Symposium introduction: aberrant prorenin-renin system behavior in diabetes.
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Albuminuria↗
Biomedical subjects
J H Laragh
Publications and source records attributed to J H Laragh.
Comparative renal hemodynamic effects of lisinopril, verapamil, and amlodipine in patients with chronic renal failure.
We investigated the effects of lisinopril, verapamil, and amlodipine in 26 hypertensive patients with chronic renal disease of varying etiologies. Blood pressure, urine protein excretion, glomerular filtration rate (GFR), and renal blood flow (RBF) (inulin and para-aminohippurate clearance) were determined before and after 2 to 3 months of therapy. All three agents lowered blood pressure with minimal side effects in many, but not all, patients. Patients who had a significant lowering of blood pressure in response to lisinopril and verapamil had favorable renal hemodynamic responses as well--GFR remained stable, RBF was stable or increased, and filtration fraction, renal vascular resistance, and proteinuria tended to decrease. Patients whose blood pressure did not decrease had less favorable responses. In the small number of patients who received amlodipine, lowering of blood pressure was associated with a small decrease in GFR. Our results demonstrate a heterogeneity in response to antihypertensive agents in patients with renal disease. We therefore conclude that treatment of such patients should be individualized, and suggest that choice of therapy depend on adequate blood pressure response in conjunction with stabilization of renal function and urine protein excretion. Our data do not support the use of a drug in these circumstances if it does not lower systemic blood pressure.
Amlodipine↗
Hypertension and a tumor of the glomus jugulare region. Evidence for epinephrine biosynthesis.
Glomus jugulare tumors have been reported to secrete norepinephrine and cause severe hypertension with features similar to pheochromocytoma. In contrast, epinephrine secretion has not been observed in these neoplasms. This has been attributed to the absence of the norepinephrine-methylating enzyme, phenylethanolamine-N-methyltransferase (PNMT), required for epinephrine synthesis. We report a patient with severe hypertension caused by a glomus tumor that secreted norepinephrine and epinephrine. Following selective venous sampling, catecholamines were quantified by radioenzymatic assay. Marked elevations in norepinephrine and epinephrine release were localized to the glomus tumor. The enzymes involved in catecholamine biosynthesis, including PNMT and tyrosine hydroxylase, were identified immunocytochemically in the tumor. The glomus tumor had staining patterns identical to those observed within normal rat glomus cell. Hypertension resolved with resection of the functioning tumor. This is the first report of PNMT in a functioning paraganglioma of the glomus jugulare region. The factors that determine why functional activity is expressed only rarely by paraganglioma remain undefined.
Adult↗
Ionic basis of hypertension in diabetes mellitus. Role of hyperglycemia.
Alterations of cell ion content have been reported acutely after oral glucose ingestion, and chronically in subjects with hypertension and noninsulin dependent diabetes mellitus (NIDDM). We have hypothesized that these ionic abnormalities, elevated cytosolic free calcium (Cai), and suppressed intracellular pH (pHi) and free magnesium (Mgi), common to both of these syndromes, may explain their frequent clinical coincidence. To investigate the potential role of glucose in this process, we utilized 19F- and 31P-NMR spectroscopy to measure Cai, Mgi, and pHi in normal human red blood cells before and 60, 120, and 180 min after in vitro incubation with glucose (15 mmol/L) and equimolar concentrations of the glucose analogs, L-glucose, 2-deoxyglucose, and 3-O-methylglucose. At each point in time (from t = 0 to t = 60, 120, 180 min), glucose induced significant (P < .05) elevations in Cai (27.2 +/- 2.2 to 68.3 +/- 7.2, 70.7 +/- 10.5, 59.8 +/- 10.1 nmol/L), while suppressing pHi (7.28 +/- 0.02 to 7.22 +/- 0.03, 7.23 +/- 0.03, 7.22 +/- 0.03), and Mgi (206 +/- 10 to 151 +/- 7, 131 +/- 7, 143 +/- 5 mumol/L). This glucose induced ionic effect was dose dependent, significant elevations in Cai being observed at 10 and 15 mmol/L, but not at the other concentrations tested. It was also specific, no changes in Cai being observed with any of the glucose analogs tested. Thus, hyperglycemia per se elevates Cai and suppresses Mgi and pHi in normal human red cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
The influence of dietary salt and plasma renin activity on myosin heavy chain gene expression in rat hearts.
The renin-angiotensin system has been implicated as a possible mediator of the cardiac adaptations that develop in response to chronic pressure overload. In order to explore this, we studied rats that had elevated plasma renin activity (PRA) secondary to 6 weeks of either dietary salt restriction or renovascular hypertension (Htn)--conditions that exert distinctly different loads on the myocardium. Separate groups of sham and Htn animals were maintained on a high salt diet that resulted in a relative (Htn) or absolute (sham) reduction in PRA. Heart weight and heart/body weight ratios were increased only in animals with Htn. The ratio of alpha/beta myosin heavy chain (MHC) mRNA was significantly decreased with Htn. This ratio was markedly increased with low salt and was not influenced by high salt intake. Thus, the circulating renin-angiotensin system does not appear to play a primary role in defining cardiac myosin heavy chain adaptations to hemodynamic loads. However, sodium restriction, either via its hemodynamic or humoral effects, is sufficient to induce a physiologic change in myosin heavy chain gene expression in rats.
Animals↗
Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade.
OBJECTIVE: To study the effects of renin-angiotensin system blockade by a novel non-peptide angiotensin II receptor antagonist, losartan, on development of hypertension and acceleration of end-organ damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). DESIGN AND METHODS: One hundred and eighty-one male SHRSP were fed a 4% sodium diet from 6 to 18 weeks of age. Seventy-eight SHRSP were treated orally with losartan, 30 mg/kg per day. One hundred and three rats constituted untreated controls. Blood pressure, plasma renin activity (PRA), renal function and end-organ damage were monitored during the transition to malignant hypertension. RESULTS: Losartan prevented a blood pressure rise during the first 4 weeks of salt loading. Thereafter, blood pressure rose slowly in losartan-treated rats; however, at each time-point studied blood pressure was significantly lower in losartan-treated rats than in control rats. Losartan treatment increased PRA during the first 4 weeks, but this effect was not sustained. Thereafter, PRA decreased to control (week 0) levels. In contrast, 2 weeks after high-sodium feeding started, untreated SHRSP failed to suppress PRA appropriately; thereafter, PRA rose significantly. Losartan affected renal pathophysiology by blunting the decline in glomerular filtration rate, controlling proteinuria and preventing or delaying the appearance of malignant nephrosclerosis. Losartan treatment significantly increased survival and completely prevented cerebrovascular infarcts. CONCLUSIONS: The results indicate that angiotensin II blockade markedly reduces both hypertension and end-organ damage in chronically salt-loaded SHRSP and that the renin-angiotensin system may play an important role in the development of hypertensive cardiovascular disease in SHRSP.
Angiotensin II↗
Sex hormones and hemostatic risk factors for coronary heart disease in men with hypertension.
OBJECTIVE AND DESIGN: It has been hypothesized that risk factors for coronary heart disease in men are linked and that the underlying factor linking them may be an alteration in the sex hormone milieu. As a test of this hypothesis, sex hormones and fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), hemostatic factors recently shown to be risk factors for myocardial infarction, were measured in men with hypertension and in healthy control subjects. RESULTS: The fasting serum testosterone and free testosterone levels were decreased and the plasma factor VII and PAI-1 levels increased in the men with hypertension. CONCLUSION: These findings are consistent with the stated hypothesis.
Blood Coagulation Factors↗
Comparison of classification of the severity of hypertension by blood pressure level and by World Health Organization criteria in the prediction of concurrent cardiac abnormalities and subsequent complications in essential hypertension.
OBJECTIVE: To determine whether classification of the severity of hypertension according to the World Health Organization (WHO) system, which utilizes additional clinical and laboratory findings, is superior to classification by blood pressure level alone in predicting prognostically important cardiac structural abnormalities and the risk of subsequent complications in asymptomatic subjects. DESIGN: Two-hundred and twenty adults with uncomplicated essential hypertension underwent baseline clinical evaluation and echocardiography; 88% were subsequently followed for a mean of 11.6 years. SETTING: University hospital. RESULTS: Left ventricular mass index and relative wall thickness were slightly greater in patients in the highest diastolic or systolic blood pressure stratum than in WHO stage II hypertensives, but these results were statistically non-significant. High peripheral resistance index was best identified by diastolic blood pressure level. Receiver operating characteristic curve analysis showed that all three methods had similar test performance in predicting abnormal left ventricular mass index, left ventricular geometry, relative wall thickness and peripheral resistance. During follow-up the proportion of patients who had a clinical event or died increased with increasing severity stratum in all three clinical classification systems, but the trends were statistically non-significant. Risk stratification by echocardiographic left ventricular mass index was most successful in identifying patients at very high and very low risk of subsequent morbid events and all-cause mortality. CONCLUSION: Classification of hypertension severity by blood pressure level has similar, although limited, effectiveness at a lower cost than the WHO criteria in identifying patients with adverse cardiac changes and an impaired long-term prognosis. Echocardiographic measurement of left ventricular mass index was more successful than other classifications in predicting subsequent morbid events.
Adult↗
Influence of sodium intake on in vivo left ventricular anatomy in experimental renovascular hypertension.
The effect of different dietary salt contents (0.0035, 0.4, and 4%) on in vivo left ventricular (LV) geometry was studied by necropsy-validated echocardiographic methods in groups of 30 two-kidney, one-clip (2K, 1C) and one-kidney, one-clip (1K, 1C) male Wistar rats and two-kidney (2K) and one-kidney (1K) shams 9 wk after surgery. The salt-deficient diet was associated with lower body weight, higher plasma renin activity in both 2K,1C and 2K shams (P < 0.004) and higher hematocrit in 2K,1C (P < 0.02). Blood pressure was increased by high-salt diet in experimental groups but not in shams (P < 0.01). Increase in dietary sodium content was associated with increased cross-sectional area index (CSAI) and LV mass index in 2K rats independently of renal artery stenosis (P < 0.0007) and also in 1K shams (P < 0.01). LV end-diastolic dimension was greater in 1K,1C and 1K shams than in 2K,1C and 2K shams at every level of sodium intake and was directly related to atrial natriuretic factor levels in both 1K,1C (r = 0.68) and 2K,1C (r = 0.59). LV hypertrophy was independently predicted by blood pressure (P < 0.0006) and high-sodium diet (P < 0.05) in 1K rats (multiple r = 0.57, P < 0.001) and by high-sodium diet (P < 0.0001) and low hematocrit (P < 0.05) in 2K rats (multiple r = 0.76, P < 0.0001). Thus provision of normal or high sodium content in the diet was a more consistent stimulus to LV hypertrophy than the level of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Adrenergic regulation of renin secretion and renal hemodynamics during deliberate hypotension in humans.
To assess the relative contributions of neural and nonneural stimuli of renin secretion, the effects of an alpha 1-agonist, phenylephrine (Phe), or a beta-agonist, epinephrine (Epi), on plasma renin activity (PRA), renal blood flow (RBF), and glomerular filtration rate (GFR) were compared during sympathetic blockade with epidural hypotensive anesthesia [mean arterial blood pressure (MAP) = 60 and 50 mmHg]. Controls (NaCl) received saline alone to maintain MAP at 50 mmHg. Epi increased PRA (ng.ml-1.h-1) from 0.9 +/- 0.6 to 3.0 +/- 1.5 at 60 mmHg MAP and 4.7 +/- 1.8 at 50 mmHg MAP, with associated decreases in RBF (-33 and -60%, respectively) and GFR (-27 and -53%, respectively). During hypotension with Phe and NaCl, PRA and RBF were unchanged from baseline but GFR decreased. Urinary Na secretion decreased comparably in all three groups. In conclusion, during sympathetic blockade with epidural anesthesia, marked reductions in both renal perfusion pressure and distal nephron Na delivery were insufficient to increase renin secretion. beta-Adrenergic stimulation (e.g., Epi) was required to increase PRA. Epi decreased RBF suggesting an angiotensin II-mediated effect.
Anesthesia, Epidural↗
Cardioreparation and the concept of modulating cardiovascular structure and function.
Hypertension and atherosclerotic cardiovascular disease represent major global health problems. Practising physicians are challenged daily by patients suffering adverse cardiovascular events, such as myocardial infarction, stroke, heart failure and sudden cardiac death. Major risk factors have been identified of which the most important is left ventricular hypertrophy. In recent years, growth factors, regulatory peptides and effector hormones of the renin-angiotensin-aldosterone system have been identified as important modulators of cell growth and behaviour. It therefore follows that a major emphasis has been placed on the importance of abnormalities in organ structure as the primary basis for impaired function of the heart and vasculature, including large and medium sized arteries and resistance vessels, or arterioles. The concept of reparation recognizes the importance of abnormalities in tissue structure to the functional basis of disease. It suggests that the structurally remodelled heart and vasculature can be restored to, or toward, normal structure and function by suitable therapy. Experimental and clinical trials which address this premise are reviewed herein.
Animals↗
Parathyroid hypertensive factor-like activity in human essential hypertension: relationship to plasma renin activity and dietary salt sensitivity.
OBJECTIVE: To determine the clinical relevance of the newly described circulating pressor factor with parathyroid hypertensive factor (PHF)-like activity. DESIGN: Plasma samples were collected from 94 normotensive and 93 essential hypertensive subjects, the latter either previously defined by dietary salt sensitivity (n = 43), or prospectively studied on both low- (< 50 mmol/day) and high-salt (> 200 mmol/day) diets (n = 16). METHODS: Blood pressure, demographic factors, plasma renin activity (PRA), urinary electrolyte excretion and bioassayable PHF-like activity were determined in the fasted state on basal and altered dietary salt intakes. RESULTS: Among the normotensive subjects significantly higher PHF-like activity and reciprocally lower PRA values were observed in Black versus Caucasian subjects, particularly among females. In the hypertensive subjects PHF-like activity levels were significantly elevated in the low- (17.1 +/- 1.5 mmHg, n = 34) and normal- (6.7 +/- 1.8 mmHg, n = 36) but not in the high-renin subgroups compared with values in the normotensive subjects (1.6 +/- 1.1 mmHg). Similarly, PHF-like activity values were significantly higher in salt-sensitive than in salt-insensitive hypertensives. Prospectively, PHF-like activity rose significantly with salt loading (4.9 +/- 1.2 to 20.4 +/- 6.2 mmHg) and was positively related (r = 0.648, P < 0.001) to the pressor response to salt. CONCLUSIONS: Elevated levels of PHF-like activity are characteristic of the low-renin or salt-sensitive state, or both, and may contribute to the hypertensive process. Elevated PHF-like activity levels found in normotensive subjects may presage the development of low-renin, salt-sensitive hypertension.
Biological Factors↗
The renin system and new understanding of the complications of hypertension and their treatment.
The renin-angiotensin-aldosterone hormonal axis is the major long-term servocontrol for regulation of both arterial blood pressure and sodium balance. It supports normotension or hypertension via angiotensin vasoconstriction and angiotensin plus aldosterone-induced renal sodium retention. Normally, in the presence of hypertension or sodium-volume excess, plasma renin activity promptly falls to zero. Accordingly, any renal secretion of renin in the face of high blood pressure is abnormal. In established essential hypertension varying degrees of abnormal plasma renin activity operate to cause or sustain the hypertension; only very low plasma renin values reflect a normal renal response. Human hypertensive disorders comprise a spectrum of abnormal plasma renin-sodium volume products. High renin, intensely vasoconstricted, hypovolemic forms (e.g., malignant, renovascular) are one extreme of the spectrum; "wet"-volume-excess low-renin forms are the other extreme (e.g., primary aldosteronism, low-renin essential hypertension). These varying, but abnormal renin-sodium products are caused by a renal lesion in which a subpopulation of ischemic nephrons hypersecretes renin and retains sodium despite systemic hypertension and sodium excess. Thus, hypertensive patients cannot suppress their renin secretion normally. The hypertension from this renal lesion is correctable by agents that reduce renin secretion or block its effect (beta blockade, CEI, renin inhibition, or angiotensin II antagonism). None of these agents lower blood pressure after binephrectomy, verifying the renal origin of renin in the cardiovascular control system. In essential hypertension, the plasma renin level appears as a continuous variable associated with greater risk of ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A symposium: systemic hypertension: contribution of trandolapril, a new angiotensin-converting enzyme inhibitor, toward patient protection. Introduction.
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Angiotensin-Converting Enzyme Inhibitors↗
Hypertension and catecholamine biosynthesis associated with a glomus jugulare tumor.
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Adult↗
Maintenance of forearm vasodilator action of atrial natriuretic factor in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.
Infusions of atrial natriuretic factor (ANF) are frequently associated with attenuated natriuretic and diuretic responses in patients with congestive heart failure. However, ANF infusions result in systemic vasodilation, suggesting that end organ responsiveness to ANF may not be uniformly decreased. To determine if the vasodilator effects of ANF were altered in heart failure, strain-gauge plethysmography was utilized to measure forearm blood flow responses to the intraarterial infusion of ANF using a dose range that was low enough to avoid systemic effects. In 9 control subjects, ANF infusions of 0.5, 1.0, 2.0 and 4.0 micrograms/min/100 ml forearm volume significantly increased forearm blood flow from 3.21 +/- 1.71 to 5.69 +/- 3.14, 6.20 +/- 2.57, 6.64 +/- 2.53 and 6.97 +/- 2.49 ml/min/100 ml forearm volume, respectively (all p less than 0.01). In 7 patients with heart failure, ANF infusion significantly increased forearm blood flow from 2.19 +/- 0.98 to 3.18 +/- 1.70, 3.76 +/- 2.0 and 4.42 +/- 2.80 ml/min/100 ml forearm volume for the 0.5, 1.0 and 2.0 micrograms doses, respectively (all p less than 0.05). By analysis of variance, the forearm blood flow responses pooled over all doses were not significantly different between the 2 groups. At the 2.0 micrograms dose, the peak increase in forearm blood flow in normal subjects represented a 107% increase over baseline compared with a 102% increase in patients with heart failure. In summary, these data demonstrate that intraarterial administration of ANF in patients with heart failure resulted in dose-related increases in forearm blood flow. The responses were not significantly different from normal subjects expressed both as an absolute response and as a percent increase.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
A decade of angiotensin-converting enzyme (ACE) inhibition.
The renin system plays a critical role in hypertension as well as in the edematous states of heart failure, cirrhosis, and nephrosis. Properly performed measurements of plasma renin, with techniques now widely available, can be used as indicators of risk and of therapeutic strategies. The results of the plasma renin measurements are equally relevant whether they are high or low. The renin profile should be part of the routine workup of the patient with hypertension of any type or of the patient with an edematous disorder. Once the renin component of hypertension is established, management with angiotensin-converting enzyme (ACE) inhibitors, such as perindopril, follows, for ACE inhibitors attack the pathophysiologic source, thus providing adequate perfusion and protection of vital organs. The role of renin's involvement in hypertensive states is elaborated, as well as that of the ACE inhibitors.
Angiotensin-Converting Enzyme Inhibitors↗
Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension.
The spectrum of left ventricular geometric adaptation to hypertension was investigated in 165 patients with untreated essential hypertension and 125 age- and gender-matched normal adults studied by two-dimensional and M-mode echocardiography. Among hypertensive patients, left ventricular mass index and relative wall thickness were normal in 52%, whereas 13% had increased relative wall thickness with normal ventricular mass ("concentric remodeling"), 27% had increased mass with normal relative wall thickness (eccentric hypertrophy) and only 8% had "typical" hypertensive concentric hypertrophy (increase in both variables). Systemic hemodynamics paralleled ventricular geometry, with the highest peripheral resistance in the groups with concentric remodeling and hypertrophy, whereas cardiac index was super-normal in those with eccentric hypertrophy and low normal in patients with concentric remodeling. The left ventricular short-axis/long-axis ratio was positively related to stroke volume (r = 0.45, p less than 0.001), with cavity shape most elliptic in patients with concentric remodeling and most spheric in those with eccentric hypertrophy. Normality of left ventricular mass in concentric remodeling appeared to reflect offsetting by volume "underload" of the effects of pressure overload, whereas eccentric hypertrophy was associated with concomitant pressure and volume overload. Thus, arterial hypertension is associated with a spectrum of cardiac geometric adaptation matched to systemic hemodynamics and ventricular load. Concentric left ventricular remodeling and eccentric hypertrophy are more common than the typical pattern of concentric hypertrophy in untreated hypertensive patients.
Adaptation, Physiological↗