Differential gene expression of bradykinin receptors 1 and 2 in peripheral monocytes from patients with essential hypertension.

Bradykinin participates in various hypertensive processes, exerted via its type 1 and type 2 receptors (BKR1 and BKR2). The aim of the study was to investigate BKR1 and BK2R gene expression in peripheral monocytes in patients with essential hypertension compared with healthy individuals. Seventeen hypertensive patients (9 males, age 56 ± 7 years) and 12 healthy individuals (7 males, age 55 ± 6) participated. Mononuclear cells isolated using anti-CD14+ antibodies and mRNAs of BKR1 and BKR2 were estimated by real-time quantitative reverse transcription-PCR. Both BKR1 and BKR2 showed significantly upregulated gene expression in the group of hypertensive patients. Specifically, BKR1 gene expression was 142.1 ± 42.2 in hypertensives versus 20.2 ± 8 in controls (P = 0.024) and BKR2 was 1222.2 ± 361.6 in hypertensives versus 259.5 ± 99.1 in controls (P = 0.038). Antihypertensive treatment resulted in a decrease in BKR1 (from 142.1 ± 42.2 to 55.2 ± 17.1, P = 0.065) and in BKR2 (from 1222.2 ± 361.6 to 256.8 ± 81.8, P = 0.014) gene expression. BKR1 and BKR2 gene expression on peripheral monocytes is upregulated in essential hypertension. This may lead to functional changes in monocytes and contribute to the development of target organ damage in hypertensive patients.

Sympathetic overactivity in hypertension and cardiovascular disease.

From the first description of its anatomy by T. Willis to the novel therapeutic manipulations, it is unanimously recognized that the sympathetic nervous system (SNS) holds a crucial role in cardiovascular homeostasis. The introduction of sophisticated techniques, as microneurography and regional norepinephrine spillover provided the evidence for the role of sympathetic overactivity in various cardiovascular disease entities. Sympathetic activation is common in patients with essential hypertension and contributes to initiation, maintenance and progression of the disease and it contributes to the manifestation of its major complications. A considerable body of evidence relates SNS overactivity with high sodium intake in experimental animals and humans and the underlying mechanisms have nowadays been elucidated. SNS activity is more pronounced in patients with resistant hypertension and there are several conditions that lead to this phenomenon, as older age, kidney disease, obesity and metabolic syndrome, mental stress and sleep apnea. SNS overactivity holds also a key physiopathological role in heart failure, acute coronary syndromes and arrhythmias. Moreover, inhibition of sympathetic overactivity by various means, including central SNS suppressing drugs, peripheral alpha- and beta- adrenergic receptor blockers, or novel approaches as renal sympathetic denervation have been used successfully in the treatment of all these disorders.

Is 44-hour better than 24-hour ambulatory blood pressure monitoring in hemodialysis?

The aim of this study is to evaluate if hemodialysis (HD) patients with similar blood pressure (BP) in the whole inter-HD period could have different target organ lesions and survival if the behavior of BP differs from the first to the second day of the inter-HD period. The present study compares 44-hour ambulatory BP monitoring (ABPM) patterns in 45 HD patients. Three BP patterns emerged: group A (n = 15) had similar BPs throughout (138 +/- 11/88 +/- 12 in the first 22 h vs. 140 +/- 11/87 +/- 12 mm Hg in the second 22-hour period); group B (n = 15) had a significant systolic BP rise from the first to the second period (132 +/- 15/80 +/- 12 vs. 147 +/- 12/86 +/- 13 mm Hg, p < 0.05); group C (n = 15) had significantly higher BPs (p < 0.05) than the other 2 groups throughout the whole inter-HD period, with no significant change between the 2 halves (172 +/- 14/108 +/- 12 vs. 173 +/- 18/109 +/- 14 mm Hg). Ventricular mass and survival during the 30-month follow-up period were statistically significantly better in group A, intermediate in group B and worse in group C. The data suggest that a 44-hour ABPM is more accurate than a 24-hour one in evaluating organ lesion and prognosis in HD patients.

Association between hypervolemia and ventricular hypertrophy in hemodialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH) is a well-known predictor of cardiovascular mortality in patients who have end-stage renal disease and are maintained on hemodialysis (HD), and LVH is not always correlated with the severity of hypertension in these patients. The purpose of this study was to investigate the role of other factors contributing to LVH. METHODS: A total of 50 patients with HD were classified in three groups according to whether their LV mass index (LVMI) was higher than (n = 15), equal to (n = 20), or lower than (n = 15) that predicted by a formula based on their ambulatory blood pressure monitoring (ABPM). RESULTS: Subjects with higher LVMI than predicted had significantly greater inter-HD weight gain (3.4 +/- 0.8 v 2.7 +/- 0.8 and 2.6 +/- 05 kg, respectively, in the other two groups, P < .05), and subjects with lower LVMI than predicted had a tendency toward a more pronounced nocturnal dipping pattern of BP (P = .07 v the other two groups), although daytime and night-time average BP levels did not differ between groups. All other clinical and laboratory parameters were similar among the three groups except higher cardiac output and various indices of LVH, which were more pronounced in the group with higher LVMI by ABPM. This group had also the lowest survival rate over the 2 to 3 years of follow-up, with five deaths versus two in each of the other two groups. CONCLUSIONS: The data suggest that correct management of inter-HD weight gain by nutritional counseling and shorter inter-HD intervals may prevent LVH and improve survival independently of BP control.

Angiotensin II as a cardiovascular risk factor.

A renin-angiotensin level that is inappropriately high for the systemic blood pressure and the state of sodium balance is now recognized to be one of the modifiable cardiovascular risk factors. Angiotensin acts both as a circulating hormone and as a locally acting paracrine/autocrine/intracrine factor. The adverse effects of angiotensin on the heart include the mechanical results of elevated resistance to the pumping function of the myocardium, as well as the effects of neurohumoral abnormalities on various cardiac structures. In addition, cardiac damage follows acute ischaemic injury or chronic energy starvation due to coronary artery disease, attributable to either mechanical obstruction (atherosclerotic and/or thrombotic) or functional stenosis (vasospasm). Activation of the renin-angiotensin system has several haemodynamic and humoral consequences, all of which may damage the myocardium. These include acute myocardial ischaemia, left-ventricular hypertrophy, arrhythmias, alterations in the coagulation-fibrinolysis equilibrium, increased oxidative stress, and pro-inflammatory activity. A brief review of some of the mechanisms by which activation of the renin-angiotensin system can inflict damage on the heart is presented.

Role of the B(2) receptor of bradykinin in insulin sensitivity.

The biological actions of bradykinin (BK) are attributed to its B(2) type receptor (B(2)R), whereas the B(1)R is constitutively absent, inducible by inflammation and toxins. Previous studies in B(2)R gene knockout mice showed that the B(1)R is overexpressed, is further upregulated by hypertensive maneuvers, and assumes some of the hemodynamic functions of the B(2)R. The current experiments were designed to further clarify the metabolic function of the B(2)R and to explore whether the upregulated B(1)R can also assume the metabolic function of the missing B(2)R. One group of B(2)R-/- mice (n=9) and one of B(2)R+/+ controls (n=8) were treated for 3 days with captopril (which produced a similar blood pressure-lowering response in both groups) and studied with the hyperinsulinemic euglycemic clamp. The knockout mice had fasting and steady-state blood glucose levels similar to those of the wild-type mice but a had tendency to higher fasting insulin levels (at 27.8+/-5.2 versus 18+/-2.9 mU/L, respectively). However, they had significantly higher steady-state insulin levels (749+/-127.2 versus 429.1+/-31.5 mU/L, P<0.05) and a significantly lower glucose uptake rate (31+/-2.4 versus 41+/-2.3 mg/kg per minute, P<0.05) and insulin sensitivity index (4.6+/-0.9 versus 10+/-0.7 P<0.001). Analysis of B(1)R and B(2)R gene expression by reverse transcription-polymerase chain reaction in cardiac muscle, skeletal muscle, and adipose tissues revealed significantly higher B(1)R mRNA level in the knockouts versus wild-type (P<0.05) at baseline and a further significant upregulation in mRNA by 1.8- to 3.2-fold (P<0.05) after insulin infusion. We conclude that absence of B(2)R confers a state of insulin resistance because it results in impaired insulin-dependent glucose transport; this is probably a direct B(2)R effect because, unlike the hemodynamic autacoid-mediated effects, it cannot be assumed by the upregulated B(1)R.

The alpha2 -adrenergic receptors in hypertension and heart failure: experimental and clinical studies.

This is a brief overview of experimental and clinical studies exploring the hemodynamic functions of the alpha2A and alpha2B adrenergic receptor (AR) subtypes in animals submitted to genetic manipulations or gene treatment, as well as the clinical effects of central sympathetic suppression with the alpha2-AR agonist clonidine in patients with ischemic heart disease and/or heart failure. The animal experiments have led us to conclude that the sympathetic outflow is regulated by activation of the presynaptic alpha2A-AR subtype, which is the predominant alpha2-AR subtype in the central nervous system and exerts a sympathoinhibitory (hypotensive) action; on the contrary, activation of the central alpha2B-AR elicits a sympathoexcitatory response (such as seen in salt-induced hypertension, which requires functionally intact alpha2B-AR). Since there are no selective pharmacologic agents yet capable of discriminating among alpha2-AR subtypes, clinical studies utilize clonidine, the central sympathetic suppressant effect of which has been used for 35 years to treat hypertension. In small clinical trials, clonidine was used successfully for treatment of acute or chronic heart failure, acute myocardial infarct or hypertensive cardiomyopathy with subclinical diastolic dysfunction. We speculate that future development of agents capable of selectively activating the alpha2A-AR or blocking the alpha2B-AR may further improve our capability to treat hypertension, ischemic heart disease and heart failure.

Effects of antisense oligodeoxynucleotide targeting of the alpha(2B)-adrenergic receptor messenger RNA in the central nervous system.

The results of previous studies with genetically engineered mice have suggested that an intact central alpha(2B)-adrenergic receptor (alpha(2B)-AR) subtype mediates the development and maintenance of salt-induced hypertension. In the present study, we sought to further define the role of this receptor by injecting antisense oligodeoxynucleotides (AS-ODNs), targeting a selected sequence of the alpha(2B)-AR mRNA, into the lateral cerebral ventricle of rats that had undergone prior subtotal nephrectomy and dietary salt loading. Cell culture studies showed that these AS-ODNs could block alpha(2B)-AR protein generation. Before AS-ODN injection, blood pressure (BP) averaged 133+/-5 mm Hg during the daytime and rose to 165+/-4 mm Hg during the nighttime activity hours (P<0.001 versus baseline average of 120+/-2 mm Hg). The injection of AS-ODNs during the early afternoon prevented the BP rise and was associated with a significant fall in heart rate (from 385+/-12 to 306+/-15 bpm, P<0.05) and symptoms of sedation that lasted for several hours, with a peak at 3 to 6 hours and full recovery by 24 hours. At that time, a second injection produced identical effects in all rats (n=9). Control rats (n=10) that received scrambled ODN injections had no changes in BP or heart rate patterns, and neither group had evidence of neurotoxicity, indicating that these effects are specifically due to translational inhibition of central alpha(2B)-AR. We conclude that a fully functional central alpha(2B)-AR is necessary for the induction of salt-dependent hypertension.

Acute effect of clonidine on left ventricular pressure-volume relation in hypertensive patients with diastolic heart dysfunction.

We sought to assess the haemodynamic effects of clonidine on left ventricular (LV) pressure-volume relation in patients with diastolic heart dysfunction due to essential hypertension. Towards this end, simultaneous recordings of LV volume (acoustic quantification) and LV pressure (micromanometer) were obtained in 10 such patients before and after drug administration and compared to baseline findings on 10 matched normal controls. The following measurements and calculations were obtained: maximal positive and negative first derivative of LV pressure (peak +dP/dt and peak -dP/dt, respectively), LV minimal and end-diastolic pressure, peak systolic blood pressure, time constant of relaxation (TAU), LV stroke work and LV stiffness constant. The two invasive indexes, LV stiffness constant and TAU classified 10/10 patients as having abnormal LV diastolic function compared with 7/10 patients so classified by Doppler studies. Central sympathetic suppression by a single oral dose of clonidine 0.125 mg in these patients resulted within 60 min in a decrease of heart rate and mean arterial pressure as well as a significant improvement of LV diastolic function indexes. Specifically, the LV stiffness constant (ml(-1)), in normal subjects was 0.0028 vs 0.0152 (P < 0.001) in hypertensive subjects at baseline, vs 0.0053 in hypertensive after clonidine (P < 0.001 vs baseline). Likewise, the E/A ratio, was 1.08 in normal subjects vs 0.88 (P < 0.0001) in hypertensives at baseline, vs 1.28 in hypertensives after clonidine (P < 0.0001 vs baseline). With clonidine the diastolic portion of the pressure-volume curve was displaced downward. In conclusion, clonidine can improve diastolic dysfunction without depressing systolic LV performance. The improvement may be attributable in part to withdrawal of direct sympathetic influence on the myocardium and in part to the indirect effect of systemic, pulmonary and coronary artery relaxation.

Maternal component in the familial aggregation of hypertension.

To assess maternal versus paternal contributions to the familial aggregation of hypertension, we examined family history data from 344 hypertensive probands (69 African American, 153 US Caucasian, 122 Greek Caucasian) ascertained without respect to parental hypertension status. The proportion of hypertensive mothers (81.7, 65.0 and 84.8% for African Americans, US Caucasians and Greek Caucasians, respectively) of these probands was significantly greater than the proportion of hypertensive fathers (50.0, 44.9 and 48.3%, respectively) in all three ethnic groups. The lifetime risk of hypertension was significantly greater for mothers compared with fathers of these hypertensive probands (p<0.001). Examination of the proband's siblings indicated that maternal history of hypertension was associated with greater lifetime risk for hypertension than paternal history (p<0.01). In conclusion, we observe a consistent maternal component in the inheritance of hypertension. Although we cannot separate a maternal genetic from epigenetic or environmental effect, our findings suggest that genetic research should include studies of the mitochondrial as well as nuclear genome. Furthermore, when assessing a patient's risk for hypertension, particular attention should be paid to the maternal family history.

Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells.

Bradykinin has vasodilatory and tissue-protective effects exerted via its B(2) type receptor, whereas the B(1) receptor is constitutively absent but inducible by inflammation and toxins. In previous studies, we found that B(2) receptor gene knockout mice exhibit overexpression of the B(1) receptor, which assumes a vasodilatory function and is further upgraded in renovascular hypertension. The present study was designed to explore the effects of excess angiotensin II (ANG II) on B(1) receptor and B(2) receptor gene expression in mouse cardiomyocytes and rat vascular smooth muscle cells (VSMC) in vivo (after a 3-day infusion of 30 ng/min ANG II in 11 wild-type and in 13 genetically engineered mice with deleted B(2) receptor gene) and in vitro (ANG II added in rat VSMC culture in the presence or absence of AT(1) or AT(2) receptor antagonist). Expression of B(1) and B(2) receptor mRNA was assessed by reverse transcriptase-polymerase chain reaction. ANG II infusion caused upregulation by 30% of the already significantly overexpressed B(1) receptors in cardiomyocytes of the B(2) receptor gene knockout mice, but in the wild-type mice it upregulated only the B(2) receptor mRNA by 47%. The addition of ANG II in VSMC culture produced a time-dependent induction of B(1) and upregulation of B(2) receptor gene expression, maximal at 3 h (by fivefold), declining almost to baseline by 24 h. The addition of losartan completely blocked this effect, whereas the AT(2) blocker PD-123319 made no difference, indicating that this is an AT(1)-mediated effect of ANG II. The data indicate that excess ANG II in subpressor doses in vivo upregulates expression of the B(2) receptor, but in its absence, the already overexpressed B(1) receptor is further upregulated, evidently assuming a counterregulatory response; in vitro, it transiently upregulates both bradykinin receptors.

Issues in hypertension: drug tolerability and special populations.

Improvements in the death rate from coronary heart disease and in the control of hypertension have leveled off in recent years, reversing a trend toward steady improvement that began in 1972. Of the roughly 20% of Americans who suffer from hypertension, only 29% achieve adequate control (<140/90 mm Hg) with treatment and nearly half receive no treatment at all. Poor adherence to therapy doubtless plays a key role in this failure. As a major cause of poor adherence, tolerability becomes an extremely important element in any discussion of effective antihypertensive treatment. Despite their efficacy in treating hypertension, diuretics, beta-blockers, and calcium channel blockers have all been associated with numerous side effects, including increased serum lipid levels, insulin resistance, and edema. With the introduction of the angiotensin converting enzyme (ACE) inhibitors, patients were able to achieve blood pressure goals with fewer side effects. These agents, however, cause an irritating cough in up to 19% of patients. A newer class of drugs, the angiotensin receptor blockers (ARB), have similar effects to the ACE inhibitors, but their highly selective nature produces even fewer side effects. Eprosartan is a structurally unique ARB. Like the other ARB, this promising new agent has a side effect profile similar to placebo, and its response rate rivals or exceeds that of enalapril. Although it remains to be seen whether the ARB can significantly reduce morbidity and mortality from cardiovascular disease, preliminary data from the Evaluation of Losartan in the Elderly (ELITE) trial appear to be promising.

Role of alpha2-adrenergic receptors in hypertension.

This is a brief review of a series of experiments conducted over the past two decades, exploring the role of the alpha2-adrenergic receptors (alpha2-AR) in salt-induced hypertension. The data suggest that salt loading alters the activity of central alpha2-AR, resulting in a hypertensive hyperadrenergic state. Studies to separate the role of each alpha2-AR subtype (alpha2A, alpha2B, and alpha2C) have used genetically engineered mice with disrupted genes for each subtype, or gene treatment in rats with antisense-oligodeoxynucleotides targeting a specific gene sequence. Taken together, the results of these studies indicate that the alpha2A-AR is centrally predominant and exerts a tonic sympathoinhibitory function, whereas peripherally it has a vasoconstrictive effect; the alpha2B-AR is responsible for the central hypertensive sympathoexcitatory response to salt, but is not expressed on vascular wall structures; and the alpha2C-AR seems to have no hemodynamic function.

Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure.

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.

Vasoactive potential of the b(1) bradykinin receptor in normotension and hypertension.

The B(1) type receptor of bradykinin (Bk B(1)R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B(1)R in blood pressure (BP) regulation, we studied mice with deleted Bk B(2)R gene with induced experimental hypertension, either salt-dependent (subtotal nephrectomy with 0.5% NaCl as drinking water) or renin/angiotensin-dependent (renovascular 2-kidney-1-clip). Compared with the wild-type controls, the B(2)R gene knockout mice had a higher baseline BP (109.7+/-1.1 versus 101.1+/-1.3 mm Hg, P:=0.002), developed salt-induced hypertension faster (in 19.3+/-2.3 versus 27.7+/-2.4 days, P:=0.024), and had a more severe end point BP (148+/-3.7 versus 133+/-3.1 mm Hg, P:<0.05). On the contrary, renovascular hypertension developed to the same extent (149.7+/-4.3 versus 148+/-3.6 mm Hg) and in the same time frame (14+/-2.2 versus 14+/-2.1 days). A bolus infusion of a selective B(1)R antagonist at baseline produced a significant hypertensive response (by 11.4+/-2 mm Hg) in the knockout mice only. Injection of graded doses of a selective B(1)R agonist produced a dose-dependent hypotensive response in the knockout mice only. Assessment of tissue expression of B(1)R and B(2)R genes by reverse transcription-polymerase chain reaction techniques revealed significantly higher B(1)R mRNA levels in the B(2)R knockout mice at all times (normotensive baseline and hypertensive end points). At the hypertensive end points, there was always an increase in B(1)R gene expression over the baseline values. This increase was significant in cardiac and renal tissues in all hypertensive wild-type mice but only in the clipped kidney of the renovascular knockout mice. The B(2)R gene expression in the wild-type mice remained unaffected by experimental manipulations. These results confirm the known vasodilatory and natriuretic function of the Bk B(2)R; they also indicate that in its absence, the B(1)R can become upregulated and assume some of the hemodynamic properties of the B(2)R. Furthermore, they indicate that experimental manipulations to produce hypertension also induce upregulation of the B(1)R, but not the B(2)R, in cardiac and renal tissues.

Regulation of plasma endothelin by salt in salt-sensitive hypertension.

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.

Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci.

To investigate the genetic control of salt-induced hypertension, we performed a quantitative trait locus analysis on male mice from a reciprocal backcross between the salt-sensitive C57BL/6J and the normotensive A/J inbred mouse strains after they were provided with water containing 1% salt for 2 weeks. Genome-wide scans performed on these mice and analyzed with a combination of conventional marker-based regressions and a novel simultaneous search for pairs revealed six significant quantitative trait loci associated with salt-induced blood pressure, two of which were interacting loci. These six loci, named Bpq1-6 for blood pressure quantitative trait loci, mapped to D1Mit334, D1Mit14, D4Mit164, D5Mit31, D6Mit15, and D15Mit13. Furthermore, five of these six loci were concordant with hypertension loci in rats, and four were concordant with hypertension loci in humans, suggesting that quantitative trait loci mapping in model organisms can be used to guide the search for human blood pressure genes.

Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study.

Hypertension is a leading cause of morbidity and mortality. Efforts to identify hypertension genes have focused on 3 approaches: mendelian disorders, candidate genes, and genome-wide scans. Thus far, these efforts have not identified genes that contribute substantively to overall blood pressure (BP) variation in the community. A 10-centiMorgan (cM) density genome-wide scan was performed in the largest families from 2 generations of Framingham Heart Study participants. Heritability and linkage for long-term mean systolic and diastolic BP phenotypes were analyzed by use of SOLAR software. Heritability estimates were based on BP measurements in 1593 families. Genotyping was performed on 1702 subjects from 332 large families, and BP data were available for 1585 (93%) genotyped subjects who contributed 12 588 longitudinal BP observations. The mean age was 47 years, and mean BP was 127/80 (systolic/diastolic) mm Hg. Long-term systolic and diastolic BP phenotypes had high heritability estimates, 0.57 and 0.56, respectively. For systolic BP, multipoint log-of-the-odds (LOD) scores >2.0 were located on chromosome 17 at 67 cM (LOD 4.7, P=0.0000016) and 94 cM (LOD 2.2). For diastolic BP, LOD scores >2.0 were identified on chromosome 17 (74 cM, LOD 2.1) and chromosome 18 (7 cM, LOD 2.1). Using a genome-wide scan, we found strong evidence for a BP quantitative trait locus on chromosome 17. Follow-up studies are warranted to identify the gene or genes in this quantitative trait locus that influence BP. Such knowledge could extend our understanding of the genetic basis of essential hypertension and have implications for the evaluation and treatment of patients with high BP.