Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: mechanisms and consequences.

Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratified by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusion of mixed amino acids. Before and during amino acid administration, we measured glomerular filtration rate (GFR), putative second messengers of amino acids (nitric oxide [NO.] metabolites and cGMP), serum insulin and amino acid concentrations, and the FE(Li)+ as an index of renal proximal tubular reabsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43+/-8.16% versus 31.0+/-13.4% rise, P:=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P:<0.01) with the change in urinary NO. metabolite excretion; a diminished rise in urinary NO. metabolite excretion in the FH+ group (P:=0.0105) suggested a biochemical mechanism for the different GFR responses between FH groups: a relative inability to convert arginine to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol. h(-1)/1.73 m(2), P:=0.001), although cGMP did not change during the amino acid infusion (P:=0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (P:=0.0013), accounting for approximately 45% of the variance in GFR response. Decline in FE(Li)+, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (r=-0.506, P:=0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FH+ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO. in the kidney. Corresponding changes in GFR and fractional excretion of Li(+) suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension.

Plasma hydrogen peroxide production in human essential hypertension: role of heredity, gender, and ethnicity.

Oxygen free radicals, including hydrogen peroxide, may mediate oxidative stress in target organ tissues and contribute to cardiovascular complications in hypertension. To examine heritability of hydrogen peroxide production, we investigated this trait in a family-based cohort consisting of family members (n=236) ascertained through probands (n=57) with essential hypertension. Significant effects on hydrogen peroxide production were found for gender and ethnicity, with men having greater values than women (P<0.001) and white subjects having greater values than black subjects (P=0.025). Hydrogen peroxide production correlated directly with plasma renin activity (P=0.015), suggesting an important interaction between circulating oxygen radicals and the renin-angiotensin system and a potential mechanism for lower hydrogen peroxide values observed in blacks. Heritability estimates from familial correlations revealed that approximately 20% to 35% of the observed variance in hydrogen peroxide production could be attributed to genetic factors, suggesting a substantial heritable component to the overall determination of this trait. Hydrogen peroxide production negatively correlated with cardiac contractility (r=-0.214, P=0.001) and renal function (r=-0.194, P=0.003). In conclusion, these results indicate that hydrogen peroxide production is heritable and is related to target organ function in essential hypertension. Genetic loci influencing hydrogen peroxide production may represent logical candidates to investigate as susceptibility genes for cardiovascular target organ injury.

Circulating amylin in human essential hypertension: heritability and early increase in individuals at genetic risk.

BACKGROUND: Human essential hypertension is a complex trait with poorly understood genetic determination. Insulin resistance is frequently associated with this trait. OBJECTIVE: To determine whether a potentially pathogenic feature of the insulin-resistant state, circulating amylin (islet amyloid polypeptide, co-released with insulin from pancreatic islet beta-cells), is already increased in prehypertensive individuals (normotensive persons at genetic risk of hypertension because of family history), whether such individuals already differ in their amylin response to beta-cell stimulation, and whether plasma amylin concentration is heritable. Such features could establish increased circulating amylin as a hereditary 'intermediate phenotype' useful in genetic analyses of hypertension. METHODS: Plasma amylin and insulin were measured in 283 medication-free individuals stratified by blood pressure status (82 hypertensive and 201 normotensive), and genetic risk (family history) of hypertension. Differences in means were tested by ANOVA, variances by F test, and frequency distributions by maximum likelihood analysis. Co-release of amylin and insulin was provoked by intravenous infusion of mixed amino acids. The effect of antihypertensive treatment was evaluated after monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade in hypertension. RESULTS: Plasma amylin was increased in hypertension (P= 0.027), and body mass index was a strong predictor of increased circulating amylin (P = 0.0001). Plasma amylin and plasma renin activity were not correlated (P = 0.395), and effective antihypertensive monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade did not affect either amylin (P = 0.87-0.97) or insulin (P= 0.55-0.59). Among normotensive individuals, those at genetic risk of hypertension (with positive family history) already had increased concentrations of amylin (P< 0.001), despite exhibiting no difference in blood pressure or body mass index compared with the family-history-negative group; however, among normotensive individuals, both family history (P = 0.043) and body mass index (P= 0.0059) were significant predictors of increased concentrations of amylin. By maximum likelihood analysis, plasma amylin was distributed heterogeneously in the normotensive individuals, with two modes best explaining the distribution (chi2 = 77.4, P< 0.001), and family-history-positive individuals completely accounting for the upper mode (chi2 = 4.63, P = 0.031). Family-history-positive normotensive individuals showed greater plasma amylin concentrations both before and during beta-cell stimulation by amino acid infusion (P = 0.014). Black (n = 111) and white (n = 172) individuals did not differ in mean (P = 0.946) or variance (P = 0.172) of plasma amylin concentrations. CONCLUSIONS: These results suggest that plasma amylin concentration is in part determined by heredity. Both basal and stimulated plasma amylin excess may identify a subgroup of individuals bearing an inherited predisposition to hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relationship to insulin resistance.

Beta2-adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in whites and African Americans.

Beta2-adrenergic receptors (beta2-AR) contribute to cardiovascular regulation by influencing several functions and previous studies suggest that a decreased function of the beta2-AR may be involved in essential hypertension. Beta2-AR are polymorphic and certain polymorphisms of these receptors are of functional importance. We focus here on the Arg16-->Gly16 beta2-AR polymorphism, which shows enhanced agonist-promoted downregulation of the receptor and which, in two recent studies, yielded opposite results in terms of association with essential hypertension: an increased frequency of the Gly16 variant in African-Caribbean hypertensives and of the Arg16 variant in offspring of Norwegian white hypertensive parents. In the current study, we genotyped 243 subjects, including both African-American and white individuals, for codon 16 polymorphism and assessed blood pressure and cardiovascular function using impedance cardiography and pressor sensitivity to phenylephrine. We found similar patterns of cardiovascular function and expression of hypertension with the two genotypes of codon 16. There was no statistically significant difference in the overall allelic distribution of the two genotypes: among African-Americans, 51% of the hypertensives and 50% of the normotensives carried the Arg16 allele, whereas among the white subjects 40% of the hypertensives and 47% of the normotensives were carriers of the Arg16 allele. Although we observed a statistically significant increase in the Arg16/Gly16 heterozygotes in the African-American population, the Gly16 allele was not significantly increased in the African-Americans compared to whites. These findings indicate that the codon 16 polymorphisms are not associated with hypertension in a mixed American study population nor do they appear to substantially impact on a variety of hemodynamic variables.

Renal kallikrein excretion: role of ethnicity, gender, environment, and genetic risk of hypertension.

BACKGROUND AND OBJECTIVE: Alterations in renal kallikrein excretion are well-described in hypertension, and kallikrein excretion may predict risk of developing hypertension, but kallikrein excretion has not been directly compared across several ethnic strata, nor have the effects of ethnicity, gender, environment, and genetic risk of hypertension been simultaneously considered as determinants of kallikrein. METHODS: We investigated determinants of kallikrein excretion in a cross-section of n = 204 normotensive subjects stratified by ethnicity (119 Caucasian, 33 African-American, 52 Asian), gender (109 men, 95 women), environment (spontaneous electrolyte intake/excretion), and heredity (genetic risk (family history) of hypertension). Results were interpreted by analysis of variance (with Bonferroni post hoc comparison corrections), analysis of covariance, multiple linear regression, and maximum likelihood. RESULTS: Urinary kallikrein activity varied substantially (F = 5.30, P = 0.006) across the three ethnic groups, with African-American values approximately 50% lower than Caucasian (P = 0.005) or Asian (P = 0.02). Ethnicity and gender (T = 3.24, P = 0.001) had independent effects on kallikrein, with women excreting approximately 50% more kallikrein than men, regardless of ethnicity. Subjects at genetic risk of hypertension were over-represented (P = 0.048) in the lower stratum of a bimodal distribution of kallikrein excretion (chi-square = 29.6, P < 0.001). Potassium excretion was diminished in African-Americans (P < 0.001 to P = 0.002), and in a multivariate analysis, potassium excretion was the strongest correlate of kallikrein excretion (T = 4.10, P = 0.0001). In a subset of Caucasian and African-American individuals, African-Americans exhibited diminished excretion of not only kallikrein and potassium, but also aldosterone (P = 0.003), suggesting a mechanistic link between potassium and kallikrein excretion in their ethnic variations. CONCLUSIONS: Kallikrein excretion is influenced by several independent determinants, both hereditary (gender, ethnicity, and genetic risk of hypertension) and environmental (potassium intake and excretion). Ethnicity and environment may interact uniquely to influence kallikrein, as demonstrated by the case of African-Americans with diminutions of both kallikrein and potassium excretion. These results suggest a mechanism whereby kallikrein excretion is diminished in African-Americans, as well as therapeutic strategies to correct this deficiency. Finally, the identified determinants of kallikrein excretion will require analytic adjustment during genetic studies of this 'intermediate phenotype' in hypertension. Journal of Human Hypertension (2000) 14, 461-468

Variability in phenylephrine response and essential hypertension: a search for human alpha(1B)-adrenergic receptor polymorphisms.

Genetic polymorphisms in drug receptors, in particular adrenergic receptors, may contribute to intersubject differences in pharmacologic response. We tested patients and first-degree normotensive and hypertensive relatives of patients with essential hypertension and found substantial intersubject variability in blood pressure response to infusion of the alpha(1)-adrenergic agonist phenylephrine. Because response to phenylephrine depends upon interaction with alpha(1B)-adrenergic receptors, we tested whether polymorphisms in this receptor contribute to the variable responses. Accordingly, we developed a polymerase chain reaction-based method, generating four exon-spanning fragments, to identify polymorphisms in the coding sequence of the two exons of the human alpha(1B)-adrenergic receptor. We sequenced the entire coding sequence of exon 1 from 51 subjects and exon 2 from 16 of these 51 subjects. Compared with the published sequence for the alpha(1B)-adrenergic receptor, we found one amino acid addition in exon 2 at position 368 (Arg) and one substitution (Arg371Gly) in all subjects. We thus suggest we have defined the correct coding sequence of the human alpha(1B) receptor. We found two "silent" polymorphisms in exon 1, one of which occurred in 3 of 51 subjects. These polymorphisms were unrelated to blood pressure status or response to phenylephrine. The 95% confidence intervals for expression of polymorphisms in exons 1 and 2 were 0 to 11%. Our data reveal that although phenylephrine response varies in humans, frequent polymorphisms in the coding sequence of the human alpha(1B)-adrenergic receptor appear not to account for this variation or for the increased blood pressure in patients with essential hypertension.

Racial differences in renal kallikrein excretion: effect of the ovulatory cycle.

BACKGROUND: Renal kallikrein excretion is diminished in essential hypertension, especially in African-Americans, and evidence exists for a major gene effect on the kallikrein phenotype. In addition, urinary kallikrein excretion differs by gender, with ovulating females having greater kallikrein excretion than males or postmenopausal females. Recent studies have shown that renal kallikrein excretion varies in females during the ovulatory cycle, with levels rising during the luteal phase and returning during the follicular phase to levels that are similar to those of males. In family studies, gender differences in urinary kallikrein excretion were present in white subjects, but not black subjects. We therefore hypothesized dysregulation of kallikrein biosynthetic responses in African-Americans. METHODS: We determined urinary kallikrein activity [chromogenic substrate S2266 (D-val-leu-arg-paranitroanilide) assay; in microU/mg creatinine] in white (N = 15) and black (N = 11) ovulating females during the ovulatory cycle. Serum progesterone, estrogen, plasma renin activity as well as urinary aldosterone, and urinary electrolytes were determined to investigate changes between mid-follicular and mid-luteal phases in the two groups. RESULTS: White and black groups were matched for age, body mass index, blood pressure, heart rate and renal function. Ovulatory cycle phases were confirmed by serum progesterone determinations, which increased significantly in whites and blacks to a comparable degree [0.84 +/- 0.14 nmol/liter (mid-follicular) to 29.77 +/- 4.70 nmol/liter (mid-luteal) in whites, 0.67 +/- 0.08 nmol/liter (mid-follicular) to 28.62 +/- 5.83 nmol/liter (mid-luteal) in blacks; P < 0.001 for cycle effect, P = NS for race effect and race X cycle interaction]. Urinary kallikrein activity increased from 623 +/- 86 microU/mg creatinine (mid-follicular) to 948 +/- 142 microU/mg creatinine (mid-luteal) in whites, but did not change in blacks during the ovulatory cycle [239 +/- 73 microU/mg creatinine (mid-follicular] to 244 +/- 41 microU/mg creatinine (mid-luteal)]. Two-way ANOVA revealed significant effects on urinary kallikrein for race (P < 0.001), cycle (P < 0.05), and race X cycle interaction (P < 0.05). Thus, white females had higher urinary kallikrein than black females, and demonstrated a significant increase in urinary kallikrein excretion during the ovulatory cycle, whereas no significant change in urinary kallikrein activity was seen in the black group. Enzyme kinetic studies and mixing studies demonstrated that these racial differences in renal kallikrein excretion were quantitative, rather than due to qualitative differences in the renal kallikrein enzyme or due to the presence of a kallikrein inhibitor. CONCLUSIONS: These results suggest pronounced blunting of menstrual cycle changes in urinary kallikrein excretion in black females. Blunted urinary kallikrein responses during the ovulatory cycle are consistent with dysregulation of renal kallikrein biosynthetic responses in African-Americans, a group at increased risk for hypertension.

Expression of altered alpha2-adrenergic phenotypic traits in normotensive humans at genetic risk of hereditary (essential) hypertension.

BACKGROUND: Essential (hereditary) hypertension is a common, though complex, trait with substantial heritability, but a still-obscure mode of inheritance. In this disorder with relatively late onset, knowledge of phenotypes with earlier penetrance would aid genetic analyses, as well as assessment of risk. OBJECTIVE: Because alpha2-adrenergic receptor alterations are among the most heritable in experimental genetic hypertension, we hypothesized enhanced expression of alpha2-adrenergic phenotypic traits in still-normotensive humans at genetic risk of hypertension. METHODS: We evaluated hemodynamic (blood pressure, cardiac output, systemic vascular resistance, stroke volume, and cardiac contractility) and biochemical (plasma drug, catecholamine, renin, and chromogranin A levels) responses to alpha2-adrenergic blockade with intravenous yohimbine in 84 normotensive subjects stratified by genetic risk of essential hypertension (67 with positive family histories and 17 with negative family histories of hypertension), as well as 18 subjects with established essential hypertension. Results were evaluated by analysis of variance, normal likelihood ratio test, and by maximum likelihood analysis for bimodality (i.e. mixtures) of response distributions. RESULTS: Blood pressure rose (P<0.001) during alpha2-adrenergic blockade, with greater response (P<0.001) in members of the hypertensive than in members of the normotensive group. Hemodynamically, the rise in blood pressure resulted from an increase in cardiac output (P<0.001), with associated increases in stroke volume (P=0.002) and cardiac contractility (P=0.006), without an overall change in systemic vascular resistance. Biochemically, plasma norepinephrine (P<0.001), epinephrine (P=0.001), and chromogranin A (P=0.02) rose, suggesting augmentation of efferent exocytotic sympathoadrenal activity. Cardiac output and stroke volume responses were correlated to increments in plasma catecholamines (especially epinephrine) for the positive group, but not for the negative group. Baseline plasma catecholamines predicted increments of stroke volume after administration of yohimbine (P=0.003-0.007) for the positive but not for the negative group. Simultaneous comparison of means and variances of cardiac output and stroke volume alpha2-adrenergic responses, by using a normal likelihood ratio test, revealed highly significant (P=0.025 to P<0.0001) differences between the groups of subjects with and without family histories of hypertension. Frequency histogram suggested that there was a bimodal distribution of responses of stroke volume to alpha2-adrenergic blockade for the normotensive group with positive family histories of hypertension; maximum likelihood analysis strongly rejected the hypothesis of a unimodal distribution, whereas the hypothesis of bimodality could not be rejected (chi2=18.4, P=0.0004). The second (exaggerated) mode of response of stroke volume to alpha2-adrenergic blockade, defined by maximum likelihood analysis, was found for 9.5% of subjects in the normotensive group with positive family histories of hypertension, and was characterized by significantly different responses of cardiac output (P=0.001), stroke volume (P<0.001), contractility (P<0.001), heart rate (P=0.03), systemic vascular resistance (P<0.001), and epinephrine (P<0.001). Even prior to alpha2-adrenergic blockade, baseline stroke volume (P=0.01), heart rate (P=0.04), systemic vascular resistance (P=0.005), and catecholamine (P=0.001-0.005) values for this subgroup were different than control values. CONCLUSIONS: We conclude that heterogeneous, bimodally distributed hemodynamic responses to alpha2-adrenergic blockade in subjects with positive family histories of hypertension suggest a discrete subgroup with early expression of perhaps Mendelian traits associated with risk of later development of hypertension. Such phenotypic traits ('intermediate phenotypes'), with earlier penetrance than hypertension itself, can be

Development and validation of a noninvasive method to determine arterial pressure and vascular compliance.

The ability not only to record automated systolic and diastolic pressure, but also to derive measurements of the rate of pressure change during the cardiac cycle, would have great potential clinical value. A new method has been developed to obtain pressure measurements at 20-ms intervals by oscillometric cuff signal pattern recognition. Derivation of noninvasive pressure measurements is based on a T tube aorta and straight tube brachial artery, and assumes that the systolic phase of the suprasystolic cuff signal and the diastolic phase of the subdiastolic cuff signal most closely approximate systolic and diastolic aortic pressures, respectively. Arterial pressures obtained by this method were compared with simultaneous invasive measurements from the thoracic aorta in 36 patients. Good agreement was observed between noninvasive and invasive methods for systolic (146 +/- 4 vs 145 +/- 5 mm Hg), diastolic (80 +/- 2 vs 77 +/- 2 mm Hg), and mean (100 +/- 3 vs 100 +/- 3 mm Hg) arterial pressures, and correlation coefficients were r = 0.94, 0.91, and 0.95, respectively. To assess the validity of measurements of the rate of pressure change, oscillometric cuff signals from a subgroup of 14 patients were analyzed in detail for the peak positive pressure derivative (dP/dt(Max)), peak negative pressure derivative (dP/dt(Min)), and time interval between peak positive and peak negative pressure derivatives [t(pp)]. Results (mean +/- SEM) were: [table in text]. The incorporation of measurements of the rate of pressure change into a physical model of the brachial artery was used to derive vascular compliance. A significant correlation was observed between vascular compliance derived from the oscillometric signal and determinations by either thermodilution or Fick methods and noninvasive pressures (n = 20, r = 0.83, p <0.001). Day-to-day variability for blood pressure and vascular compliance derived by the noninvasive method did not differ by >4%, representing a reproducible measure of vascular structure and function. We conclude that the measurement of absolute pressure and rate of pressure change show good correlation with catheter data and that vascular compliance can be reliably assessed by this new method. The technology should provide a valuable noninvasive tool for the assessment of both cardiac function and vascular properties.

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.

Hereditary intermediate phenotypes in African American hypertension.

OBJECTIVE: Essential hypertension is a heterogeneous and multifactorial disorder and is at least twice as frequent among African Americans as in the general population. Inheritance of high blood pressure is complex, with the gene(s) responsible for hypertension still remaining elusive. A useful strategy for investigating the heritability of hypertension is to evaluate 'intermediate phenotypes'--simple Mendelian or monogenic traits that are associated with hypertension. These intermediate steps may identify potential pathophysiological factors that antedate the development of high blood pressure and suggest candidate genes. We are attempting to identify and characterize several such intermediate phenotypes, in particular as these might apply to hypertension in African Americans. METHODS: We studied several physiological and biochemical candidate intermediate phenotypes in untreated black and white patients with essential hypertension and in their normotensive counterparts stratified by genetic risk of hypertension. RESULTS AND CONCLUSIONS: Promising intermediate phenotypes, which may be useful for studies in African American families, include baroreceptor sensitivity to low and high pressure stimuli, cold pressor test responses, and biochemical markers such as plasma chromogranin A, dopamine-beta-hydroxylase and urinary kallikrein excretion. Identification of genes involved in complex traits such as hypertension may be facilitated by the intermediate phenotype approach, combined with recent advances in quantitative genetics and linkage mapping. Further studies are needed to pinpoint the nature of genes in African American hypertension.

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)

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.

Factitious pheochromocytoma: novel mimickry by Valsalva maneuver and clues to diagnosis.

Factitious pheochromocytoma usually occurs in patients surreptitiously ingesting adrenergic medications. We encountered a case of factitious pheochromocytoma where in the subject mimicked hemodynamic (profound hypertension) and biochemical (plasma catecholamine elevation) manifestations of the illness by consciously altering autonomic function with Valsalva maneuver. Clues to this presentation included visible performance of Valsalva maneuver, marked disparity between blood pressures recorded in the presence and absence of the subject's knowledge, normal urinary catecholamine and metabolite excretion, and normal plasma chromogranin A. We reproduced, in part, the hemodynamic and biochemical manifestations of this presentation with Valsalva maneuver in healthy subjects.

Does lipophilicity of angiotensin converting enzyme inhibitors selectively influence autonomic neural function in human hypertension?

INTRODUCTION: Angiotensin II has both central nervous system and peripheral effects on autonomic function. Ramipril is among the more lipophilic angiotensin converting enzyme (ACE) inhibitors, and hence can penetrate the central nervous system readily. METHODS: We investigated whether rampiril has selective effects on autonomic control of the circulation in human hypertension, compared with the more hydrophilic ACE inhibitor enalapril. Blood pressure, hemodynamics and measurements of autonomic function were obtained in 13 essential hypertensive subjects after 10 days on placebo, and after crossover monotherapy with 10 days on enalapril versus 10 days on ramipril. RESULTS: Both enalapril and ramipril lowered systolic, diastolic and mean arterial blood pressures significantly, with no reflex increase in heart rate. Plasma renin activity increased substantially on each of the ACE inhibitors. There were no significant effects of either agent on plasma catecholamines (norepinephrine or epinephrine) or chromogranin A, biochemical indices of efferent sympatho-adrenal outflow. There were also no significant changes after either agent in baroreflex sensitivity (to high- and low-pressure stimuli), the response to cold stress or sympathetic (alpha-adrenergic) participation in blood pressure maintenance. There was a marginal effect of ACE inhibition on alpha 1-adrenergic pressor sensitivity, but the two compounds did not differ significantly in this respect. CONCLUSION: Autonomic control of circulatory function was maintained well after either lipophilic (ramipril) or hydrophilic (enalapril) ACE inhibitors, and the lipophilic compound ramipril had no additional effects on autonomic function beyond those shown by the hydrophilic agent enalapril.

Effects of an oral prostaglandin E1 agonist on blood pressure and its determinants in essential hypertension.

Arachidonic acid metabolites such as prostaglandins of the E series have well-documented effects on blood pressure (BP). Recently, a stable analogue of prostaglandin E1 (misoprostol) became available for oral use in humans, being primarily indicated for prevention of peptic disease induced by cyclo-oxygenase inhibitors. We hypothesised that misoprostol would exert antihypertensive actions and therefore performed a randomised, placebo-controlled clinical trial in 15 essential hypertensives to characterise the effects of a 400 micrograms oral dose of misoprostol on BP and its haemodynamic, autonomic and biochemical determinants. There was a modest (from 105.3 +/- 2.7 to 101.9 +/- 2.7 mmHg, P = 0.006) decrease in mean arterial pressure 20 minutes after the dose, accompanied by a decrease in systemic vascular resistance and a compensatory rise in cardiac output and heart rate. Baroreflex gain was unaltered by misoprostol, as were plasma renin activity, catecholamines and chromogranin A. Even this transient antihypertensive effect was abolished by cyclooxygenase inhibitor pretreatment. We conclude that oral misoprostol exerts a modest but transient antihypertensive effect that is unlikely to be of either therapeutic benefit or concern in essential hypertension.

Cerebrospinal fluid chromogranin A is unchanged in Alzheimer dementia.

Several lines of evidence link chromogranin A (CgA), the major soluble protein in catecholamine storage vesicles, with the cholinergic nervous system, abnormalities of which may play a central role in memory deficits in Alzheimer dementia. Because of reported elevations of CgA in Alzheimer brains and its presence in the senile plaque lesions of such brains, we evaluated the concentration of CgA in cerebrospinal fluid of Alzheimer dementia patients and matched controls. CgA was detectable in each sample, but the results in dementia showed substantial overlap with and no significant (p = 0.55) difference from the results in healthy controls. We conclude that measurement of cerebrospinal fluid CgA offers no diagnostic assistance in Alzheimer dementia.