Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat

BACKGROUND: After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density. The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure. METHODS AND RESULTS: Seven days after coronary ligation (MI), rats were randomized to enalapril (n = 8; 500 micrograms.kg-1.d-1), losartan (n = 9; 3 mg.kg-1.d-1), or placebo (n = 8) and treated for 6 weeks. Sham-operated rats (n = 10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg.kg-1.min-1 over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg.mL-1.min-1.g-1, all P < .05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol.mg protein-1.min-1, P < .05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol.mg protein-1.min-1, P < .05 versus MI-placebo). CONCLUSIONS: The present study demonstrates that both chronic ACE inhibition and AT1 receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV. These results suggest that inhibition of generation of angiotensin II and AT1 receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction.     

In vitro pharmacological properties of KRH-594, a novel angiotensin II type 1 receptor antagonist

Although most people are thought to receive their highest acute exposures to gasoline while refueling, relatively little is actually known about personal, nonoccupational exposures to gasoline during refueling activities. This study was designed to measure exposures associated with the use of an oxygenated fuel under cold conditions in Fairbanks, Alaska. We compared concentrations of gasoline components in the blood and in the personal breathing zone (PBZ) of people who pumped regular unleaded gasoline (referred to as regular gasoline) with concentrations in the blood of those who pumped an oxygenated fuel that was 10% ethanol (E-10). A subset of participants in a wintertime engine performance study provided blood samples before and after pumping gasoline (30 using regular gasoline and 30 using E-10). The biological and environmental samples were analyzed for selected aromatic volatile organic compounds (VOCs) found in gasoline (benzene, ethylbenzene, toluene, m-/p-xylene, and o-xylene); the biological samples were also analyzed for three chemicals not found in gasoline (1,4-dichlorobenzene, chloroform, and styrene). People in our study had significantly higher levels of gasoline components in their blood after pumping gasoline than they had before pumping gasoline. The changes in VOC levels in blood were similar whether the individuals pumped regular gasoline or the E-10 blend. The analysis of PBZ samples indicated that there were also measurable levels of gasoline components in the air during refueling. The VOC levels in PBZ air were similar for the two groups. In this study, we demonstrate that people are briefly exposed to low (ppm and sub-ppm) levels of known carcinogens and other potentially toxic compounds while pumping gasoline, regardless of the type of gasoline used.     

Angioedema associated with angiotensin II receptor antagonist losartan

Angioedema has not been associated with losartan therapy in hemodialysis patients, as it has been with angiotensin converting enzyme (ACE) inhibitors. We report the case of a hemodialysis patient who previously had angioedema after therapy with ACE inhibitors and again had angioedema while taking losartan. We suggest caution in using losartan in patients with known sensitivity to ACE inhibitors manifested by angioedema.     

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.     

Regulation of angiotensin II type 1 (AT1) receptor function

We studied protein binding and structural features of perfect and imperfect composite (gt)n(ga)m blocks from different HLA-DRB1 alleles in their original genomic and artificial environments. The major retarded protein/DNA complex of the genomic (gt)n(ga)m fragments comprises a zinc-dependent protein present in nuclear extracts from different cell types. The protein binding is characterized by moderate affinities independent of the polymorphic form of the physiological microsatellite allele. The binding affinity depends on the 5' and 3' adjacent single copy parts. DNase I footprinting of genome-derived fragments revealed that the 5' adjacent sequence and the (gt)n repeat are preferentially protected on the (gt)n(ga)m strand. Comparing three alleles, a regular pattern of footprints was not detectable in the (gt)n part, indicating that the zinc-dependent protein recognizes structural rather than sequence-specific features in this region. Chemical probing resulted in a pattern characteristic for Z-DNA in the (gt)n tract of the fragments. However, EMSA experiments using the Z-DNA specific monoclonal antibody mABZ-22 did not prove the presence of Z-DNA. As demonstrated by chemical modifications of the different (ga)m targets, only one of three (gt)n(ga)m fragments formed intramolecular triplexes of the type H-y3 and H-y5. DNase I footprinting revealed only weak protection, if any, in the homopurine tract. Rather, the (tc)m strands are hypersensitive for DNase I. This is probably due to structural conversions into intramolecular *H-triplexes after binding of HIZP.     

Effects of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition on cardiac beta-adrenergic signal transduction

PURPOSE: To present 10 years experience with direct fluoroscopically guided percutaneous jejunostomy. MATERIALS AND METHODS: Percutaneous jejunostomy was performed in 62 patients, most of whom had undergone major abdominal surgery. A new or replacement jejunostomy was created for alimentation in 20 and 21 patients, respectively. Jejunostomy was performed for interventional procedures of the bile ducts or intestine in 13 patients and for retrograde gastroesophageal drainage in eight. The distended jejunum was accessed with a 21-gauge needle, immobilized with a gastric anchor, and catheterized with a 10-14-F locking loop drain. RESULTS: The technical success rate was 19 of 20 (95%) for new feeding jejunostomy and 17 of 21 (81%) for replacement feeding jejunostomy. Jejunostomy facilitated drainage, dilation, stone extraction, and recanalization in the bile ducts or intestine in all 13 patients. Retrograde jejunoesophagogastrostomy suction effectively replaced painful nasogastric suction in all eight patients. Two patients who underwent replacement jejunostomy required laparotomy for possible leakage; there was no important procedure-related morbidity and no procedure-related mortality. CONCLUSION: The technical success and complication rates of feeding percutaneous jejunostomy compare favorably with those of surgery or endoscopy. Percutaneous jejunostomy is a useful and underused approach to managing bowel and biliary obstruction.     

Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice

Many lines of evidence have suggested that angiotensin II (AngII) plays an important role in the development of cardiac hypertrophy through AngII type 1 receptor (AT1). To determine whether AngII is indispensable for the development of mechanical stress-induced cardiac hypertrophy, we examined the activity of mitogen-activated protein kinase (MAPK) family and the expression of the c-fos gene as hypertrophic responses after stretching cultured cardiac myocytes of AT1a knockout (KO) mice. When cardiac myocytes were stretched by 20% for 10 min, extracellular signal-regulated protein kinases (ERKs) were strongly activated in KO cardiomyocytes as well as wild type (WT) myocytes. Both basal and stimulated levels of ERKs were higher in cardiomyocytes of KO mice than in those of WT mice. Activation of another member of the MAPK family, p38(MAPK), and expression of the c-fos gene were also induced by stretching cardiac myocytes of both types of mice. An AT1 antagonist attenuated stretch-induced activation of ERKs in WT cardiomyocytes but not in KO cardiomyocytes. Down-regulation of protein kinase C inhibited stretch-induced ERK activation in WT cardiomyocytes, whereas a broad spectrum tyrosine kinase inhibitor (genistein) and selective inhibitors of epidermal growth factor receptor (tyrphostin, AG1478, and B42) suppressed stretch-induced activation of ERKs in KO cardiac myocytes. Epidermal growth factor receptor was phosphorylated at tyrosine residues by stretching cardiac myocytes of KO mice. These results suggest that mechanical stretch could evoke hypertrophic responses in cardiac myocytes that lack the AT1 signaling pathway possibly through tyrosine kinase activation.     

Up-regulation of angiotensin type 2 receptor mRNA by angiotensin II in rat cortical cells

The present experiment demonstrates that the exposure of angiotensin II (AII) produced an up-regulation of the AT2 receptor mRNA level in rat cortical cells. AII (10(-9)-10(-5) M) exerted a marked increase of AT2 receptor mRNA in a dose-dependent manner. The maximum increase was observed at 3 hr of AII stimulation and lasted 3 hr. The up-regulation of AT2 receptor mRNA was antagonized by PD123319, an AT2 receptor antagonist, but not by SC-52458, an AT1 receptor antagonist, thus suggesting that the increase in AT2 receptor mRNA is mediated via AT2 receptor. This increase is blocked by serine/threonine phosphatase inhibitor okadaic acid, but not by the phosphotyrosine phosphatase inhibitor sodium vanadate, thus suggesting the involvement of serine/threonine phosphatase in this process. Protein kinase C inhibitor, H-7 and calphostin C, did not inhibit the AII-induced up-regulation significantly. In addition, calcium ionophore, A23187 had no effect. These findings suggest that the AT2 receptor mRNA expression by AII is regulated by the activity of serine/threonine phosphatase in the cortical neurons. This observation is also the first example concerning the regulation of AT2 receptor within the brain.     

Chromosomal localization of angiotensin II type 1 receptor isoforms in the rat

The cDNA sequences of two different isoforms of the rat angiotensin II type 1 receptors, AT1A and AT1B, have been reported. A single set of polymerase chain reaction primers was used to amplify sequence from both AT1A and AT1B from rat genomic DNA. Genomic DNA from a panel of rat x mouse somatic hybrid cell lines which had been characterized as to the rat chromosomal content was then amplified with these primers. The amplified products from rat AT1A and AT1B were distinguished from each other and those of the mouse by the use of differential restriction patterns. Using this method, AT1A was localized to rat chromosome 17 and AT1B to rat chromosome 2.     

Treatment of subacute cardiac rupture after myocardial infarction

Five successfully treated cases of subacute cardiac rupture after myocardial infarction are described. There were 4 men and 1 woman, ranging in age from 51 to 71 years. Two patients had systemic hypertension. Rupture occurred during the first myocardial infarction in all patients. The interval from the onset of myocardial infarction to cardiac rupture ranged from 1 to 6 days (mean 4 days). In one patient, the rupture was repaired under cardiopulmonary bypass using an autologous pericardial patch over the infarcted myocardium. Two patients underwent sutureless repair with fibrin glue; one of them developed a left ventricular pseudoaneurysm 2 years after the operation, requiring resection. These three patients were operated on through a median sternotomy. The remaining two patients were treated for cardiac tamponade by pericardial drainage through a subxiphoid incision; one died 38 days after the operation due to congestive heart failure. The four surviving patients are currently well 22, 39, 41 and 60 months after surgery. In summary, a conservative approach may be effective for treatment of subacute cardiac rupture.     

Inhibitory activity of IL-1 receptor antagonist depends on the balance between binding capacity for IL-1 receptor type 1 and IL-1 receptor type II

A series of mutants of human IL-1 receptor antagonist (IL-1ra) has been designed by comparison of IL-1ra and IL-1beta structures in order to increase receptor antagonist capacity. Upon in vitro and in vivo assay of IL-1 antagonism, the IL-1ra mutants DoB 0039 (N91-->R), DoB 0040 (T109-->A) and DoB 0041 (N91/T109-->R/A) could inhibit IL-1beta effects more efficiently than wild-type IL-1ra, with DoB 0041 being the most active. Analysis of the receptor-binding capacity of the IL-1ra mutants showed that all three mutants could inhibit binding of IL-1alpha or IL-1beta to IL-1RI-bearing cells more efficiently than wild-type IL-1ra. Conversely, binding of IL-1beta to IL-1RII-bearing cells could be inhibited by DoB 0041 much less efficiently than by wild-type IL-1ra. It is known that the two types of IL-1 receptors (IL-1RI and IL-1RII) play different roles in the regulation of IL-1 activity, with IL-1RI being solely responsible for cell triggering upon IL-1 binding, whereas IL-1RII acts as a scavenger of IL-1 and can thus be considered as a natural IL-1 inhibitor. Thus, the enhanced inhibitory capacity of DoB 0041 as compared with wild-type IL-1ra is explained in terms of better binding to the activating receptor IL-1RI and poorer interaction with the inhibitory receptor IL-1RII.     

Expression and localization of angiotensin II type 1 receptor mRNA in rat ocular tissues

OBJECTIVE: Hereditary hemorrhagic telangiectasia (HHT) is an inherited abnormality passed down as a dominant autosomal feature. Recurrent epistaxis usually constitutes the major clinical manifestation of this disease. The unsatisfactory results of conservative therapy have stimulated a research interest for the role of laser photocoagulation in telangiectatic vessels associated with this clinical entity. METHOD: The Nd:YAG laser was used to treat a group of 11 individuals suffering from HHT, all of whom had been previously treated using other modalities. RESULTS AND CONCLUSION: The excellent results of Nd:YAG laser irradiation are addressed in view of all treatment modalities proposed for the treatment of recurrent epistaxis in HHT.     

Protein kinase C modulation of cardiomyocyte angiotensin II and vasopressin receptor desensitization

Brain catecholamines have been implicated in the regulation of gonadotrophin release. It has been recently reported that noradrenaline (NA), applied within the hypothalamic paraventricular nucleus, suppresses the pulsatile release of LH in the rat through a corticotrophin-releasing hormone (CRH)-dependent mechanism. Prolactin (PRL) is also able to suppress hypothalamic GnRH release following activation of the CRH-releasing neurone. Given that PRL stimulates the release of NA from hypothalamic explants and that NA stimulates the release of hypothalamic CRH, we hypothesized that this neurotransmitter may be involved in the intrahypothalamic neuroendocrine circuit mediating the inhibitory effects of PRL on GnRH release. To test this hypothesis, we evaluated the effects of PRL on GnRH release in the presence of alpha- or beta-adrenergic receptor antagonists using a static hypothalamic organ culture system which enabled us to evaluate immunoreactive GnRH (iGnRH) release from individually incubated, longitudinally halved hypothalami. As previously shown, PRL at a concentration of 100 nM inhibited basal iGnRH release by about 35%. Phentolamine, a non-selective alpha-adrenergic receptor antagonist, prazosin, an alpha 1-receptor antagonist, and yohimbine, an alpha 2-receptor antagonist, overcame the inhibitory effect of PRL on iGnRH release in a concentration-dependent fashion. In contrast, propranolol, a non-selective beta-adrenergic receptor antagonist, atenolol, a beta 1-receptor antagonist, and ICI-118,551, a beta 2-receptor antagonist, had no effect. None of these compounds had any effect on basal iGnRH release. These findings suggested that an alpha-adrenergic mechanism is involved in the suppressive effects of PRL on GnRH release. Since the activation of alpha-adrenergic receptors increases hypothalamic CRH release, we evaluated whether PRL stimulates CRH release via an alpha-adrenergic mechanism. PRL stimulated basal CRH release by about twofold and this effect was inhibited by phentolamine in a concentration-dependent fashion. In conclusion, alpha-, but not beta-, adrenergic receptors mediate the inhibitory effects of PRL on GnRH release in vitro. We speculate that, at least under these experimental conditions, PRL inhibits GnRH release through an alpha-adrenergic mechanism which activates the CRH-secreting neurone.     

Pharmacological profiles of a novel non-peptide angiotensin II type I receptor antagonist HR720 in vitro and in vivo

The relationship, in 539 individuals infected with the human immunodeficiency virus (HIV), between two prognostic markers, the CD4 count and beta-2-microglobulin (B2M), and the development of the acquired immunodeficiency syndrome (AIDS) and death was investigated. Cox proportional hazards models were used to determine the risk of AIDS or death. In a multivariate model which adjusted for demographic factors and treatment, the most recent measurements of B2M (relative hazard (RH) 1.37 per g/l higher) and CD4 count (RH 2.17 per log-unit lower) were both significantly associated with the development of AIDS. Similarly, in a multivariate model which additionally adjusted for the development of AIDS as a time dependent covariate, there was a strong relationship with risk of death for the most recent measurements of B2M (RH 1.34 per g/l higher), and CD4 lymphocyte count (RH 1.91 per log-unit lower). A difference in the level of B2M could be used among patients with similar CD4 counts as an indicator of increased risk of progression to AIDS or death. Using the most recent values of these markers provides a better estimate of the risk of AIDS or death, compared to the more common method of analysis, where baseline values of the markers are used.     

Beta 2-adrenergic receptor and angiotensin II receptor modulation of sympathetic neurotransmission in human atria

BACKGROUND: Cultures of epidermal cells are commonly used to study skin biology and differentiation. Recently a method to culture nail matrix cells has been established. OBJECTIVE: We report the biologic characteristics of nail matrix cells in vitro compared with those of epidermal keratinocytes. METHODS: Human nail matrix cells were isolated and cultured in defined medium. Electron-microscopic examination, growth rate, integrin expression and keratin synthesis pattern were evaluated. In addition, the cells were cultured in serum-containing medium. RESULTS: Nail matrix cells appear to be larger than human epidermal keratinocytes and, at the ultrastructural level, they contain a higher euchromatin/heterochromatin ratio and a lower nucleus/cytoplasm ratio and have a higher growth rate. The synthesis of "hard" keratins was detected at all calcium concentrations. Immunofluorescence analyses showed the expression of alpha 2, alpha 3, and alpha 6 integrin subunits. When cultured in serum-containing medium, nail matrix cells produced an outgrowth of epithelium and a spontaneous migration phenomenon associated with a tendency to stratify in a semilunar area that resembles the architecture of the nail matrix. The pluristratified epithelium showed characteristic markers of nail differentiation. CONCLUSION: Culture of nail matrix cells may represent a useful model to study the biologic properties of nail structure, alterations in some nail diseases and the effects of drugs.     

Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients

BACKGROUND: The angiotensin II receptor antagonist losartan is an effective antihypertensive agent with unique uricosuric properties. This study evaluates the uricosuric effects of losartan in 10 hypertensive heart transplant patients with hyperuricemia. METHODS: The patients were randomized to receive losartan 50 mg once daily and enalapril 20 mg once daily for 4 weeks according to a double-blind crossover design. Office blood pressure, plasma uric acid levels, and urinary uric acid excretion were monitored throughout the study. RESULTS: Plasma uric acid levels decreased significantly after 4 weeks of treatment with losartan (P<0.05) but not with enalapril. On day 1 and after 1 month of treatment, a significant increase in uric acid excretion was observed only with losartan. Significant decreases in office systolic and diastolic blood pressures were obtained with enalapril but not with losartan. CONCLUSIONS: Losartan effectively lowers plasma uric acid levels in hyperuricemic heart transplant patients.