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Biomedical subjects

J H Laragh

Publications and source records attributed to J H Laragh.

At least 91 records · Page 5Linked to original sources
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

Relation of left ventricular hypertrophy, afterload, and contractility to left ventricular performance in Goldblatt hypertension.

To analyze the determinants of left ventricular (LV) performance (myocardial afterload, chamber size, mass, and contractility) in Goldblatt hypertension, 19 anesthetized one-kidney, one-clip (1K1C) and 28 two-kidney, one-clip (2K1C) male Wistar rats were studied 58 to 62 days after clipping, together with 19 sham-operated and 13 normal rats (controls), by M-mode echocardiography using necropsy-validated methods of measurement. The LV fractional shortening was inversely related to end-systolic stress in all groups (r = -0.89 to -0.95, all P less than .00001): 7 2K1C (25%) and 9 1K1C (47%) had fractional shortening above the upper confidence limit in control animals. Both 1K1C and 2K1C with high LV performance had severe hypertension, inadequate LV hypertrophy, with resultant high wall stress (both P less than .005), increased LV chamber dimension (P less than .005 and P less than .05, respectively) and high afterload-corrected fractional shortening (both P less than .001); 2K1C also had high plasma renin activity and atrial natriuretic factor levels (both P less than .01). Rats with normal LV performance exhibited mild hypertension, adequate LV hypertrophy (normalizing wall stress), and normal LV chamber size and afterload-corrected fractional shortening. Thus, 8 1/2 weeks after clipping, adequate LV hypertrophy allows maintenance of normal LV function by normalizing myocardial afterload in a majority of rats with Goldblatt hypertension, whereas increased LV contractility (and possibly use of preload reserve in 1K1C) maintains normal LV function in the presence of inadequate LV hypertrophy and elevated wall stress, in a substantial minority of rats that developed more severe Goldblatt hypertension.

Animals↗
PubMed1992

Left ventricular mass as a measure of preclinical hypertensive disease.

The ability to identify the hypertensive patient who is destined to suffer a morbid or fatal complication in the long presymptomatic phase of this condition, when its natural history would be most subject to amelioration, is limited by the weak relation between the level of blood pressure and the occurrence of complications. Recent research indicates that the level of left ventricular (LV) mass--most conveniently measured by echocardiography--reflects the combined effects of a variety of factors involved in the pathophysiology of hypertension, including obesity, exaggerated blood pressure responses to everyday activity, high sodium intake and blood viscosity, and genetic factors predisposing to hypertension. Prospective studies indicate that LV mass is a stronger predictor of subsequent morbid events and death than blood pressure or other conventional risk factors except age. Preliminary findings of close relations between LV mass and arterial disease and between the change in LV mass during antihypertensive treatment and subsequent events contribute to explaining the strong predictive value of LV mass. Further research is needed to clarify the biologic basis of these observations and to determine whether stratification of hypertensive patients based on their level of LV mass can improve the treatment of hypertension.

Echocardiography↗
PubMed1992

Inhibition of human renin by rat plasma. Rat angiotensinogen is a competitive inhibitor of the human renin-substrate interaction.

Human renin can cleave rat angiotensinogen, yet infusion of human renin into rats causes only a modest increase in blood pressure. We therefore investigated whether there is a factor in rat plasma which inhibits human renin activity. The addition of 20% normal rat plasma to human plasma had a slight, but not significant, inhibitory effect on the rate of angiotensin formation, while nephrectomized rat plasma, which had a seven-fold higher concentration of angiotensinogen, caused a dose dependent inhibition (20 to 70%). The rat plasma inhibitor copurified with angiotensinogen. Analysis of the kinetics of the human renin-human substrate reaction and of the human renin-rat substrate reaction revealed that the rate of angiotensin I production in the presence of both substrates could be entirely accounted for by assuming that rat and human angiotensinogens are competitive inhibitors of each other. These results show that human renin can cleave rat substrate but the reaction rate is extremely slow relative to the cleavage of human angiotensinogen. They also indicate that rat angiotensinogen is an effective competitive inhibitor of the human renin-substrate reaction. These results may be relevant to the development of renin inhibitors and to transfection studies involving heterologous renin or substrate genes.

Angiotensinogen↗
PubMed1992

Atrial natriuretic peptide synthesis in atrial tumors of transgenic mice.

Transgenic mice harboring a chimeric gene linking mouse protamine 1 5'-flanking sequence to the coding sequence of the simian virus 40 T-antigen develop spontaneous rhabdomyosarcomas of the right atria. The presence of the tumors is accompanied by dramatic elevations in plasma atrial natriuretic peptide (ANP) immunoreactivity (1,698 +/- 993 vs. 60 +/- 18 fmol/ml for controls) and hematocrit (56 +/- 8 vs. 51 +/- 2 for controls). The immunoreactive ANP (irANP) present in the tumors is similar in size to irANP found in normal mouse atria. ANP mRNA transcripts present in the tumors also appear to be very similar in overall size and 5'-termini to those produced in normal cardiac tissue. Microscopically, the tumors are composed of a disorganized array of densely packed abnormal-appearing cells. Immunocytochemistry and in situ hybridization analysis reveal considerable heterogeneity in ANP gene expression. ANP peptide and mRNA are detectable throughout the parenchyma of the tumors, but absolute levels of expression vary widely among different cells in the population. These tumors represent a potentially valuable model for the study of inappropriate ANP secretion and may provide a tissue source for the development of an ANP-producing atrial cell line.

Amino Acid Sequence↗
PubMed1992

Cardiac secretion of atrial natriuretic factor with exercise in chronic congestive heart failure patients.

We have previously reported a fivefold increase of plasma atrial natriuretic factor (ANF) in patients with congestive heart failure (CHF) compared with normal subjects. However, given the marked increase of ANF under basal conditions, the extent to which ANF secretion can further increase under physiological stress is not been clarified in CHF. We therefore evaluated ANF secretion during ergometric exercise in 11 patients with CHF, with peripheral venous ANF samples obtained at rest and peak exercise. In seven patients, simultaneous peripheral venous and right ventricular ANF samples were obtained to estimate myocardial ANF secretion. Hemodynamic characteristics of exercise included a significant increase of heart rate, mean arterial pressure, and cardiac output (all P < 0.01); reduction of systemic vascular resistance (P < 0.001); and increase of right atrial and pulmonary wedge pressures (P < 0.001). ANF was abnormally elevated at baseline (108 +/- 58 fmol/ml) yet increased further to 183 +/- 86 fmol/ml with exercise (P < 0.003). A step-up of right ventricular ANF, particularly during exercise, was consistent with active myocardial secretion, despite elevated baseline ANF levels.

Adult↗
PubMed1992

Lewis K. Dahl Memorial Lecture. The renin system and four lines fo hypertension research. Nephron heterogeneity, the calcium connection, the prorenin vasodilator limb, and plasma renin and heart attack.

As the major regulator of arterial blood pressure and sodium balance, the renin axis supports normotension or hypertension via angiotensin-mediated vasoconstriction and angiotensin plus aldosterone-induced renal sodium retention. In this endocrine servo control, renal renin is released by hypotension or salt depletion; conversely, with hypertension or volume excess, plasma renin activity falls to zero. Accordingly, any renal renin secretion is abnormal in the face of arterial hypertension. Human hypertensive disorders comprise a spectrum of abnormal vasoconstriction-volume products (renin-sodium profiles). Excess plasma renin activity for the sodium balance is created by nephron heterogeneity in which a subpopulation of ischemic nephrons hypersecretes renin and retains sodium. This excess renin impairs adaptive natriuresis of neighboring normal nephrons. Research defining the pivotal role of vascular cytosolic calcium for transducing sodium or renin-mediated vasoconstriction explains the selective value of calcium antagonists for correcting the sodium-volume-mediated, and beta-blockers or angiotensin converting enzyme inhibitors for correcting renin-mediated, arteriolar vasoconstriction. The renin precursor prorenin appears to be physiologically active, causing selective vasodilation that offsets renin-mediated vasoconstriction. Overactivity of prorenin may be involved in the hyperperfusion vascular injuries of diabetes mellitus and toxemias. Prorenin underactivity may facilitate renin-mediated ischemic vascular injury. In essential hypertension, undue plasma renin activity is powerfully and independently associated with heart attack risk. Conversely, patients with low renin activity are protected from heart attack despite higher blood pressures and greater age. Also, renin or angiotensin administration consistently causes vascular injury in the heart, brain, and kidneys of animals. These data suggest new potentials for the prevention of cardiovascular sequelae (heart attack and stroke) by using explicit strategies to curtail plasma renin activity.

Calcium↗
PubMed1992

Role of renin secretion and kidney function in hypertension and attendant heart attack and stroke.

Control of blood pressure usually has not, by itself, affected the incidence of heart attack in hypertensive patients. This suggests a need for cause-specific therapy targeted against mechanisms that engage the risks of myocardial infarction. Study of the renin system, the ongoing, long-term servo-control over blood pressure and electrolyte homeostasis may provide answers. Inappropriately high renin production, generating the powerful vasoconstrictor, angiotensin II, may cause ischemic vascular damage in the heart, kidney and brain, predisposing to infarction. Many clinical situations associated with high plasma renin levels are accompanied by striking vascular damage, heart attack, or stroke. A recent prospective study of 1,717 hypertensive patients shows an unequivocally positive relationship between myocardial infarction and high-renin status regardless of other risk factors such as smoking, hypercholesteremia, or diabetes. The data also suggest the possibility that renin is a continuous variable, since the risk of heart attack was significantly weaker in medium-renin than in high and significantly greater than in low renin subjects. These observations are in keeping with concept that any renin secretion in the face of arterial hypertension is abnormal, since the truly normal kidney completely turns off its renin secretion. Thus the renin-sodium profile appears to be especially useful for evaluating the large fraction of patients who develop heart attacks in the absence of these other risk factors. Although, these findings suggest that a renin test should be performed routinely in hypertensive patients, the better to assess prognosis and design appropriate anti-renin therapy.

Blood Pressure↗
PubMed1992

In vivo left ventricular anatomy in rats with two-kidney, one clip and one-kidney, one clip renovascular hypertension.

OBJECTIVES: To evaluate differences in left ventricular structural changes related to different hemodynamic patterns. DESIGN: One-kidney, one clip (1K1C; volume-dependent hypertension) rats were two-kidney, one clip (2K1C; high-resistance hypertension) to determine whether these two types of Goldblatt rats showed different types of left ventricular adaptation. METHODS: M-mode echocardiography was used to study 28 2K1C and 19 1K1C Wistar rats 8 weeks after surgery and 55 age-matched control animals. RESULTS: Systolic blood pressure was equally high in the two models; the 1K1C rats had a larger left ventricular chamber and normal plasma renin activity (PRA), whereas in the 2K1C rats PRA was increased and the left ventricular chamber was normal. The atrial natriuretic factor was significantly increased only in the 2K1C rats and was related to PRA. The left ventricular mass index was increased in both models, but more in the 1K1C than the 2K1C rats. CONCLUSIONS: In both models the degree of left ventricular hypertrophy was associated with the interacting effects of the hemodynamic component superimposed on the primary hemodynamic pattern (i.e. blood pressure as an expression of pressure overload in the primarily volume-dependent 1K1C rats and the left ventricular chamber size as an expression of volume overload in the high-resistance 2K1C rats). The interaction between pressure and volume increased the left ventricular wall thickness in both models, with additional chamber enlargement in the 1K1C rats. In these rats, the increase in left ventricular mass was more pronounced due to the greater volume load on the heart.

Adaptation, Physiological↗
PubMed1992

Angiotensin II receptor antagonist delays renal damage and stroke in salt-loaded Dahl salt-sensitive rats.

OBJECTIVE: To study the effects of blockade of the renin-angiotensin system upon the development of hypertension, end-organ damage and mortality in Dahl salt-sensitive (DSS) rats using an angiotensin II receptor antagonist, losartan. DESIGN AND METHODS: DSS rats (n = 186) were fed 8% NaCl from 6 to 16 weeks of age. One group received losartan whilst the control group was untreated. Changes in blood pressure and plasma renin activity (PRA), as well as renal and cerebrovascular damage and survival were assessed during the study. RESULTS: Losartan blunted the blood pressure rise only transiently. Salt loading suppressed PRA in both groups until week 4 and thereafter it rose more markedly in the treated group. With no treatment renal lesions were first detected at 2 weeks, and strokes at 6 weeks. However, losartan transiently decreased the incidence and delayed the progression of renal damage and cerebrovascular lesions (strokes) and increased survival. PRA correlated with renal damage and the incidence of strokes in both groups. Blood pressure only partially affected survival, but did not correlate with stroke incidence. CONCLUSIONS: These results indicate that whereas the rise in blood pressure is dependent upon sodium loading, morbidity and mortality in salt-loaded DSS rats are associated with activation of the renin-angiotensin system and are only partially related to blood pressure.

Angiotensin II↗
PubMed1991

Gender differences in left ventricular anatomy, blood viscosity and volume regulatory hormones in normal adults.

Gender differences in left ventricular (LV) anatomy, whole blood and plasma viscosity, and blood volume regulatory hormones were studied in 110 normotensive employed adults (28 black and 34 white men [mean age 51 +/- 12 years], 20 black and 28 white women [mean age 53 +/- 12 years]). LV mass and wall thicknesses were positively related to whole blood viscosity, primarily because of higher values of both variables in men. LV chamber size was inversely related to hematocrit and to blood viscosity (p less than 0.002) in women but not in men. Whole blood viscosity increased with age in men (p less than 0.01), but tended to decrease in women; older women also had better LV function, larger LV chambers, and a trend toward increasing LV mass. Atrial natriuretic factor increased with age in women but not in men (r = 0.60, p less than 0.001), and plasma renin activity decreased (r = -0.35, p less than 0.02). Thus, in women, increase in LV chamber size with age and associated changes in LV systolic function, atrial natriuretic factor levels and plasma renin activity suggest plasma volume expansion related to the aging process. These findings also suggest that an increase in LV volume load with age may contribute to previously reported increases in LV mass in older women.

Adolescent↗
PubMed1991

Exercise-induced secretion of atrial natriuretic factor and its relation to hemodynamic and sympathetic stimulation in untreated essential hypertension.

This study evaluates the release of atrial natriuretic factor (ANF) during maximal exercise in 7 patients with untreated moderate to severe hypertension with invasive monitoring of hemodynamic characteristics in relation to sympathetic activity. Peripheral venous ANF (fmol/ml) was determined at rest and maximal exercise producing a respiratory exchange ratio of 1.14 +/- 0.10. In 5 of 7 patients, simultaneous right ventricular and peripheral venous ANF samples could be obtained to assess exercise myocardial secretion of ANF. With exercise, mean blood pressure increased from 150 +/- 26 to 192 +/- 29 mm Hg (p less than 0.001), pulmonary wedge pressure increased from 7 +/- 3 to 18 +/- 10 mm Hg (p less than 0.05) and ANF increased from 11.7 +/- 8.2 to 25.7 +/- 15.9 (p less than 0.02). This ANF response correlated weakly with pulmonary wedge pressure (r = 0.497, p = not significant), since patients without an increase in pulmonary wedge pressure had no increase in ANF. However, changes in pulmonary wedge pressure and plasma norepinephrine during exercise were inversely correlated (r = -0.811, p less than 0.02), with the greatest increase in norepinephrine occurring with a minimal increase in pulmonary wedge pressure. Similarly, ANF and plasma norepinephrine were inversely correlated during exercise (r = -0.869, p less than 0.05). A significant increase in right ventricular ANF indicated myocardial secretion. Plasma ANF therefore increased because of active myocardial production during exercise in patients with moderate to severe hypertension. These findings further suggest a directionally opposing relation between ANF release resulting from increased atrial tension and sympathetic nervous system influence on cardiac performance during exercise.

Adult↗