Cardiac pathophysiology and its heterogeneity in patients with established hypertensive disease. The first Robert C. Tarazi lecture.
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Antihypertensive Agents↗
Biomedical subjects
J H Laragh
Publications and source records attributed to J H Laragh.
Percutaneous angioplasty in renovascular hypertension.
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Angioplasty, Balloon↗
How common is white coat hypertension?
Twenty-one percent of 292 patients with untreated borderline hypertension (clinic diastolic blood pressures persistently between 90 and 104 mm Hg) were found to have normal daytime ambulatory pressures (defined from a population of normotensive subjects). These patients were defined as having "white coat" hypertension, and they were more likely to be female and younger, to weigh less, and to be more recently diagnosed than patients whose pressure was elevated both in the clinic and during ambulatory monitoring. Patients with white coat hypertension did not show a generalized increase of blood pressure lability, nor an exaggerated pressor response while at work. The phenomenon is more pronounced when blood pressure is measured by a physician than by a technician. In such patients, the pressor response may be relatively specific to the physician's office and lead to significant misclassification of hypertension.
Adult↗
Relation of blood pressure and body build to left ventricular mass in normotensive and hypertensive employed adults.
Left ventricular muscle mass is increased in the presence of large body size, high blood pressure and obesity, but the relative contributions to ventricular mass of these and other factors have not been elucidated. Accordingly, echocardiographic left ventricular mass in unmedicated employed adults (162 normotensive, 145 borderline hypertension and 317 with established essential hypertension) was related to height, weight, lean body mass, body mass index, systolic and diastolic blood pressure, age, gender, race and 24 h urinary sodium and potassium excretion. In the total population, body mass index, systolic blood pressure and height were the most significant (p less than 0.0001) independent correlates of left ventricular mass, whereas gender and age made smaller contributions. In each normotensive and hypertensive subgroup, body mass index and height remained highly significant independent predictors of left ventricular mass, systolic blood pressure became a weaker predictor (0.001 less than p less than 0.02) and only among patients with established hypertension was diastolic blood pressure a weak independent determinant (p less than 0.05) of ventricular mass. The increase in left ventricular mass attributable to obesity was due to eccentric hypertrophy because end-diastolic relative wall thickness was similar in obese and nonobese subjects in each blood pressure group. Thus obesity, as measured by body mass index, is as important a potential determinant of left ventricular muscle mass as is systolic blood pressure and it is of greater statistical significant in an adult employed population than is diastolic blood pressure, height, gender, age or dietary sodium intake.
Blood Pressure↗
Pathophysiology of diastolic hypertension.
Two different mechanisms for long-term vasoconstriction that sustain diastolic hypertension in the experimental and clinical forms of primary aldosteronism and renovascular hypertension can also be identified and quantified among patients with essential hypertension. The first is renin-independent, requires antecedent sodium retention, and appears related to abnormal membrane transport of calcium. This vasoconstriction is identified by low plasma renin and ionized calcium values and is correctable by sodium depletion or calcium channel or alpha-blockade. The second is renin-mediated but also involves an increase in cytosolic calcium. This mechanism is quantifiable by the plasma renin level and by the hypotensive response to an anti-renin-system drug (CEI inhibitor, saralasin, beta-blocker). At the very extremes of the range of plasma renin values encountered in hypertensive patients, one of the two mechanisms predominates, whereas in the medium range of renin values either or both mechanisms can be operative.
Calcium↗
A modern plan for treating hypertension.
Essential hypertension is a heterogeneous spectrum of pathophysiologic disturbances, not a single entity. Identification and characterization of two different vasoconstrictor mechanisms--one renin-mediated, the other sodium-volume mediated--has made it possible not only to apply antihypertensive drug therapy on a more rational basis but to screen out a significant number of cases of curable (high-renin) renovascular disease as well as many cases of curable (low-renin) primary aldosteronism. An array of five major drug types makes long-term monotherapy for essential hypertension an achievable goal. Converting enzyme inhibitors and beta-blockers counteract the renin-mediated vasoconstriction; diuretics, calcium-channel antagonists, and alpha-blockers oppose the low-renin sodium-volume-mediated form of vasoconstriction. This information brings us closer to the primary goal of modern therapy: to give each patient the fewest drugs in the smallest amounts and with the least frequency possible for the often lifetime commitment that antihypertensive therapy involves.
Angiotensin-Converting Enzyme Inhibitors↗
Regulation of glomerular filtration rate in chronic congestive heart failure patients.
The purpose of this study was to identify the factor(s) that characterize impaired glomerular filtration rate (GFR) in congestive heart failure (CHF) patients. We studied 34 patients, measuring systemic hemodynamics, vasoactive hormones, and sodium and volume status. Renal plasma flow (para-aminohippurate) and GFR (inulin) were assessed by steady-state clearance techniques. Both linear and multiple regression analyses were performed. Impaired GFR was characterized by reduction of renal blood flow and renal fraction of cardiac output, and by an increase of renal vascular resistance. The correlation between GFR and filtration fraction (r = 0.492, P less than 0.003) indicated that individuals with greatest impairment of GFR had the lowest filtration fraction and increased overall renal vascular resistance, indicating dependence of GFR on afferent, rather than efferent vasoconstriction, under conditions of low renal perfusion. Mean vasoactive hormones and blood volume were increased, but without clear cut correlation with GFR. The greatest impairment of GFR was observed in elderly CHF patients, as renal blood flow and function demonstrated an age-dependent decline, in addition to the adverse effects of CHF. In a multiple regression model, renal blood flow and filtration fraction accounted for 69% and 25%, respectively, of the variability of GFR, with a co-linear influence of age. Thus, we have identified age-related, abnormal renal hemodynamic patterns in CHF, and the fragile nature of GFR in the elderly CHF population.
Adult↗
A new venture in medical communication.
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Hypertension↗
A longitudinal study of urinary creatinine and creatinine clearance in normal subjects. Race, sex, and age differences.
The purpose of this study was to examine the variability of 24-hour urinary and serum creatinine levels and creatinine clearance in normal subjects and to develop nomograms for assessing the adequacy of 24-hour urine collections. The data were from a longitudinal research program examining biochemical, hormonal, and hemodynamic parameters in normal subjects. Bloods and 24-hour urine specimens were collected at yearly intervals from 144 people over 9 years, and from an additional 110 over 4 years. The subjects were originally distributed equally by sex, race (black, white), blood pressure (three groups within the normal range), and age (three groups). Men had 33% higher urine creatinines per weight than females (P less than 0.001). Because they only had 8% higher creatinine clearance per weight they also exhibited 21% higher serum creatinine. Blacks had 5% higher urine creatinine per weight than whites, perhaps reflecting greater muscle mass, but their serum creatinines were not different from those of whites, reflecting a 5% higher creatinine clearance by weight than whites (P less than 0.01). Interestingly, older black men (age greater than 60 years) had 12% lower urine creatinine/weight than younger black men (P less than 0.001). They also had 13% lower creatinine clearance by weight, resulting in no net difference in serum creatinine. The intraindividual variability in urine creatinine excretion averaged 15% and did not differ between blacks and whites and men and women. The within individual variability in serum creatinine and creatinine clearance averaged 14 and 20%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Renal responses to atrial natriuretic factor in patients with congestive heart failure.
It is now recognised after many years of speculation regarding the role of mammalian atria in the direct regulation of intravascular volume, that atrial myocites produce a peptide hormone that results in natriuresis and diuresis, under the condition of atrial distention. This atrial natriuretic factor (ANF) is secreted in normal subjects and is increased in patients with congestive heart failure. Atrial natriuretic factor may be administered exogenously and the results of studies performed by our group indicate that natriuresis and diuresis are induced in normal subjects but not in patients with congestive heart failure. These findings, when taken together, suggest that ANF is increased in heart failure patients in response to the atrial distention associated with ventricular dysfunction and intrinsic renal insufficiency. The mechanism for the blunted renal response to atrial natriuretic factor in heart failure patients requires further clarification.
Atrial Natriuretic Factor↗
On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship.
We propose herein that there are two functionally abnormal nephron populations in essential hypertension: (1) a group of ischemic nephrons with impaired sodium excretion which chronically hypersecrete renin. Numerically, these ischemic nephrons comprise a minor subgroup since most patients with essential hypertension exhibit no overt evidence of renal insufficiency. (2) In reaction to this, a more numerous group of normal nephrons appears in adaptive hypernatriuresis. They have an increased distal sodium supply and consequently, a chronically suppressed renin secretion. One difference between patients with renovascular hypertension and those with essential hypertension is the intermingling of these two populations of nephrons. In our hypothesis, the adapting hyperfiltering normal nephrons accomplish the hypernatriuresis in response to saline infusion, that is characteristic of all essential hypertension. However, the unsuppressed secretion of renin, that arises from the ischemic nephron population attenuates this compensatory natriuresis in the following ways: (1) by inappropriately acting on the hyperfiltering nephrons to enhance proximal tubular sodium reabsorption; (2) by activating TGF-mediated afferent constriction in these nephrons, and (3) simultaneously, the reactive secretion of renin from ischemic nephrons is diluted by non-participation of the adapting hypernatriuretic nephrons so that plasma renin settles at a level which is insufficient to fully compensate GFR in the ischemic nephrons. These adaptive responses provide a basis for the observation that the inhibition of renin activity with converting enzyme inhibitors in essential hypertension increases renal blood flow and sodium excretion. They also explain why converting enzyme inhibitors can effectively reduce blood pressure, even when renin levels are not absolutely elevated, since any circulating renin imposed upon the adapting hypernatriuretic nephrons inappropriately impairs their sodium excretion. In addition, the theory explains why basal renin secretion is either not suppressed or inadequately suppressed in patients with essential hypertension. As a result, whole kidney homeostatic function is compromised because individual nephrons are responding to their individual stimuli to fulfil their individual need, rather than acting in concert with other nephrons. The net effect of this uncoordinated response is to shift total renal function so that systemic arterial hypertension is sustained by abnormal sodium retention for the inappropriately high plasma renin level, or vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)
Homeostasis↗
The antihypertensive effects of calcium channel blockade: role of sodium and calcium metabolism.
To study the relation of calcium channel blockade to sodium and calcium metabolism, we measured blood pressure (BP), serum ionized calcium (Ca-io), plasma renin activity (PRA), and 1,25-dihydroxy-vitamin D (1,25D), before and after administration of nitrendipine to essential hypertensive (EH) outpatients on both low and high dietary salt intakes, and on fixed (10 mg b.i.d.) and titrated dose (10-30 mg b.i.d.) schedules. Nitrendipine lowered BP (% delta DBP = -14.9 +/- 3 vs. 1 +/- 3.5, p less than 0.001) and raised Ca-io (0.08 +/- 0.04 vs. -0.04 +/- 0.05 mEq/L, p less than 0.05) in salt-sensitive (SS) but not salt-insensitive (SI) subjects. % delta DBP was related to PRA (r = 0.69, p less than 0.001), to the rise in Ca-io (r = -0.63, p less than 0.01), and to the suppression of circulating 1,25D (r = 0.80, p less than 0.001). Similarly, at doses (10-30 mg b.i.d.) titrated to achieve normotension, nitrendipine uniformly elevated PRA (1.4 +/- 0.3 to 3.5 +/- 0.7 ng/ml/h, p less than 0.05) and Ca-io (2.34 +/- 0.02 to 2.44 +/- 0.02 mEq/L, p less than 0.05). We conclude that the antihypertensive efficacy of nitrendipine appears greatest among SS and lower renin patients, and is related to the drug's ability to alter calcium metabolism. The state of calcium metabolism may thus underlie the sensitivity to calcium blockade and may contribute to its effects.
Blood Pressure↗
The ovarian prorenin-angiotensin system. Lessons from IVF.
Recent evidence suggests that prorenin and other active components of the renin-angiotensin system may be linked to ovarian physiology. Prorenin, the inactive form of the enzymatically active renin, is present in the fluid of mature human ovarian follicles in concentrations more than 10 times higher than that found in the plasma of women undergoing ovarian stimulation. Only 1% of the renin in follicular fluid is in active form. Concentrations of prorenin in fluid of immature follicles are lower than levels detected in concomitantly aspirated mature follicles. Study of prorenin levels disclosed a positive correlation to testosterone and E2 in fluids of mature follicles. Plasma prorenin increases about twofold at midcycle at the time of the LH surge; the peak of prorenin is sustained for about 40 hours. In patients undergoing ovarian stimulation for IVF, hCG administration results in much higher plasma prorenin levels and the height of prorenin response is directly related to the number of mature follicles. It peaked 4 to 6 days after hCG injection and then fell, close to baseline, by about 12 days after hCG administration. Examination of the time course of hormonal changes in response to hCG revealed a temporal relationship between prorenin and both plasma E2 and progesterone. In women who conceived, prorenin began to rise again on days 8 to 12 after embryo transfer when endogenous hCG was detected in the blood. No such changes in prorenin occurred in women with ovarian failure who conceived after transfer of a donor egg. These findings indicate that prorenin is produced by the mature follicle and the corpus luteum in response to LH/hCG. Since angiotensin II affects intracellular calcium and phospholipase activity, there are many potential roles for prorenin via angiotensin II action. Putative actions of the ovarian renin system may include control of oocyte maturation, ovulation, ovarian blood flow, and ovarian steroid biosynthesis. Future work to elucidate the function of this new renin system may have relevance to many basic and clinical aspects of human reproduction.
Enzyme Precursors↗
Reduction of atrial natriuretic factor circulating levels by endogenous sympathetic activation in hypertensive patients.
The effects of endogenous activation of sympathetic nervous system on systemic and regional hemodynamics and on plasma levels of atrial natriuretic factor (ANF) were studied in subjects with essential hypertension. Stimulation of sympathetic nervous system was reflex-induced by a selective deactivation of carotid baroreceptors obtained by increasing external neck-tissue pressure (NTP) by means of a neck chamber. The effects of graded levels (+30, +45, and +60 mm Hg) and one single and sustained level (+45 mm Hg for 15 min) of NTP were studied. As expected, NTP caused reflex increases in blood pressure, heart rate, and forearm vascular resistance, whereas atrial pressures did not change significantly and cardiac output tended to increase. In the studies based on graded levels of NTP, immunoreactive ANF (irANF) progressively fell (from 31.7 +/- 10 to 13.3 +/- 4 fmol/ml; p less than .05) and the changes in irANF were significantly correlated with those observed in FVR (r = -.671, p less than .001). Both hemodynamic and irANF changes were prevented by adrenergic blockade (phentolamine + propranolol). During +45 mm Hg NTP for 15 min, the levels of irANF fell both in the pulmonary artery and in the inferior vena cava. The irANF arteriovenous difference also fell during this maneuver. These data show that, in hypertensive patients, factors other than atrial wall tension may influence ANF release. They also show that endogenous sympathetic activation may reduce ANF release.
Atrial Natriuretic Factor↗
Wideband external pulse recording during cuff deflation: a new technique for evaluation of the arterial pressure pulse and measurement of blood pressure.
Analysis of the external brachial pulse recorded during standard blood pressure cuff deflation with use of a transducer with a wide frequency response has revealed a reproducible pattern with three distinct components that we have labeled K1, K2, and K3. K1 is a low-amplitude, low-frequency signal that is present with cuff pressures above systolic pressure. K2 is a triphasic signal appearing at systolic pressure and disappearing at diastolic pressure, which approximately corresponds to the audible Korotkoff sound. K3 appears with cuff pressure between systolic and diastolic pressure and continues to be present below diastolic pressure. Intra-arterial pressure recordings made with a high-fidelity Millar catheter-tip manometer revealed K2 and K3 analogs. K3 resembles the intra-arterial pressure waveform and when calibrated according to the pulse pressure, noninvasive dK3/dt determinations correlated well with intra-arterial dP/dt measurements. The appearance/disappearance property of K2 was designated as the "K2 algorithm" and represents a new, objective noninvasive method for measurement of blood pressure. The K2 algorithm compares favorably with intra-arterial measurements, is more accurate than the auscultatory technique, and may be especially useful in clinical situations in which the auscultatory technique does not work well.
Adolescent↗
The reproducibility of average ambulatory, home, and clinic pressures.
The reproducibility of ambulatory, home, and clinic blood pressures was compared in 13 untreated mildly hypertensive and 14 normotensive subjects. Each subject had two sets of daily ambulatory recordings, home self-measured readings (over 6 days), and clinic measurements taken 2 weeks apart. Comparisons over the 2 weeks within and among the methods of measurements were made using a repeated-measures analysis of variance. The results showed that there was no consistent average change in the ambulatory or home pressures and no change in clinic diastolic pressures, but the clinic systolic pressure of the hypertensive subjects dropped 6 mm Hg (p less than 0.05), while that of the normotensive subjects showed no significant change. Test-retest correlations of each of the three methods were similar in magnitude, indicating a similar level of reliability. Test-retest correlations of the ambulatory standard deviations, however, were low, indicating a low reliability of this measure of daily pressure variability. These results suggest that the reproducibility of ambulatory pressures may be as good or better than that of home or clinic measurements. They also suggest that the average ambulatory pressure may be preferable as the measurement in clinical trials, since it may be less influenced by measurement anxiety, particularly in hypertensive subjects.
Activities of Daily Living↗
Diagnosis ex juvantibus. Individual response patterns to drugs reveal hypertension mechanisms and simplify treatment.
Heterogeneity of response to antihypertensive therapy is a well-recognized clinical phenomenon. An agent that is antihypertensive in one patient may increase blood pressure in another or have no effect in a third. We believe that this variety of individual response to drug treatment can provide a new framework for the study of hypertensive subjects. Different patterns of response elicited by sequential trials of individual drugs with different mechanisms of action (diuretics, calcium channel blockers, alpha-blockers, beta-blockers, and converting enzyme inhibitors) should provide another means to classify hypertensive patients into biologically relevant groups. The documentation and analysis of this therapeutic heterogeneity in relation to renin profiling and to other physiological and demographic parameters may add a new dimension to the investigation of the pathophysiology of hypertension; it may serve as a basis for more appropriate stratification of participants in clinical trials and may ultimately contribute to a more rational approach to patient management.
Animals↗
Prorenin secretion from human testis: no evidence for secretion of active renin or angiotensinogen.
To determine if the testis secretes active renin and prorenin, we collected internal spermatic venous blood from 29 young men undergoing varicocelectomy and measured plasma prorenin and active renin together with angiotensinogen and testosterone. Prorenin was higher in internal spermatic venous plasma than in peripheral plasma (+5.3 +/- 1.2 (+/- SE) ng/mL.h [+1.21 ng/(L.s)]; P less than 0.001) as was testosterone [+344 +/- 32 ng/mL [(+1193 nmol/L; P less than 0.001], but there was no significant difference in either active renin (-0.74 +/- 0.45 ng/mL.h [-0.17 ng/(L.s)] or angiotensinogen [+12 +/- 24 ng/mL (+0.01 mumol/L)]. These results demonstrate that the testis secretes prorenin, but not active renin or angiotensinogen, into the general circulation. They support the hypothesis that extrarenal renin systems cannot process prorenin to renin.
Adult↗