SUMMARY To determine if hypertension could be produced in normal rats by feeding them a fructose-enriched diet, Sprague-Dawley rats were fed either normal chow or a diet containing 66% fructose as a percentage of total calories for approximately 2 weeks. At the end of this period systolic blood pressure had increased from 124 ± 2 to 145 ± 2 (SEM) mm Hg in the fructose-fed rats, whereas no change occurred in the control group. In addition, hyperinsulinemia and hypertriglyceridemia were associated with hypertension in fructose-fed rats. The addition of clonidine to the drinking water inhibited fructose-induced hypertension, but not the increase in plasma insulin or triglyceride concentration seen in fructose-fed rats. Thus, the metabolic changes associated with fructose-induced hypertension are unlikely to be secondary to an increase in sympathetic activity. Whether or not this is also true of the hypertension remains to be clarified. IT has been apparent for some time that increases in dietary carbohydrate intake can raise blood pressure in experimental animals. '• 2 In particular, the ability of sucrose feeding to accentuate the magnitude of the blood pressure elevation already present in spontaneously hypertensive rats has been documented. 3 " 3 Since sucrose feeding stimulates sympathetic nervous system activity, 6 it has been suggested that sucroseinduced increases in sympathetic activity may elevate blood pressure in susceptible animals.4 Indirect support for this hypothesis was provided by the observation that rats with sucrose-induced hypertension had faster heart rates and larger hypotensive responses to a-adrenergic blockade with phentolamine than did their normotensive controls.7 This point of view has recently received added support from the demonstration that hypertension produced by sucrose feeding is associated with evidence of increased catecholamine Received March 13, 1987; accepted June 21, 1987. secretion. 5 However, the physiological effects of sucrose are not limited to an increase in sympathetic activity, and rats fed a high sucrose diet also become insulin-resistant and hyperinsulinemic.8 ' 9 Since several recent observations have documented an association between hyperinsulinemia and hypertension in humans, 10 " 12 it seemed important to see if a similar phenomenon could be found in carbohydrate-induced hypertension in rats. Thus, the current study was initiated to address this issue, and we have taken a somewhat different approach than has been conventionally used in an effort to broaden the nature of inquiry. First, we used normal Sprague-Dawley rats, not animals with spontaneous hypertension, to see if high carbohydrate diets can induce hypertension in rats with no apparent genetic propensity to become hypertensive. Second, we used fructose, not sucrose, as the source of dietary carbohydrate. Fructose feeding can also cause insulin resistance and hyperinsulinemia in normal rats.'14 If fructose also produces hypertension, it would suggest that the insulin resistance and hyperinsu...

Endothelial cell derived relaxing factor (EDRF) mediated relaxation of blood vessels is impaired in vessels exposed to lipoproteins in vitro and in arteries of hyperlipidemic humans and animals. To investigate the mechanism by which lipoproteins impair the effects of EDRF, which is likely nitric oxide (NO) or a related molecule, we have bioassayed EDRF/NO activity by measuring its ability to increase cGMP accumulation in rat fetal lung cultured fibroblasts (RFL-6 cells). Low density lipoprotein modified by oxidation (ox-LDL) induced a concentration-dependent inhibition of EDRF activity that had been released from bovine aortic endothelial cells (BAEC) stimulated with bradykinin or the calcium ionophore A23187. In addition, lipoproteins directly impaired authentic NO-induced stimulation of cGMP accumulation in the detector cells; stimulation by sodium nitroprusside was unaffected. Ox-LDL or oxidized HDL3 were highly potent in blocking NO-stimulated cGMP accumulation with EC50's of -1 Ag/ml. Lipid extracted from ox-LDL blocked NO-stimulated cGMP accumulation to about the same extent as intact ox-LDL, while the protein component of ox-LDL did not inhibit the cGMP response. These results suggest that the lipid component of oxidized lipoproteins inactivate EDRF after its release from endothelial cells. (J. Clin.

Multimorbidity-the presence of multiple chronic conditions in a patient-has a profound impact on health, health care utilization, and associated costs. Definitions of multimorbidity in clinical care and research have evolved over time, initially focusing on a patient's number of comorbidities and the associated magnitude of required care processes, and later recognizing the potential influence of comorbidity characteristics on patient care and outcomes. In this article, we review the relationship between multimorbidity and quality of care, and discuss how this relationship may be mediated by the degree to which conditions interact with one another to generate clinical complexity (comorbidity interrelatedness). Drawing on established theoretical frameworks from cognitive engineering and biomedical informatics, we describe how interactions among conditions result in clinical complexity and may affect quality of care. We discuss how this comorbidity interrelatedness influences the value of existing quality guidelines and performance metrics, and describe opportunities to quantify this construct using data widely available through electronic health records. Incorporating comorbidity interrelatedness into conceptualizations of multimorbidity has the potential to enhance clinical and research efforts that aim to improve care for patients with multiple chronic conditions.

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Activation of alpha1 adrenergic receptors stimulates mitogenesis in human vascular smooth muscle cells (HVSMCs). To examine signaling pathways by which activation of alpha1 receptors may induce mitogenesis in HVSMCs, we have found that alpha1 receptor stimulated-DNA synthesis and activation of mitogen-activated protein (MAP) kinase are blocked by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase). To determine directly if activation of alpha1 receptors stimulated PI 3-kinase, in vitro assays of kinase activity were performed in immunocomplexes precipitated by an antibody against the p85 alpha subunit of PI 3-kinase. Noradrenaline stimulated a time- and concentration-dependent activation of PI 3-kinase in the presence of a beta adrenergic receptor antagonist. Noradrenaline-stimulated PI 3-kinase activation was blocked by antagonists of alpha1 receptors and by pertussis toxin, suggesting that alpha1 receptors activate PI 3-kinase via a pertussis toxin-sensitive G protein. Direct activation of protein kinase C by a phorbol ester did not stimulate PI 3-kinase; also, a Ca2+ L-channel blocker did not inhibit noradrenaline-stimulated PI 3-kinase activity. Increased PI 3-kinase activity was detected in both anti-Ras and anti-phosphotyrosine immunoprecipitates from noradrenaline-stimulated HVSMCs. Moreover, noradrenaline stimulated formation of active Ras-GTP complexes. Because blockade of PI 3-kinase by wortmannin inhibited formation of this complex, this result suggests that Ras might be a target of PI 3-kinase. Noradrenaline stimulated tyrosine phosphorylation of the p85 subunit of PI 3-kinase, and a phosphorylated tyrosine protein could be co-immunoprecipitated with anti-p85 of PI 3-kinase. These results demonstrate that stimulation of alpha1 receptors activates PI 3-kinase in HVSMCs and that alpha1 receptor-activated PI 3-kinase is associated with an increase in active Ras-GTP and activation of tyrosine protein phosphorylation. These pathways may contribute to alpha1 receptor-stimulated mitogenic responses including activation of MAP kinase and DNA synthesis in HVSMCs.

Aims Recent studies in patients with cardiovascular diseases suggest potential for the use of orally administered l‐arginine, the precursor of nitric oxide, as a therapeutic agent. This crossover study was designed to examine the pharmacokinetics of single i.v. and oral doses of l‐arginine in healthy volunteers (n=10). Methods A preliminary control study (n=12) was performed to assess the variation in plasma l‐arginine concentrations when ingesting a normal diet. The observed variation was taken into account when interpreting the pharmacokinetic data obtained after exogenous administration. Results The mean baseline plasma concentration of l‐arginine in the control study was 15.1±2.6 μg ml−1. After intravenous administration (30 g over 30 min), the plasma concentration reached 1390±596 μg ml−1. The disappearance of l‐arginine appeared biphasic, with an initial rapid disappearance due to concentration‐dependent renal clearance followed by a slower fall in plasma concentrations due to nonrenal elimination. The peak concentration after oral administration (10 g) was 50.0±13.4 μg ml−1, occurring 1 h after administration. Renal elimination was not observed after oral administration of this dose. The absolute bioavailability of a single oral 10 g dose of l‐arginine is ≈20%. Conclusions This study provides basic knowledge of l‐arginine pharmacokinetics in healthy humans. Intravenous and oral administrations show at minimum a biphasic pattern. Further studies will assess whether a similar profile is observed when the drug is administered to patients.

With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the phenyl group of the phenylcarbamoyl moieties, and with N-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the inhibitory action of these compounds against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition.