels of ionized calcium. A calcium deficiency in diabetes can be postulated on the basis of disturbed vitamin D metabolism.54-61Impaired l-hydroxylation of 25-OH vitamin D is seen in diabetic rats. A decrease in vitamin D-dependent calcium-binding protein levels in the central nervous system and the kidney of humans with Type I diabetes has also been reported.5gv60Reduced levels of 1, 25-(OH)-2-D3 and increased levels of the inactive metabolite, 24,25-(OH)2D3, have also been described in diabetic children61 Therefore, at any given level of calcium intake there may be decreased calcium absorption. There is considerable evidence that dietary deficiencies in calcium62-70and abnormalities in calcium metabolism7*-g7 may play a role in the pathogenesis and maintenance of the essential hypertension seen in nondiabetics, particularly in salt-sensitive animal models and in salt-sensitive human subpopulations. Decreased levels of both ionized calcium53p6gand total
calcium70 have been reported in patients with essential hypertension compared with normotensives. Similarly, animal models of hypertension, including the spontaneously hypertensive rat (SHR),71,g7models of reduced renal mass,72 the deoxycorticosteroid raV2 and the New Zealand genetically hypertensive rat,72 have lower serum ionized or total calcium, or both, than normotensive controls. At the same time that extracellular calcium levels are reduced, intracellular levels of calcium are increased. Intracellular free calcium concentrations are increased in the platelets*lJz erythrocytes83 and adipocytes84 of hypertensives, while extracellular calcium levels are decreased.arJ4 Furthermore, the calcium bound to the erythrocyte inner membrane surface is reduced in SHRS~~-~~ and in human hypertensives.75-7* A relative calcium deficiency could also result, in part, from increased urinary calcium loss, as suggested in some animal models. In hypertensive models, the increase in parathyroid hormone (PTH) resulting from decreased levels of ionized calcium may be less effective in calcium retention than in normotensives. As would be predicted, PTH levels are elevated in several models of hypertension, including the SHR.72~g0~g1~ga Chronic infusion of PTH, however, causes a significantly smaller increment in renal cyclic adenosine monophosphate production in SHRs than in normotensive Wistar Kyoto rats. g1Furthermore, deoxycorticosteroidg2 and Dahl salt-sensitiveg3 hypertensive rats exhibit hypercalciuria, and fractional and total urinary calcium excretion is elevated in human hypertensives.*g*g4*g6 Diminished ability to appropriately reduce urinary calcium excretion in hypertensives may be due to a defect in the calcium-calmodulin-dependent activation of renal adenylate cyclase.g8 The apparent paradoxic association of decreased extracellular calcium levels with increased intracellular concentrations remains to be fully explained. However, an abnormality in the functioning of critical membrane pumps, included sodium/potassium adenosine triphosphatase (Na/K-ATPase), magnesium (Mg)-ATPase and the calcium (Ca)-ATPases; Na/hydrogen (H) antiport seems a likely explanation. Basal Ca-ATPase activity is decreased in erythrocyte membranes from hypertensive subjects;7gboth the affinity of the pump for calcium and its activity are reduced.80 Calcium efflux is thus reduced and intracellular calcium levels increased,e2-85causing an increase in vascular tone. In the diabetic, a relative magnesium deficiency, caused by increased urinary magnesium loss, could also contribute to decreased Na-K ATPase and Ca-ATPase activity, since magnesium may play a critical role in the functioning of these enzymes.*OOJO1 Additionally, the relative insulin resistance associated with diabetes could lead to reduced activity of the Ca2+ + MgZ+-ATPase enzyme, as seen in fat cell plasma membranes.102 Shakir et aPo3 recently reported that sodium restriction induces a greater increase in renal Na/K-ATPase in diabetic humans than in controls, suggesting that a high salt intake in diabetics could contribute to reduced enzyme activity. Reduction in
June 15, 1966
glomerular Na/K-ATPase and disturbances in glomerular Na-H exchange have recently been reported in streptozotocin-diabetic rats105J06Also, insulin has been shown to stimulate Na-K ATPase activity directly, to the extent that insulin deficiency could contribute to decreased enzyme activity.lo4 An additional consideration is that PTH may act as a calcium ionophore, so that the elevated levels of PTH associated with reduced ionized calcium levels eventuate in increased intracellular calcium. Studies in a variety of mammalian cells,107-110including the human erythrocyte, Ilo have documented a role for PTH in increasing the intracellular calcium concentrations. Lindner et ala5 also recently suggested that a circulating plasma factor in human hypertensives may increase cytosolic calcium concentrations in platelets, although they postulate a “natriuretic hormone.” Also, the hypertensive effect of acute hypercalcemia in humans is realized only when the parathyroid glands are intact; it is completely abolished by parathyroidectorny.lll Both Gennari et allI and Iseki et a1112argued that the hypertension of hyperparathyroidism is a consequence of PTH action. The counterargument may be offered that PTH is a known vasodilator.lls However, this effect probably requires levels of PTH that exceed the physiologic range. For example, intravenous injections of 100 U/kg of parathyroid extract produce an acute hypotensive effect; in addition, parathyroid extract (1 U/ml) inhibits contraction of isolated aorta in response to phenylephrine, reduces 45Ca influx and increases 45Caefflux from isolated rat aorta.l14 In contrast, lower levels of parathyroid extract (0.1 U/ml] have the opposite effect, increasing 45Cainflux in isolated aorta. Thus, the hypotensive effect of PTH is exerted only at high concentrations and may mask the physiologic role of PTH as a calcium ionophore and vasoconstrictive agent. Increasing dietary calcium lowers vascular resistance and systemic pressure in hypertensive rats,115-11* whereas calcium restriction causes vasoconstriction in the SHR as well as in normotensive Wistor Kyoto and pregnant rats.‘17J1* Paradoxically, increasing serum calcium reduces vascular resistance in the New Zealand genetically hypertensive rat,73an effect attributed to a membrane-stabilizing effect of calcium.86-88 A similar relation has been noted in normotensive rats.** By increasing membrane stability and then reducing the inward leak of calcium, increased extracellular calcium could lead to a paradoxical decrease in intracellular calcium levels. Several studies in humans have already demonstrated an antihypertensive effect of supplemental calcium.11g-123 Resnick et al, however, emphasized that a beneficial effect of calcium on hypertension may be confined to certain hypertensive subpopulations. In addition to the correlation between ionized calcium and renin levels noted previously,53 they have also recently reported positive correlations between calcitrio1 levels and renin levels, and between PTH levels and renin levels.lz3 Resnick et aPz4 demonstrated a decrease in blood pressure with exogenous calcium in
a salt-sensitive black hypertensive population. These observations have led Resnick et a1124J25 to speculate that antihypertensive effects of calcium supplementation would be largely confined to salt-sensitive patients, such as the elderly hypertensive or the black hypertensive. Because diabetic hypertension is characterized by volume expansion, diabetics may also benefit from exogenous calcium in the setting of a high-salt intake. Other workers, however, have rejected the hypothesis that calcium has any antihypertensive effects under any circumstances,126J27and indeed the “calcium hypothesis” has resulted in a sometimes-acrimonious debate.lz8J2gHowever, baseline differences in the calcium or sodium intakes of subjects in the studies yielding negative results could easily explain their failure to document an antihypertensive effect of calcium supplementation. Subjects already consuming large quantities of dietary calcium presumably would not obtain any further benefit from additional calcium supplementation. Similarly, only subjects on a high-baseline salt intake would be expected to show any improvement with calcium supplementation. Also, calcium supplementation may potentiate hypomagnesemia by increasing urinary excretion of magnesium,lz3 or by reducing intestinal absorption of magnesium.130 Because recent studies131-1sssuggest that hypomagnesemia may contribute to hypertension, some patients with a borderline magnesium status may be pushed over into significant hypomagnesia by calcium supplementation and thus fail to have the antihypertensive properties of calcium. As noted, the hypertensive effect of hypomagnesemia may relate to reduced functioning of the membrane Ca ATPases and Na-K ATPase. Salt sensitivity in the diabetic population could also reflect a decreased ability to generate natriuretic substances such as dopamine136 in the face of high-salt intake. Recent studies from our group suggest that the antihypertensive effects of increased calcium intake in patients receiving a high-salt diet may partially relate to increased renal generation of dopamine.137J38Dietary calcium supplements were shown to increase renal sodium excretion in the SHR137and in salt-sensitive black hypertensives. 13*However, a recent balance study performed by Luft et a113gfailed to demonstrate any natriuretic effect of calcium supplementation. Luft’s study lasted only 8 days, however, and a longer period may be required to demonstrate increased urinary sodium excretion; also, his subjects had not been specifically shown to be salt-sensitive. Accordingly, it will be important to determine whether dietary calcium supplementation increases the ability of diabetics to increase renal dopamine production either in response to an acute saline infusion or to the more chronic challenge of a high dietary salt intake. In summary, the prevalence of diabetes continues to increase in the United States with the aging of the population. Hypertension plays a major role in accelerating the vascular damage that accounts for most of the excess morbidity and mortality produced by diabe-
tes. Because of the size of the diabetic oooulation at risk, a better understanding of etiologic mechanisms underlying diabetic hypertension will obviously have very wide applicability. The possibility that a subtle calcium deficiency exists in the setting of a high-salt intake clearly deserves further exploration. I
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