Comparative efficacy and safety of amlodipine/benazepril combination therapy and amlodipine monotherapy in severe hypertension.

This multicentre, double-blind, trial in subjects with severe hypertension compared the efficacy and tolerability of two parallel drug regimens: A/B (amlodipine/benazepril: 5/20 or 10/40 mg daily, if necessary) with A (amlodipine: 5 or 10 mg daily, if necessary). The principal dependent variable was the proportion of patients achieving goal blood pressures (BP<140/90 mm Hg or BP<130/80 mm Hg in diabetes or chronic kidney disease) in the two groups within 6 weeks. In the 259 randomized subjects, BP control rates were higher with A/B at 2, 4 and 6 weeks (10.5, 22, and 33.6%, respectively) compared with A (5.7, 16, and 25.8 %, respectively). Corresponding trended BP reductions from baseline at 2, 4 and 6 weeks were about 5 mm Hg greater with A/B (-21+/-16, -26+/-17 and -30+/-17 mm Hg, respectively, compared with A (-16+/-17, -23+/-18 and 25+/-19 mm Hg, respectively, P<0.01). Both regimens were well tolerated; incidences of peripheral oedema at weeks 4 and 6 were similar (A/B: 13 and 20% versus A: 20 and 22%, P=not significant). We conclude that titration of amlodipine and benazepril in single-pill combinations is more effective than titration of amlodipine alone for rapid BP control in patients with severe hypertension.

Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.

The strategy of initiating hypertension treatment with combination versus single-drug therapy was formally tested in a prospective, double-blind, parallel-group trial in blacks with stage 2 hypertension (mean sitting systolic BP (MSSBP) >or=160 and <200 mm Hg). Participants were randomized equally to amlodipine/valsartan (A/V) (n=286) or amlodipine (A) monotherapy (n=286). After 2 weeks, there was forced titration of A/V 5/160 mg to A/V 10/160 mg and of A 5 to A 10 mg followed by 10 additional weeks of treatment. If SBP was >or=130 mm Hg at week 4, the protocol allowed optional titration of A/V to the 10/320 mg dose and, at week 8, hydrochlorothiazide 12.5 mg was optionally added to both A/V and A if SBP >or=130 mm Hg. Amlodipine/valsartan at week 8 lowered MSSBP last observation carried forward significantly>A (33.3 vs 26.6 mm Hg, P<0.0001). Lowering of MSSBP with A/V significantly exceeded that of A in several specified subgroups-the elderly (>or=65 years), isolated systolic hypertension, and those with body mass index (BMI) >or=30 kg/m(2). More patients treated with A/V than A achieved BP control (<140/90 mm Hg) both at weeks 8 (49.8 vs 30.2%; P<0.0001) and 12 (57.2 vs 35.9%; P<0.0001). Both treatment regimens were well tolerated. In conclusion, the strategy of initiating combination antihypertensive drug therapy in blacks with stage 2 hypertension with amlodipine /valsartan achieves greater and quicker reductions in BP as well as significantly higher BP control rates than starting treatment with amlodipine monotherapy.

Repair of left ventricular aneurysm: long-term results of linear repair versus endoaneurysmorrhaphy.

BACKGROUND: Recently, endoaneurysomorrhaphy has been proposed as a more physiologic repair of postinfarction left ventricular aneurysm than is linear repair. There are only a few studies comparing the short-term and long-term results of the two techniques. METHODS: Clinical outcomes and echocardiographic measurements of left ventricular volume and sphericity in 27 patients who underwent endoaneurysmorrhaphy were compared with those in 20 patients who had linear repair. RESULTS: The two groups were matched with respect to age, gender, comorbid risk factors, functional class, urgency of the operation, and concomitant procedures. Preoperatively, left ventricular ejection fraction was lower in the endoaneurysmorrhaphy group (0.25 +/- 0.08 versus 0.30 +/- 0.09; p = 0.03). Follow-up was available in 44 patients (94%) and ranged from 2 to 86 months (mean, 41.0 +/- 26.5 months). Thirty-day operative mortality, perioperative complications, 5-year survival, and freedom from cardiac death were similar. Early postoperative percentage increase in left ventricular ejection fraction was greater after endoaneurysmorrhaphy (0.51 +/- 0.64 versus 0.18 +/- 0.48; p = 0.036). Long-term functional improvement was significantly better in the endoaneurysmorrhaphy group: At the time of last follow-up, 88% of patients were in New York Heart Association class I/II, compared with 53% after linear repair (p = 0.01). There were no measurable differences between the groups with respect to left ventricular ejection fraction (0.28 +/- 0.11 versus 0.27 +/- 0.11; p = 0.90), left ventricular volume (171.6 +/- 59.1 versus 169.9 +/- 54.4 mL; p = 0.94), and sphericity index (0.61 +/- 0.09 versus 0.61 +/- 0.12; p = 1.0). CONCLUSIONS: Despite having a similar effect on left ventricular geometry, endoaneurysmorrhaphy resulted in a greater increase in postoperative left ventricular ejection fraction and a substantially improved long-term clinical outcome.

Left ventricular dysfunction during infrarenal abdominal aortic aneurysm repair.

BACKGROUND: Clinical observations suggest that pulmonary artery occlusion pressure (PAOP) underestimates the resuscitative volumes required prior to release of aortic cross-clamp. METHODS: To investigate pressure-volume relationships associated with repair of abdominal aortic aneurysm (AAA), we simultaneously monitored PAOP by pulmonary artery catheter (PAC) and estimated left ventricular (LV) diastolic volume using two-dimensional transesophageal echocardiography (TEE) in 22 patients undergoing AAA repair. Data from PAC monitoring and TEE were collected before, during, and after aortic occlusion. TEE cross-sectional images were obtained at the mid-papillary level. RESULTS: Overall, PAOP correlated with left ventricular end-diastolic area (LVEDA), but the correlation was not particularly strong (r = 0.37, P < 0.0001). Even within individual patients, LVEDA varied widely for a given PAOP. The strength of the correlation between PAOP and LVEDA also appeared to deteriorate during the course of surgery. The best correlation was seen prior to aortic cross-clamping (r = 0.50, P < 0.0001), but fell somewhat during aortic cross-clamping (r = 0.41, P < 0.0001), and even further after unclamping (r = 0.25, P = 0.005). CONCLUSION: This study demonstrates a relatively weak correlation between PAOP and LVEDA using intraoperative TEE during AAA repair. Furthermore, the strength of the correlation worsened during surgery, particularly after unclamping. Although unclear at this time, this finding may be attributable to changes in LV compliance. We found TEE to be a valuable adjunct in guiding volume resuscitation of patients undergoing AAA repair.

Structural organization and chromosomal assignment of the gene encoding the human heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a recently identified, potent smooth muscle cell mitogen of macrophage origin. It is expressed in a highly regulated fashion in vascular endothelial and smooth muscle cells, indicating a potentially important role for this gene in atherosclerosis. In addition, the HB-EGF precursor has recently been found to function as a receptor for diphtheria toxin. Using an HB-EGF cDNA probe, we cloned the human gene encoding HB-EGF. The HB-EGF gene contains six exons and five intervening sequences spanning 14 kb of DNA. By primer extension and S1 nuclease analysis, we located a major transcription start site (corresponding to an A residue) 14 bp beyond the 5' end of the HB-EGF cDNA. There were no TATAAA or CCAAT consensus sequences upstream of the transcription start site. The density of primer extension bands generated by RNA from endothelial cells treated with tumor necrosis factor-alpha (TNF-alpha) was 10 times higher than that of bands generated by the control, indicating that TNF-alpha increased the level of HB-EGF mRNA. Using transient reporter gene transfection experiments, we show that 2.0 kb of HB-EGF 5'-flanking sequence has promoter activity in bovine aortic endothelial cells. By analysis of DNA isolated from human-mouse somatic hybrid cell lines, we assign the HB-EGF gene to chromosome 5. By functional study, chromosome 5 has been associated with diphtheria toxin susceptibility.

Properties of immunoaffinity purified 106-kDa Ca2+ release channels from the skeletal sarcoplasmic reticulum.

The sulfhydryl-gated 106-kDa Ca(2+)-release channel (SG-106) was purified by biotin-avidin chromatography from skeletal sarcoplasmic reticulum (SR) vesicles and used as an antigen to raise polyclonal antibodies. Western blots showed that the antisera crossreacted with the antigenic SG-106 and not with SR Ca2+, Mg(2+)-ATPase or with junctional foot proteins (JFPs) (Zaidi et al., 1989, J. Biol. Chem. 264(36), 21, 725-21, 736; 21, 737-21, 747). Polyclonal antibody-affinity columns were used to selectively purify SG-106-kDa proteins which, upon incorporation in planar bilayers, revealed the presence of a cationic channels with properties similar to "native" Ca(2+)-release channels obtained through the fusion of SR vesicles with planar bilayers. In agreement with measurements of Ca2+ release from SR vesicles, sulfhydryl oxidizing and reducing agents (i.e., 2,2'-dithiodipyridine and dithiothreitol) respectively increased and decreased the open-time probability of 106-kDa Ca(2+)-release channels. In contrast with reports on JFPs, ryanodine at 0.5-1 nM increased the open-time probability and at 2-10 nM locked 106-kDa Ca(2+)-release channels in a closed state rather than an open subconductance state. The SG-106 was activated by millimolar ATP, inhibited by millimolar Mg2+, and blocked by micromolar ruthenium red. Adriamycin (2-10 microM) caused a transient activation of SG-106 Ca(2+)-release channels, followed by closure in about 5 min, and intermittent activation to a subconductance state. Polyclonal antibodies used to purify the SG-106 also activated the channel when added to the cis side but not the trans side of the bilayer. Thus, SG-106 channels possess features that are similar to "native" SR Ca(2+)-release channels, are immunologically distinct from JFPs, and interact in seconds with nanomolar ryanodine in planar bilayers.

Genetic regulation of endothelin-1 in vascular endothelial cells.

Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle cell mitogen synthesized and secreted by endothelial cells. This vasoactive peptide is genetically regulated by many of the cytokines, hormones, and physical forces that are involved in vascular disease processes. Transcriptional regulation of the ET-1 gene depends upon the cis-acting elements of the ET-1 promoter and their interaction with the protooncogene products Fos and Jun as well as other DNA-binding proteins.

Disulfide linkage of biotin identifies a 106-kDa Ca2+ release channel in sarcoplasmic reticulum.

Reactive disulfide reagents (RDSs) with a biotin moiety have been synthesized and found to cause Ca2+ release from sarcoplasmic reticulum (SR) vesicles. The RDSs oxidize SH sites on SR proteins via a thiol-disulfide exchange, with the formation of mixed disulfide bonds between SR proteins and biotin. Biotinylated RDSs identified a 106-kDa protein which was purified by biotin-avidin chromatography. Disulfide reducing agents, like dithiothreitol, reverse the effect of RDSs and thus promoted active re-uptake of Ca2+ and dissociated biotin from the labeled protein indicating that biotin was covalently linked to the 106-kDa protein via a disulfide bond. Several lines of evidence indicate that this protein is not Ca2+, Mg2+-ATPase and is not a proteolytic fragment or a subunit of the 400-kDa Ca2+-ryanodine receptor complex (RRC). Monoclonal antibodies against the ATPase did not cross-react with the 106-kDa protein, and polyclonal antibodies against the 106-kDa did not cross-react with either the ATPase or the 400-kDa RRC. RDSs did not label the 400-kDa RRC with biotin. Linear sucrose gradients used to purify the RRC show that the 106-kDa protein migrated throughout 5-20% linear sucrose gradients, including the high sucrose density protein fractions containing 400-kDa RRC. Protease inhibitors diisopropylfluorophosphate used to prevent proteolysis of 400-kDa proteins did not alter the migration of 106-kDa in sucrose gradients nor the patterns of biotin labeling of the 106-kDa protein. Incorporation of highly purified 106-kDa protein (free of RRC) in planar bilayers revealed cationic channels with large Na+ (gNa+ = 375 +/- 15 pS) and Ca2+ (gCa2+ = 107.7 +/- 12 pS) conductances which were activated by micromolar [Ca2+]free or millimolar [ATP] and blocked by micromolar ruthenium red or millimolar [Mg2+]. Thus, the SR contains a sulfhydryl-activated 106-kDa Ca2+ channel with apparently similar characteristics to the 400-kDa "feet" proteins.