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L M Resnick

Publications and source records attributed to L M Resnick.

At least 91 records · Page 5Linked to original sources
PubMed1989

The effects of calcium channel blockade on blood pressure and calcium metabolism.

To study the relation of calcium channel blockade to calcium metabolism, we measured serum ionized calcium (Ca++i0), magnesium (Mg), calcitonin (CT), and 1,25-dihydroxyvitamin D (1,25-D) before and after short-term therapy with verapamil 120 mg three times daily in essential hypertensive subjects on low (10 mEq) and high (200 mEq) dietary sodium intakes. Salt-sensitive compared with salt-insensitive subjects on high v low dietary salt intake had lower Ca++i0 (P less than .05), higher 1,25-D (P less than .02), and a greater hypertensive responsive to verapamil (% delta DBP = 17.7 v -8.2, P less than .05). The % delta DBP was related to the initial CT (r = 0.68, P less than .05), initial 1,25-D (R = -0.89, P less than .01), and to the drug-induced % delta 1,25 D (R = .60, P less than .05). Thus, lower initial calcium and calcitonin levels, higher initial levels of 1,25-D, and a greater drug-induced suppression of 1,25-D were associated with an enhanced hypotensive response to verapamil. Verapamil elevated Ca++i0 (2.46 +/- 0.04 to 2.53 +/- 0.04 2.00 mEq/L, P less than .05), and suppressed Mg (2.00 +/- 0.03 to 1.84 +/- 0.03 mEq/L, P less than .01) and 1,25-D levels (66.7 +/- 8.1 to 51.6 +/- 5.7 pg/mL, P less than .05). These results suggest interactive effects of sodium and calcium metabolism in essential hypertension, especially among salt-sensitive individuals. We conclude that alterations of calcium metabolism may underlie the sensitivity to verapamil therapy and may contribute to its hypotensive effects.

Blood Pressure↗
PubMed1989

Calcium metabolism in the pathophysiology and treatment of clinical hypertension.

Two parallel lines of research increasingly implicate calcium in the pathophysiology of hypertension. Studies at the molecular-cellular level reveal that, as part of a second messenger system, calcium plays a critical role in cellular responses that are of special relevance to blood pressure homeostasis. Investigations at the epidemiological and clinical levels have also increasingly involved calcium in hypertension, although the data produced are often contradictory, suggesting alternately that hypertension involves excess calcium and that the disorder is associated with a calcium deficiency. In our own research, which emphasizes both the biochemical and the clinical heterogeneity of the hypertensive process, we have found that divalent cation metabolism may be shifted in both directions away from average normotensive values among different types of hypertension. In addition, these calcium metabolic shifts appear to mediate the pressor effects of salt in both human and experimental forms of hypertension and may help identify individuals for whom different therapeutic regimens would be appropriate. We have developed a working cellular hypothesis in which all forms of hypertension are seen as calcium-dependent. One form is more critically dependent on extracellular calcium and is characterized by low plasma renin activity, dietary salt sensitivity, and therapeutic responsiveness to oral calcium supplementation and to calcium-channel blockade. At the opposite extreme, the intracellular calcium-dependent, angiotensin II-mediated form is characterized by high renin, lack of salt sensitivity, and preferential response to beta-blockade and converting-enzyme inhibition.

Administration, Oral↗
PubMed1989

Effects of calcitonin, calcitonin analogues, and calcitonin gene-related peptide on basal in vitro renin secretion.

We investigated the relation of calcitonin as a calcium-active hormone to its more recently described effects on peripheral vascular tone. Basal renal renin secretion in vitro in rat kidney slices was studied in the presence of salmon calcitonin (SCT, 4400 U/mg), amino acid substituted analogues of SCT, 16-alanine SCT (6200 U/mg) and 12,16,19 tri-alanine SCT (350 U/mg), and of rat calcitonin gene-related peptide (rCGRP). All calcitonin species at the same hypocalcemic activity (1 U/mL) modestly but significantly suppressed renin secretion from control levels (9.79 +/- 0.44 to 7.51 +/- 0.53, 7.70 +/- 0.72, and 7.78 +/- 0.90 Goldblatt units/g/h for SCT, 16-ala SCT, and tri-ala SCT, P less than .05 for all calcitonins v control), whereas rCGRP had no effect. Thus, on a molar basis, the renin suppressing effects of the various calcitonin species paralleled their bioassay-defined calcium sequestering activity, 16-ala SCT greater than SCT much greater than tri-ala SCT. Lower concentrations of SCT (10(-2) U/mL and 10(-4) U/mL, approximately 6 X 10(-10) and 6 X 10(-12) mol/L, respectively) had virtually identical effects. Moreover, verapamil (5 X 10(-6) mol/L) blocked the SCT-induced suppression of renin secretion (9.79 +/- 0.44 v 9.36 +/- 1.05 GU/g/h, P = NS). We conclude that the juxtaglomerular apparatus is a calcitonin-responsive system, in which calcitonin and its analogues act to suppress basal renin secretion in vitro. This effect seems to depend on and may be mediated by modulating cellular calcium uptake, and suggests a wider, calcium-related role for calcitonin than had previously been suspected.

Animals↗
PubMed1989

Hydrochlorothiazide is not additive to verapamil in treating essential hypertension.

Calcium channel blockers, a newer class of antihypertensive medications, have gained considerable acceptance as monotherapeutic agents, particularly in low renin hypertension where diuretics are also most effective. To study whether thiazide diuretics exert an additional antihypertensive effect in the setting of calcium channel blockade, we gave verapamil hydrochloride (360 mg/d) or hydrochlorothiazide (25 mg/d) alone and in combination in an open study to 13 hypertensive patients with mild to moderate essential hypertension. Both verapamil and hydrochlorothiazide lowered blood pressure (170 +/- 17/109 +/- 6 mm Hg pretreatment to 150 +/- 25/95 +/- 8 mm Hg with verapamil; 170 +/- 5/109 +/- 2 mm Hg pretreatment to 164 +/- 25/103 +/- 10 mm Hg with hydrochlorothiazide), but addition of hydrochlorothiazide to verapamil resulted in no added benefit (150 +/- 25/95 +/- 8 mm Hg vs 150 +/- 20/95 +/- 6 mm Hg). Furthermore, while hydrochlorothiazide lowered serum potassium values (4.2 +/- 0.25 mmol/L to 3.7 +/- 0.35 mmol/L) and stimulated plasma renin activity (1.5 +/- 1.3 ng/mL/h) pretreatment to 3.3 +/- 2.7 ng/mL/h with verapamil), verapamil only modestly elevated renin activity (1.5 +/- 1.3 ng/mL/h pretreatment to 2.7 +/- 2.5 ng/mL/h with verapamil) and did not lower potassium values. Altogether, the data suggest that in essential hypertension, at least for verapamil, concurrent diuretic therapy may not be helpful or warranted.

Blood Pressure↗
PubMed1988

The antihypertensive effects of calcium channel blockade: role of sodium and calcium metabolism.

To study the relation of calcium channel blockade to sodium and calcium metabolism, we measured blood pressure (BP), serum ionized calcium (Ca-io), plasma renin activity (PRA), and 1,25-dihydroxy-vitamin D (1,25D), before and after administration of nitrendipine to essential hypertensive (EH) outpatients on both low and high dietary salt intakes, and on fixed (10 mg b.i.d.) and titrated dose (10-30 mg b.i.d.) schedules. Nitrendipine lowered BP (% delta DBP = -14.9 +/- 3 vs. 1 +/- 3.5, p less than 0.001) and raised Ca-io (0.08 +/- 0.04 vs. -0.04 +/- 0.05 mEq/L, p less than 0.05) in salt-sensitive (SS) but not salt-insensitive (SI) subjects. % delta DBP was related to PRA (r = 0.69, p less than 0.001), to the rise in Ca-io (r = -0.63, p less than 0.01), and to the suppression of circulating 1,25D (r = 0.80, p less than 0.001). Similarly, at doses (10-30 mg b.i.d.) titrated to achieve normotension, nitrendipine uniformly elevated PRA (1.4 +/- 0.3 to 3.5 +/- 0.7 ng/ml/h, p less than 0.05) and Ca-io (2.34 +/- 0.02 to 2.44 +/- 0.02 mEq/L, p less than 0.05). We conclude that the antihypertensive efficacy of nitrendipine appears greatest among SS and lower renin patients, and is related to the drug's ability to alter calcium metabolism. The state of calcium metabolism may thus underlie the sensitivity to calcium blockade and may contribute to its effects.

Blood Pressure↗
PubMed1988

Recognizing and treating two types of long-term vasoconstriction in hypertension.

Long considered a single clinical entity, essential hypertension is now recognized as a heterogeneous spectrum of pathophysiologic disturbances, based on extensive clinical, pharmacologic and biochemical evidence. Two distinctly different mechanisms for long-term vasoconstriction can be identified and quantified in the spectrum of patients with essential hypertension, although the causes of this group of disorders are still obscure. The first vasoconstrictor mechanism is renin-angiotensin mediated and involves an increase in vascular smooth muscle cytosolic free calcium mobilized from intracellular sites. The degree of activity of this mechanism can be assessed by plasma renin level and/or by the hypotensive response to circulating anti-renin-system drugs (such as CEI inhibitors and beta blockers). The second vasoconstrictor mechanism, on the other hand, is renin-independent. It appears to require antecedent renal sodium retention and to be related to abnormal membrane influx of calcium. A low plasma renin level identifies this kind of vasoconstriction, which is also characterized by a low serum ionized calcium. Low-renin vasoconstriction is correctable by sodium depletion or by calcium channel or alpha adrenergic blockade. Depending on the state of sodium balance, these two vasoconstrictor mechanisms contribute reciprocally to maintenance of arteriolar tone in models of experimental hypertension, normotensive and hypertensive people, and in the vasoconstriction of edematous states, such as congestive heart failure. One of the two mechanisms also sustains diastolic hypertension in the experimental and clinical forms of renovascular hypertension and primary aldosteronism. Thus, both experimentally and clinically, at the polar extremes of the range of plasma renin values, one of the two mechanisms predominates: it is possible that, in the medium range of renin values, both mechanisms contribute to vasoconstriction. In our proposed unifying, analytic model, arteriolar vasoconstriction is associated with increased intracellular calcium and decreased magnesium levels in vascular smooth muscle. In the vasoconstriction consequent to sodium-volume expansion, cytosolic calcium is increased by an increased membrane influx. In renin-mediated vasoconstriction, receptor-operated channels mobilize cytosolic calcium instead from intracellular stores. These interrelationships provide a basis for stratifying hypertensive patients pathophysiologically and for applying simpler, more specific, and more rational therapies. Thus, the array of modern pharmacologic agents can often be rationally directed at one or the other, or both, of these two vasoconstrictor mechanisms.

Animals↗
PubMed1988

Intracellular free magnesium in hypertension: relation to peripheral insulin resistance.

In order to study the importance of altered intracellular ion metabolism in hypertension, we used 31P nuclear magnetic resonance (NMR) spectroscopy to measure intracellular free magnesium levels in normotensive (n = 19), essential hypertensive (n = 17) and diet-controlled diabetic (n = 6) subjects given a standard 100-g oral glucose load. The intracellular Mg level was significantly lower in hypertensives compared with normotensives (183 +/- 7 versus 232 +/- 10 mumol/l, P less than 0.001), and for all subjects was closely linked to both systolic (r = -0.84, P less than 0.001) and diastolic (r = -0.76, P less than 0.001) pressure. Hypertensives also showed a significantly greater insulinaemic response to glucose loading (P less than 0.001), and intracellular Mg was also closely and inversely linked to the integrated insulin response (r = -0.78, P less than 0.001). Despite the absence of hyperinsulinaemia, diabetics had the lowest intracellular Mg levels (156 +/- 8 mumol/l). Thus, suppressed intracellular Mg is linked to hypertension and to decreased tissue insulin sensitivity, and is not consequent to the hyperinsulinaemia itself. We suggest that intracellular Mg may provide a common pathophysiological basis for understanding the clinical association of hypertension and diabetes mellitus.

Blood Pressure↗
PubMed1987

Hypocalciuria in preeclampsia.

We studied 40 women in the third trimester of pregnancy to determine whether alterations in serum calcium levels or in urinary calcium excretion would distinguish patients with preeclampsia from normal pregnant women or women with other forms of gestational hypertension. Our population included 10 normal pregnant women, 5 pregnant women with transient hypertension, 6 with chronic hypertension, 7 with chronic hypertension and superimposed preeclampsia, and 12 with preeclampsia. The serum levels of ionized calcium, phosphate, and 1,25-dihydroxyvitamin D were not different among the various groups. In contrast, the mean (+/- SD) 24-hour urinary calcium excretion in the patients with preeclampsia or hypertension with superimposed preeclampsia was significantly lower (42 +/- 29 and 78 +/- 49 mg) than that in normal pregnant women (313 +/- 140 mg per 24 hours), women with transient hypertension (248 +/- 139 mg per 24 hours), or women with chronic hypertension (223 +/- 41 mg per 24 hours) (P less than 0.0001). The hypocalciuria in the women with preeclampsia was associated with a decreased fractional excretion of calcium. Although the mean creatinine clearance was reduced in the women with preeclampsia, the range of values overlapped with those in the other groups. In contrast, we observed little or no overlap with respect to calcium excretion. We conclude that preeclampsia is associated with hypocalciuria due to increased tubular reabsorption of calcium. Measurement of calcium excretion may be useful in distinguishing preeclampsia from other forms of gestational hypertension.

Adult↗
PubMed1987

Uniformity and diversity of calcium metabolism in hypertension. A conceptual framework.

Calcium metabolism plays an important role in blood pressure homeostasis, although it remains unclear to what extent calcium contributes to or, alternatively, protects against clinical hypertension. To resolve this confusion, hypertensive subgroups were first defined by plasma renin activity, dietary salt sensitivity, sensitivity to calcium channel blockade, and calcium metabolic indices. Using these classification schemes, different patterns of calcium metabolism emerged, each predictive of divergent clinical responses. Patients with low plasma renin activity, low serum ionized calcium levels, and dietary salt sensitivity, such as black and elderly hypertensive patients, may preferentially benefit from calcium supplementation. It is postulated that calcium-regulating hormones and the renin-angiotensin-aldosterone system coordinately monitor dietary mineral intake, and transduce these environmental signals at the cellular level by altering cellular calcium uptake and disposition. Analysis of these hormonal systems is useful diagnostically in defining those patients who would most benefit from non-pharmacologic dietary forms of treatment.

Adult↗
PubMed1987

Intracellular pH in human and experimental hypertension.

31P NMR spectroscopy was utilized to evaluate intracellular pH in erythrocytes from normotensive (n = 15) and from untreated (n = 16) and treated (n = 24) human essential hypertensive individuals. Intracellular erythrocyte pH was also measured in normotensive rats on different dietary calcium intakes as well as in volume-dependent deoxycorticosterone/saline and renin-dependent, 2 kidney, 1 clip (2K-1C) Goldblatt hypertensive rat models. Untreated essential hypertensives had significantly lower intracellular pH values compared with normotensive subjects [7.17 +/- 0.02 vs. 7.28 +/- 0.02 (mean +/- SEM), significance level = 0.01]. Treated hypertensives had intracellular pH values indistinguishable from normotensives [7.27 +/- 0.02 (mean +/- SEM)]. Similarly, pH values for each rat model varied inversely with blood pressure, regardless of whether increased dietary calcium intake lowered pressure (normotensive and deoxycorticosterone/saline hypertensive rats) or elevated it (2K-1C Goldblatt hypertensive rats). These results demonstrate that lower intracellular pH values are commonly observed in various hypertensive states and suggest that they may contribute to the pathophysiology of the hypertensive process. Alterations in intracellular pH may also underlie the clinically observed linkage of hypertension with other disease syndromes, such as diabetes mellitus and obesity.

Animals↗
PubMed1987

Calcium, the renin-aldosterone system, and the hypotensive response to nifedipine.

Ionic, hormonal, and blood pressure responses to a single oral dose of the calcium channel blocker nifedipine were assessed in 25 essential hypertensive subjects. When grouped according to their renin-sodium profile, low renin subjects had a greater hypotensive response to nifedipine (change in diastolic blood pressure -20.0 +/- 1.4 vs -6.4 +/- 1.0%; p less than 0.005) than did high renin hypertensive subjects. The initial level of serum ionized calcium predicted the blood pressure response to nifedipine (r = 0.70, p less than 0.001), as did the initial plasma renin activity (r = 0.65, p less than 0.005). Nifedipine induced a transient rise in serum ionized calcium (from 2.22 +/- 0.02 to 2.28 +/- 0.02 mEq/L; p less than 0.01), while plasma renin activity was consistently elevated compared with initial values at 30 (p less than 0.01), 60 (p less than 0.01), and 120 (p less than 0.05) minutes after drug administration. By comparison, plasma aldosterone levels did not rise and even declined at 30 (p less than 0.01), 60 (p less than 0.05), and 120 (p less than 0.05) minutes after nifedipine. These results suggest that low renin hypertension is more critically dependent on extracellular calcium than are higher renin forms and demonstrate that levels of serum ionized calcium, plasma renin activity, or both may predict the sensitivity of blood pressure to calcium channel blockade. Lastly, calcium may play a pivotal role in vivo in coupling renin stimulation to adrenal aldosterone responses.

Aldosterone↗
PubMed1987

The antihypertensive effect of verapamil at extremes of dietary sodium intake.

Restricting sodium intake is a primary recommendation for patients with hypertension, including those receiving drug treatment. Few studies, however, have examined the impact of different levels of sodium intake on the effectiveness of antihypertensive drugs. We administered two courses of verapamil to 13 patients with essential hypertension during a low-sodium (NaCl, 9 meq/d) and high-sodium (212 meq/d) diet. Overall, verapamil was an effective antihypertensive agent, but expressed its greatest potency in the lower-renin, sodium-sensitive subgroup. Moreover, the antihypertensive efficacy of verapamil was not blunted by the high-sodium intake (change in systolic/diastolic blood pressure, 18.8/17.7 in sodium sensitive patients compared with -11.4/-8.7 in sodium insensitive patients; p less than 0.05). Thus, dietary sodium restriction may not be necessary or appropriate in the treatment of essential hypertension with verapamil; salt-induced cellular calcium uptake may be involved in the phenomenon of sodium sensitivity.

Adult↗
PubMed1986

Alterations of dietary calcium intake as a therapeutic modality in essential hypertension.

Alterations of calcium metabolism in hypertensive disease have been increasingly observed, although the specific manner in which these alterations contribute to the increased blood pressure remains unclear. We have studied calcium metabolism in essential hypertension and have adopted an approach based on analysis of renin system activity, which emphasizes the heterogeneity of human hypertensive disease. With this approach we have defined parallel deviations of plasma renin activity, circulating ionized calcium, and calcium-regulating hormones, which suggest a calcium deficiency in some hypertensives and, an excess of calcium in others. These deviations can be used to predict and may mediate the blood pressure sensitivity of hypertensives to dietary salt, and may also target those individuals most likely to benefit from oral calcium supplementation. Calcium itself has enhanced antihypertensive effects in low renin subjects, having lower ionized calcium and higher endogenous 1,25-dihydroxyvitamin D values, and in subjects on higher dietary salt intakes. Calcium may alter pressure, at least in part, by suppressing endogenous vitamin D metabolites and by stimulating calcitonin secretion. We hypothesize that calcium-regulating hormones participate in the physiology of the renin-angiotensin system and in the pathophysiology of human hypertension.

Blood Pressure↗
PubMed1986

Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism.

Circulating levels of the calcium-regulating hormones, calcitonin, calcitriol, and parathyroid hormone, were analyzed in relation to plasma renin activity in 10 persons with normal blood pressure and in 51 persons with essential hypertension. Calcitriol (p less than 0.008) and parathyroid hormone (p less than 0.01) levels were elevated in hypertensives with low renin activity, whereas calcitonin levels were higher in patients with high renin activity (p less than 0.008), compared with normotensive controls and other hypertensive patients. Continuous relationships were observed between calcitriol levels and plasma renin activity in all patients (r = -0.65, p less than 0.001) and between parathyroid hormone levels and urinary sodium excretion in hypertensive patients with low renin activity (r = -0.63, p less than 0.01). Together, these results support a linkage between calcium metabolism and renin-sodium factors in essential hypertension. Calcium-regulating hormones and the renin-aldosterone system may coordinately mediate the blood pressure effects of differing dietary calcium and sodium intakes at the cellular level by altering cellular handling of monovalent and divalent ions.

Calcitonin↗