Aldosterone synthase (CYP11B2)­344T/C polymorphism and renoprotective response to losartan treatment in diabetic nephropathy

Objective. It has been suggested that an aldosterone synthase gene polymorphism (CYP11B2 ­344T/C) is predictive of the blood pressure lowering effect of angiotensin II receptor blockers in essential hypertension. We investigated whether this polymorphism is predictive of reductions in blood pressure and albuminuria and preservation of glomerular filtration rate (GFR) during short‐term and long‐term treatment with losartan in 57 hypertensive type‐1 diabetic patients with diabetic nephropathy. Material and methods. After a 4‐week washout period, patients received losartan (100 mg o.d.) and were followed for a mean follow‐up of 36 months. At baseline, after 2 and 4 months, and every 6 months thereafter, GFR (⁵¹Cr‐EDTA‐clearance), albuminuria and 24‐h blood pressure were determined. The CYP11B2 ­344T/C polymorphism was determined by standard polymerase chain reaction (PCR). Results. The TT, CT and CC genotypes were found in 28 %, 58 % and 14 % of patients, respectively. At baseline albuminuria and blood pressure did not differ between genotype groups. Plasma aldosterone levels (geometric mean (95 % CI)) were similar at baseline: 87 (60–125), 77 (53–112), and 89 (49–161) pg mL^?1 and during follow‐up (not significant). After initiation of losartan treatment, comparable mean (SE) reductions in blood pressure and albuminuria were seen in patients with TT, CT and CC genotypes (p >0.6 between groups). After long‐term follow‐up, there was a tendency towards a difference in systolic blood pressure reduction (p = 0.07, one‐way ANOVA), suggesting a poorer response in patients with the CC genotype. No significant difference in rate of decline in GFR (median (range)) was seen between groups (TT, CT, CC): 4.2 (?1.0 to 16.0), 3.2 (?1.6 to 13.8) and 2.6 (?0.1 to 11.0) mL min^?1year^?1, respectively (p = 0.5). Conclusions. Compared to a previous smaller study of angiotensin II receptor blockade in essential hypertension, we could not confirm that CYP11B2 ­344T/C genotypes contribute towards explaining the observed variability in response to treatment with angiotensin II receptor blockers, which could be due to lack of power.     

Aldosterone synthase (CYP11B2)-344T/C polymorphism and renoprotective response to losartan treatment in diabetic nephropathy

OBJECTIVE: It has been suggested that an aldosterone synthase gene polymorphism (CYP11B2 -344T/C) is predictive of the blood pressure lowering effect of angiotensin II receptor blockers in essential hypertension. We investigated whether this polymorphism is predictive of reductions in blood pressure and albuminuria and preservation of glomerular filtration rate (GFR) during short-term and long-term treatment with losartan in 57 hypertensive type-1 diabetic patients with diabetic nephropathy. MATERIAL AND METHODS: After a 4-week washout period, patients received losartan (100 mg o.d.) and were followed for a mean follow-up of 36 months. At baseline, after 2 and 4 months, and every 6 months thereafter, GFR (51Cr-EDTA-clearance), albuminuria and 24-h blood pressure were determined. The CYP11B2 -344T/C polymorphism was determined by standard polymerase chain reaction (PCR). RESULTS: The TT, CT and CC genotypes were found in 28 %, 58 % and 14 % of patients, respectively. At baseline albuminuria and blood pressure did not differ between genotype groups. Plasma aldosterone levels (geometric mean (95 % CI)) were similar at baseline: 87 (60-125), 77 (53-112), and 89 (49-161) pg mL(-1) and during follow-up (not significant). After initiation of losartan treatment, comparable mean (SE) reductions in blood pressure and albuminuria were seen in patients with TT, CT and CC genotypes (p >0.6 between groups). After long-term follow-up, there was a tendency towards a difference in systolic blood pressure reduction (p = 0.07, one-way ANOVA), suggesting a poorer response in patients with the CC genotype. No significant difference in rate of decline in GFR (median (range)) was seen between groups (TT, CT, CC): 4.2 (-1.0 to 16.0), 3.2 (-1.6 to 13.8) and 2.6 (-0.1 to 11.0) mL min(-1)year(-1), respectively (p = 0.5). CONCLUSIONS: Compared to a previous smaller study of angiotensin II receptor blockade in essential hypertension, we could not confirm that CYP11B2 -344T/C genotypes contribute towards explaining the observed variability in response to treatment with angiotensin II receptor blockers, which could be due to lack of power.     

Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol

OBJECTIVES: Marked interpatient variability exists in blood pressure response to beta-blocker monotherapy. We tested the hypothesis that 2 common polymorphisms in the gene for beta(1)-adrenergic receptor are associated with antihypertensive response to metoprolol in patients with uncomplicated hypertension. METHODS: Forty hypertensive men and women aged 35 to 65 years were studied. Baseline studies included 24-hour ambulatory blood pressure monitoring. Patients took 50 mg metoprolol twice daily with weekly titration to response or 200 mg twice daily. After a minimum of 4 weeks at stable dose, treatment phase 24-hour ambulatory blood pressure monitoring was repeated. The codon 49 and 389 genotypes for beta(1)-adrenergic receptor were determined by polymerase chain reaction with restriction fragment length polymorphism. Multilinear regression was performed to determine the impact of genotype and other variables on blood pressure response to metoprolol. RESULTS: Patients homozygous for Arg at codon 389 had a nearly 3-fold greater reduction in daytime diastolic blood pressure (-13.3% +/- 8.4% versus -4.5% +/- 8.2%, P =.0018) compared with those who carried the variant allele. The haplotype pair (diplotype) for beta(1)-adrenergic receptor was also a significant predictor of response, with patients having the Ser49Arg389/Ser49Arg389 diplotype demonstrating a decline in blood pressure of 14.7 mm Hg versus 0.5 mm Hg in patients with the Gly49Arg389/Ser49Gly389 diplotype. In multiregression analysis, baseline daytime diastolic blood pressure, codon 389 genotype, and codon 49 genotype were significant predictors of blood pressure after treatment. CONCLUSIONS: Our data suggest that beta(1)-adrenergic receptor polymorphisms are important determinants of antihypertensive response to metoprolol. In the future, codon 49 and 389 genotypes or beta(1)-adrenergic receptor haplotypes might be used to predict the diastolic blood pressure response to metoprolol in patients with hypertension.     

Effects of delapril in combination with indapamide on blood pressure and left ventricular mass in elderly hypertensive patients

We present a single-blinded, placebo-controlled trial of the effects on blood pressure and left ventricular mass and of the safety of a combined antihypertensive treatment with delapril, a new nonsulfhydryl angiotensin-converting enzyme inhibitor, and indapamide, a sulfonamide diuretic. We studied 28 elderly patients aged 65-85 years (mean age, 69 +/- 1) with sitting systolic/diastolic blood pressure of 160-200/95-115 mm Hg (at the end of the placebo period). After a 2-week placebo run-in, patients took 30 mg delapril in combination with 1.25 mg indapamide once daily for 24 weeks. Twenty-four-hour ambulatory blood pressure was monitored and M- and B-mode echocardiography were performed before and after 24 weeks of treatment. Blood pressure decreased from 156 +/- 1.5/101 +/- 1 mm Hg before treatment to 133 +/- 1/73 +/- 1 mm Hg after treatment. The total blood pressure burden also decreased; the percentage of measurements with a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure > or = 90 mm Hg decreased from 48.7% +/- 5%/31.5% +/- 4.3% to 23.5% +/- 4%/20.5% +/- 2.9% (p < 0.0005 and p < 0.05). The area under the curve of the 24-hour blood pressure decreased from 250 +/- 41/103 +/- 21 mm Hg to 97 +/- 21/37 +/- 8.5 mm Hg (p < 0.001 and p < 0.005). The left ventricular mass index (LVMI) in the 15 patients with pretreatment left ventricular hypertrophy was reduced after therapy from 167.5 +/- 8.5 g/m 2 to 152.2 +/- 7.6 g/m 2 (p < 0.05). A positive correlation was observed between percent changes of the area under the curve of the 24-hour diastolic blood pressure and percent changes of LVMI (r = 0.6; p < 0. 05) in the 15 patients with left ventricular hypertrophy. Only 2 patients reported side effects: 1 developed skin rash and 1 developed headache. The safety of the treatment was confirmed by laboratory tests. In elderly hypertensive patients, the combination of delapril and indapamide at low doses reduced blood pressure and had favorable effects on LVMI with few side effects.     

Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism

OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin-angiotensin system act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA antagonism in the presence of endothelin 1 (ET-1), norepinephrine (NA), and angiotensin II (ANGII). METHODS: Thirty-seven individuals were included in a randomized, double-blind, placebo-controlled, crossover trial with 100 mg darusentan. Systemic hemodynamics and plasma ET-1, NA, and ANGII concentrations were assessed. Local studies were performed in the dorsal hand veins (n=18) and skin microcirculation (n=12), respectively. RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96). Venoconstriction to ET-1 and NA was not affected by ET A blockade in either group; however, carriers of the 825T allele demonstrated a markedly enhanced venoconstriction to ET-1 and NA (median effective concentration [ED50] for ET-1 after darusentan [placebo]: 2.5 +/- 0.2 pmol/min for CT/TT [2.7 +/- 0.3 pmol/min], P=.42; 3.9 +/- 0.6 pmol/min for CC [4.6 +/- 0.3 pmol/min], P=.42; P=.046 [P=.0005] for CT/TT versus CC) (ED50 for NA after darusentan [placebo]: 5.2 +/- 1.2 ng/min for CT/TT [7.3 +/- 1.2 ng/min], P=.20; 32.9 +/- 7.1 ng/min for CC [19.7 +/- 5.5 ng/min], P=.75; P=.0008 [P=.026] for CT/TT versus CC). Darusentan dilated veins at baseline in CC homozygous subjects (+0.21 +/- 0.05 mm, P=.004 versus placebo). Systemic ET A antagonism inhibited constriction to ET-1 and also to NA and ANGII in the skin microcirculation without differences according to genotype (ET-1, P=.017 for all individuals versus placebo; NA, P=.0005; and ANGII, P=.002). CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men. However, it determined venoconstriction to exogenous ET-1 and NA. Darusentan markedly inhibited not only ET-1-induced but also NA-induced and ANGII-induced vasoconstriction in the skin microcirculation. In contrast, it had no effects on either ET-1-mediated or NA-mediated venoconstriction, indicating that, in the presence of high local ET-1 concentrations, constrictive endothelin B receptors may be of greater importance in the venous vasculature than has been recognized so far.     

Association of the C-344T polymorphism of CYP11B2 gene with essential hypertension in Hani and Yi minorities of China

BACKGROUND: Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a C-344T polymorphism in the promoter region of the CYP11B2 gene has been reported to be in association with high blood pressure. We investigated the association between this polymorphism and essential hypertension in Hani (n=305 individuals) and Yi (n=233 individuals) minorities of China. METHODS: CYP11B2 genotyping with polymerase chain reaction-restriction fragment length polymorphism was performed in 267 normotensive subjects and 271 essential hypertensive subjects. At the same time, the T(-344)C polymorphism detection in 33 subjects was also performed by sequencing. RESULT: The frequency of CYP11B2 C-344T genotype in normotensive controls and essential hypertensive cohort in Hani population were TT: 0.729 vs. 0.610; CT + CC: 0.271 vs. 0.390, respectively. The frequency of CYP11B2 C-344T genotype in normotensive controls and essential hypertensive cohort in Yi population were TT: 0.612 vs. 0.475; CT + CC: 0.388 vs. 0.525, respectively. The frequency of CC + CT genotype in the essential hypertensive group was significantly higher than that in the normotensive controls in both Hani and Yi populations (P<0.05). CONCLUSION: The -344C allele of the CYP11B2 may play a role in genetic predisposition to developing essential hypertension in Hani and Yi minorities of China.     

Usefulness of moexipril and hydrochlorothiazide in moderately severe essential hypertension.

The purpose of this study was to assess the efficacy and tolerability of the angiotensin-converting enzyme inhibitor moexipril alone and in combination with hydrochlorothiazide versus hydrochlorothiazide monotherapy in patients with stage II and III essential hypertension. This was a double-blind, randomized, multicenter trial that evaluated moexipril (15 and 30 mg once daily), hydrochlorothiazide (25 and 50 mg once daily), and combinations of the drugs (15 mg moexipril/25 mg hydrochlorothiazide and 30 mg moexipril/50 mg hydrochlorothiazide) in 272 hypertensive patients whose seated diastolic blood pressure (BP) was 100 to 114 mm Hg. The primary efficacy variable was the mean change from baseline in seated diastolic BP at the end of the dosing period. Secondary efficacy measures included changes in systolic BP and standing BP. The lower doses of moexipril and hydrochlorothiazide reduced diastolic BP similarly (-8.0 +/- 1.4 versus -8.1 +/- 1.4 mm Hg; p = NS) as did higher doses of the monotherapeutic regimens (moexipril, -9.7 +/- 1.2 mm Hg versus hydrochlorothiazide, -11.0 +/- 1.2 mm Hg, p = NS). Combinations of moexipril and hydrochlorothiazide reduced diastolic BP significantly more than either monotherapy (lower doses, -16.0 +/- 1.4 mm Hg; p < 0.001; higher doses, -17.9 +/- 1.2 mm Hg; p < 0.001). Similar trends were observed for the systolic BP. Discontinuation rates due to adverse events were 0% for the moexipril monotherapy patients and 3% to 5% in patients on diuretic or combination treatment. These data demonstrate that 15 and 30 mg moexipril once daily lower BP similarly to hydrochlorothiazide in patients with stage II and III hypertension. There is also an additive effect when combining the two agents that lowers BP more significantly than either monotherapy.     

The link between angiotensin-converting enzyme genotype and pulmonary artery pressure in patients with COPD

OBJECTIVE: The insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of cardiovascular diseases. In patients with primary pulmonary hypertension, the homozygous ACE DD genotype is more prevalent than the non-DD genotype. However, the relationship of ACE gene polymorphism to secondary pulmonary hypertension remains unclear, and ethnicity may be one of the factors that can modulate the effects of ACE genotypes reported in different studies. We hypothesized that in patients with chronic obstructive pulmonary disease (COPD) the presence of the D allele in the ACE gene polymorphism is associated with increased pulmonary artery pressure (Ppa). PATIENTS AND METHODS: Bodyplethysmography was used to assess lung function in 66 consecutive patients with COPD; pulmonary artery pressures were determined using echocardiography. ACE gene I/D polymorphism was identified with the polymerase chain reaction. 118 healthy persons served as the control group. All patients and controls were Caucasian. Genotype II was identified in 15 patients with COPD, genotype ID in 31 and genotype DD in 20. In the control group, genotype II was identified in 19 persons, genotype ID in 68 and genotype DD in 31. The distribution of ACE gene polymorphism did not differ between patients and the control group. RESULTS: In patients with COPD, no differences were seen between the three genotype groups in mean age, smoking history, hemoglobin concentrations or ventilometric or blood gas variables. Both systolic and mean Ppa differed significantly between the II, ID and DD groups (Systolic Ppa: 24.4 +/- 2.2 versus 31.3 +/- 2.5 and 36.7 +/- 3.9 mm Hg, respectively, ANOVA, p < 0.05; Mean Ppa: 13.0 +/- 1.5 versus 17.5 +/- 1.4 and 21.2 +/- 2.8 mm Hg, respectively, ANOVA, p < 0.05). In multiple linear regression analysis, the I/D ACE gene polymorphism (p < 0.05), SaO2 (p < 0.05) and the duration of COPD (p < 0.02) were independent predictors of systolic and mean Ppa. CONCLUSION: The results of the study suggest that I/D ACE gene polymorphism is linked to pulmonary artery pressure in Caucasian patients with COPD.     

A randomized,double-blind,controlled trial of vitamin C in the management of hypertension and lipids

The effect of vitamin C on blood pressure is not well established. This is a randomized, double-blind control trial. Eligible patients were followed for 8 months. Patients were randomized to 500, 1000, or 2000 mg vitamin C. During each visit, a history including medication change was obtained and standardized blood pressure measurements were performed. A 1-week dietary diary was filled out before each visit. Multiple regression analysis and subsequent multiple comparisons were used for data analysis. Fifty-four patients satisfied our criteria and agreed to participate. Thirty-one patients (mean age, 62 +/- 2 years; 52% men, 90% whites) were randomized to the three doses of vitamin C. Overall compliance was 48 +/- 2%. Both mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased during the vitamin C supplementation phase [mean SBP dropped by 4.5 +/- 1.8 mm Hg (P <.05) and DBP by 2.8 +/- 1.2 mm Hg (P <.05)]. There was no difference between the three vitamin C groups (P =.48). This effect was significant for only 1 month of supplementation, but the trend persisted. There was no reported intolerance to vitamin C. There was no change in lipid levels after 6 months of treatment. Vitamin C supplementation lowers blood pressure in mildly hypertensive patients. There is no additional benefit for a higher dose than 500 mg daily. The effect of vitamin C is most likely to be only short term.     

Alcohol-induced arterial hypertension and genetic polymorphism of alcohol-metabolizing enzymes

AIM: To study arterial pressure (AP) and heart rate (HR) in patients suffering from alcohol withdrawal syndrome (AWS) with relation to genetic polymorphism of alcohol dehydrogenase-2 (ADG2) and aldehyde dehydrogenase-2 (AlDG2). MATERIAL AND METHODS: AP and HR were analysed for 36 alcoholics (83 hospitalizations, including repeated ones) with genotypes ADG2 and AIDG2 at admission to and discharge from narcological hospital. RESULTS: ADG2 genotypes distribution was the following: ADG2-1/1--61.1% (n = 22); ADG2-1/2--36.1% (n = 13); ADG2-2/2--2.8% 9n = 1). All the patients had a genotype AIDG2-1/1. A hypertensive reaction occurred in 75.9% inpatients with AWS. At admission, patients with genotype ADG2-1/1 had significantly higher systolic AP and HR vs those with allele ADG2-2: 146.6 +/- 17.0 mmHg against 141.2 +/- 14.9 mmHg, 95.6 +/- 13.9 b/min vs 88.5 +/- 12.2 b/min, respectively. In homozygous genotype ADG2-1/1 AP and HR were higher than in heterozygotes: SAP 152.3 +/- 12.9 mm Hg vs 145.2 +/- 16.2 mm Hg, pulse pressure 57.2 +/- 11.9 vs 50.0 +/- 15.1 mm Hg, HR 96.8 +/- 13.4 b/min vs 87.7 +/- 12.0 b/min. The groups had similar mean diastolic pressure. At discharge, AWS standard therapy resulted in a significant lowering of AP and HR in the study group. Mean values of the parameters in groups with different genotypes did not differe at discharge. CONCLUSION: Population of alcoholics from the Moscow Region had allele polymorphism ADG2. Genetic polymorphism AlDG2 is not typical for this group. Hypertensive reaction was registered in the majority of alcoholics in AWS. Higher systolic, pulse pressure and heart rate were significantly higher in the AWS group with genotype ADG2-1/1. Controlled alcohol withdrawal entails a significant reduction of AP and HR.     

Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome

To establish whether angiotensin-converting enzyme 2 (ACE2) gene A/G single nucleotide polymorphism is associated with hypertension in Chinese patients with metabolic syndrome. The study was conducted in 353 patients with metabolic syndrome. The alleles of the ACE2 A/G polymorphism, which is located on the X chromosome, were detected using polymerase chain reaction and subsequent cleavage by Alu I restriction endonuclease. G allele frequencies in patients with metabolic syndrome were 36.6% in female subjects and 43.4% in male subjects, respectively. Female patients with metabolic syndrome who carry the GG genotype had a significantly higher diastolic blood pressure compared with other genotypes. Multivariate logistic regression showed that female gender (P = 0.019) and carrying only the G allele (odds ratio 2.83 [95% CI 1.36 to 5.91]; P = 0.005) were significantly associated with increased diastolic blood pressure. It is concluded that the ACE2 A/G polymorphism is associated with hypertension in patients with metabolic syndrome.     

Cerebral blood flow during the acute therapy of severe hypertension with oral clonidine

A major risk associated with the acute treatment of severe hypertension is a reduction in cerebral blood flow (CBF) with ischemic injury to the central nervous system. The authors studied CBF before and after the acute treatment of severe hypertension (diastolic blood pressure greater than 115 mm Hg) with clonidine in 13 patients. One patient did not reach goal blood pressure (diastolic blood pressure 105 mm Hg or a decrease by 30 mm Hg) after clonidine alone. In the remaining 12 patients, oral clonidine reduced supine blood pressure from 201.7 +/- 5.0/126.3 +/- 2.1 mm Hg to 149.4 +/- 5.3/96.8 +/- 1.7 mm Hg over an average time period of 85 +/- 7 minutes. Although mean CBF for the group did not change (72.6 +/- 4.2 v 73.7 +/- 3.5 mL/100 mg/min), a significant (greater than 10%) change occurred in 9 of the 12 patients (5 increases and 4 reductions). The magnitude and direction of the change were dependent upon initial CBF (r = -0.65, P less than .05); patients with low pretreatment CBF experienced an increase, whereas those with high initial flow exhibited a decrease. No significant adverse effects were observed. These data confirm previous reports that clonidine is effective in the acute treatment of severe hypertension and demonstrate that its effects on CBF are determined by the pretreatment levels of flow.     

The gain-of-function G389R variant of the beta1-adrenoceptor does not influence blood pressure or heart rate response to beta-blockade in hypertensive subjects.

Mutation scanning of the beta1-adrenoceptor gene has identified a polymorphism, G389R, that markedly affects G-protein coupling of the receptor and resulting cAMP production. We have investigated the effect of this functionally active polymorphism on clinical response to beta-adrenoceptor blockade. Two cohorts of untreated hypertensive patients randomly assigned to a beta1-selective beta-blocker at the start of antihypertensive therapy were studied retrospectively to see if the G389R polymorphism influenced the response in terms of blood pressure and heart rate. The blood pressure and heart rate responses to treatment were assessed 4 weeks later and compared with the G389R genotype, ascertained by PCR/restriction fragment length polymorphism. The falls in blood pressure and heart rate for the first group (n = 92) by genotype were: GG, 20.1 +/- 3.5/13.9 +/- 2.7 mmHg (systolic/diastolic blood pressure), 18.4 +/- 2.2 beats/min; GR, 20.0 +/- 2.2/15.0 +/- 1.3 mmHg, 16.5 +/- 1.5 beats/min; RR, 20.8 +/- 2.3/13.4 +/- 1.1 mmHg, 16.0 +/- 1.4 beats/min. For the second group (n = 55) the corresponding falls were: GG, 17.0 +/- 4.3/11.2 +/- 3.4 mmHg, 12.0 +/- 3.5 beats/min; GR, 16.6 +/- 1.8/14.4 +/- 1.1 mmHg, 13.1 +/- 2.1 beats/min; RR, 18.0 +/- 1.6/13.0 +/- 1.4 mmHg, 14.4 +/- 1.4 beats/min. The G389R genotype also failed to have a significant effect on pretreatment blood pressure or heart rate in either group. These data suggest that, despite clear functional differences between the G389R receptor variants expressed in vitro, the polymorphism does not affect the haemodynamic response of hypertensive subjects to chronic beta1-adrenoceptor blockade.     

Enalaprilat, an intravenous angiotensin-converting enzyme inhibitor, in hypertensive crises

The effect of enalaprilat (MK-422), a newly synthesized, intravenous, nonsulfhydryl, angiotensin-converting enzyme inhibitor, was studied in seven patients with either severe or malignant hypertension. All subjects initially received a 1 mg bolus injection of enalaprilat followed in 30 minutes by 10 mg. Five subjects received an additional 40 mg. Mean (+/- SE) pretreatment blood pressure for the group was 226 +/- 9/141 +/- 7 mm Hg. Five minutes after the 1 mg enalaprilat dose, blood pressure decreased to 211 +/- 10/131 +/- 9 mm Hg and further fell to 201 +/- 14/123 +/- 11 mm Hg at 30 minutes. The maximal reduction in blood pressure to 169 +/- 14/112 +/- 10 mm Hg occurred 30 minutes after the 10 mg dose. No further blood pressure reduction was observed in those subjects who received the additional 40 mg dose. Within the entire group, five subjects exhibited sustained blood pressure reduction. No adverse side effects or symptomatic hypotension occurred in any subject.     

Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes

OBJECTIVE: To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2'deoxyguanosine (8-OHdG) as an index of oxidative DNA damage. RESULTS: The diabetic subjects with the TC+TT genotypes displayed a significantly lower average IMT (1.13 +/- 0.31 vs. 1.31 +/- 0.34 mm; P = 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors. Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P = 0.0042) and p22 phox CC genotype (P = 0.0151). In nondiabetic subjects, the average IMT of the TC+TT group was not different from that of the CC group (0.85 +/- 0.14 vs. 0.94 +/- 0.30 mm, P = 0.417). Fasting plasma insulin concentration (41.4 +/- 15.6 vs. 64.2 +/- 59.4 pmol/l, P = 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 +/- 0.66 vs. 2.60 +/- 2.56, P = 0.0066) were significantly lower in the TC+TT group than in the CC group. CONCLUSIONS: These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects.     

Abnormal Adrenal Responsiveness and Angiotensin II Dependency in High Renin Essential Hypertension

Adrenal responsiveness to angiotensin II (AII) and the diastolic blood pressure responses to saralasin were studied in 19 patients with high renin essential hypertension (HREH) on a 10-meq Na(+)/100 meq K(+) diet. The increment in plasma renin activity (PRA) between supine and upright positions was used as an estimate of the acute stimulation of the adrenal gland by endogenous AII; the normal increment in plasma aldosterone divided by the increment in PRA was >3.8. 7 of 19 had abnormal upright posture responses with significantly greater mean PRA increments (24+/-6 ng/ml per h) and significantly smaller plasma aldosterone increments 47 +/- 16 ng/dl) (P < 0.036) compared to the increments observed in HREH patients with normal adrenal responsiveness (PRA = 15 +/- 1 ng/ml per h; plasma aldosterone = 87 +/- 17 ng/dl). When AII was infused at doses of 0.1-3 ng/kg per min, only patients with normal posture responses had normal plasma aldosterone increments; plasma aldosterone levels failed to significantly increase even at the highest infusion rate in the patients with the abnormal upright posture responses. The AII competitive inhibitor, saralasin (0.3-30 mug/kg per min) was then infused to study the occurrence of angiotensinogenic hypertension in both HREH subgroups. The mean decline in diastolic blood pressure to saralasin in the subnormal adrenal responsive patients (-15 +/- 3 mm Hg) was significantly greater than in the normal adrenal responsive group (-3 +/- 2 mm Hg) (P < 0.02).It is concluded that patients with HREH are not a homogeneous population; approximately one-third have AII-dependent hypertension. In these patients, the mechanism responsible for the elevated renin and blood pressure could be a compensatory increase secondary to decreased adrenal responsiveness to AII. In the remainder, the high PRA levels have little, if any, causal role in the pathogenesis of the hypertension but could reflect a marker of other pathophysiologic processes.     

Evaluation of isradipine (PN 200-110) in mild to moderate hypertension

The efficacy and safety of isradipine (PN 200-110), a new dihydropyridine calcium antagonist, was evaluated in 87 hypertensive patients in a placebo-controlled, double-blind, randomized multicenter trial. After a 3-week single-blind washout phase, isradipine (or matching placebo) was administered for 4 weeks, beginning at 2.5 mg b.i.d. with increments of 2.5 mg b.i.d. at weekly intervals if supine diastolic blood pressure remained greater than or equal to 90 mm Hg. At the end of 1 week average supine blood pressure in the isradipine group (n = 45) fell from a baseline of 156 +/- 13/104 +/- 4 mm Hg to 146 +/- 14/97 +/- 7 mm Hg. By week 4 blood pressure was reduced by 19/14 mm Hg compared with 4/5 mm Hg in the placebo group (P less than 0.001 between groups). Supine and standing pulse rates were slightly increased initially with isradipine therapy but returned to baseline with increasing isradipine doses. Blood pressure responses at week 4 were good or excellent (supine diastolic less than or equal to 90 mm Hg or greater than or equal to 10 mm Hg decrease from baseline) in 87% of isradipine-treated patients and in 26% of placebo-treated patients. Headache, edema, abdominal discomfort, and constipation occurred slightly more frequently in isradipine-treated patients than in placebo-treated control subjects. The results indicate that isradipine, administered as monotherapy in doses of 2.5 to 10 mg b.i.d., is safe and effective in patients with mild to moderate essential hypertension.     

Peripheral dopaminergic blockade for the treatment of diabetic orthostatic hypotension

This study was designed to evaluate the effects of domperidone, a peripheral dopaminergic antagonist, in diabetic patients with symptomatic orthostatic hypotension. Nine patients were admitted to the hospital, placed on a diet containing 150 mEq sodium, and studied for periods of 4 hours, on different days, in the following conditions: (1) supine position, (2) upright posture (UP), (3) UP after 10 mg domperidone, intravenously in bolus, and (4) UP after 3 days of domperidone, 30 mg orally. Before domperidone the mean blood pressure observed in supine position of 132 +/- 37/75 +/- 6 mm Hg fell to 75 +/- 22/57 +/- 13 mm Hg after 2 hours in UP. Acute domperidone did not change the blood pressure response to UP. After 3 days of oral domperidone and in UP for 2 hours, the mean blood pressure value of 89 +/- 21/61 +/- 8 mm Hg was higher than that before domperidone (p less than 0.05), with relief of symptoms in all patients. This blood pressure response to UP has been maintained in six patients who completed 6 months of therapy. No differences were observed in plasma renin activity, aldosterone, sodium, and potassium and in 4-hour urinary excretion of aldosterone, epinephrine, norepinephrine, and dopamine, determined during the UP tests. Administration of domperidone for 3 days reduced the falls in creatinine clearance and the urinary excretion of sodium and potassium induced by UP but did not alter the blood pressure and aldosterone dose-response curves to angiotensin II. Although the mechanism of action is not defined, it is concluded that domperidone is effective for the treatment of orthostatic hypotension in patients with diabetes.     

The Efficacy of Esmolol versus Lidocaine to Attenuate the Hemodynamic Response to Intubation in Isolated Head Trauma Patients

OBJECTIVE: To assess the effect of esmolol vs lidocaine to attenuate the detrimental rise in heart rate and blood pressure during intubation of patients with isolated head trauma. METHODS: This was a prospective, double-blind, randomized study, performed at an urban, county teaching emergency department. Participants were 30 patients with isolated head trauma. Each underwent a standardized intubation protocol including esmolol or lidocaine, both at 2 mg/kg. RESULTS: Esmolol was used in 16 patients and lidocaine in 14. Mechanisms of injury included 12 assaults, 6 motor vehicle collisions, 6 falls, 4 auto-vs-pedestrian crashes, and 2 bicycle incidents. Mean ethanol level was 0.116+/-0.133 SD (range 0-0.482). Mean Glasgow Coma Scale (GCS) score was 7.9+/-4.0 SD. Cranial computed tomography (CT) hemorrhagic findings included 9 subdural/epidural hematomas, 6 cortex hemorrhages, and 2 multi-hemorrhages. Eleven patients received surgical intervention: 9 patients received a craniotomy, and 2 a ventricular catheter. The 2-minute time interval around intubation was used to assess each drug's efficacy. The mean difference change between groups for heart rate was 4.0 beats/min (95% CI = -17.7 to 9.7 beats/min), for systolic blood pressure was 1.3 mm Hg (95% CI = -27.8 to 30.4 mm Hg), and for diastolic blood pressure was 2.6 mm Hg (95% CI = -27.1 to 21.9 mm Hg). The power of this study was 90% to detect a 20-beat/min difference in heart rate, a 35-mm Hg difference in systolic blood pressure, and a 20-mm Hg difference in diastolic blood pressure. CONCLUSIONS: Esmolol and lidocaine have similar efficacies to attenuate moderate hemodynamic response to intubation of patients with isolated head trauma.     

Blood pressure elevation in a patient treated with salsalate

OBJECTIVE: To report a case of increased blood pressure associated with the use of salsalate in an elderly patient with no prior history of hypertension. CASE SUMMARY: A 78-year-old white man with no prior history of hypertension initiated salsalate therapy for low-back pain. Over the 15 months prior to the initiation of salsalate, his blood pressure averaged 127 +/- 7 mm Hg systolic and 84 +/- 6 mm Hg diastolic (mean +/- SD). After initiation of salsalate, he experienced significant elevations in blood pressure, which led to a preliminary diagnosis of hypertension. Blood pressure after initiation of salsalate averaged 150 +/- 13 mm Hg systolic and 95 +/- 5 mm Hg diastolic. No changes in medications or medication doses (with the exception of warfarin) occurred in the 18 months prior to or during salsalate therapy. His weight remained stable. A detailed review of his medical records and history revealed no other causes for these elevations in blood pressure. Salsalate therapy was discontinued and his blood pressure returned to normotensive levels (119 +/- 2 mm Hg systolic and 81 +/- 2 mm Hg diastolic). DISCUSSION: Nonsteroidal antiinflammatory drug (NSAID)-induced elevations in blood pressure have been well documented in patients receiving antihypertensive medications. Due to its relative weak inhibition of cyclooxygenase and lack of published literature in hypertensive patients, salsalate is considered to have little or no effect on blood pressure. Our report documents a possible case of salsalate-induced hypertension in a previously normotensive elderly man. Observational studies suggest that NSAID use may increase the risk of developing hypertension in older patients. CONCLUSIONS: Clinicians should be aware of the possible effects of NSAIDs on blood pressure. Blood pressure monitoring following the initiation of salsalate may be warranted, particularly in older patients.