Search PubMed⌕ Search

Biomedical subjects

L M Resnick

Publications and source records attributed to L M Resnick.

At least 73 records · Page 4Linked to original sources
PubMed1993

Parathyroid hypertensive factor-like activity in human essential hypertension: relationship to plasma renin activity and dietary salt sensitivity.

OBJECTIVE: To determine the clinical relevance of the newly described circulating pressor factor with parathyroid hypertensive factor (PHF)-like activity. DESIGN: Plasma samples were collected from 94 normotensive and 93 essential hypertensive subjects, the latter either previously defined by dietary salt sensitivity (n = 43), or prospectively studied on both low- (< 50 mmol/day) and high-salt (> 200 mmol/day) diets (n = 16). METHODS: Blood pressure, demographic factors, plasma renin activity (PRA), urinary electrolyte excretion and bioassayable PHF-like activity were determined in the fasted state on basal and altered dietary salt intakes. RESULTS: Among the normotensive subjects significantly higher PHF-like activity and reciprocally lower PRA values were observed in Black versus Caucasian subjects, particularly among females. In the hypertensive subjects PHF-like activity levels were significantly elevated in the low- (17.1 +/- 1.5 mmHg, n = 34) and normal- (6.7 +/- 1.8 mmHg, n = 36) but not in the high-renin subgroups compared with values in the normotensive subjects (1.6 +/- 1.1 mmHg). Similarly, PHF-like activity values were significantly higher in salt-sensitive than in salt-insensitive hypertensives. Prospectively, PHF-like activity rose significantly with salt loading (4.9 +/- 1.2 to 20.4 +/- 6.2 mmHg) and was positively related (r = 0.648, P < 0.001) to the pressor response to salt. CONCLUSIONS: Elevated levels of PHF-like activity are characteristic of the low-renin or salt-sensitive state, or both, and may contribute to the hypertensive process. Elevated PHF-like activity levels found in normotensive subjects may presage the development of low-renin, salt-sensitive hypertension.

Biological Factors↗
PubMed1992

Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders.

We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic beta cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion--all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.

Aldosterone↗
PubMed1992

Abnormal 1,25-dihydroxyvitamin D metabolism in preeclampsia.

We previously reported that preeclampsia is associated with hypocalciuria (N Engl J Med 1987; 316:715). The purpose of this study was to determine whether alterations in calcium regulatory hormones are present in preeclampsia and, if so, whether they are responsible for hypocalciuria. Thirty-two pregnant women were studied in the second and third trimesters of pregnancy (11 women with preeclampsia, nine with chronic hypertension, and 12 normotensive women). 1,25-Dihydroxyvitamin D, C-terminal parathyroid hormone, ionized calcium, and urinary calcium excretion were measured. 1,25-Dihydroxyvitamin D was significantly lower in the women with preeclampsia in the third trimester when the disease developed (37.8 +/- 15 pg/ml) than in women with chronic hypertension (75 +/- 15 pg/ml, p less than 0.05) and normal women (65 +/- 10 pg/ml, p less than 0.05). Parathyroid hormone was higher, but not significantly, in those with preeclampsia. Ionized calcium was not significantly different among the three groups. Urinary calcium excretion was abnormally low for pregnancy (less than 50 mg/24 hr) in all but one women with preeclampsia. We conclude that 1,25-dihydroxyvitamin D is reduced in preeclampsia and may lead to hypocalciuria by causing decreased intestinal absorption of calcium, stimulation of parathyroid hormone, and increased distal renal tubular resorption of calcium. The cause of reduced 1,25-dihydroxyvitamin D in preeclampsia is unknown and may be due to either diminished renal or placental production of the hormone.

Calcitriol↗
PubMed1992

Renal divalent cation excretion in secondary hypertension.

1. To determine whether abnormal renal calcium excretion is unique to primary genetic hypertension, blood pressure and 24 h urinary excretion of calcium, magnesium, sodium and creatinine were measured in deoxycorticosterone-saline and two-kidney, one-clip Goldblatt hypertensive rats and in their respective controls on low (0.2%) and high (1.8%) dietary calcium intakes. 2. Calcium supplementation lowered blood pressure (P < 0.05) in deoxycorticosterone-saline rats and in control saline-loaded rats, raised blood pressure in two-kidney, one clip rats, and had no effect in sham-operated control rats. 3. On both diets, calcium excretion was higher in hypertensive than in normotensive rats. The high calcium diet increased urinary calcium excretion in all rats, but the changes in urinary calcium excretion closely paralleled the diet-induced changes in blood pressure. Thus, urinary calcium excretion in deoxycorticosterone-saline animals, in whom calcium lowered blood pressure the most, rose the least (107%). Urinary calcium excretion rose the most in two-kidney, one-clip animals (1113%), whose blood pressure also rose the most. 4. Urinary magnesium excretion was also abnormal in hypertensive rats compared with normotensive rats, falling on the high compared with the low calcium diet in normotensive rats, but not in either hypertensive strain. Furthermore, urinary magnesium excretion was closely linked to urinary calcium excretion in saline-loaded control rats (r = 0.78; P = 0.008), but was dissociated from urinary calcium excretion in deoxycorticosterone-saline rats (r = 0.02; not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cellular ions in hypertension, insulin resistance, obesity, and diabetes: a unifying theme.

The clinical linkage of hypertensive cardiovascular disease, left ventricular hypertrophy, and accelerated atherosclerosis with a spectrum of metabolic disturbances including peripheral insulin resistance, hyperinsulinemia, obesity, and frank non-insulin dependent diabetes mellitus, has been increasingly appreciated. However, the underlying biologic basis mediating this clinical association remains unclear. Nuclear magnetic resonance techniques have been used to measure various intracellular ion species in human erythrocytes and have found that common, shared intracellular abnormalities of cytosolic free calcium, free magnesium, and pH occur in each of these clinical syndromes. Specifically, essential hypertension is characterized by higher fasting free cytosolic calcium concentrations and reciprocally lower intracellular free magnesium and pH levels compared with those of normotensive control subjects. Furthermore, for all subjects, free calcium and free magnesium levels were closely related both to the left ventricular mass and to the degree of insulin resistance present. Moreover, these same intracellular ionic lesions were found in normotensive obese and/or non-insulin diabetic individuals. Last, evidence has recently been provided that the cardiovascular consequences of increased dietary sugar and salt intake may well be determined by their concurrent influence on cellular ion metabolism. These data led to a hypothesis for a central role for altered cellular ion homeostasis in mediating the clinical linkage of cardiovascular and metabolic disease. According to this ionic hypothesis, essential hypertension, non-insulin dependent diabetes, and their frequently associated features of obesity, left ventricular hypertrophy, and accelerated atherosclerosis all derive from and reflect different clinical manifestations of the same underlying cellular lesion, characterized at least in part by elevated cytosolic free calcium and suppressed free magnesium levels.

Calcium↗
PubMed1991

The pressor effect of sodium-volume expansion is calcium mediated.

To investigate the calcium dependence of salt-induced hypertension we concurrently measured blood pressure and serum ionized calcium in conscious normotensive female dogs undergoing five infusions: 1) sodium chloride (0.9%) 2) calcium chloride (10 mg/kg), 3) combined sodium chloride and calcium chloride, 4) nicardipine (1 micrograms/kg/min), and 5) combined sodium chloride and calcium chloride in the presence of nicardipine. While saline and calcium chloride infusions individually did not affect blood pressure, saline combined with calcium chloride significantly and consistently raised mean arterial pressure (MAP) (delta MAP = 7 +/- 2 mm Hg, P less than .001 v baseline). Serum ionized calcium (Caio) levels increased within the normal range with the infusion of calcium alone (1.32 +/- 0.03 to 1.48 +/- 0.01 mmol/L, P less than .005). Extracellular Caio rose less with the combined NaCl-CaCl2 infusion (delta Caio 0.10 +/- 0.01 v 0.16 +/- 0.02 mmol/L, P less than .02). The difference in calcium elevations could not be attributed to volume expansion alone, since saline infusion itself did not affect serum ionized calcium (1.32 +/- 0.3 to 1.31 +/- 0.01 mmol/L, P = NS). Furthermore, nicardipine prevented the pressor effect of the combined saline-calcium infusion. (delta MAP = -2 +/- 3 v 7 +/- 2 mm Hg, P less than .001), and restored the rise in extracellular Caio to that seen with the nonpressor calcium infusion (delta Caio 0.15 +/- 0.01 mmol/L v 0.16 +/- 0.02 mmol/L, P = NS). Altogether, these data demonstrate that the rise in blood pressure and ionized calcium following an acute infusion of sodium and calcium chloride are interdependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Insulin resistance, carbohydrate metabolism, and hypertension.

Hypertension and diabetes are common diseases in Westernized civilizations, and in the United States, the frequency of both diseases is increasing as the society ages. Factors contributing to the high prevalence and increasing frequency of these diseases include obesity, hyperinsulinemia and insulin resistance, genetic factors, and abnormal cellular handling of calcium and other cations. Obesity is a strong early predictor for the development of hypertension as a person progresses from childhood into adult life. Important factors contributing to obesity-related hypertension likely include enhanced sympathetic nervous system activity and insulin resistance and hyperinsulinemia. Recent evidence has also shown that many nonobese adults with untreated hypertension have insulin resistance and hyperinsulinemia. This observation strongly suggests that the disease called "hypertension" is characterized by fundamental metabolic abnormalities as well as by hemodynamic abnormalities. Recent observations have shown that impaired cellular responses to insulin are associated with increased vascular smooth muscle contraction. Insulin appears to attenuate the vascular response to both receptor-mediated and voltage-mediated calcium-induced contractions. Thus, insulin resistance, and the resultant reduction in the normal attenuating effect of insulin on vascular smooth muscle responses, appear to be associated with abnormal vascular smooth muscle handling of calcium and with exaggerated vascular contraction.

Animals↗
PubMed1991

Intracellular ions in salt-sensitive essential hypertension: possible role of calcium-regulating hormones.

To study the blood pressure, ionic, and hormonal responses to chronic dietary salt loading, we measured RBC pHi, Mgi, Nai, and Cai, and compared these with serum levels of Ca-io, 1,25-D, and free levels of PHF in salt-sensitive and salt-insensitive essential hypertension subjects on low and high (200 mEq/day less than UNaV less than 50 mEq/day) dietary salt intakes. As a group, salt loading significantly increased diastolic blood pressure (7.6 +/- /3%), Nai (25.5 +/- /8%) and Cai (27.0 +/- /11%), while Mgi (-14.2 +/- 7%) and pHi (-0.03 +/- /0.01 pH units) fell. Significant changes in pHi, Cai, and Mgi occurred only in SS individuals, who also exhibited elevated levels of 1,25-D and of PHF in association with suppression of Ca-io. Altogether, the pressor response to salt was inversely related to the basal pHi (p less than 0.001), and to the degree of salt-induced suppression of Ca-io (p less than 0.001) and Mgi (p less than 0.001), while being directly related to the basal PHF (p less than 0.001) and to the salt-induced stimulation of 1,25-D (p less than 0.005). We hypothesize that elevated levels of 1,25-D and PHF coordinately shift intracellular cation levels and stimulate cellular calcium uptake from the extracellular space. As such, these calcium-regulating hormones may be responsible, at least in part, for salt-sensitive hypertension.

Biological Factors↗
PubMed1991

Cellular ions in hypertension, diabetes, and obesity. A nuclear magnetic resonance spectroscopic study.

To investigate the cellular basis linking hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and obesity, we used 31P and 19F nuclear magnetic resonance spectroscopy to measure intracellular pH (pHi), free magnesium (Mgi), and cytosolic free calcium (Cai) in erythrocytes of obese and NIDDM subjects with and without hypertension. Compared with normotensive, nondiabetic controls (Cai, 25.2 +/- 1.4 nM; Mgi, 232 +/- 8 microM), Cai was elevated in both normotensive (36.8 +/- 2.7 nM, sig = 0.005) and hypertensive (43.4 +/- 2.9 nM, sig = 0.001) NIDDM subjects, and Mgi was concomitantly suppressed (normotensive: 206 +/- 11 microM, sig = 0.05; hypertensive: 196 +/- 8 microM, sig = 0.001). Similar but less striking changes were noted in obese subjects. Values of pHi were significantly lower (sig = 0.05) in all hypertensive groups compared with their normotensive controls. Continuous relations were observed for all subjects between Cai and diastolic blood pressure (r = 0.649, p less than 0.001) and body mass index (r = 0.565, p less than 0.001), between Mgi and diastolic blood pressure (r = -0.563, p less than 0.001) and fasting blood glucose (r = -0.580, p less than 0.001), and in diabetics, between pHi and diastolic blood pressure (r = -0.680, p less than 0.001). Thus, the constellation of elevated Cai and suppressed Mgi and pHi levels is characteristic of the hypertensive state. These abnormalities of cellular ion handling in whole or in part common to hypertension, diabetes, and obesity may contribute to the pathophysiology of these syndromes and may help to explain their frequent clinical coexistence.

Calcium↗
PubMed1991

Calcium metabolism in hypertension and allied metabolic disorders.

Data suggest a critical role for Ca metabolism in the pathophysiology of hypertensive disease. Intracellularly, all hypertension displays elevated cytosolic free-Ca2+ and suppressed free-Mg2+ levels. Extracellularly, however, heterogeneous defects in Ca and Mg metabolism are observed. This apparent divergence may be explained by considering all hypertension as the expression, in varying degrees, of two underlying Ca-related mechanisms: one (salt sensitive, low renin, Ca(2+)-antagonist sensitive) dependent on inappropriate cellular Ca2+ uptake from the extracellular space and the other (salt insensitive, renin dependent, Ca(2+)-antagonist insensitive) dependent on increased cellular Ca2+ release from intracellular sites. Recent work highlights the role of 1,25-dihydroxyvitamin D3 and the newly described parathyroid hypertensive factor in volume-dependent low-renin forms of hypertension. Altered cellular ion handling may also explain metabolic and clinical correlates of hypertension, e.g., peripheral insulin resistance, hyperinsulinemia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). Thus, all subjects with NIDDM, whether hypertensive or not, display the same elevated cytosolic free-Ca2+ and suppressed free-Mg2+ levels observed in hypertension. Furthermore, adiposity, the level of blood pressure, and fasting and postglucose hyperinsulinemia are all closely and quantitatively related to intracellular free-Ca2+, free-Mg2+, and pH levels. This suggests a broader hypothesis, in which hypertension, obesity, insulin resistance, and NIDDM, each usually considered a distinct clinical entity, represent different clinical expressions of a common defect in cellular ion handling, hence explaining their frequent clinical coexistence in the general population.

Calcitonin↗
PubMed1990

Hypertension and peripheral insulin resistance. Possible mediating role of intracellular free magnesium.

To investigate the association of hypertension and insulin resistance, we utilized 31P-NMR spectroscopy to noninvasively assess intracellular free magnesium levels (Mgif) in erythrocytes of normotensive (n = 20) and essential hypertensive (n = 20) subjects given an oral 100 g glucose load. In hypertensive compared with normotensive subjects, fasting glucose and insulin levels were similar, but the integrated insulinemic responses to glucose were 45% greater (312 +/- 13.4 v 215 +/- 7.5 microU/mL, P less than .001). In hypertension, Mgif levels were significantly reduced (183 +/- 9 v 251 +/- 9 mumol/L, P less than .001), and for all subjects were closely and inversely related to systolic (r = -0.77, P less than .001) and diastolic (r = -0.81, P less than .001) blood pressures, and to the integrated insulin response (r = -0.72, P less than .001). Furthermore, while insulin responses were also related to the underlying systolic (r = 0.69, P less than .001) and diastolic (r = .73, P less than .001) pressures, these relations were no longer significant when adjusted for Mgif levels. We hypothesize that hypertension and peripheral insulin resistance may be different clinical expressions of a common abnormal intracellular ionic environment, characterized at least in part by suppressed levels of intracellular free magnesium.

Erythrocytes↗
PubMed1990

Calcium, parathyroid hormone, and vitamin D in the "prehypertensive" Dahl salt-sensitive rat.

The purpose of this study was to determine if alterations of calcium and calcium regulating hormones precede the onset of NaCl-induced hypertension in the Dahl salt-sensitive (S) rat. After a 5-day balance study, serum ionized calcium, parathyroid hormone (PTH), and 1,25-dihydroxy vitamin D concentrations were measured in Dahl-S and salt-resistant (R) rats that had been maintained on a "normal" (1%) or high (7%) NaCl intake. Blood pressure was higher in Dahl-S than Dahl-R (P less than .01), but was not affected by 5 days of high NaCl. On both NaCl intakes, urine calcium excretion was increased, serum calcium was decreased, and serum PTH and 1,25 dihydroxy vitamin D were increased in Dahl-S compared to Dahl-R (P less than .01). On the high NaCl intake, fecal calcium was greater in Dahl-S than in Dahl-R, and net 5-day calcium balance was less positive in Dahl-S (P less than .05). Thus, alterations of calcium, PTH, and vitamin D precede NaCl-induced hypertension in Dahl-S. These alterations may contribute to the development of hypertension in this animal model.

Animals↗
PubMed1990

Calciotropic hormones in human and experimental hypertension.

Although altered cellular calcium handling plays a critical role in the pathophysiology of hypertension, little attention has been focused on the impact of calcium regulating hormones on this process. Recent research provides evidence that parathyroid hormone, calcitonin, 1,25-dihydroxyvitamin D, as well as newly described factors such as calcitonin gene-related peptide (CGRP), exert target-organ-specific actions in cardiac and peripheral vascular tissues, are linked to the renin-aldosterone system, and thus to the control of sodium metabolism, and may directly participate in the hypertensive process, especially in low renin and salt sensitive forms of hypertensive disease. The metabolic set-point of these linked renin and calcium hormone systems, which serve to transduce environmental dietary mineral signals at the cellular level, determines the blood pressure consequences of sodium and calcium loading and/or restriction, and helps to explain the heterogeneous and seemingly inconsistent effects of these dietary maneuvers on blood pressure. Measurement of renin and calcium factors in hypertension thus provides a physiological basis for individualized therapeutic recommendations in human hypertension.

Animals↗
PubMed1990

A new circulating hypertensive factor in the plasma of essential hypertensive subjects.

The pressor responses to dialyzed plasma extracts from normotensive (n = 15) and essential hypertensive (n = 14) human subjects were evaluated in anesthetized Sprague-Dawley rats. Hypertensive but not normotensive plasma raised mean arterial pressure (23.6 +/- 3.6 versus -0.5 +/- 2.5 mmHg, P less than 0.0001), and this effect was correlated significantly with its ability to stimulate 45Ca uptake in rat tail artery vascular smooth muscle (r = 0.883, P less than 0.002). These data suggest a humoral contribution to the pathophysiology of essential hypertension in at least some individuals. The time-course and molecular weight distribution of the dialyzed plasma suggest that this effect is not due to known vasopressor substances, but to a factor we tentatively term plasma hypertensive factor.

Animals↗
PubMed1990

The effects of sodium and calcium in clinical hypertension: mediating role of vitamin D metabolism.

On the basis of this work, we believe it is reasonable to suggest that calcium regulating hormones in general, and 1,25 dihydroxyvitamin D in particular, contribute to the pathophysiology of human essential hypertension, especially salt sensitive forms. As such, levels of plasma renin activity, circulating ionized calcium, and serum 1,25 D levels both contribute to and serve as predictors of dietary salt-sensitivity and the potential benefit of increased oral calcium intake. Mechanistically, the different metabolic set points of these factors, determined on a genetic and/or environmental basis, serve to determine the heterogeneous blood pressure responses to similar dietary and mineral intakes. In this scheme, these monovalent and divalent ion regulating hormones transduce environmental mineral signals at the cellular level, thus determining their ultimate blood pressure effects. The cellular mechanism by which these altered metabolic hormonal set points serve to shift levels of intracellular cytosolic free calcium and other critical determinants of blood pressure, are the focus of current research.

Animals↗
PubMed1989

Hypertension and abnormal glucose homeostasis. Possible role of divalent ion metabolism.

Recent epidemiologic and clinical evidence emphasizes the association of hypertension, peripheral insulin resistance, hyperinsulinemia, and/or frank diabetes mellitus. The underlying basis for this clinical association remains unknown, and much attention has been focused on a possible role for hyperinsulinemia in these processes. However, evidence also suggests direct hypotensive effects of insulin. It is therefore unclear to what extent hyperinsulinemia contributes to, rather than merely reflects, these multiple metabolic abnormalities. Recent research links both hypertension and diabetes to common defects in calcium and magnesium metabolism, at least in part described by increased cytosolic free calcium, suppressed intracellular free magnesium, and their associated intracellular and hormonal alterations. Thus, hypertension, peripheral insulin resistance, and hyperinsulinemia may be different clinical manifestations of a common underlying cellular defect in divalent ion metabolism.

Animals↗
PubMed1989

Calcium and calcium regulating hormones in the "prehypertensive" Dahl salt sensitive rat (calcium and salt sensitive hypertension).

The purpose of this study was to determine if alterations of calcium and calcium regulating hormones precede the onset of NaCl induced hypertension in the Dahl salt sensitive (S) rat. After a 5 day balance study, serum ionized calcium, PTH, and 1,25 dihydroxy vitamin D concentrations were measured in Dahl-S and salt resistant (R) rats that had been maintained on a "normal" (1%) or high (7%) NaCl intake. Blood pressure was higher in Dahl-S than R (P less than .01), but was not affected by 5 days of high NaCl. On both NaCl intakes, urine calcium excretion was increased, serum calcium was decreased, and serum PTH and 1,25 dihydroxy vitamin D were increased in Dahl-S compared to Dahl-R (P less than .01). On the high NaCl intake, fecal calcium was greater in Dahl-S than in Dahl-R, and net 5 day calcium balance was less positive in Dahl-S (P less than .05). In contrast to NaCl, a high dietary intake of sodium with anions other than chloride (NaAA) fails to produce hypertension in the Dahl-S rat. NaAA loading resulted in decreased urine calcium excretion (P less than .01), and after 5 days of the high NaAA diet, serum calcium and PTH did not differ in Dahl-S and Dahl-R. Thus, alterations of calcium, PTH, and vitamin D precede NaCl-induced hypertension in Dahl-S. These alterations may contribute to the development of hypertension in this animal model.

Animals↗