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Biomedical subjects

J H Laragh

Publications and source records attributed to J H Laragh.

At least 55 records · Page 3Linked to original sources
PubMed1994

The high-risk hypertensive patient and the potential for brain imidazoline receptor binding by rilmenidine.

It is a fact that sympathetic outflow is a player in most, if not all, hypertensive conditions. A selective, effective, and relatively benign means of controlling it remains high on every clinician's wish list. In this supplement we examine the neurobiologic and pharmacologic evidence that the wish is nearing fulfillment. Recent evidence has documented the existence of nonadrenergic receptors in the brainstem, other than the well-known alpha 2-adrenergic receptors, that bind the imidazoline portion of vasoactive molecules. Pharmacologic science has wasted little time in developing compounds rich in imidazoline-like structures that, by supplanting norepinephrine (the natural cerebral neurotransmitter for sympathetic nervous system outflow) quiet sympathetic outflow, restrain heart rate and vasomotor influence, and reduce the negative quality-of-life effects induced by earlier centrally acting agents. This is because specific ligands for the imidazoline-preferring receptors appear to lower blood pressure without attendant drowsiness, dry mouth, and impaired mentation. Rilmenidine, the subject of this supplement, is the newest such agent, and the scientists involved in its development and clinical trials have produced heartening data. These developments presage good news in the clinic, and I am excited by their potential, particularly that for gaining deeper insight into human pressor phenomena.

Animals↗
PubMed1994

Diagnosis and treatment of primary hyperaldosteronism.

OBJECTIVE: To characterize the clinical and laboratory features of primary aldosteronism and to evaluate which diagnostic tests can discriminate surgically curable forms of this syndrome. DESIGN: Retrospective analysis of the following data from 82 patients with primary aldosteronism: blood pressure, serum electrolytes, urinary aldosterone and electrolytes, computed tomographic scans, plasma renin and aldosterone before and during upright posture, atrial natriuretic peptide, and adrenal vein aldosterone and cortisol. Clinical outcomes assessed after treatment included blood pressure, serum electrolytes, and plasma renin activity. RESULTS: Drug therapy was discontinued before diagnostic tests were done in 56 of 82 patients (34 with adenomas and 22 with hyperplasia). Compared with patients with hyperplasia, those with adenomas had higher systolic (184 mm Hg and 161 mm Hg, respectively; P < 0.001) and diastolic blood pressures (112 mm Hg and 105 mm Hg; P = 0.03), lower serum potassium levels (3.0 mmol/L and 3.5 mmol/L; P < 0.001), and higher serum CO2 (P = 0.001), atrial natriuretic peptide (P = 0.008), and urinary 18-methyl oxygenated cortisol metabolite levels (P = 0.02). In patients with adenomas, aldosterone secretion lateralized to one adrenal gland and did not increase during the postural stimulation test; preoperative urinary aldosterone levels were correlated with diastolic pressures (r = 0.58; P = 0.001). Hypertension was "cured" postoperatively in approximately 35% of patients with adenomas and those with hyperplasia (P > 0.2) but was "improved" more frequently in those with adenomas (P = 0.002). Cured patients from both groups were younger than those not cured (mean ages, 43 years and 54 years, respectively; P = 0.002) and had lower preoperative mean plasma renin activity (0.17 ng/mL per hour and 0.50 ng/mL per hour; P < 0.001). All patients with adenomas in whom aldosterone secretion lateralized were either cured or improved. CONCLUSION: Of the 51 patients with primary aldosteronism who had adrenalectomy (43 patients with adenomas and 8 with hyperplasia), those most likely to be cured were younger and had lower plasma renin activity. In patients with adenomas who were cured or improved, aldosterone secretion was more likely to lateralize. Tests that distinguished adenomas from adrenal hyperplasia included the postural stimulation test, urinary excretion rates of 18-oxocortisol and 18-hydroxycortisol, and adrenal vein sampling.

Adenoma↗
PubMed1994

Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension.

OBJECTIVES: This study examined left ventricular performance in relatively unselected hypertensive patients by use of physiologically appropriate midwall shortening/end-systolic stress relations. BACKGROUND: Supranormal left ventricular function has been reported in hypertensive patients, possibly due to an artifact of mismatching endocardial rather than midwall fractional shortening to mean left ventricular end-systolic stress. METHODS: Samples of 474 hypertensive patients (150 women, 324 men) and 140 normal subjects (68 women, 72 men) were drawn from a large urban employed population. The inverse relations (p < 0.0001) of both echocardiographic endocardial and midwall fractional shortening to end-systolic stress in normal subjects were used to calculate the ratios of observed to predicted endocardial and midwall fractional shortening in hypertensive patients. Midwall shortening was calculated from an elliptic model, taking into account the epicardial migration of the midwall during systole. RESULTS: Use of midwall fractional shortening in hypertensive patients reduced the proportion of patients with function above the 95th percentile of normal from 22% to 4% (p < 0.0001) and fractional shortening as a percent of predicted from 107% (p < 0.001 vs. 100% in normotensive control subjects) to 95% (p < 0.0001; p < 0.001 vs. 101% in normotensive control subjects). Midwall shortening was below the 5th percentile of normal in 16% of hypertensive patients instead of 2% with endocardial shortening (p < 0.0001): They tended to be older than other hypertensive patients and had concentric left ventricular hypertrophy. Among hypertensive patients, those with concentric left ventricular hypertrophy or remodeling had reduced midwall shortening as a percent of predicted from end-systolic stress (p < 0.0001). CONCLUSIONS: Use of the physiologically more appropriate midwall shortening/end-systolic stress relation 1) markedly reduces the proportion of hypertensive subjects identified as having high endocardial left ventricular function; and 2) identifies a substantial subgroup of patients with reduced left ventricular function who have concentric geometry of the left ventricle, a pattern associated with high cardiovascular risk.

Adult↗
PubMed1994

Angiotensinogen dependency of blood pressure in two high-renin hypertensive rat models.

In this analysis we investigated whether angiotensinogen (Aogn) levels were related to blood pressure (BP) in two hypertensive rat models when renin secretion was either under physiologic regulation or out of control. These relationships were investigated using BP data from previous reports in which SHRsp and Dahl S rats were studied for 10 to 12 weeks while ingesting a high-salt diet with and without the angiotensin II (AngII) antagonist losartan. During the first 4 weeks of high-salt diet, plasma renin concentration (PRC) was appropriately suppressed but it subsequently increased paradoxically in both strains. During the first 4 weeks, when renin secretion was under normal control, as indicated by its suppression by the high-salt diet and by an inverse relationship between PRC and BP (r = -0.69, P < .001 and r = -0.53, P < .01 in Dahl S and SHRsp, respectively), there was no relationship between BP and plasma Aogn. In contrast, when renin secretion increased paradoxically, the inverse relationship between BP and PRC was lost and a positive relationship was found between BP and plasma Aogn in both Dahl S rats (r = 0.70, P < .01) and SHRsp (r = 0.57, P < .01). There was no relationship between BP and Aogn in either strain during treatment with losartan either before or after 4 to 6 weeks of salt feeding. These results show Aogn dependency of BP, but only under conditions in which renin cannot feed back normally. The Aogn relationship to BP was most likely dependent on the vasoconstrictor effect of AngII since it was lost during AngII AT1 receptor antagonism.

Angiotensin II↗
PubMed1994

Modern strategies to prevent coronary sequelae and stroke in hypertensive patients differ from the JNC V Consensus Guidelines.

In recent years, government agencies of many countries have established consensus guidelines for the evaluation and treatment of hypertension. Once published, guidelines tend to be perceived as directives by a variety of health care providers. Unfortunately, these guidelines often do not reflect the practices of most hypertension experts. This report summarizes the opinions of seven hypertension experts concerning the impact of "official" guidelines on clinical practice. In addition, the individual therapeutic recommendations of these panel members are summarized. Their different treatment strategies reflect the diversity of first rate treatment plans that aim to reduce the cardiovascular sequelae in individual patients with essential hypertension. Most importantly, not one of these seven treatment strategies followed the "preferred" treatment of the U.S. guidelines, which recommend diuretics and beta-blockers as first-line therapy. The present authors approach the treatment of hypertension as a means to reduce cardiovascular events. Thus, reduction of blood pressure is not the most important therapeutic endpoint. The panel believes that whereas many different drugs can produce effective blood pressure reduction, the modern primary goal of antihypertensive drug therapy is to select a regimen most likely to prolong the quality and duration of life. In real terms, this means that the primary goal of treatment is the prevention of the major vascular sequelae of hypertension (heart attack, ventricular remodeling, hypertrophy, heart failure, and stroke) that shorten useful life. There are a number of effective hypertensive treatments, which can be selected based on individual patient requirements. However, many consensus guidelines do not allow the flexibility required to optimize individual patient treatment. As a result, health care providers should not feel compelled to regard the preferences of "official" guidelines as the best, modern, state-of-the-art therapy for an individual patient. All seven experts who are deeply involved in the daily care of patients preferred drugs other than beta-blockers and diuretics (the Joint National Committee [JNC] choices) for first-line therapy of hypertension.

Cardiovascular Diseases↗
PubMed1994

Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence.

A comprehensive review of physiological and molecular biological evidence refutes claims for synthesis of renin by cardiac and vascular tissues. Cardiovascular tissue renin completely disappears after binephrectomy. Residual putative reninlike activity, where investigated, has had the characteristics of lysosomal acid proteases. Occasional reports of renin or renin mRNA in vascular and cardiac tissues can be ascribed to failure to remove the kidneys 24 hours beforehand, overloading of detection systems, problems with stringency in identification, and illegitimate transcripts after more than 25 cycles of polymerase chain reaction. Others, using more stringent criteria, have failed to detect cardiac and vascular renin mRNA. Accordingly, a growing number of investigators have concluded that the kidneys are the only source of cardiovascular tissue renin. Although prorenin is secreted from extrarenal tissues as well as from the kidneys, there is no evidence that it is ever converted to renin in the circulation. The kidney is the only tissue with known capacity to convert prorenin to renin and to secrete active renin into the circulation. Accordingly, renin of renal origin determines plasma and hence, extracellular fluid renin levels. In these loci, angiotensin (Ang) I, formed by renin cleavage of circulating and interstitial fluid angiotensinogen, is in turn cleaved by angiotensin converting enzyme, located in plasma and extracellular fluids and on the luminal surface of pulmonary and systemic vascular endothelial cells, to Ang II, which perfuses and bathes the heart and vasculature. Consistent with this model, plasma renin and angiotensin and the antihypertensive action of renin inhibitors, converting enzyme inhibitor, or Ang II antagonists all disappear after binephrectomy. Thus, the plasma renin level, via Ang II formation, determines renin system vasoconstrictor activity, the antihypertensive potential of anti-renin system drugs, and the risk of heart attack in hypertensive patients. This analysis redirects renin research to renal mechanisms that create the plasma renin level, to renal prorenin biosynthesis and its processing to renin, and to their regulated secretion, extracellular distribution, and possible binding to by target tissues. In this context, it is still possible that changes in circulating and interstitial renin substrate or available converting enzyme might exert subtle modulating influences on Ang II formation. However, this analysis redefines the importance of plasma renin measurements to assess clinical situations, because plasma renin is the only known initiator driving the cardiovascular renin-angiotensin system, and its strength can be measured.

Angiotensin I↗
PubMed1994

Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults.

Although it is recognized that both hypertension and obesity are associated with increased left ventricular mass, the relative impacts of obesity, arterial hypertension, and gender on the prevalence of ventricular hypertrophy remain uncertain. Accordingly, echocardiographic left ventricular mass normalized for height to the power of the allometric or growth relation between ventricular mass and height was compared in 164 normotensive subjects (85 men [24 obese] and 79 women [28 obese], aged 45 +/- 12 years) and 475 hypertensive patients (325 men [126 obese] and 150 women [85 obese], aged 54 +/- 10 years) from an adult employed population. Gender-specific upper normal limits were used to identify ventricular hypertrophy. Left ventricular mass/height 2.7 was higher in obese than normal-weight normotensive subjects (P < .004) independently of the level of blood pressure and identified a higher prevalence of hypertrophy (mainly eccentric) in obese than in normal-weight normotensive subjects (14% versus 5%, P < .04), a difference that was not detected by left ventricular mass/body surface area. Left ventricular mass/height identified hypertrophy in 52% of obese and 30% of normal-weight hypertensive patients (P < .0001) because of higher prevalences in obese than normal-weight patients of both eccentric (34% versus 20%) and concentric ventricular hypertrophy (18% versus 10%). The increase in left ventricular mass was independent of blood pressure values in obese normotensive women (but not men), and the prevalence of supranormal left ventricular mass/height 2.7 was even higher in hypertensive obese women (58%) than men (49%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

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.

Analysis of Variance↗
PubMed1994

Estradiol- and progesterone-related increases in the renin-aldosterone system: studies during ovarian stimulation and early pregnancy.

To investigate the degree to which endogenous increases in estradiol (E2) and progesterone (P4) are associated with changes in the renin system, we studied eight patients undergoing ovarian stimulation for in vitro fertilization (FSH/human menopausal gonadotropin or clomiphene citrate for 5-11 days, followed by hCG). Three conceived and were followed for up to 62 days after hCG treatment. The others were followed until the end of the luteal phase. During the follicular phase, E2 increased 10-fold, PRA increased 2-fold, and absolute levels of E2 and P4 were positively correlated (r = 0.63; P < 0.05). After ovulation, which was induced by hCG, E2 fell by 50% (day 7), but there was a 50-fold increase in P4 and a further 5-fold increase in PRA. By day 14, E2 increased again in the women who conceived, to levels even higher than those in the follicular phase, and both P4 and PRA increased 2- to 3-fold between days 7 and 14. In contrast, E2, P4, and PRA returned toward baseline levels in the nonpregnant women. On day 21, E2, P4, and PRA remained very high in the pregnant women [E2, 2297 +/- 255 pg/mL (8430 pmol/L); P4, 103 +/- 22 pg/mL (328 pmol/L); PRA, 33 +/- 8 ng/mL.h (9.17 ng/L.s)]. During the luteal phase and early pregnancy, there was a positive relationship between PRA and P4 (r = 0.68; P < 0.05). There was also a positive relationship between PRA and E2 (r = 0.54; P < 0.05); compared to the follicular phase level, PRA was 4-fold higher in the luteal phase at any E2 level. Like renin, urinary aldosterone excretion (UA) increased 5-fold during the luteal phase (day 7) and by a further 3-fold between days 7 and 21 in the pregnant women, reaching very high levels [135 +/- 28 micrograms/day (375 nmol/day); n = 3]. PRA and UA positively correlated (r = 0.59; P < 0.08). Plasma angiotensinogen increased from 2146 +/- 283 ng angiotensin-I/mL (n = 8) to 3682 +/- 607 (n = 8) on day 7 and to 5353 +/- 799 (n = 3) on day 21. Urinary sodium excretion did not fall, and urinary potassium did not increase in coordination with the changes in renin and aldosterone. There was no hypokalemia. These results demonstrate marked increases in plasma renin and UA in coordination with increases in plasma E2 and P4 during ovarian stimulation and early pregnancy, and coordinated falls during luteolysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Response to the captopril test is dependent on baseline renin profile.

OBJECTIVE: To determine prospectively the relationship between the renin-sodium profile and the renin response to captopril challenge in patients with essential hypertension. DESIGN: A standard captopril test was performed in 108 uncomplicated, untreated hypertensive subjects with normal renal function and urinary sodium excretion in the range 50-240 mmol/day. The subjects were selected from a working population with a low expected prevalence of renovascular disease. METHOD: The captopril test was considered positive if the captopril-induced rise in plasma renin activity met all three criteria established by Müller et al. Patients with a positive test and those meeting only one or two of the three criteria were further investigated for renovascular hypertension by measuring renal venous renins and by digital subtraction intravenous angiography. Renin responses were analyzed according to baseline renin-sodium profile. RESULTS: Nine of 108 subjects had a false-positive captopril test result. Among the subjects with a low or normal renin-sodium profile, 1% (one of 82) had a false-positive result. In contrast, false-positive results were seen in 31% (eight of 26) of high-renin subjects. False-positive test results were not related to urinary sodium excretion or to excessive decrease in blood pressure. The magnitude of the renin response to captopril was strongly and directly related to the baseline plasma renin activity. CONCLUSION: An exaggerated renin response to captopril challenge is common in patients with high-renin essential hypertension. Therefore, in a population with a low probability of renovascular hypertension, caution is recommended in interpreting a positive test result in patients with a high baseline renin.

Adult↗
PubMed1994

Is the higher incidence of ischemic disease in patients with hypertension and diabetes related to intracellular depletion of high energy metabolites?

To study mechanisms underlying ischemia in hypertension and non-insulin dependent diabetes mellitus (NIDDM), 31P-magnetic resonance spectroscopy was used to evaluate adenosine triphosphate and 2,3 diphosphoglycerate (2,3 DPG) levels in erythrocytes of control (n = 21), hypertensive (n = 22), and NIDDM (n = 10) subjects. Compared to adenosine triphosphate levels in controls (2.22 +/- 0.10 mM), both hypertensive (1.89 +/- 0.10 mM, sig = 0.05 versus normal) and NIDDM subjects (1.57 +/- 0.13 mM, sig = 0.05 versus normal) exhibited lower values. NIDDM subjects also displayed suppressed levels of 2,3 DPG (6.84 +/- 0.48 mM, sig = 0.05 versus normal and EH), compared to hypertensives (8.34 +/- 0.27 mM). These data suggest cellular energy metabolism is disrupted in hypertension and NIDDM. Both conditions may thereby sensitize tissues to ischemic damage, lower adenosine triphosphate levels by decreasing energy reserves, and lower 2,3 DPG levels by inhibiting hemoglobin-oxygen dissociation.

2,3-Diphosphoglycerate↗
PubMed1993

Intracellular and extracellular magnesium depletion in type 2 (non-insulin-dependent) diabetes mellitus.

To investigate alterations of magnesium metabolism in Type 2 (non-insulin-dependent) diabetes mellitus, we utilized a new magnesium-specific selective ion electrode apparatus to measure serum ionized magnesium (Mg-io) in fasting subjects with and without Type 2 diabetes, and compared these values to levels of serum total magnesium, and of intracellular free magnesium (Mgi) analysed by 31P-NMR spectroscopy. Both Mg-io (0.630 +/- 0.008 vs 0.552 +/- 0.008 mmol/l, p < 0.001) and Mgi (223.3 +/- 8.3 vs 184 +/- 13.7 mmol/l, p < 0.001), but not serum total magnesium, were significantly reduced in Type 2 diabetes compared with non-diabetic control subjects. Furthermore, a close relationship was observed between serum Mg-io and Mgi (r = 0.728, p < 0.001). We suggest that magnesium deficiency, both extracellular and intracellular, is a characteristic of chronic stable mild Type 2 diabetes, and as such, may predispose to the excess cardiovascular morbidity of the diabetic state. Furthermore, by more adequately reflecting cellular magnesium metabolism than total serum magnesium levels, Mg-io measurements may provide a more readily available tool than has heretofore been available to analyse magnesium metabolism in a variety of diseases.

Blood Glucose↗
PubMed1993

Comparison of left ventricular mass and geometry in black and white patients with essential hypertension.

To assess racial difference in cardiac responses to elevated blood pressure, we compared echocardiographic measurements of left ventricular (LV) mass and the wall thickness to chamber dimension ratio (relative wall thickness) in 380 white and 47 black patients with uncomplicated essential hypertension consecutively enrolled in echocardiographic research studies at The New York Hospital Hypertension Center. Diastolic blood pressure and weight were slightly greater in black as compared with white subjects (104 +/- 18 v 98 +/- 11 mm Hg; P = .014 and 82 +/- 17 v 77 +/- 15 kg; P = .037, respectively), however the groups were similar with respect to age, duration of hypertension, cholesterol level, cigarette smoking, past use of antihypertensive therapy, family history of heart disease, and height. On average, LV mass indexed for body surface area and relative wall thickness were significantly greater in blacks than whites (119 v 105 g/m2; P = .02 and 0.46 v 0.39; P = .003) and blacks had twice the prevalence of LV hypertrophy (41% v 19%; P < .001) or concentric remodeling (21% v 12%; P < .05). The magnitude of increased LV mass and relative wall thickness in blacks was similar in men (132 v 110 g/m2; P = .01 and 0.44 v 0.39; P = .04) and in women (107 v 94 g/m2; P = .11 and 0.48 v 0.39; P = .02). In multivariate analyses, systolic blood pressure, age, and race were consistently predictors of increased LV mass and abnormal cardiac geometry. Cholesterol level was not independently associated with increased LV mass but was weakly associated with increased relative wall thickness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗