Renovascular hypertension: structural changes in the renal vasculature

Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.     

Anomalous origin of the left coronary artery from the pulmonary trunk. Potential for false negative diagnosis with cross sectional echocardiography.

Cross sectional echocardiography can identify anomalous origin of the left coronary artery from the pulmonary trunk. It has been suggested that identification of the left coronary artery arising from the aorta using this technique excludes the diagnosis. In three such infants the anomalous origin of the left coronary artery was identified in each by cross sectional echocardiography. In all three cases, however, an echo free linear structure apparently arising from the aorta, resembling a normal left coronary artery, was imaged. Anatomical sections in one patient, simulating cross sectional echocardiographic cuts, showed that this structure was almost certainly the transverse sinus of the pericardium. False positive cross sectional echocardiographic diagnosis of this condition is also possible because of the failure to image a normally arising left coronary artery. Thus identification of the anomalous origin of the left coronary artery from the pulmonary trunk appears to be the only reliable echocardiographic finding in this condition, and contrast cineaortography remains necessary in patients in whom the diagnosis is suspected clinically or electrocardiographically.     

A search for heterogeneity in insulin dependent diabetes mellitus (IDDM): HLA and autoimmune studies in simplex, multiplex and multigenerational families

HLA antigens (A, B, C and DR loci), serum islet cell antibodies, thyrogastric antibodies, and insulin antibodies were studied in 77 families (25 simplex, 42 multiplex, and 10 multigenerational). In order to test for intrafamilial constancy and intergroup variation, we compared simplex with multiplex families, HLA identical and non identical siblings within families, as well as groups of families characterized by different DR alleles (DR3, DR4, and DR3/DR4) for various immunologic and clinical characteristics. These comparisons did not reveal all the distinct subgroups suggested by different cross-sectional population studies, but did provide evidence for a compound form having an aggregation of different high risk alleles. This study suggests that in many cases (and possibly especially in families with multiple affected individuals), there are several different genetic influences leading to IDDM.     

The effect of terbutaline in exercise-induced asthma.

A double blind study of 5 asthmatic subjects in remission demonstrated that the severity of bronchoconstriction after exercise was decreased by a single oral dose of 5 mg of terbutaline. The effect lasted for at least 6 hours and was significantly better than the protection afforded by 20 mg of metaproterenol, which was itself more effective than a placebo. In these doses, neither terbutaline nor metaproterenol affected heart rate or blood pressure at rest or in exercise, and no drug-induced side effects were found.     

Intramyocardial Injection of DNA Encoding Vascular Endothelial Growth Factor in a Myocardial Infarction Model

In a previous study, we observed that one injection of 500g of DNA for the plasmid encoding for vascular endothelial growth factor (ph VEGF₁₆₅) into one site in a rat myocardial infarction model resulted in neovascularization confined to angiomatous structures that did not contribute to regional myocardial blood flow. The purpose of the present study was to determine whether a lower dose (125g DNA), which is the same as that being used in some clinical trials, injected into four separate sites could enhance collateral flow and vascularity to the ischemic bed without inducing angiomas. Rats received injections of 125g DNA of the plasmid encoding phVEGF₁₆₅ or control DNA at four separate sites within the anterior free wall of the left ventricle (LV) supplied by the left coronary artery. The left coronary artery was ligated and hearts analyzed at 4 weeks. In vitro studies confirmed that the phVEGF₁₆₅ used was capable of producing VEGF polypeptide in mammalian cells. The infarct size (percentage of endocardial circumference that infarcted) was similar in controls (42±6%) and treated hearts (39±7%); the LV cavity area did not differ between groups. The number of vascular structures per high-power field within the infarct scar was 10.50±0.68 in controls and 10.00±0.85 in phVEGF₁₆₅-treated rats. Relative regional myocardial blood flow determined by radioactive microspheres and expressed as a ratio of radioactive counts within the scar divided by radioactive counts in the noninfarcted ventricular septum was similar in control (0.74±0.25) and treated hearts (0.88±0.30) (p=not significant). No angiomatous structures were observed. Injections of 125g of DNA of phVEGF₁₆₅ into myocardium to become ischemic had no effect on infarct size or LV cavity size. Unlike higher doses of 500g of DNA, it did not cause gross angiomatous structures; however, it failed to improve neovascularization or regional myocardial blood flow in this rodent model of acute myocardial infarction.     

Meobentine sulfate: antiarrhythmic and electrophysiologic effects assessed by programmed electrical stimulation and ambulatory monitoring in patients with complex ventricular tachyarrhythmia. Report of a multicenter evaluation

Five cardiology centers conducted open-label prospective trials of meobentine sulfate, an intravenously and orally available analog of bethanidine, to assess its potential for treatment of recurrent, drug refractory ventricular tachycardia (VT) or fibrillation (VF), and complex ventricular arrhythmias. The study population comprised 26 patients (mean age, 61 years); 18 were men. Coronary artery disease was present in 15, cardiomyopathy in six, and valvular heart disease in three. Patients presented with both VT and VF (seven), sustained VT alone (12), or frequent ventricular ectopy (PVCs) and nonsustained VT (seven). Of the 26 patients, 5 were enrolled in antiarrhythmic studies (chronic PVC suppression) and 21 were enrolled in programmed electrical stimulation (PES) studies. Two of five in the chronic PVC study showed greater than 75% arrhythmia suppression. Among 21 patients in PES studies, there were eight intravenous (16 mg/kg) and 19 oral trials (400 to 1000 mg every 6 hours, 3 days/dose interval). Five of 22 patients showed efficacy at repeat PES study (neither VT nor VF), one showed partial efficacy, and four were not restudied because of clinical arrhythmia (three) and/or adverse effects (two). Overall, three patients (12%) were continued on the drug for an extended period of time. Adverse experience included hypotension in 50% and gastrointestinal effects (nausea, vomiting, or diarrhea) in 56% (oral trials only). Adverse reactions led to drug discontinuation in six and dosage reduction in eight patients. Thus, meobentine may prevent induction of VT or VF or reduce frequency of complex PVCs in selected patients refractory to other antiarrhythmic agents, but the response rate is relatively low. Symptomatic hypotension or gastrointestinal adverse effects are common and may limit utility of meobentine as a chronic oral antiarrhythmic agent.     

Multiple myeloma in a patient with sickle cell anemia: Interacting effects on blood viscosity

Described here is a case of multiple myeloma in a patient with sickle cell anemia. Viscometric studies were made by comparing the patient's whole blood, plasma and washed red blood cells with those of a normal control subject and a patient with sickle cell anemia. Results showed that the increased viscosity of the patient's whole blood as compared with that of the control patient with sickle cell anemia was mainly due to erythrocytic Interaction with the circulating abnormal immunoglobulin. It is postulated that the increased frequency of vaso-occlusive crisis that occurred in our patient in the months before the diagnosis and treatment of multiple myeloma, was due to this cell-protein interaction with the resulting enhancement of whole blood viscosity and the sickling phenomena.     

Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes

Background

Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes.

Methods

1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as ≥70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk factors.

Results

Patients averaged 64 ± 11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA = 0.911 (n = 1725), AG = 0.086 (n = 164), and GG = 0.003 (n = 5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median = 1.11 mg/dL) than wild-type (AA) subjects (1.23 mg/dL, adjusted P = .044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR = 0.67, CI = 0.46-0.99, adjusted P = .048) and diabetes (11% vs. 18%, OR = 0.63, CI = 0.42-0.95, adjusted P = .029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy.

Conclusions

The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.     

beta-lapachone,a novel plant product,overcomes drug resistance in human multiple myeloma cells

OBJECTIVE: To evaluate the anti-tumor potential of beta-lapachone in multiple myeloma (MM) cell lines (U266, RPMI8226, and MM.1S); MM cell lines resistant to dexamethasone (MM.1R), melphalan (RPMI8226/LR5), doxorubicin (RPMI8226/DOX40), and mitoxantrone (RPMI8226/ MR20); and MM cells from patients (MM1-MM4). MATERIALS AND METHODS: Cytotoxicity of beta-lapachone was assessed by MTT and [3H]-thymidine uptake assays. Apoptosis was analyzed using propidium iodide staining, DNA fragmentation, TUNEL assay, caspase-9 colorimetric assay, and immunoblotting for caspase-3, poly (ADP-ribose) polymerase (PARP), and caspase-8 cleavage products. Paracrine growth of MM cells was assessed by [3H]-thymidine uptake in cultures of bone marrow stromal cells (BMSCs) and MM cells. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in the culture supernatants was measured by specific enzyme-linked immunosorbent assays (ELISAs). RESULTS: beta-lapachone showed significant cytotoxicity in MM cells (IC(50): 4-8 microM). In contrast, normal peripheral blood mononuclear cells (PBMCs) and BMSCs from MM patients were relatively resistant (IC(50): 8-16 microM). IL-6 did not protect against beta-lapachone-induced apoptosis in MM.1S cells, and dexamethasone showed additive cytotoxicity. beta-lapachone also decreased binding of MM.1S cells to BMSCs; abrogated IL-6 and VEGF secretion triggered by adhesion of BMSCs to MM.1S cells; reduced proliferation of MM.1S cells adherent to BMSCs; and decreased intracellular adhesion molecule-1 (ICAM-1) expression on MM.1S cells. Furthermore, beta-lapachone induced typical PARP cleavage, increased caspase-9 proteolytic activity, and activation of caspase-3, without activation of caspase-8 in U266 cells. CONCLUSION: These studies provide a framework for clinical evaluation of beta-lapachone to improve the outcome for patients with MM.