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Salt sensitivity of blood pressure is a cardiovascular risk factor, independent of and in addition to hypertension. In essential hypertension, a conglomerate of clinical and biochemical characteristics defines a salt-sensitive phenotype. Despite extensive research on multiple natriuretic and antinatriuretic systems, there is no definitive answer yet about the major causes of salt-sensitivity, probably reflecting the complexity of salt-balance regulation. The endothelins, ubiquitous peptides first described as potent vasoconstrictors, also have vasodilator, natriuretic and antinatriuretic actions, depending on their site of generation and binding to different receptors. We review the available data on endothelin in salt-sensitive essential hypertension and conclude that abnormalities of renal endothelin may play a primary role. More importantly, the salt-sensitive patient may have blood pressure-dependency on endothelin in all states of salt balance, thus predicting that endothelin receptor blockers will have a major therapeutic role in salt-sensitive essential hypertension.

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BACKGROUND: Salt dependency of blood pressure (BP) characterizes most models of experimental hypertension in which endothelins play a significant vasoconstrictor role. Despite this, there are no data on the regulation of plasma endothelin by salt balance in human hypertension. METHODS AND RESULTS: Plasma endothelin was measured in 47 patients with essential hypertension. Endothelin, catecholamine, and plasma renin activity (PRA) responses to 24-hour sodium deprivation (decreasing Na) were assessed in 29 of these patients. Endothelin was higher in hypertensive patients (4.6+/-0.2 fmol/mL) than in 20 control subjects (3.3+/-0.3 fmol/mL, P:<0.002), was correlated with BP, and was negatively associated with PRA (P:<0.04). Salt-sensitive, salt-resistant, and indeterminate groups were defined by the tertiles of the t statistic for the difference in BP before and after decreasing Na. Systolic BP falls were -15+/-1, -2+/-2, and -9+/-1 mm Hg, respectively. PRA, its response to decreasing Na, and its level after decreasing Na were lowest (albeit nonsignificant) in salt-sensitive patients. Baseline catecholamine and endothelin levels did not differ among the groups. In response to decreasing Na, catecholamines increased more significantly in salt-sensitive patients (+2.4+/-0.9 nmol/L) than in the other groups (0.4+/-0.2 and 0.7+/-0.2 nmol/L for indeterminate and salt-resistant groups, respectively; P:<0.03), whereas endothelin increased in the salt-sensitive group (0.8+/-0.3 fmol/mL), decreased in the salt-resistant group (-0.4+/-0.3 fmol/mL), and sustained minimal change in the indeterminate group (0.2+/-0.3 fmol/mL) (P:<0.04). Thus, endothelin levels in the salt-depleted state were highest in salt-sensitive patients (5.2+/-0.4 fmol/mL) versus the other groups (3.4+/-0.4 and 4.4+/-0.4 fmol/mL for salt-resistant and indeterminate groups, respectively) (P:<0.02). Changes in endothelin during decreasing Na and levels after decreasing Na were correlated with changes in catecholamines (P:<0.02). CONCLUSIONS: -Our data suggest that salt-depleted salt-sensitive hypertensives with blunted renin responses exhibit enhanced catecholamine-stimulated endothelin levels and may therefore respond better than unselected patients with essential hypertension to endothelin receptor blockers.

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This chapter on new methods of molecular biology applied to the investigation of the renin-angiotensin system (RAS) contains a description of a clinical case in its first section. There are two reasons for this. First, the case will illustrate the importance of increased understanding of the RAS, because of research by basic scientists, for clinical scientists, clinicians, and human health. Second, and more importantly, describing the applicability of scientific advances in the understanding of RAS to a particular patient is a fitting tribute to two remarkable clinician scientists, Irvin Page and Eduardo Braun Menendez, the co-discoverers of angiotensin II (Ang II) in the United States and Argentina, respectively (1,3). Their insurmountable curiosity was driven by a desire to help patients, at a time at which human hypertension was an untreatable and devastating problem.

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Historically, physiological modulation of the activity of the renin-angiotensin system (RAS) was thought to be mediated only by changes in renin secretion. Hence, altered dietary sodium (Na) intake, changes in renal perfusion pressure, and/or renal adrenoreceptor activity would lead to changes in renin release and plasma angiotensin II (Ang II) concentration, which in turn contribute to regulation of blood pressure and sodium balance. Later, it became apparent that angiotensinogen availability and Ang-converting enzyme activity are also rate-limiting factors that influence the activity of RAS. Finally, over the past few years, evidence has accumulated that indicates the number of Ang II receptors and their subtypes are of great importance in regulating the activity and function of RAS. Cloning of the Ang II receptor genes, development of specific receptor-antagonist ligands, and establishment of genetically mutated animal models have led to greater understanding of the role of Ang II receptors in the regulation of RAS function and activity. This review focuses on the functions and regulation of Ang II receptors in vascular tissues and in the adrenal gland. The authors suggest that identification of control elements for Ang II receptor expression, which are tissue-specific, may provide a basis for future therapeutic manipulation of Ang II receptors in cardiovascular disease states.

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Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (P=0.0005) and refines the location of the blood pressure QTL.

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The effects of 10 weeks of treatment with atenolol (n = 9) or the converting enzyme inhibitor zofenopril (n = 25) on plasma atrial natriuretic peptide (ANP) were studied in 34 essential hypertensive patients. After 4 weeks on placebo, pretreatment ANP, 56 +/- 7 pg/ml, was slightly but not significantly higher than that of 29 controls (41 +/- 4) and correlated with age (r = 0.44), ECG score for left ventricular hypertrophy (LVH) (r = 0.51) and serum creatinine (r = 0.67), and negatively with creatinine clearance (r = -0.39). Atenolol reduced blood pressure (BP) by 0 +/- 6/8 +/- 2 mm Hg (ns/P < 0.01), and zofenopril by 14 +/- 4/6 +/- 2 (P < 0.01/P < 0.01), not significantly different between the two agents. Heart rate was decreased by atenolol (-16 +/- 4 bpm, P < 0.01) but not by zofenopril (+1 +/- 2 bpm, ns). Atenolol increased ANP in all patients but one (delta = +42 +/- 9 pg/ml, P < 0.01), while zofenopril did not change it significantly (-6 +/- 6 pg/ml), due to 15 patients exhibiting decreases and 10 increases in plasma ANP. The effect of atenolol on ANP positively correlated with duration of hypertension (r = 0.74), ECG score for LVH (r = 0.73) and serum creatinine (r = 0.68). Individual changes in ANP by zofenopril negatively correlated with pretreatment ANP (r = -0.69), ECG score for LVH (r = -0.44) and serum creatinine (r = -0.41). No correlations were found between BP, heart rate or their changes by treatment and the effect of either agent on plasma ANP. Multiple linear regression showed that the change in ANP was explained by the therapeutic agent used, the pretreatment plasma level of ANP, and the ECG score for LVH (F = 12.5, P < 0.001, r2 = 0.56). We conclude that the effect of antihypertensives on plasma ANP is independent of their action on BP, but dependent on an interaction between the type of drug employed and those clinical characteristics of the patient that reflect pre-existing hypertensive target organ damage.

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To investigate the role of the renin-angiotensin system in the regulation of adrenal growth in deoxycorticosterone (DOC)-salt hypertensive rats, and the adrenal gene expression of angiotensin AT1 and AT2 receptors, three groups of uninephrectomized rats + DOC pellet + 0.9% NaCl were given water (DOC), losartan (DOC-L), or ramipril (DOC-R) by gavage. Controls had sham surgery and water gavage. Tail-cuff systolic and mean intra-arterial blood pressures were significantly higher in the three DOC groups than in controls and not different among the groups. Adrenal weight of DOC was slightly but not significantly greater than that of controls, while those of DOC-L and DOC-R were greater than that of controls (P < .01). Northern blots showed that AT1 and AT2 gene expression was significantly reduced in DOC (by 33% and 60%), while that of AT1 (but not AT2) was significantly reduced further (versus control and DOC) in DOC-L and DOC-R. There were negative correlations between adrenal weight and AT1 (r = -.80, P < .0001) or AT2 (r = -.60, P < .005). We conclude that DOC-salt hypertension downregulates adrenal AT1 and AT2 gene expression by different mechanisms. Removal of the effects of angiotensin by losartan or ramipril downregulates AT1 further and promotes adrenal growth, indicating the presence of an AT1-mediated growth-inhibitory action of angiotensin II on the adrenal gland. These observations constitute an additional example of a growth-inhibitory role for the AT1 receptor, opposite to its more common growth-promoting actions in other organs and tissues.

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We studied outcome of management of metabolic cardiovascular risk factors in 155 randomly chosen Hispanic hypertensive patients (mean age, 63 +/- 1 years; 79% female) screened for dyslipidemia. Hypertriglyceridemia (n = 12) or high risk-adjusted low-density lipoprotein cholesterol (LDL-C) (n = 89) was found in 65%. Triglycerides did not change (6.16 +/- 0.58 to 7.44 +/- 2.34 mmol/L; P = NS) over 2.2 +/- 0.5 years. Only 58 patients with high LDL-C were treated, and 8 had no follow-up lipid tests. In the other 50, LDL-C decreased by 10 +/- 3% (P < .001) over 2.8 +/- 0.2 years but attained goal in only 12. In a subset of 24 patients with extended follow-up (3.8 +/- 0.2 years), there was an initial marked decline in LDL-C, followed by a rebound to baseline levels. In 29 of 54 patients with normal LDL-C, lipid testing was markedly overused compared with recommendations. Obesity (n = 94, 61%) did not improve in those with repeated data (+0.6 +/- 0.8 kg; P = NS; n = 40) over 2.7 +/- 0.3 years. Forty-four of 63 patients with type II diabetes had repeated measurement of glycosylated hemoglobin, with no change (10.5 +/- 0.5% to 11.2 +/- 0.5%; P = NS) over 2.2 +/- 0.3 years. Ten-year risk of coronary events (Framingham cohort parametric regression) calculated for 61 patients with known untreated blood pressures (169 +/- 3/98 +/- 1 mm Hg) was 21.0 +/- 1.7%, with a skewed distribution reaching high values (66%) and attributable in large part (72%) to modifiable risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

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We investigated whether patients with cough due to angiotensin-converting-enzyme inhibitors have a common pattern of airway responses to methacholine inhalation. Studies assessing only presence or absence of hyperresponsiveness to this agent have produced conflicting results. Spirometric testing before and after methacholine was performed in 14 hypertensive patients at least two weeks after discontinuation of these inhibitors, when cough had abated or disappeared. Subjects were predominantly female (86%) nonsmokers (93%), with high prevalence of respiratory atopic illnesses (57%) probably due to ethnic background (72% Hispanic). Premethacholine spirometric values were normal. Postmethacholine bronchoconstriction of varying degrees was observed in seven patients, but reached the level of hyperresponsiveness in only one patient with asthma. The other seven subjects exhibited no bronchoconstriction. The two groups did not differ in age, concomitant illnesses (e.g., atopy) and medications, or blood pressure reduction. We conclude that airway responses to cholinergic stimulation do not exhibit a common pattern and are randomly distributed in hypertensive patients who develop cough induced by angiotensin-converting-enzyme inhibitors.

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Predictive models for the pressor response to the outpatient clinic visit (PRC) in essential hypertensives with and without diabetes are proposed. The hypotheses are derived from previous studies about the univariate correlates of this response. PRC was measured with ambulatory monitors. Twenty-four hour blood pressures and average PRCs were similar in the two groups. Diabetics had faster 24-h heart rates, decreased heart rate variability, a broader range of PRCs and more depressor responders. PRC of nondiabetics correlated with duration of hypertension and was dependent on race; the predictive model had R2 of 0.19. In contrast, PRC of diabetics exhibited correlations with age, weight, BP and blood glucose and the model had R2 of 0.71. The data suggest that: diabetics had autonomic dysfunction, that their PRC can be modelled with predictors that are accepted correlates of autonomic neuropathy, and that these predictors attenuated PRC or its buffering. If these results were confirmed by prospective application of the model to a larger group of patients, 'true' blood pressures could be estimated by subtraction of predicted PRC from office blood pressures in diabetic, but not in nondiabetic, hypertensive patients.

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A 61-year-old man presented with a mass in the right upper quadrant of the abdomen. Computer tomography scanning (CT) had initially suggested that the location was in the head of the pancreas. Further examination with ultrasonography and celiac angiography documented that the mass was an aneurysm of the common hepatic artery. The successful approach to its surgical management is described.

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To assess whether there is a role for ambulatory blood pressure monitoring (ABPM) in screening for hypertension, we conducted Bayesian analysis of office blood pressure (OBP) as a diagnostic "test" in populations with different prior probabilities (PP) of hypertension. OBP was considered a positive test if systolic blood pressure was greater than 140 mm Hg or diastolic pressure was greater than 90 mm Hg. Chosen daytime ABPM cutoffs for a "gold standard" diagnosis of hypertension were systolic pressure of 139 and diastolic pressure of 88 mm Hg. Sensitivity and specificity of OBP were determined in 72 patients with established hypertension (PP = 1). After 3 weeks off therapy, OBP was 168 +/- 3/101 +/- 1 and ABPM was 151 +/- 2/94 +/- 1 mm Hg. Systolic ABPM was in the normotensive range in 17 patients and diastolic in 15 patients. OBP was falsely positive in 14 and 15 of these patients, respectively. Thus, sensitivity and specificity of OBP were 0.8909 and 0.1765 (systolic) and 0.9825 and 0 (diastolic). These data cannot be extrapolated to populations with lower PPs for use of Bayes' theorem. Hence, we calculated sensitivity and specificity for PP = 0 from published series of ABPM in normotensive subjects and used our measurements and these calculations in arithmetic interpolations for populations with PP 0.1-0.9. Sigmoid relations between PP and predictability of hypertension by a positive OBP were disclosed by use of Bayes' theorem. Their best-fit cubic polynomials predict that an elevated OBP will misdiagnose hypertension 46-50% of the time in a general population (PP = 0.2) but only 8-9% in a specialty practice (PP = 0.9).(ABSTRACT TRUNCATED AT 250 WORDS)

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We investigated the magnitude of the pressor response to the clinic with ambulatory monitors by comparing blood pressure readings related to the medical visit with all clinic-unrelated readings during the day. One hundred studies were conducted on 51 hypertensive patients who were placed either on placebo (67) or on monotherapy with hydrochlorothiazide, atenolol, or the converting enzyme inhibitors captopril or zofenopril. On placebo, clinic-related systolic (162 +/- 2), diastolic (101 +/- 1), and pulse (61 +/- 2) pressures (mm Hg) were significantly higher than the respective clinic-unrelated values (149 +/- 2, 93 +/- 1, and 56 +/- 1 mm Hg). Heart rates were not different. Despite significant reductions of blood pressure, the same pattern was found during treatment. After initiating the monitoring and while in transit to job or home (initial component of the clinic-related readings), systolic (166 +/- 2 mm Hg) and pulse (64 +/- 2 mm Hg) pressures were higher than those during return to the office the next day (final component, 158 +/- 3 and 58 +/- 2 mm Hg). Blood pressures of both components, however, were significantly higher than the clinic-unrelated ones. In 19 repeat studies carried out 2-24 months apart on placebo, the average pressor response did not change from the first (13 +/- 3/11 +/- 2) to the second (13 +/- 4/11 +/- 2 mm Hg) procedure. No correlation, however, was found between the first and second study responses of individual patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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The vasoconstrictor and vasopressor actions of vasopressin have been revealed in recent research through the use of highly specific and sensitive radioimmunoassays, employment of peptide antagonists, and comparison with an animal model which has hereditary absence of this hormone, the Brattleboro rat. Factors now known to modify the pressor effect of vasopressin are the baroreflexes, local vascular prostaglandin production, and a specific interaction with angiotensin II. In experimental models the volume retaining, but not the vasoconstrictor effect of vasopressin is necessary for mineralocorticoid-salt hypertension. Vasopressin contributes directly to the increase in arterial pressure of glycerol induced acute renal failure. In nephrectomized rats, plasma vasopressin is elevated and contributes directly to maintenance of pressure. Vasopressin antagonism may reduce arterial pressure in Goldblatt 1 and 2 kidney hypertension and in one genetic model, spontaneously hypertensive rat (SHR), but the peptide is not necessary for hypertension in these models. Plasma vasopressin is reduced in primary aldosteronism, but may be elevated in malignant hypertension. In essential hypertension, there is considerable disagreement among various studies in which plasma vasopressin, urine vasopressin excretion, platelet associated vasopressin, or vasopressin-neurophysin were measured as to whether there is evidence for increased secretion of vasopressin. Only preliminary studies of vasopressin antagonism in clinical hypertension have been reported. At present, there is no conclusive evidence that elevated vasopressin secretion occurs or is necessary for any form of clinical hypertension.

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The effect of vasopressin infusion on the pressor dose responses to angiotensin II and norepinephrine was studied in pentobarbital-anesthetized and unanesthetized nephrectomized rats. Pressor vasopressin (2-15 ng X kg-1 X min-1) given to anesthetized rats decreased sensitivity to angiotensin II in a dose-dependent manner (r = 0.88), an effect completely reversible by dPMeTyrAVP, a vasopressin vascular antagonist. Subpressor vasopressin (0.5-1 ng X kg-1 X min-1) given to unanesthetized rats diminished sensitivity to angiotensin II in the presence or absence of pentolinium (10 mg/kg). Shifts in dose-response curves to angiotensin II were always parallel. In contrast, dose responses to norepinephrine were not modified by vasopressin in pentolinium-treated rats and showed a small nonparallel rightward shift in animals without pentolinium. In animals without pentolinium, the baroreflex-mediated reduction in heart rate elicited by angiotensin II was not altered by vasopressin infusion. Our data suggest that vasopressin reduces angiotensin II pressor action by diminishing pressor sensitivity to the peptide. They indicate that the effect may be specific, mediated through the vascular receptor for vasopressin and independent of actions of this hormone on the autonomic nervous system.

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Participation of vasopressin and the renin-angiotensin system in the maintenance of systemic arterial pressure was evaluated in unanesthetized adrenalectomized rats. Adrenalectomized and sham-operated rats with implanted arterial and venous catheters were given 1% sodium chloride and 2.5% glucose as drinking fluid for 72 hours following adrenalectomy. Serum and urine samples were obtained for measurement of electrolyte and solute concentration. The pattern of serum electrolytes, serum osmolality, and renal excretion of electrolytes, solute, and water observed in the adrenalectomized rats was entirely consistent with previous observations in this model. Mean arterial pressure of unanesthetized unrestrained adrenalectomized rats was significantly lower than controls. In adrenalectomized rats, dPMeTyrAVP reduced mean arterial pressure 9 +/- 1 mm Hg, p less than 0.001; captopril then caused an additional reduction of 17 +/- 2 mm Hg, p less than 0.01. Neither antagonist altered arterial pressure in the control group. Our results indicate that vasopressin and the renin-angiotensin system play a compensatory pressor role in adrenal insufficiency, preventing a larger decrease of arterial pressure in this model of chronic hypotension.

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A single dose of guanabenz was examined for effects upon blood pressure, heart rate, plasma catecholamines, and plasma renin activity in a randomized, double-blind, crossover design. Eight patients were studied when supine, standing, and during submaximal exercise. Guanabenz reduced blood pressure in subjects who were supine or standing. Heart rate was lowered only in the supine subjects. Guanabenz induced reduction in plasma catecholamines subjects in all positions and the reduction correlated with the placebo level for both norepinephrine and epinephrine. Plasma renin activity was not significantly affected by guanabenz. The results indicate that the central alpha-agonist action of guanabenz reduces sympathoadrenal function to a greater extent in hyperadrenergic hypertensive patients than in those without this disorder.

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The effect of captopril was explored in salt-depleted methylprednisolone (MP)-hypertensive rats. MP treatment raised BP by 41+/-2 mmHg over 2 weeks. Controls (C) had no change in BP. Sodium balance and weight data indicated a greater salt depletion in MP than in C. On day 15, captopril reduced BP in both MP (20+/-4 mmHg) and C (31+/-4 mmHg). The effect was significantly smaller in MP than in C (p less than 0.05). Plasma renin activity (PRA) was similarly elevated in both groups, consistent with salt depletion. Serum (SCE) and lung-converting enzyme (LCE) activity were similar in MP and C. The diminished antihypertensive effect of captopril in MP is therefore not attributable to differences in PRA, SCE, or LCE. Our data suggest that depressor actions of captopril unrelated to the renin-angiotensin system are impaired in MP. Glucocorticoid-induced changes in vasodilator systems may explain these findings.

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