As already noted, cytosolic [Ca2+] functions as a ubiquitous second messenger-mediating cell response to a wide variety of specific control signals. High basal levels presumably trigger inappropriate (i.e., unsignaled) cell responses or, equivalently, lower the response threshold for appropriate stimuli. This effect of PTH is found, for example, in arteriolar smooth muscle, in platelets, and in fat tissue. The first is associated with increased vascular tone, and t~e last with enhanced lipogenesis. Presumably, the pathogenesis of the premenstrual and polycystic ovary syndromes have an analogous basis.
Hypertensive Disorders
The relationship of the hypertensive disorders to low calcium intake is also discussed Weinberger. Here, we need only mention that, although data from observational studies are mixed, the controlled trials have almost always shown a blood pressure lowering effect of calcium supplementation, and meta-analyses of calcium intervention trials in essential hypertension, preeclampsia, and pregnancy-induced hypertension have unfailingly found a lowering of risk in individuals given augmented calcium intake (38 - 41) even when the data have been assembled so as to minimize the calcium effect size. At a population level, the effect of high calcium intake is probably small (a blood pressure lowering on the order of 2 - 5 mm Hg), probably because hypertension is a heterogeneous disorder, with only a fraction of cases exhibiting sensitivity to PTH, and with the calcium effect necessarily confined to only these patients.
More recently, the Dietary Approaches to Stop Hypertension (DASH) study exhibited a much larger effect, using food sources of calcium, combined with a high fruit and vegetable diet. The full DASH diet effect (which is probably more than the sum of its parts) was estimated to be capable of producing a 27% reduction in stroke and a 15% reduction in coronary artery disease at a population level-the largest effect reported to date. The impressive size of the effect found in this study has been attributed not solely to the calcium content of the diet, but to the higher potassium intake as well, and to the shift to an alkaline ash diet-or both. It seems likely that the relative resistance of the skeletal remodeling apparatus to PTH in blacks, coupled with their typically low calcium intakes, is a part of the explanation for the high prevalence of hypertensive disease in this racial group.
As already noted, blacks exhibit high serum levels ofPTH and 1, 25(OH)2D, both of which, of course, decrease when calcium intake is increased. It may also be that the larger overall response to the high calcium diet in DASH (relative to other calcium supplementation trials) was due precisely to the high proportion of African-Americans in the DASH study cohort (62%). In addition to the results of calcium intervention trials, there are several corollary lines of evidence implicating dysregulation of the calcium economy in the genesis of the hypertensive disorders. McCarron and associates have shown both a renal calcium leak and lower bone mineral density in hypertensives and Brickman and colleagues have shown higher circulating PTH and 1, 25(OH)2D levels and higher platelet cytosolic [Ca2+] in hypertensives. Such observational studies do not establish the causal direction in the association, but low bone mineral density and high PTH levels are inescapable reflections of negative calcium balance, whether due to inadequate intake or excessive loss.
Hence the human data are highly consistent at several levels. Also, it is interesting to note that the salt-sensitive rat models of hypertension require low calcium diets (with consequent elevation of PTH secretion and of 1, 25(OH)2D levels) for their expression and, for any given calcium intake level, the spontaneously hypertensive rat (SHR) exhibits lower serum [Ca2+] and higher PTH than normotensive animals. Unfortunately, widespread acceptance of the role of calcium in the hypertensive disorders has been impeded by the antisalt advocates as if sodium sensitivity and calcium dependency could not each be involved in different sub-sets of the population.
