Intracellular ionic consequences of dietary salt loading in essential hypertension. Relation to blood pressure and effects of calcium channel blockade.

To study the ionic basis of salt sensitivity in hypertension, 19F-, 13P-, and 23Na-nuclear magnetic resonance techniques were used to measure cytosolic free calcium (Cai), pH (pHi), free magnesium (Mgi), and sodium (Nai) in erythrocytes of essential hypertensive subjects (n = 19). Individuals were studied for 2 mo each on low- (UNaV < 50 meq/d) and high- (UNaV > 200 meq/d) salt diets, with the concomitant administration of nifedipine (10 mg t.i.d.) or placebo tablets for 1 mo of each diet. Salt loading elevated Cai and Nai while suppressing Mgi and pHi; these changes occurred predominantly in salt-sensitive subjects (n = 9). Nifedipine blunted the pressor response to salt loading > 50% (delta diastolic BP [high-low salt vs placebo] = 5 +/- 2 vs 14 +/- 2 mmHg, P < 0.05) and reversed salt-induced ionic changes, lowering Cai and elevating Mgi and pHi. Regardless of the definition of salt sensitivity, continuous relationships were observed between the pressure response to salt loading, the levels of Cai (r = 0.726, P < 0.001), Nai (r = 0.747, P < 0.001), and pHi (r = -0.754, P < 0.001), and the salt-induced change in Mgi (r = -0.757, P < 0.001). Altogether, these results emphasize the reciprocal and coordinate nature of intracellular ionic changes in response to dietary salt loading and calcium channel blockade in essential hypertension. They suggest that salt sensitivity is mediated by cellular calcium accumulation from the extracellular space, in association with magnesium depletion and acidification. Lastly, interpretation of intracellular ion measurements in the future will require concurrent assessment of dietary salt intake.

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)

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.

Calcium metabolism in essential hypertension: relationship to altered renin system activity.

Hypertensive disease is associated with various abnormalities of calcium metabolism although how these abnormalities relate to the elevated pressure remains unclear. Based on the use of renin-sodium profiling, we have defined heterogeneous deviations in circulating levels of ionized calcium and magnesium as well as of the calcium-regulating hormones parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D (1,25D), which parallel similar deviations in plasma renin activity. Essential hypertensive subjects with a profile of low renin, lower ionized calcium, and elevated 1,25D respond best to the calcium channel blocker nifedipine, demonstrate an enhanced sensitivity to the blood pressure effects of dietary salt loading, and have significantly lower blood pressures in response to oral calcium supplementation. Hypertensive subjects with the opposite metabolic profile--higher renin activity, higher serum ionized calcium, and lower 1,25D levels--are relatively insensitive to the blood pressure effects of either dietary salt loading or nifedipine, and show no significant hypotensive response to calcium supplements. Altogether, these alterations of calcium ionic and hormonal metabolism suggest that the hormonal control of calcium metabolism is linked to renin system activity as well as to the pathophysiology of the hypertensive process.

Cardiovascular effects of atrial natriuretic factor in anesthetized and conscious dogs.

Atrial natriuretic factor lowers blood pressure in normotensive and hypertensive animal models. The present study examined the mechanism of the blood pressure-lowering effect in 10 normotensive dogs. Four awake dogs previously instrumented with electromagnetic flow probes for measurement of cardiac output and catheters for systemic hemodynamic and cardiac dynamic measurements were studied. After a 30-minute control period, a 3 micrograms/kg bolus followed by 0.3 micrograms/min/kg of a 24-residue synthetic atrial natriuretic factor was infused for 30 minutes, followed by a 1-hour recovery period. Mean arterial pressure fell significantly during infusion (control, 125 +/- 4; infusion, 108 +/- 5; recovery, 125 +/- 9 mm Hg; p less than 0.05) and was accompanied by a slight but significant bradycardia (control, 144 +/- 7; infusion, 134 +/- 5; recovery, 145 +/- 7 beats/min; p less than 0.05). Significant reductions in cardiac output (control, 2.66 +/- 0.60; infusion, 2.18 +/- 0.60; recovery, 2.74 +/- 0.60 L/min; p less than 0.05), stroke volume (control, 18.4 +/- 3.9; infusion, 16.0 +/- 4.2; recovery, 19.0 +/- 3.7 ml/beat; p less than 0.05), and maximum increase in rate of change of left ventricular systolic pressure (control, 2475 +/- 200; infusion, 2088 +/- 216; recovery, 2487 +/- 243 mm Hg/sec; p less than 0.05) were also observed during infusion. No significant changes in total peripheral resistance or central venous pressure were noted, although the latter tended to fall during infusion. A similar pattern was observed in six pentobarbital-anesthetized dogs, except that infusion of atrial natriuretic factor did not induce bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide: a new factor in hormonal control of blood pressure and electrolyte homeostasis.

Recent research has led to the discovery and characterization of a hormone secreted by the atria that has powerful vasodepressor and natriuretic properties. A series of atrial peptides varying only in length and exhibiting these activities have been isolated, so that it is not yet clear which of these is the active hormone. The factors that determine its secretion remain to be characterized although preliminary evidence suggests that sodium-volume loading and/or intraatrial distension may be centrally involved. Atrial hormone acts in four different ways to oppose or counter the actions of the renin angiotensin aldosterone system. Thus, it produces vasorelaxation, which is especially pronounced in angiotensin-preconstricted blood vessels; it blocks angiotensin-induced aldosterone secretion by the adrenal cortex; it inhibits renin secretion by the kidneys; and its natriuretic action opposes the sodium-retaining action of aldosterone. Accordingly, the atrial-natriuretic and vasorelaxant hormone may play a role complementary to the renin angiotensin-aldosterone system in the long-term regulation of sodium balance and arterial pressure. In this construction the renin system acts primarily to defend sodium balance and blood pressure, with the atrial hormone playing an increasingly active counterpart in situations involving sodium-volume surfeit and/or high blood pressure. The physiologic properties of the new atrial hormone already suggest a major role for it in sodium-volume, blood pressure homeostasis, and for understanding and treating hypertensive-cardiovascular diseases.

Renin, calcium metabolism and the pathophysiologic basis of antihypertensive therapy.

The renin-angiotensin-aldosterone system regulates blood pressure and volume homeostasis in addition to sodium and potassium metabolism, and may be linked to divalent cation metabolism as well as hypertensive disease. In essential hypertension, circulating serum magnesium and Ca++, and the calcium regulating hormones, parathyroid hormone, calcitonin and 1,25 dihydroxyvitamin (1,25D) are different in the various renin subgroups. Elevated blood pressure induced by such maneuvers as dietary salt loading is associated with exacerbations of these calcium metabolic deviations, and appears related to salt-induced changes in serum Ca++ or 1,25D levels. Short- or longer-term lowering of blood pressure with the calcium-channel blocker, nifedipine, or with calcium or magnesium supplementation is associated with a shift of renin system activity and calcium metabolic indexes back to average normotensive values in those subjects most susceptible to these hypotensive agents. These observations suggest that deviations in calcium metabolism in essential hypertension may be related to the pathophysiology of the hypertensive process. Further, renin system activity and calcium metabolic indexes such as serum Ca++ levels may help target specific subgroups of hypertensive populations most susceptible to various dietary or drug maneuvers, and thus may provide a basis to better understand and treat clinical hypertension.

The significance of calcium and calcium channel blockade in essential hypertension.

A role for calcium in human hypertensive disease has been suggested. However, the various, apparently contradictory, abnormalities of calcium metabolism observed in experimental and clinical hypertension do not allow for unambiguous description of the specific manner in which calcium contributes to the hypertensive process. We studied calcium metabolism in essential hypertension and used renin-sodium profiling, which reveals the biochemical heterogeneity of clinical hypertension. We observed renin-linked, heterogeneous deviations in circulating levels of the divalent cations, magnesium and ionized calcium, in addition to deviations in the calcium-regulating hormones, parathyroid hormone (PTH), calcitonin (CT), and 1,25 dihydroxyvitamin D (1,25 D). These renin-calcium metabolic deviations may both predict and contribute to the pathophysiology of salt-induced hypertension, the blood pressure effects of oral calcium supplementation, as well as the short and longer term effectiveness of calcium channel blockade. Altogether, these data suggest an intimate linkage between the hormonal control of calcium metabolism, the renin-angiotensin system and blood pressure regulation in human hypertension.

Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis.

The renin-angiotensin-aldosterone axis exerts major control over sodium and potassium balance and arterial blood pressure. These three functions are continuously regulated by changes in angiotensin II and aldosterone levels in response to wide variations in dietary intake of sodium and potassium. In addition, changes in intrarenal physical factors cause changes in the supply of distal tubular sodium that, in turn, work to determine sodium and potassium excretion and to modulate the release of renal renin. However, certain aspects of sodium homeostasis cannot be fully explained either by the activity of the renin system or by intrarenal physical factors, and this has led investigators to search for other natriuretic hormonal mechanisms. Recently, it has become clear that atrial tissue contains a group of peptides, at least one of which is probably secreted as a regulatory hormone. In animals, these atrial peptides produce immediate, marked natriuresis associated with a rise in glomerular filtration rate (but no alteration of total renal flow) and a simultaneous decrease in arterial blood pressure. Atrial peptides also inhibit renal renin secretion and adrenal cortical secretion of aldosterone, and they oppose the vasoconstrictive action of angiotensin II. One of these atrial peptides may therefore be the long-sought natriuretic hormone, though in a different form and shape than was envisioned. The fact that atrial peptide works to oppose the renin system at four points suggests that this new hormone could have a major complementary role in long-term regulation of blood pressure and electrolyte homeostasis. In this construction the renin system primarily defends sodium balance and blood pressure, with the atrial hormone having an increasing counter-influence in situations involving high blood pressure or sodium surfeit. We can soon expect to learn more about this atrial hormone, including which peptide is the active circulating hormone, what induces or inhibits its release, and what part it plays in cardiovascular diseases.

Calcium metabolism and the renin-aldosterone system in essential hypertension.

Despite recent appreciation of a role for calcium in clinical hypertension, evidence at present is conflicting. Thus, certain studies suggest increased calcium availability may be associated with increased levels of blood pressure, while others suggest that a calcium deficiency may contribute to the pathogenesis of hypertensive disease. Our own group has thus far demonstrated deviations of circulating levels of ionized calcium and of magnesium in essential hypertension, linked with concurrent deviations in the activity of the renal pressor hormone, renin. Furthermore, calcium metabolic indices may predict and even determine dietary sodium sensitivity in hypertension, as well as the blood pressure responsiveness to antihypertensive drug therapy. Moreover, oral calcium supplementation may itself possess antihypertensive actions in specifically targeted renin subgroups of essential hypertensive subjects. Altogether, these results link calcium metabolism, renin system activity, and the pathogenesis of hypertensive disease. It may ultimately be calcium-regulating hormones, which determine cellular disposition of calcium, rather than circulating levels of calcium itself, that mediate the blood pressure and possibly even the renin deviations observed among differing hypertensive individuals.

Antihypertensive and aldosterone-lowering effects of synthetic atrial natriuretic factor in renin-dependent renovascular hypertension.

A 24-amino acid residue synthetic atrial natriuretic factor (ANF) antagonizes angiotensin II-induced vascular contractility and aldosterone production in isolated blood vessels and adrenal cells, respectively. To determine the significance of these effects in vivo, the blood pressure and aldosterone responses to synthetic ANF were evaluated in rats with two-kidney, one clip hypertension (n = 5) and in sham-operated controls (n = 4). In the latter, ANF caused a slight fall in mean blood pressure (-7 +/- 3%) and inconsistent changes in plasma renin and aldosterone. In hypertensive rats, ANF decreased blood pressure by 31 +/- 7 mmHg (17 +/- 3%), comparable to the effect of the angiotensin antagonist saralasin (31 +/- 4 mmHg). Plasma renin activity increased from 48 +/- 15 to 79 +/- 23 ng/ml/h. Despite this, ANF caused marked suppression of plasma aldosterone (from 97 +/- 28 to 20 +/- 8.9 ng/100 ml). These results show that ANF can exert potent antihypertensive and aldosterone-lowering effects in vivo, at least when the renin-angiotensin system is stimulated.

Evaluation of calcium-mediated vasoconstriction in chronic congestive heart failure.

Intercellular vascular smooth muscle calcium results in vasoconstriction and is therefore a potentially adverse mechanism of increased afterload in chronic congestive heart failure. Therefore, an evaluation was made of supine and tilt hemodynamic data, sympathetic reflexes, and the hormonal response to calcium channel antagonism after administration of nifedipine in nine patients with severe chronic congestive heart failure. After a 10 mg oral dose, the peak hemodynamic response occurred at 30 minutes and was characterized primarily by afterload reduction, improvement of systemic flow, and reduction of pulmonary hypertension. Despite reduction of supine blood pressure, there was no orthostatic hypotension during head-up tilt at the same time of peak response. Reflex responses to sympathetic stimulation (cold pressor test) were improved but still attenuated when compared with normal responses. Plasma renin activity increased significantly, but a dissociation of the aldosterone response was observed. Plasma catecholamine levels were not significantly altered. In summary, calcium antagonism resulted in significant afterload reduction and hemodynamic improvement in chronic congestive heart failure. This was associated with improved reflex responsiveness and, potentially, altered other vasoconstrictor hormones independently of the hemodynamic response. Calcium antagonism may provide a means to further understand vasoconstrictor mechanisms in heart failure and enhance therapy in appropriate patient subsets.

Converting enzyme inhibition to identify and treat renin-mediated or sodium-volume related forms of increased peripheral resistance in hypertension and in congestive heart failure.

Ten years of experience with three different converting enzyme inhibitors (CEI; teprotide, captopril and enalapril) in over 300 hypertensive patients reveals that CEI act largely to block renin-angiotensin mediated vasoconstriction. Thus, their effectiveness or lack of it is predicted by the baseline plasma renin measurement. Accordingly, responses to these pharmacological agents can be used to identify and quantify renin-mediated vasoconstriction in the spectrum of hypertensive diseases. The converse is also generally true. Patients failing to respond to CEI exhibit low renin values and their increased peripheral resistance appears related to other mechanisms, possibly involving a subtle increase in total body sodium. Thus, low renin states such as low-renin essential hypertension, primary aldosteronism, and anephric man exhibit little or no response to CEI. The relationship between the renin system activity and effectiveness of CEI reflects a specific interference with a particular pathogenic mechanism which is further supported by the fact that two other types of renin system inhibitors (beta-blockers and saralasin) are similarly effective or ineffective according to the operant renin profile also by studies in patients with congestive heart failure without hypertension in whom the same relationships can be demonstrated. Like hypertensives, heart failure patients exhibit a broad spectrum of renin activity values, and their pretreatment renin levels predict the responses to CEI. We have also found that plasma renin values in heart failure are dependent on sodium intake. When salt is administered, renin falls and patients then become unresponsive to CEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Limitations of transcendental meditation in the treatment of essential hypertension.

20 hypertensive patients participating in a professionally supervised programme of transcendental meditation showed no significant change in blood-pressure after a 6-month study. Although there were small reductions in systolic blood-pressure and in pulse-rate early in the trial, these changes had disappeared by 6 months. At no time did the mean diastolic pressure fall significantly. Plasma-renin activity did not change during the study. It is concluded that while the general feeling of wellbeing experienced by most patients may provide a useful adjunct to conventional treatments, it is unlikely that transcendental meditation contributes directly towards the lowering of blood-pressure.