Margaret Bresnahan

Role of vasopressin in essential hypertension: racial differences.

Background Arginine vasopressin (AVP), in addition to being an antidiuretic hormone, might also have pressor effects relevant to the maintenance of hypertension. Results from several experimental and clinical studies suggested that the pressor function of AVP is more important in low-renin hypertension and in the salt-loaded state and that it might be further maximized under sympathetic suppression. Objective To assess whether selective vasopressin receptor inhibition lowers the blood pressure in a racially diverse group of low-renin hypertensive subjects. Methods Thirty-nine hypertensive subjects (16 Caucasian, 23 African-American) eating a 200 mmol/day sodium diet were administered a single intravenous dose of a selective vasopressin receptor antagonist and their blood pressure was monitored constantly for the ensuing 3 h. The protocol was repeated 3 days later after treatment with a single oral dose of 0.4 mg clonidine. Results Of these patients, 54% had their blood sampled for determination of hormone profiles. African-Americans with hypertension had higher baseline plasma AVP levels than did Caucasians (1.13 ± 0.05 versus 0.37 ± 0.06 pg/ml, respectively, P < 0.05), and lower plasma renin activity (0.34 ± 0.07 versus 1.03 ± 0.08 ng/ml per h, respectively, P < 0.05). Selective vasopressin receptor inhibition lowered the mean arterial pressure in African-Americans but not that in Caucasians (lowering by 28 ± 4 mmHg in African-Americans versus lowering by 5 ± 3 mmHg in Caucasians, P < 0.05). Moreover, vasopressin receptor blockade further reduced the arterial pressure in African-Americans but not that in Caucasians after pretreatment with clonidine. Conclusion AVP seems to play a more important role as a pressor hormone in maintaining the elevation of arterial pressure in African-American hypertensives than it does in Caucasian hypertensives.

Sympathoinhibitory Function of the α2A-Adrenergic Receptor Subtype

Abstract —Presynaptic α 2 -adrenergic receptors (α 2 -AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the α 2A -AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted α 2A -AR gene to their wild-type controls. At baseline, the α 2A -AR gene knockouts (n=11) versus controls (n=10) had higher systolic BP (123±2.5 versus 115±2.5 mm Hg, P P P 2A -AR gene knockouts (n=14) and controls (n=14) became hypertensive, but the former required 15.6±2.5 days versus 29.3±1.4 days for the controls ( P P 2A -AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.

Suppressing Sympathetic Activation in Congestive Heart Failure A New Therapeutic Strategy

Neurohormonal activation with increased plasma renin activity and norepinephrine and vasopressin levels is characteristic of congestive heart failure and contributes to further decompensation and poor prognosis. We treated 20 such patients with the centrally acting sympathoinhibitory drug clonidine 0.15 mg BID and obtained hemodynamic measurements by cardiac catheterization and plasma neurohormone levels before and 2 to 3 hours after the first dose; in 7 patients, these measurements were taken again after 1 week of therapy. The initial dose produced significant decreases of 8% in mean arterial pressure, 23% in right atrial pressure, 21% in pulmonary capillary wedge pressure, 19% in mean pulmonary artery pressure, and 12% in heart rate, a 17% increase in stroke volume; and no significant changes in cardiac output and systemic vascular resistance. All changes remained virtually constant after 1 week. Plasma norepinephrine decreased by 28% after the initial dose and 62% after 1 week (P < 0.1), whereas plasma renin activity remained essentially unchanged. Plasma vasopressin tended to increase, its levels being inversely correlated with those of posttreatment norepinephrine (r = -.48 P < .03). Patients with baseline norepinephrine levels > 0.400 ng/mL has significantly poorer baseline hemodynamic parameters and tended to show more improvement with clonidine, although their data remained significantly worse than patients whose baseline norepinephrine was within the normal range. Sympathetic suppression with clonidine in congestive heart failure reduces preload, heart rate, and arterial pressure, all indexes of myocardial energy demand; the lack of significant reduction in systemic vascular resistance and increase in cardiac output might be attributable in part to enhanced release of vasopressin.2+ f2p4

Regulation of Plasma Endothelin by Salt in Salt-Sensitive Hypertension

BackgroundSalt 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 ResultsPlasma endothelin was measured in 47 patients with essential hypertension. Endothelin, catecholamine, and plasma renin activity (PRA) responses to 24-hour sodium deprivation (↓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 ↓Na. Systolic BP falls were −15±1, −2±2, and −9±1 mm Hg, respectively. PRA, its response to ↓Na, and its level after ↓Na were lowest (albeit nonsignificant) in salt-sensitive patients. Baseline catecholamine and endothelin levels did not differ among the groups. In response to ↓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 ↓Na and levels after ↓Na were correlated with changes in catecholamines (P <0.02). ConclusionsOur 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.

Identification of a polymorphic glutamic acid stretch in the α2b-adrenergic receptor and lack of linkage with essential hypertension

Essential hypertension, a clinically significant elevation in blood pressure with no recognizable cause, is believed to be attributable to the collective effect of genetic predisposing factors in combination with specific environmental factors, such as diet and stress. Of the genetic causes, genes coding for proteins involved in blood pressure regulation, such as the alpha- and beta-adrenergic receptors, are obvious candidates. The alpha2-adrenergic receptor plays a key role in the sympathetic nervous system by mediating the effects of epinephrine and norepinephrine. To evaluate the potential role between the alpha2B receptor and essential hypertension, we scanned the alpha2B-receptor gene for genetic variation in 108 affected sibling pairs. The screening revealed two major forms of the receptor. They differ by the presence of either 9 or 12 glutamic acid residues in the acidic domain of the third cytoplasmic loop of the protein. Investigation of the pattern of this variation in hypertensive sibling pairs suggests that the alpha2B receptor locus does not contribute substantially to genetic susceptibility for essential hypertension.

Effect of Aging on Vasopressin, Catecholamines, and Alpha2-Adrenergic Receptors

To characterize normal changes with aging, we measured plasma levels of epinephrine, norepinephrine, and vasopressin, as well as alpha2‐adrenergic receptor numbers (Bmax) and the antagonist dissociation constant (Kd) from platelet‐derived membranes of white, younger (aged 28 ± 6 years, n = 30) and older (aged 70 ± 4 years, n = 41) normotensive, healthy volunteers. There were no differences in resting vasopressin or epinephrine levels at 0.83 ± 0.83 and 360 ± 120 pmol/L in the younger versus 1.0 ± 0.2 and 450 ± 420 in the older subjects, respectively. However, plasma norepinephrine was significantly higher in the older (2.87 ± 1.34 nmol/L) versus the younger subjects (1.50 ± 0.53 nmol/L, P < .01). Platelet alpha2‐receptor numbers were significantly lower in the older subjects at 289 ± 79 fmol/mg protein versus 388 ± 81 fmol/mg protein in the younger subjects (P < .01), compatible with but not proof of down‐regulation by norepinephrine. However, Kd, representing receptor affinity, was similar in both groups. Therefore, studies of hormone and receptor status in various pathologic conditions should always take into account the normal changes attributable to the age of the subject population.

Effects of bradykinin and prostaglandin inhibition on systemic and regional hemodynamics in conscious normotensive rats.

These experiments were designed to study the effects of inhibition of endogenous bradykinin and/or prostaglandins on systemic and regional hemodynamics in conscious normotensive rats, using the radioactive microsphere technique. Administration of either a bradykinin antagonist (50 micrograms/min for 5 min) or indomethacin (10 mg/kg) alone, decreased the cardiac output by an average of 17.58 and 25.94%, respectively (P less than 0.05), without significant change in total peripheral resistance. Regional blood flow decreased and local vascular resistance increased in most organs. Coronary and renal blood flow decreased by an average of 16.45 and 17.26% with bradykinin antagonist and 23.85 and 19.80% with indomethacin, respectively (P less than 0.05). Indomethacin but not bradykinin antagonist also decreased cerebral blood flow by an average of 47.57% (P less than 0.01). Infusion of the bradykinin antagonist following prior prostaglandin inhibition with indomethacin did not induce further changes in either systemic or regional hemodynamics, except in the liver where a significant additional increment in vascular resistance was observed. Our data suggest that most organs have similar patterns of regional vascular sensitivity to bradykinin and prostaglandins (including the heart, kidney, testis, stomach, skin and adrenal). The major differences were in the cerebral vasculature, which was much more sensitive to prostaglandins, and in the liver, spleen and small intestine, which were more sensitive to bradykinin. We conclude that both hormonal systems participate to a varying extent in the maintenance of resting vascular tone in most organs; however, in some cases, their effects may be additive and in others they may work in opposite directions.

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and Humoral Correlates in Essential Hypertension: Relationship Between Patterns of LVH and Myocardial Ischemia

While evaluating 45 hypertensive patients with left ventricular hypertrophy (LVH) for enrollment in a clinical research protocol, we had the opportunity to compare anatomic and functional characteristics of those with LVH and ischemia on an exercise tolerance test (ETT), but without coronary artery disease by angiography (group I, n=8), versus those with a normal ETT (group II, n=37). There were no differences in age, sex, severity, and duration of hypertension between the two groups, but group I patients were significantly more overweight and had a worse lipid profile. Blood pressure at peak ETT was higher in group I despite shorter exercise duration, although resting and ambulatory pressures were similar. Group I patients had evidence of more pronounced cardiac enlargement and LVH by both ECG and echo criteria and a characteristic pattern of more pronounced thickening at the apex, but both groups had equally good systolic function and similar degrees of mild diastolic dysfunction. Analysis of 24-hour ambulatory ECG showed a significantly greater propensity to ventricular arrhythmias in group I, as shown by the presence of late potentials in 4 patients, the presence of couplets in 3, runs of ventricular tachycardia in 2 (while none of group II patients had late potentials or complex arrhythmias), and an average frequency of isolated premature ventricular contractions approximately three times higher in group I than group II patients. Our data demonstrate that hypertensives with LVH associated with myocardial ischemia at stress but with normal coronary arteriograms tend to be more overweight, attain a higher systolic blood pressure at ETT despite a shorter duration, have a higher propensity for severe arrhythmias, and have an adverse lipid profile. LVH in these subjects is more pronounced by both ECG and echo criteria and is characterized by predominantly apical hypertrophy with left atrial and ventricular dilatation rather than overall LV wall thickening.

Central catecholamines and alpha-adrenoceptors in acute hypertension induced by intracerebroventricular hypertonic saline.

We measured the tissue content of catecholamines and the numbers and affinities of alpha 1- and alpha 2-adrenergic receptors in specific areas of the hypothalamus and medulla oblongata of rats treated with intracerebroventricular microinjection of hypertonic saline, in comparison to controls treated with an equal volume of iso-osmolar dextrose solution. Rats given 20 microliter of 4% NaCl into the lateral ventricle showed an average rise in blood pressure of 14 +/- 2 mmHg and a decrease in heart rate of 63 +/- 11 beats/min (P less than 0.001 for both), associated with dopamine suppression in the anteroventral area of the third ventricle (AV3V) and increased concentrations of dopamine in the C2 region of the medulla and of epinephrine in the area postrema. Affinities of medullary alpha 2-adrenoceptors were decreased in the saline-treated rats, whereas the number of receptors tended to be higher. It is suggested that sodium may produce its pressor effect by diminishing the affinity of central alpha 2-adrenoceptors for neurotransmitters, resulting in disinhibition of certain sympathoinhibitory neurons and increased sympathetic outflow.