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Dilevalol is a drug prescribed to lower high blood pressure. Dilevalol is a beta-adrenergic antagonist and works by blocking the release of chemicals in the body which raise blood pressure. It is similar to the drug labetalol but is four times more potent. To measure the effectiveness of dilevalol in lowering blood pressure, 101 patients with a diastolic blood pressures of greater than 120 mm Hg were given a supine intravenous bolus, a single shot of dilevalol administered while the patient is lying down. A reduction of from 30 mm Hg to 100 mg Hg was achieved in 62 of the patients. Dilevelol was not as effective in treating high blood pressure in black males. Older patients showed better results than younger patients. Dilevalol did not lower blood pressure as much in patients who had previously taken beta-adrenergic antagonists. Transfer to oral dilevalol drug therapy in combination with diuretics, which are drugs that effectively lower blood pressure by lowering blood volume, was able to stabilize blood pressure at an average level of 160 over 100 mm Hg. Intravenous bolus or oral dilevalol is a safe and effective blood pressure lowering agent in the treatment of severe hypertension.

Many hypertensive patients who fail to achieve goal blood pressure (BP) or have side effects are referred to special clinics for management. In our experience many will need 4 or more BP meds for control. In the last 3 years we have evolved an effective approach to control BP in this outpatient setting. The near simultaneous release of two new long acting drug combinations, Ziac, which contains the long acting beta blocker bisoprolol (2.5, 5 and 10 mg) combined with 6.25 mg of hydrochlorothiazide (HCTZ) and Lotrel which contains the calcium channel blocker amlodipine and the ACEI benazapril (2.5/10, 5/10 and 5/20) suggested a useful way to approach these difficult patients. This “LoZi” cocktail combined the administration of 4 classes of drugs in only two pills once a day with the ability to start at a low dose and titrate up. HCTZ was usually added at 25 mg/d. LoZi produces increasing blockade of the 4 major BP control systems: vasoconstriction, RAAS, SNS and sodium retention. We used this cocktail in 21 referred patients who had a BP of 183 ± 24(SD)/108 ± 12 on their referral medications at first consultation. At the second visit (2–4 weeks) the BP had decreased to 152 ± 7/90 ± 10. The combination has been effective in patients with severe HTN due to renal artery stenosis, mineralocorticoid excess and in HTN with resistant CHF. In 10% of the pts the ACEI was stopped because of cough and in 5% the Zi because of BB side effects. Our impression is that LoZi is a simple and effective combination to improve BP control in this group of patients. Controlled trials comparing this combination approach to others will be of interest in patients with “drug resistant” hypertension.

Omapatrilat is a vasopeptidase inhibitor (VPI) that potentiates the physiologic effects of vasodilator peptides (for example, atrial natriuretic peptide [ANP]) and inhibits the renin-angiotensin-aldosterone system. The BP effects of omapatrilat were compared with that of lisinopril in 57 salt-sensitive hypertensives (SSH) identified by the Grim-Weinberger Protocol. In general, SSH do not respond well to ACE-inhibitors. Twenty-four SSH were randomized to receive omapatrilat 40 mg and 33 to receive lisinopril 20 mg for 3 weeks after a 1-week lead-in dose of 10 mg. BP and neurohormonal assessments were made before dosing (baseline) and on day 28. Both treatments significantly reduced mean 24-hour ambulatory diastolic and systolic BP (ADBP, ASBP). Compared with lisinopril, omapatrilat produced significantly greater reductions in mean 24-hour ADBP and ASBP: (See Table) ADBPaASBPaOmapatrilat 40 mg-9.3b (-11.6, -6.9)-15.4c (-19.6, -11.3)Lisinopril 20 mg-5.1 (-7.1, -3.1)-7.2 (-10.8, -3.7)a mm Hg (95% CI); b P = 0.008 vs. lisinopril; c P = 0.004 vs. lisinopril Characteristic of a VPI, omapatrilat significantly (P < 0.001) increased urinary excretion of ANP by 42.6 ± 2.6 ng/24 hour compared with baseline levels and significantly increased (P < 0.05) plasma ANP levels from 54.0 ± 5.7 pg/mL at trough (0 hr) to 63.0 ± 7.2 pg/mL at peak (4 hr). Lisinopril had no effect on urinary ANP and reduced plasma ANP. Both agents produced marked suppression of ACE activity. Mean percent change from baseline for the two treatments were similar 4-hours after dosing on day 28 (-98 ± 2% substrate hydrolyzed/minute). In conclusion, although omapatrilat and lisinopril had similar inhibition of ACE, omapatrilat was more effective at lowering BP in SSH indicating significant contribution of a non-ACE inhibitory mechanism.

BP and Na intake have rarely been correlated in free living African Americans (AA). We tested for an effect of Na intake on BP in volunteers for a hypertension primary prevention project that is testing stress reduction by Transcendental Meditation. We screened 1,300+ AAs age 18–80. Seated BP (3 times at up to 3 visits) was obtained by trained and certified observers (Shared Care) using AHA guidelines. If mean BP was =140/90 on the second visit participants were asked to return with a 24 hour urine and a blood sample was collected (Na, K, creatinine (Cr)) on return. We used the Cr in the Cockcroft-Gault formula to eliminate incomplete urine collections (41/195 = 21% were excluded). Age, gender, height, weight, years of education and BMI were used as explanatory variables for BP. Mean ± SD were: age 39 ± 9 yr., 59% were female, Education = 13 ± 2 yr., Ht 167 ± 10 cm, Wt 87 ± 28 kg, BMI 31 ± 10 kg/m2, 24 hr ENa 143 ± 82 mM, and EK = 41 ± 20 mM. The average of all visit SBP was highly correlated with age (r = .45, p .001), ENa (r = .22, p = .02, EK (r .22, p = .01), Wt (r = .22, p = .001) and BMI (r = .22, p. = 01). The effect of ENa on SBP was not related to age, BMI, or wt and was seen only in women. The significant correlation of ENa and systolic BP (taken over 3 visits) in this study suggests AA women without established HTN range may be more salt sensitive than those with established HTN and that it is important to assess the BP-Na relationship by taking BP at several visits.

Current evidence suggests that the pathophysiology and treatment of salt sensitive hypertension (SSH) differs by ethnic origin. We evaluated the frequency of SSH in 104 hypertensive subjects from 7 centers: 47 African Americans (AA), 32 Caucasians (C), and 25 Hispanics from the Caribbean (H-C) in an efficacy trial of omapatrilat (OMA). Only the SSH subjects were randomized to 10 mg of either OMA or lisinopril (L), with doses increased to 40 mg OMA or 20 mg L over 4 weeks. The RAAS and natriuretic neurohormonal profiles of these SSH were also studied. The Grim-Weinberger saline/furosemide protocol was used to identify SSH: Mean arterial blood pressure (MAP, taken by a Spacelabs 2007) decreased by at least 10 mm Hg from the end of a 4hr saline infusion (500ml/hr saline) compared to the MAP at the end of 24 hrs of salt depletion induced by 1 day of a 20 mM Na diet and furosemide at 10 am, 2 pm and 6 pm. SSH was present in 61 (59%) of all subjects. In H-C SSH was detected in 80%, in AA in 66% and in C in 34%. Baseline neurohormones [mean ± SD (N)] are tabulated (See Table) NeurohormoneAfri. AmerCauc.Hisp. -CPRA (ng AI/mL/h)0.4 ± 0.4 (23)2.1 ± 2.8 (10)0.5 ± 0.4 (12)Plasma ANP (pg/mL)51.5 ± 22 (21)53.9 ± 23 (10)54.4 ± 21 (12)Plasma ACE activity*6.1 ± 1.6 (23)5.0 ± 2.4 (10)6.1 ± 1.2 (12)U-ANP (ng/24 h)16.8 ± 4.7 (28)20.9 ± 7.9 (11)14.3 ± 4.4 (15)* % substrate hydrolyzed/min. A higher prevalence of salt sensitivity was seen in African Americans and Hispanics from the Caribbean than Caucasians. Higher plasma renin activity and urinary ANP with lower ACE activity were shown in Caucasian SSH.

The first link in the chain of high blood pressure (BP) control is accurate equipment and technique. As part of a public health effort to improve hypertension control (HTN) control, one of us (RM) conducted 22 classes in standardized blood pressure measurement from 1996–1999 at 1 hospital (H), 12 clinics (C), 5 nursing homes (NH), and 4 home health agencies (HHA). We checked BP equipment and queried about knowledge of standard technique. Staff questioned the need for a “BP class”. None of the sites used mercury manometers and all had aneroid devices (AD). None of the NH or HHAs knew ADs need frequent calibration. Seven of the 13-C&H had an aneroid equipment maintenance schedule, q 6 months but 6 others had NEVER checked ADs. We checked 49 ADs in use at 3 of 6 that did not have a maintenance program and 33% (16/49) did not pass AAMI standards, 14 read at least 6 mm too low and the average was 10 too low. None of 359 staff followed the AHA guidelines necessary for taking an accurate and reliable BP. No one knew how to select the correct BP cuff size. One NH had only one regular size cuff to use on 66 residents. One HHA had only regular cuffs. These results suggest that the first link in the chain of community control of BP, accurate and reliable measurement of BP in the clinic, may be a major cause of poor control. Our data suggests that up to 33% of the BPs taken in these settings, where prevalence of HTN exceeds 50%, will be measured as falsely low. An average error of 10 mm Hg too low will miss 67% of all patients with diastolic HTN and 30% of all with systolic HTN for those who use these health care sites. Efforts to improve BP equipment accuracy and technique in the clinical setting will likely improve BP control and decrease morbidity and mortality from HTN.

Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that contribute to hypertension. This communication describes evidence for heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic African American sib pairs. Outpatient anthropomorphic measurements were obtained in 203 affected sib pairs; 68 of these sib pairs were further evaluated on an inpatient CRC, off antihypertensive and lipid lowering medications. Heritability (h ± SE) was estimated with an association model. Mean values for the 68 sib pairs are as follows: age, 46 ± 1 yrs; daytime BP (based on 24 hr monitoring) 143 ± 2/86 ± 1 mmHg; nighttime BP, 136 ±2/80 ± 1 mmHg; BMI 33.0 ± 0.5 kg/m2; cholesterol, 204 ± 5 mg/dl. Higher h estimates for systolic (S) and diastolic (D) blood pressure were observed by averaging multiple measurements over 24 hours than with single readings. Significant h (p<0.01) was observed for average nighttime SBP (.69 ± .14) and DBP (.51 ± .21), but not for daytime SBP or DBP. Although h for baseline BP was not significant, h became significant (<0.01) for BP responses to the following: DBP in response to upright posture (.83 ± .07); SBP (.48 ± .19) and DBP (.70 ± .12) in response to standardized psychological stress (math test); SBP (.75 ± .11) and DBP (.74 ± .13) in response to norepinephrine (NE) infusion. Similarly, h was significant (p<0.001) for PAH clearance (.89 ± .07) and inulin clearance (.99 ± .01) in response to NE, but not at baseline. Significant h (p<0.01) was also observed for BMI, % body fat, skinfold thickness, left ventricular mass, cardiac index, stroke volume, peripheral resistance, Na/Li countertransport, plasma renin, and plasma cAMP, cGMP, LDL and HDL cholesterol, and leptin. These h estimates identify those hypertension-related phenotypes that may facilitate identification of genetic determinants of hypertension in African Americans.

Pulse pressure (PP) is a powerful predictor of cardiovascular morbidity and mortality but the association of PP with diet has not been well studied. We investigated the association of PP and diet using the NHANES-III data on all participants =20 years (n = 17,030). The data included demographics, dietary factors by 24 hr recall, and PP (SBP-DBP). Univariate (UV) and multivariate analyses (MV) were performed using simple weighted, stepwise, and best subset regression as well as principal component analysis. The MV model included interactions for PP was developed using a 50% random sample and then tested on the remaining sample. The sample age was 48.8 ± 0.2 yrs (mean ± SE) and 53.3% were female. Ethnicity was 41.8% white, 27.6% African American and 27% Hispanic. Body mass index (BMI) was 27.1 ± 0.2. Mean intake for sodium (Na) was 3.3 ± 0.02 g, potassium (K) 2.7 ± 0.01 g, calcium (Ca) 761 ± 4 mg, magnesium (mg) 280 ± 1 mg, protein (Prot) 79.1 ± 0.4 g, alcohol (EtOH) 43.2 ± 0.8 g, and total kilocalories (Kcal) 2,062 ± 8 kcal. The mean PP in our sample was 51.7 + 0.1 mm of Hg. Increasing age was associated with an increase in PP (r = .581, p < 0.001) and the rate of increase (ß) was 0.52 mm of Hg/year (p < 0.001). There was no gender effect (p = 0.9). African Americans had higher PP (+2.33 mm Hg, p < 0.001). In UV, but not MV, PP was associated with BMI (ß = 0.29 mm of hg per unit of BMI, p < 0.001) and Mg (ß = 0.29 mm of Hg per unit of BMI, p < 0.001) and Mg (ß = 1.6 mm of Hg per g of Mg, p < 0.001). In the MV PP was positively associated with Na, Prot, and EtOH (p < 0.001). PP was not associated with K or Ca. With increasing age, the association of PP with Na, prot, and EtOH decreased (p < 0.001). The association between PP and EtOH was lower in females (p < 0.001). In the final multivariate model r was .601 (p < 0.001). The association of PP with modifiable dietary factors (Na, Prot, and EtOH) suggests that dietary interventions may decrease PP and its health risks.

The contribution of angiotensin-(1–7) [Ang-(1–7)] to the antihypertensive actions of omapatrilat (OMA), a novel vasopeptidase inhibitor, was evaluated in 15 salt-sensitive, low renin, hypertensive subjects as a sub-study of a multi-center randomized, double-blind, parallel study of 4 wks duration. As illustrated in the Figure, OMA (40 mg) caused statistically significant rises in the urinary excretion of both Ang-(1–7) (upper panel) and atrial natriuretic peptide (ANP, middle panel) throughout the dosing period at day 28 of treatment (-After). The effects of OMA on Ang-(1–7) and ANP excretion were associated with a sustained control of blood pressure as denoted by the differences in the 24 hr ambulatory systolic blood pressure measurements at days 0 (SBP, before) and 28 of treatment (SBP, After). A single molecule inhibiting neutral endopeptidase and angiotensin converting enzyme effectively controlled salt-sensitive hypertension by a mechanism related to inhibition of NEP 24.11 for which Ang-(1–7) is a substrate. These data are the first to show a role of Ang-(1–7) to the antihypertensive renal response of a novel vasopeptidase inhibitor in the treatment of essential hypertension.