Calcium antagonists and cardiovascular prognosis: a homogeneous group?
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Calcium Channel Blockers↗
Biomedical subjects
J H Laragh
Publications and source records attributed to J H Laragh.
Plasma renin activity and plasma prorenin are not suppressed in hypertensives surviving to old age.
An age related decline in plasma renin activity (PRA) has been described in normotensive and hypertensive subjects. Moreover, hypertensive patients are reported to have lower plasma prorenin levels. We therefore investigated whether that pattern of renin and prorenin suppression was apparent in white hypertensives and normotensives surviving to an older age. The study population consisted of 65 untreated hypertensives (office blood pressure > or = 160/95 mm Hg; mean age 79 +/- 6 SD; range 69 to 94 years) and 26 normotensives (mean age 77 +/- 8; range 66 to 99 years). The PRA in this population of older hypertensives (1.7 +/- 1.6 ng/mL/h) was not significantly different from normotensives of similar age (1.5 +/- 0.8 ng/mL/h). PRA was not correlated to age in either normotensives and hypertensives, but was inversely correlated to office blood pressure in the hypertensives (r = -0.25; P = .05). Plasma prorenin was also not significantly lower in older hypertensives (14.6 +/- 8.6 ng/mL/h) than in the normotensive controls (15.1 +/- 7.0 ng/mL/h). In normal subjects, but not in hypertensive patients, there was a positive relationship between plasma prorenin and age (r = 0.82; P < .001). However, elderly normotensive men had lower plasma prorenin levels (11.6 +/- 4.1 ng/mL/h) than normotensive women (18.6 +/- 7.4 ng/mL/h; P < .05). "Total renin" (PRA + plasma prorenin) was also lower in elderly normotensive men compared to women (13.2 +/- 3.9 ng/mL/h v 20.0 +/- 7.5 ng/mL/h; P < .05). In conclusion, neither PRA nor plasma prorenin are suppressed in normotensive or hypertensive subjects who survive to an old age. However, since an inverse relationship between PRA and age has been reported, it remains to be determined whether the renin/prorenin parameters were suppressed at any time or if normal renin and normal prorenin patients preferentially survive to an old age. The wide spectrum of plasma renin levels in the elderly indicates that treatment of these patients too can profitably be guided by pretreatment plasma renin levels.
Aged↗
Specific prorenin/renin binding (ProBP). Identification and characterization of a novel membrane site.
Renin can be detected in cardiovascular and other tissues but it disappears after bilateral nephrectomy indicating that tissues can take up or bind renal renin from the circulation. If renin uptake is the result of specific binding, plasma prorenin may be a natural antagonist of tissue directed renin-angiotensin systems. To investigate if specific prorenin/renin uptake occurs in rat tissues, binding studies were performed, with rat microsomal membrane preparations using recombinant rat prorenin metabolically labeled with 35S-methionine as a probe. A high affinity binding site for both renin and prorenin was identified. Affinities for prorenin and renin were approximately 200 and 900 pmol/L, respectively. Binding was reversible, saturable, and pH and temperature dependent. The relative binding capacities of membranes from various rat tissues were as follows (fmol/mg): renal cortex (55), liver (54), testis (63), lung (31), brain (18), renal medulla (15), adrenal (17), aorta (7), heart (4), and skeletal muscle (1). Bound prorenin was displaced by rat and human renin or prorenin but not by the prosequence of rat prorenin, angiotensin I or II, rat or human angiotensinogen, the renin inhibitor SQ30697, atrial natriuretic factor, amylase, insulin, bovine serum albumin, hemoglobin, heparin, lysozyme, ovalbumin, cytochrome C, pepsin, pepsinogen, ribonuclease A, mannose-6-phosphate, alpha-methyl mannoside, gonadotropin releasing hormone, or an antibody to hog renin binding protein. these results demonstrate specific binding of prorenin to a site in rat tissues, herein named ProBP, that also binds renin. It is possible that differences in prorenin/renin binding capacity determine the activity of tissue-directed renin-angiotensin systems and that prorenin is a natural antagonist. Alternatively, a prorenin/renin receptor may have been identified that may function by transducing an intracellular signal.
Amino Acid Sequence↗
Midwall LV mechanics in rats with or without renovascular hypertension: effect of different Na+ intakes.
Supranormal left ventricular (LV) function has been reported in one-kidney, one-clip (1K,1C) and two-kidney, one-clip (2K,1C) Goldblatt hypertension. However, this finding might be at least partially due to mismatching endocardial rather than midwall fractional shortening to mean end-systolic stress. Accordingly, relations of echocardiographic endocardial and midwall shortening to circumferential end-systolic stress were calculated in 40 Wistar rats on 0.4% NaCl (r = -0.92, SE of estimate = 4.3% and r = -0.62, SE of estimate = 3.2%, both P < 0.0001). Midwall shortening as a percentage of predicted was related to LV chamber diameter in normal animals (r = 0.56, P < 0.0001). Endocardial and midwall shortening were compared as percentage of the normal values predicted from wall stress in 34 2K,1C and 19 1K,1C on 0.4% Na+ 8-9 wk after surgery. Use of midwall shortening reduced the number of these hypertensive rats with supranormal observed-to-predicted shortening ratio from 28 to 7.5% (P < 0.0001). Salt-deprived and high-salt diets (0.0035 and 4% NaCl, respectively) were given to 16 and 18 additional controls, 9 and 7 2K,1C, and 7 and 7 1K,1C. Salt-deprived sham animals had greater endocardial and midwall shortening (106 +/- 7 and 111 +/- 10% of predicted, both P < 0.002) than sham rats on 0.4% NaCl, whereas 4% NaCl had no effect. Five of sixteen salt-deprived sham rats had supranormal observed-to-predicted midwall shortening ratios for LV chamber size, suggesting an enhanced inotropic state. Salt-deprived and high-salt diets had negligible effects on LV performance in Goldblatt rats. Thus use of midwall shortening reduces the number of renovascular hypertensive rats with apparently increased LV function. Salt deprivation stimulates LV myocardial function in normal rats independent of chamber dimension (i.e., an indirect measure of preload) but does not influence LV performance in Goldblatt hypertension 8 wk after renal artery clipping.
Animals↗
Plasma and renal prorenin/renin, renin mRNA, and blood pressure in Dahl salt-sensitive and salt-resistant rats.
We measured plasma prorenin and renin levels, renal renin mRNA, renal anti-renin and anti-prorenin-prosequence immunoreactivity, and blood pressure in maturing Brookhaven Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats during 14 days of low (0%), medium (0.4%), or high 4%) NaCl diets. Blood pressure was higher in Dahl S rats and did not increase with high NaCl. Seven-week-old Dahl R rats had twofold and sixfold higher levels of plasma prorenin and renal prosequence immunoreactivity, respectively, which by 9 weeks were the same as in Dahl S rats. The anti-renin antiserum, BR1-5, was found to detect prorenin better than renin; Dahl S rats had suppressed renal anti-renin immunoreactivity relative to Dahl-R rats. Dahl R rats were unresponsive to high NaCl, whereas in Dahl S rats, plasma renin and renal prosequence immunoreactivity fell by 90% (P < .01), renal anti-renin immunoreactivity and renal renin MRNA fell by 35% (P < .05 for both), and plasma prorenin fell by 30% (P = NS). NaCl depletion increased prorenin/renin parameters similarly in both strains. There were direct relationships among all of the prorenin/renin parameters. Between low and high salt diets in Dahl S rats, plasma renin increased 20-fold, plasma total renin (renin plus prorenin) and renal renin mRNA both increased threefold, and plasma prorenin increased twofold. The results indicate that under steady-state conditions, plasma and renal renin/prorenin parameters change concordantly and that plasma total renin (renin plus prorenin) reflects changes in renal renin mRNA. The lower blood pressure of Dahl R rats is associated with later maturation-related declines in plasma and renal prorenin. Suppression of plasma renin may delay the salt-induced blood pressure rise in Dahl S rats. Finally, the renin system and blood pressure of Dahl R rats have remarkable disregard for a high salt diet.
Animals↗
Influence of obesity on left ventricular midwall mechanics in arterial hypertension.
The evaluation of the effect of obesity on left ventricular systolic performance may differ in relation to the method used to measure left ventricular function and to the type of study population. Whether obesity worsens left ventricular midwall mechanics in arterial hypertension has never been investigated. Accordingly, we assessed echocardiographic left ventricular midwall shortening-circumferential end-systolic stress relations in 156 normotensive and normal-weight (reference) adults, 94 normotensive and overweight (1985 National Institutes of Health partition values) to obese (body mass index > 30 kg/m2) adults, 263 hypertensive and normal-weight adults, and 224 hypertensive and overweight-to-obese adults. There was an inverse relation of midwall shortening to circumferential end-systolic stress in all groups (all P < .005). Left ventricular performance as a ratio of observed to predicted midwall shortening fell below the fifth percentile in 4 of 94 (4%) of overweight-to-obese normotensive individuals. Eighty-eight of 487 hypertensive subjects (18.1%) exhibited depressed midwall shortening as a percentage of the value predicted from wall stress, with no difference between normal-weight (50 of 263 [19%]) and overweight (38 of 224 [17%]) subjects. Sixty-one normotensive and 131 hypertensive subjects were frankly obese. After adjustment for sex and age, midwall shortening, as either absolute values or a percentage of predicted, was not statistically different among obese, overweight, and normal-weight subjects in both normotensive and hypertensive groups. For each quartile of observed-to-predicted midwall shortening ratio, obese subjects had greater left ventricular end-diastolic volume than normal-weight subjects among both normotensive and, more evidently, hypertensive subjects. A predicted midwall shortening was generated from both wall stress and left ventricular volume with the use of multiple regression analysis. High body mass index, mean blood pressure, aging, and male sex independently predicted low afterload and left ventricular volume-independent midwall left ventricular performance (multiple R = .31, P < .0001). Thus, (1) midwall left ventricular systolic performance in asymptomatic overweight or frankly obese individuals is comparable to that in normal-weight individuals in both the presence and absence of arterial hypertension; (2) however, maintenance of normal life ventricular performance in obese individuals is associated with the use of Starling reserve; and (3) this compensatory mechanism is especially evident when arterial hypertension and obesity coexist.
Adult↗
Renin and prorenin: advances and declines in methodology.
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Enzyme Precursors↗
Chronic carvedilol reduces mortality and renal damage in hypertensive stroke-prone rats.
The effects of carvedilol, a novel vasodilating beta-blocker and antioxidant, and propranolol on survival, neurobehavioral deficits, cardiovascular parameters, plasma renin, plasma aldosterone levels and renal pathology were determined in stroke-prone spontaneously hypertensive rats. Stroke-prone spontaneously hypertensive rats were allowed access to 1% NaCl as the drinking solution and a high fat diet supplemented with carvedilol (1200 or 2400 ppm) or propranolol (2400 ppm). The control group consisted of stroke-prone spontaneously hypertensive rats placed on the same diet with no drug supplement. Animals fed propranolol had a blood level of 864 +/- 68 ng/ml, whereas carvedilol-fed animals had blood levels of 24 +/- 4 ng/ml at 1200 ppm and 471 +/- 145 ng/ml at 2400 ppm. Carvedilol and propranolol treatment resulted in significant beta adrenoceptor blockade. Both compounds reduced heart rate, but had no significant effects on systolic arterial blood pressure. Carvedilol- and propranolol-treated animals also exhibited significant, prolonged protection from neurobehavioral deficits and mortality (P < .01). Elevated plasma renin activity and aldosterone levels seen in untreated controls were significantly decreased by propranolol (P < .05), and to a considerably greater extent by the same dose of carvedilol (P < .01). Carvedilol decreased renal histopathological damage and cardiac hypertrophy to a greater extent (P < .01) than propranolol (at equal doses). Both carvedilol (P < .01)- and propranolol (P < .01)-treated animals had considerably reduced renal damage at 18 weeks of treatment. Carvedilol reduced renal damage more than propranolol (P < .05). In addition, the lower (1200 ppm) dose of carvedilol, which decreased neurobehavioral deficits and mortality, had no significant effects on organ mass or renal function, but significantly (P < .01) reduced renal damage. These data indicate that both beta adrenoceptor blockers, especially carvedilol to a considerably greater degree, convey significant protection in a genetic model of severe hypertension that results in renal and cardiovascular organ pathology, neurobehavioral deficits and premature death.
Adrenergic beta-Antagonists↗
Exercise renography in untreated subjects with essential hypertension.
UNLABELLED: Exercise induced renal dysfunction is reported to occur in treated hypertensive patients but not seen normotensive subjects. It is unclear if this phenomenon is related to the disease or to treatment. METHODS: Four normal volunteers and 15 hypertensive subjects (antihypertensive medications were discontinued for more than 4 wk) were studied with upright radionuclide renography at rest and during bicycle exercise. The amount of exercise was sufficient to increase the heart rate at least 20 bpm above the resting value. All subjects were healthy, without evidence of left ventricular hypertrophy renal disease or hypertensive retinal disease. BUN, serum creatinine concentration and urinalysis were normal in all subjects. Renograms were performed for 12-15 min after injection of either 1 mCi[123]orthoidohippurate (OIH) or 2-7 mCi 99mTc-mercaptoacetyltriglycine (MAG3). Visual analysis and mean transit time calculation were performed on the rest and exercise studies. RESULTS: Seven of 14 hypertensive subjects and none of the normal volunteers demonstrated abnormal prolongation in renal transit during exercise which was not seen on the resting renogram. Four of these seven subjects had a history of hypertension for 2 yr or less. CONCLUSION: About 50% of individuals with mild-to-moderate hypertension and normal renal function may have abnormal renal transit of renal excretion agents during exercise, although their baseline studies are normal. This finding is unassociated with therapy and appears to be related directly to the pathophysiology of essential hypertension.
Adult↗
Rilmenidine and the high risk hypertensive patient.
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Animals↗
Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk.
OBJECTIVES: We sought to determine whether growth influences the relation between left ventricular mass and body size and whether use of different body size indexes affects the ability of ventricular mass to predict complications of hypertension. BACKGROUND: Allometric (or growth) signals between left ventricular mass and height have recently been reported to improve previous approaches for normalization of ventricular mass for body size. METHODS: Residuals of left ventricular mass-height2.7 relations were analyzed in a learning series of 611 normotensive, normal-weight subjects 4 months to 70 years old and, separately, in 383 children (< 17 years old) and 228 adults. Ten-year cardiovascular morbidity in a test series of 253 hypertensive adults was compared with groups with normal or high baseline left ventricular mass normalized for body weight, height, body surface area and allometric powers of height. RESULTS: The dispersion of residuals of ventricular mass versus height2.7 increased with increasing height or age in children but not in adults, suggesting that the effect of other variables on ventricular growth increases during body growth and stabilizes in adulthood. Therefore, we derived separate allometric signals for adults (predicted ventricular mass = 45.4 x height2.13, r = 0.48) and children (32.3 x height2.3, r = 0.85) (both p < 0.0001). Patients with left ventricular hypertrophy had 3.3 times higher cardiac risk with elevated left ventricular mass/height2.7 (p < 0.001), 2.6 to 2.7 times higher risk with left ventricular mass indexed for height, height2.13 and body surface area (all p < 0.01) and 1.7 times the risk with ventricular mass/weight (p > 0.1). CONCLUSIONS: These results show the following: 1) Variability of left ventricular mass in relation to height increases during human growth; 2) allometric signals of left ventricular mass versus height are lower in adults and children than those obtained across the entire age spectrum; 3) height-based indexes of left ventricular mass at least maintain and may enhance prediction of cardiac risk by hypertensive left ventricular hypertrophy; and 4) the allometric signal derived across the entire spectrum of age appears to be more useful for prediction of cardiovascular risk than that computed in adults.
Adult↗
Serum sex hormone levels and renin-sodium profile in men with hypertension.
Both a high renin-sodium profile and abnormal levels of sex hormones have been linked to myocardial infarction (MI) in men. The present study was carried out in men with hypertension to determine whether renin-sodium profile and sex hormone levels are related to each other. Renin-sodium profile, estradiol, testosterone, sex-hormone binding globulin (SHBG), and risk factors for MI, ie, cholesterol, insulin, glucose, and blood pressure, were determined in 45 men with hypertension. The mean serum estradiol level of the 13 men with high renin profile (30.1 +/- 6.5 pg/mL) was significantly higher (P = .01) than that of the nine men with low renin profile (22.6 +/- 3.9), while the mean level of the 23 men with normal renin profile was intermediate (26.2 +/- 5.3). The levels of estradiol and plasma renin activity correlated in the 45 patients before (r = 0.48, P = .001) and after (r = 0.46, P = .002) controlling for age. The mean estradiol-to-testosterone ratio was also higher (P = .04) and the mean SHBG level lower (P < .02) in the high renin group, but the mean testosterone level was not significantly different between the high and low renin groups. Although none of the risk factors was significantly different between the high and low renin groups, all of the mean values in the high renin group were in the direction of increased MI risk. These findings suggest that in men with hypertension, renin profile may be related to estradiol level and possibly to risk factors for MI.
Blood Glucose↗
Low urinary sodium is associated with greater risk of myocardial infarction among treated hypertensive men.
A sodium-reduced diet is frequently recommended for hypertensive individuals. To determine the relationship of sodium intake to subsequent cardiovascular disease, we assessed the experience of participants in a worksite-based cohort of hypertensive subjects. The 24-hour urinary excretion of sodium (UNaV), potassium, creatinine, and plasma renin activity was measured in 2937 mildly and moderately hypertensive subjects who were unmedicated for at least 3-4 weeks. Morbidity and mortality in these systematically treated subjects were ascertained. Men and women were stratified according to sex-specific quartiles of UNaV. Subjects in these strata were similar in race, cardiovascular status, and pretreatment and intreatment blood pressure. Subjects with lower UNaV were thinner, excreted less potassium, and had higher plasma renin activity. During an average 3.8 years of follow-up, a total of 55 myocardial infarctions occurred. Myocardial infarction and UNaV were inversely associated in the total population and in men but not in women, who sustained only nine events. In men, age- and race-adjusted myocardial infarction incidence in the lowest versus highest UNaV quartile was 11.5 versus 2.5 (relative risk, 4.3, 95% confidence interval, 1.7-10.6). No association was observed between non-cardiovascular disease mortality (n = 11) and UNaV. There was a significant linear trend in proportions of myocardial infarction by UNaV quartile, with a break point after the lowest UNaV quartile.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Renin-angiotensin-aldosterone system for blood pressure and electrolyte homeostasis and its involvement in hypertension, in congestive heart failure and in associated cardiovascular damage (myocardial infarction and stroke).
The renin-angiotensin-aldosterone hormonal servo-control system plays a major role in defending normotension and sodium and potassium balance. Derangements of the system involving either excess renin-angiotensin vasoconstriction or too much sodium-volume retention for the plasma-renin level can be implicated in sustaining the hypertension of most human hypertensive disorders. When plasma renin levels are inappropriately or inordinately increased, ischemic vascular injury to the heart, brain and kidneys becomes increasingly evident. In this setting, pharmacologic suppression or blockade of plasma renin activity protects from further cardiovascular damage in experimental models, in human hypertensive disorders and in human congestive heart failure. Still other studies suggest that excessive plasma prorenin levels may be involved in the vasodilator hyperperfusion vascular injury of diabetes mellitus. Recent findings provide considerable promise for pharmacologic strategies that suppress or block plasma renin activity in patients with hypertension or with congestive heart failure for achieving long-term protection from the major cardiovascular sequellae that shorten useful life. Future research to define better the factors that control renal renin gene expression and renal renin secretion could lead to even better treatment and prevention strategies.
Aldosterone↗
Commentary: plasma renin methodology.
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Animals↗
Plasma renin methodology: inadequate sensitivity and accuracy of direct renin assay for clinical applications compared with the traditional enzymatic plasma renin activity assay.
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Humans↗
Angiotensinogen depletion by high renin levels in hypertensive rats: no evidence for tonic stimulation of angiotensinogen by angiotensin II.
OBJECTIVE: Data concerning the effect of angiotensin II (Ang II) on plasma angiotensinogen levels are conflicting. Although Ang II is reported to stimulate the biosynthesis of angiotensinogen, plasma angiotensinogen is often depleted by renin when the level of renin, and therefore Ang II, increases. In the present study we used the Ang II subtype 1 (AT1) receptor antagonist losartan to investigate whether rising plasma Ang II levels stimulate angiotensinogen production to counteract the falling plasma angiotensinogen levels caused by increasing renin activity in plasma. METHOD: Angiotensinogen was measured in plasma from two previously reported studies in which 6-week-old stroke-prone spontaneously hypertensive rats (SHRSP) or Dahl salt-sensitive (Dahl-S) rats were fed high-salt diets (4 and 8% sodium chloride, respectively) for 10-12 weeks with or without losartan. RESULTS: As reported previously, plasma renin was suppressed during the first 4 weeks of the high-salt diet but then paradoxically increased in both strains. When plasma renin increased, plasma angiotensinogen levels fell to 45 and 62% of the baseline value. The plasma renin concentration was negatively correlated with plasma angiotensinogen both in SHRSP and in Dahl-S rats (r = -0.76, P < 0.001 and r = -0.60, P < 0.001, respectively). In Dahl-S rats losartan treatment was associated with lower levels of plasma angiotensinogen but caused greater increases in plasma renin. When differences in renin were taken into account, plasma angiotensinogen levels were not different in losartan-treated and untreated Dahl-S rats. Similarly to Dahl-S rats, plasma angiotensinogen fell in SHRSP when renin increased, but SHRSP had higher plasma angiotensinogen levels during losartan treatment because plasma renin concentration was lower. CONCLUSION: The present study shows, in two strains of hypertensive rat, that an increase in plasma renin levels is associated with a fall in plasma angiotensinogen levels. Concurrent treatment with an Ang II AT1 receptor antagonist does not augment this fall, except to the extent that renin rises further. The results provide no evidence for a significant tonic stimulatory effect of Ang II on plasma angiotensinogen levels.
Administration, Oral↗
Midwall left ventricular performance in salt-loaded Dahl rats: effect of AT1 angiotensin II inhibition.
OBJECTIVE: The relationship between left ventricular midwall shortening and circumferential end-systolic stress was studied in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats after 6-8 weeks of an 8% Na+ diet with or without losartan, an AT1 angiotensin II receptor antagonist. MATERIALS AND METHODS: Losartan was given in drinking water to 13 Dahl S and 13 Dahl R rats, while 14 control Dahl S and 14 control Dahl R rats were given tap water, for 8 weeks. The endpoint was the last blood pressure and echocardiographic examination after 8 weeks or before death for rats which did not survive the entire period. Tail blood pressure was measured in awake animals and two-dimensional guided M-mode echocardiography was used. RESULTS: The left ventricular midwall shortening-circumferential end-systolic stress relationship in 45 normotensive Wistar rats was used to calculate the ratio of observed to predicted left ventricular midwall fractional shortening. At the endpoint, afterload-independent midwall shortening was higher in Dahl S rats on losartan or tap water, and in Dahl R rats on losartan than in weight-matched normotensive Wistar rats (all P<0.05). Afterload-independent midwall shortening was related to the left ventricular chamber dimension in a learning series of 109 rats (64 Goldblatt and 45 normotensive rats on a normal sodium diet; r = 0.73) and was adjusted in Dahl rats to a constant left ventricular internal diameter (6.9 mm) by the learning regression equation. The adjusted afterload-independent midwall shortening was still higher in Dahl S rats on losartan than in controls (P<0.02). Left ventricular internal diameter-adjusted afterload-independent midwall shortening was inversely related to the left ventricular mass in both Dahl S and Dahl R groups (r = -0.40 and -0.72, both P<0.04). CONCLUSIONS: (1) Midwall left ventricular performance was higher in Dahl S than Dahl R rats on a high-salt diet; (2) this elevation was partially independent of an increase in left ventricular chamber size, an indirect measure of preload; and (3) in Dahl S rats on losartan, increased left ventricular performance is related to improved contractility, associated with a blunted development of left ventricular hypertrophy.
Angiotensin Receptor Antagonists↗