Justine H. Cervenka

Baroreflex sensitivity and heredity in essential hypertension.

BackgroundAbnormalities in baroreflex control of heart rate may be important in the pathogenesis of essential hypertension. Methods and ResultsTo investigate the influence of heredity on baroreflex function, we measured baroreflex sensitivity in 40 untreated patients with essential hypertension grouped by the presence (FH+) or absence (FH−) of a family history of hypertension and in 24 normotensive counterparts. Baroreflex sensitivity was assessed by both high-pressure (phenylephrine bolus) and low-pressure (amyl nitrite inhalation) stimuli. Subject groups were matched for age, blood pressure, body weight, and race. Baroreflex sensitivity (in milliseconds per millimeter of mercury) assessed by amyl nitrite inhalation was 24.3 2.8 in FHnormotensives, 12.3±1.7 in FH+ normotensives, 15.4±3.3 in FH− hypertensives, and 8.1±1.2 in FH+ hypertensives. Baroreflex sensitivity assessed by phenylephrine bolus was 28.8±5.6 in FH− normotensives, 19.3±2.8 in FH+ normotensives, 19.1±2.0 in Fl− hypertensives, and 13.6±1.3 in FH+ hypertensives. Two-factor analysis of variance showed significant effects on baroreflex sensitivity for blood pressure status (normotensive versus hypertensive) and for family history of hypertension. After control line (controlling) for the effects of several variables, including age, mean arterial pressure, body weight, and race through multiple linear regression analysis, the effect of family history of hypertension on baroreflex sensitivity was still highly significant. Indeed, of all variables investigated, family history of hypertension was the strongest unique baroreflex sensitivity predictor. ConclusionsThese data suggest that the impairment in baroreflex sensitivity in hypertension is in part genetically determined and may be an important hereditary component in the pathogenesis of essential hypertension.

Chromogranin A in Human Hypertension: Influence of Heredity

Multiple heritable traits are associated with essential (genetic) hypertension in humans. Because chromogranin A is increased in both human and rodent genetic hypertension, we examined the influence of heredity and blood pressure on chromogranin A in humans. In estimates derived from among- and within-pair variance in monozygotic versus dizygotic twins, plasma chromogranin A displayed significant (F15,18 = 2.93, P = .016) genetic variance (sigma 2 g), and its broad-sense heritability was high (h2B = 0.983). Plasma chromogranin A was increased in essential hypertension (99.9 +/- 6.7 versus 62.8 +/- 4.7 ng/mL, P < .001) but was influenced little by genetic risk for (family history of) hypertension (in normotensive or hypertensive subjects), by race, or by several antihypertensive therapies (angiotensin-converting enzyme inhibitor, diuretic, or beta-adrenergic antagonist). In normotensive subjects at genetic risk for essential hypertension, neither basal nor sympathoadrenal stress-evoked chromogranin A differed from values found in subjects not at risk. In established essential hypertension, plasma chromogranin A responses to adrenal medullary (insulin-evoked hypoglycemia) or sympathetic neuronal (dynamic exercise) activation were exaggerated, whereas responses to sympathoadrenal suppression (ganglionic blockade) were diminished, suggesting increased vesicular stores of chromogranin A and an adrenergic origin of the augmented chromogranin A expression in this disorder. We conclude that plasma chromogranin A displays substantial heritability and is increased in established essential hypertension. Its elevation in established hypertension is associated with evidence of increased vesicular stores of the protein and with adrenergic hyperactivity but is influenced little by customary antihypertensive therapies. However, the chromogranin A elevation is not evident early in the course of genetic hypertension.

Is physiologic sympathoadrenal catecholamine release exocytotic in humans

In cultured cells and isolated perfused organs, catecholamines are coreleased with chromogranin A (CgA) from adrenal chromaffin cells and sympathetic neurons. The corelease suggests that exocytosis is the mechanism of catecholamine secretion. To investigate whether physiologic catecholamine secretion is exocytotic in humans, we measured plasma norepinephrine, epinephrine, and CgA responses to differentiated stimuli of sympathoadrenal discharge. The CgA radioimmunoassay antibody recognized authentic CgA in normal human adrenal chromaffin vesicles. Insulin-induced hypoglycemia and caffeine ingestion, in decreasing order of potency, selectively stimulated epinephrine release from the adrenal medulla. During hypoglycemia, plasma levels of epinephrine and CgA rose, and peak plasma levels of epinephrine and CgA correlated, suggesting that gradations in epinephrine release represented gradations in exocytosis. However, significant increments in plasma CgA were not observed after caffeine ingestion. Furthermore, the rise of CgA levels during hypoglycemia lagged 60 minutes behind those of epinephrine. A less-pronounced temporal dissociation between CgA and epinephrine release was also shown in isolated chromaffin cells in vitro. Selective adrenal vein catheterization suggested a barrier to CgA transport across the adrenal capillary wall. Short-term, high-intensity dynamic exercise, assumption of the upright posture, prolonged low-intensity dynamic exercise, and smoking, in decreasing order of potency, stimulated norepinephrine release from sympathetic nerve endings. Only the first sympathetic neuronal stimulus resulted in significant increments in plasma CgA, increments considerably less than those attained during adrenal medullary activation by insulin hypoglycemia. During high-intensity exercise, peak plasma norepinephrine and CgA levels correlated, suggesting that gradations in norepinephrine release represented gradations in exocytosis. The human adrenal medulla was a far more prominent tissue source of CgA than human sympathetic nerves--adrenal medullary homogenates contained 97-fold more CgA (micrograms/g) than sympathetic nerve homogenates. In conclusion, catecholamine secretion during selective stimulation of either sympathetic nerves or the adrenal medulla is, at least in part, exocytotic. Furthermore, stimulation of the former results in comparatively modest changes in plasma CgA compared with changes attained during stimulation of the latter. CgA appears to be transported by a route different from that of catecholamines from adrenal medullary chromaffin cells to the circulation in vivo.

Chromogranin A. Storage and release in hypertension.

The chromogranins/secretogranins are a family of acidic, soluble proteins with widespread neuroendocrine distribution in secretory vesicles. Although the precise function of the chromogranins remains elusive, knowledge of their structure, distribution, and potential intracellular and extracellular roles, especially that of chromogranin A, has greatly expanded during recent years. Chromogranin A is coreleased with catecholamines by exocytosis from vesicles in the adrenal medulla and sympathetic nerve endings. Thus, measurement of its circulating concentration by radioimmunoassay may be a useful probe of exocytotic sympathoadrenal activity in humans, under both physiological and pathological conditions. Here, we explore the storage, structure, and function of chromogranin A, and parameters that influence its circulating levels. We have also measured plasma chromogranin A concentrations in different groups of patients with hypertension, including those with pheochromocytoma.

Renal hemodynamics in essential hypertension. Racial differences in response to changes in dietary sodium.

Previous studies have suggested striking racial differences in hypertension-related renal disease. To explore potential mechanisms responsible for these differences, we investigated changes in renal hemodynamics in white and black essential hypertensive patients in response to alterations in dietary sodium. Patients were untreated, age-matched, and blood pressure-matched white (n = 59) and black (n = 22) males with essential hypertension. Studies were conducted on an inpatient metabolic ward and included assessment of blood pressure, urinary sodium excretion, glomerular filtration rate, renal plasma flow, and renal blood flow after 5 days each of high and low salt diets. In response to high dietary salt intake, both white and black patients demonstrated significantly higher mean arterial pressure, renal plasma flow, and renal blood flow, and there were no racial differences in the changes in these parameters. However, whites and blacks differed significantly in glomerular filtration rate, with black hypertensive patients showing an increase in glomerular filtration rate (+17.3 +/- 5.3 mL/min per 1.73 m2, F = 7.586, P = .007) and white hypertensive patients showing no change (-0.2 +/- 3.3 mL/min per 1.73 m2) in response to high dietary sodium. These data demonstrate racial differences in the autoregulation of glomerular filtration rate in response to changes in dietary sodium. These differences suggest that glomerular hyperfiltration in response to a high salt diet may be a mechanism contributing to the racial disparity in hypertension-related renal disease.

Divergent Effects of Dihydropyridine and Phenylalkylamine Calcium Channel Antagonist Classes on Autonomic Function in Human Hypertension

Calcium channel antagonists differ by class in reported frequency of side effects that suggest reflex sympathoadrenal activation. Do such differences result from differential effects on autonomic and baroreflex function? The present study compared acute and chronic effects of two classes of calcium channel antagonists, the dihydropyridine type (felodipine) and the phenylalkylamine type (verapamil), on efferent sympathetic outflow and baroreflex slope in 15 essential hypertensive subjects. Blood pressure, heart rate, hemodynamics, and biochemistries were determined at baseline and after acute (first dose) and chronic (4 weeks) administration of the drugs versus placebo. Acutely, felodipine caused a greater decrease in blood pressure associated with a larger decline in systemic vascular resistance than the corresponding effects produced by verapamil. Chronically, there were similar, significant declines in blood pressure (P = .001) and systemic vascular resistance (P = .001) after each drug. Acutely, increased sympathetic activity after felodipine was suggested by reflex tachycardia (from 69 +/- 3 to 74 +/- 2 beats per minute, P = .014) and elevation of plasma norepinephrine (from 264 +/- 25 to 323 +/- 25 pg/mL, P = .037), whereas after verapamil the corresponding changes were closely similar to those after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial Compliance by Cuff Sphygmomanometer Application to Hypertension and Early Changes in Subjects at Genetic Risk

Abnormalities of the arterial pulse waveform reflect changes in cardiovascular structure and function. These abnormalities may occur early in the course of essential hypertension, even before the onset of blood pressure elevation. Previous studies of cardiovascular structure and function have relied on invasive intra-arterial cannulation to obtain the arterial pulse wave. We evaluated arterial structure and function using a noninvasive cuff sphygmomanometer in hypertensive (n = 15) and normotensive (n = 36) subjects stratified by genetic risk (family history) for hypertension. Using a simple physical model in which the aorta was assumed to be a T tube and the brachial artery a straight tube, we determined vascular compliance and peripheral resistance by analyzing the brachial artery pulsation signal from a cuff sphygmomanometer. Essential hypertensive subjects tended to have higher peripheral resistance (P = .06) and significantly lower vascular compliance (P = .001) than normotensive subjects. Vascular compliance correlated with simultaneously determined pulse pressure in both groups (n = 51, r = .74, P < .0001). Higher peripheral resistance (P = .07) and lower vascular compliance (P = .04) were already found in still-normotensive offspring of hypertensive parents (ie, normotensive subjects with a positive family history of hypertension) than in normotensive subjects with a negative family history of hypertension. Multivariate analysis demonstrated that both genetic risk for hypertension (P = .030) and blood pressure status (P = .041), although not age (P = .207), were significant predictors of vascular compliance (multiple R = .47, P = .011). However, by two-way ANOVA, genetic risk for hypertension was an even more significant determinant (F = 7.84, P = .007) of compliance than blood pressure status (F = 2.69, P = .089). Antihypertensive therapy with angiotensin-converting enzyme inhibitors (10 days, n = 10) improved vascular compliance (P = .02) and reduced resistance (P = .003) significantly; treatment with calcium channel antagonists (4 weeks, n = 8) tended to improve vascular compliance (P = .07) and significantly reduced peripheral resistance (P = .006). We conclude that arterial vascular compliance abnormalities detected by a noninvasive cuff sphygmomanometer reflect treatment-reversible changes in vascular structure and function. Early changes in vascular compliance in still-normotensive individuals at genetic risk for hypertension may be a heritable pathogenetic feature of this disorder.

Autonomic function in hypertension. Are there racial differences

Previous biochemical assessment of sympathetic nervous system activity including plasma catecholamines, plasma renin activity, and plasma dopamine-beta-hydroxylase levels has suggested racial differences in the contribution of the sympathetic nervous system to the pathogenesis or maintenance of hypertension. We, therefore, performed physiological and pharmacological studies in white and black subjects with essential hypertension and their age-matched normotensive counterparts to assess autonomic and sympathetic nervous system function. One hundred one male subjects (47 white hypertensive, 17 black hypertensive, 22 white normotensive, and 15 black normotensive subjects) were evaluated for baroreceptor reflex sensitivity to low-pressure (amyl nitrite inhalation) and high-pressure (phenylephrine infusion) stimuli; cold pressor test heart rate and blood pressure responses; and blood pressure response to phentolamine alpha-adrenergic blockade. Hypertensive subjects exhibited an increase in resting heart rate, a decrease in baroreceptor reflex sensitivity, and an exaggerated decline in mean arterial pressure in response to phentolamine. These abnormalities were present to a comparable degree in black and white hypertensive subjects. Cold pressor testing revealed greater increases in heart rate in blacks as compared with whites; however, this racial difference was present regardless of blood pressure status, occurring in black normotensive and black hypertensive subjects to a comparable degree. Cold pressor test blood pressure increments were similar in the four groups. We conclude that both white hypertensive and black hypertensive subjects demonstrate similar abnormalities in autonomic and sympathetic nervous system function including blunting of baroreceptor reflex sensitivity and an increased alpha-adrenergic receptor participation in blood pressure maintenance. The results do not suggest major racial differences in autonomic pathogenetic mechanisms in hypertension.

Chromogranin a immunoreactivity in human cerebrospinal fluid: Properties, relationship to noradrenergic neuronal activity, and variation in neurologic disease

Although measurement of chromogranin A in the bloodstream is of value in sympathoadrenal investigations, little is systematically known about chromogranin A in cerebrospinal fluid, despite substantial knowledge about its occurrence and distribution in brain. We therefore applied a homologous human chromogranin A radioimmunoassay to cerebrospinal fluid, in order to evaluate the properties and stability of cerebrospinal fluid chomogranin A, as well as its relationship to central noradrenergic neuronal activity, to peripheral (plasma) chromogranin A, and to disease states such as hypertension, renal failure and Parkinsonism. Authentic, physically stable chromogranin A immunoreactivity was found in cerebrospinal fluid (at 37-146 ng/ml; mean, 87.0 +/- 6.0 ng/ml in healthy subjects), and several lines of evidence (including 3.39 +/- 0.27-fold higher chromogranin A in cerebrospinal fluid than in plasma) indicated that it originated from a local central nervous system source, rather than the periphery. Cerebrospinal fluid chromogranin A values were not influenced by administration of effective antihypertensive doses of clonidine or propranolol, and were not related to the cerebrospinal fluid concentrations of norepinephrine, methoxyhydroxyphenylglycol, or dopamine-beta-hydroxylase; thus, cerebrospinal fluid chromogranin A was not closely linked to biochemical or pharmacologic indices of central noradrenergic neuronal activity. Cerebrospinal fluid chromogranin A was not changed (P > 0.1) in essential hypertension (84.2 +/- 14.0 ng/ml) or renal failure (72.2 +/- 13.4 ng/ml), despite a marked (7.1-fold; P < 0.001) increase in plasma chromogranin A in renal failure, and a modest (1.5-fold; P = 0.004) increase in plasma chromogranin A in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Fosenopril, an angiotensin-converting enzyme inhibitor, and propranolol: comparative effects at rest and exercise on blood pressure, hormonal variables, and plasma potassium in essential hypertension.

SummaryFosenopril sodium, a prodrug, is converted to its active diacid during and after intestinal absorption. Its excretion is equally divided between hepatic and renal routes. This placebo-controlled, randomized, double-blind, parallel group study evaluated the efficacy and safety of fosenopril compared to propranolol, at rest and during exercise, on blood pressure, plasma potassium, plasma renin activity, and plasma aldosterone. Exercise testing utilized bicycle ergometry, and individual subjects underwent an identical exercise protocol on placebo and on active treatment. The fosenopril group comprised nine subjects who were matched to nine subjects on propranolol. Blood pressure fell significantly and equally at rest (fosenopril-157/103 to 141/95 mmHg, p<0.005; propranolol-159/100 to 149/90 mmHg p<0.005) and during exercise in both groups. Plasma potassium fell significantly at rest (4.25 to 3.98 mmol/l, p<0.05) and during exercise (5.18 to 4.87 mmol/l, p<0.05) on fosenopril, but rose in subjects on propranolol during exercise (4.99 to 5.44 mmol/l, p<0.01). Plasma renin activity rose on fosenopril and fell on propranolol. Plasma aldosterone was uninfluenced by either drug. Fosenopril was well tolerated and its antihypertensive profile is similar to that of beta blockers and other ACE inhibitors.