Abstract-Nitric oxide plays a pivotal role in regulating vascular tone. Different studies show endothelial function is impaired during hyperglycemia. Dark chocolate increases flow-mediated dilation in healthy and hypertensive subjects with and without glucose intolerance; however, the effect of pretreatment with dark chocolate on endothelial function and other vascular responses to hyperglycemia has not been examined. Therefore, we aimed to investigate the effects of flavanol-rich dark chocolate administration on (1) flow-mediated dilation and wave reflections; (2) blood pressure, endothelin-1 and oxidative stress, before and after oral glucose tolerance test (OGTT 1 Atherosclerotic pathology is a common sequela to T2DM, with macrovascular and microvascular diseases being among the leading causes of morbidity and mortality in patients with T2DM.2 Even after adjustment for conventional risk factors, individuals with T2DM exhibit a 2-to 4-fold increased risk of mortality in comparison with individuals without diabetes.3 Thus, several investigations have been directed to the potential adverse effects of hyperglycemia on the arterial wall. Observational data reveal high blood glucose concentrations are a risk factor for mortality, even in nondiabetic individuals. 4 Postprandial hyperglycemia has also been implicated in the development of cardiovascular disease. Elevated postprandial glucose may have a direct toxic effect on the vascular endothelium mediated by oxidative stress, independent of other cardiovascular risk factors, such as hyperlipidemia.2,5 A highcarbohydrate meal has been described to increase oxidative stress and favor proinflammatory effects. 5Several in vivo studies have found impaired nitric oxide (NO)-mediated endothelial function during acute episodes of hyperglycemia.6-10 NO is a key endothelium-derived relaxing factor and plays a pivotal role in the maintenance of basal vascular tone and vascular responses to dilative stimuli. [11][12][13] NO acts to negate the actions of endothelium-derived contracting factors such as angiotensin II and endothelin-1 (ET-1), as well as inhibit platelet aggregability 11-13 and endothelial activation.11-13 Therefore, reduced NO bioavailability may contribute to the onset and progression of endothelial dysfunction, including impaired vasodilative and increased adhesive properties, leading to atherogenesis.11-13 Additionally, endothelium-derived NO may act to regulate arterial stiffness and wave reflec-

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SUMMARY Nine patients with uncomplicated essential hypertension received, according to a randomized sequence, captopril (25 mg three times daily), nifedipine (10 mg three times daily), and both drugs for 1 week, with each treatment period separated by a 1-week interval during which a placebo was given. Captopril significantly reduced blood pressure and plasma aldosterone, increased plasma renin activity (PRA), and did not change heart rate. Nifedipine exerted a similar effect on blood pressure and PRA, but it increased heart rate and did not change aldosterone. Captopril plus nifedipine further reduced blood pressure and increased PRA, did not change heart rate, and reduced aldosterone to values similar to those after captopril alone. The hypotensive effect of captopril was highly predictable by basal PRA values, and that of nifedipine by age, while PRA increments induced by captopril were unrelated to those induced by nifedipine. These data indicate that: 1) captopril and nifedipine exert an additive effect on blood pressure and renin; 2) captopril counteracts the heart rate increase induced by nifedipine; 3) nifedipine does not influence the aldosterone inhibition induced by captopril. It is suggested that the association of the two drugs can be usefully employed in the treatment of hypertension. (Hypertension 5 (supp III): III-154-III-156, 1983) KEY WORDS • hypertension • renin-aldosterone • calcium antagonists C APTOPRIL, an orally active inhibitor of angiotensin-converting enzyme, seems to exert its hemodynamic and humoral effect mainly by reducing angiotensin II formation.1 Since both vascular 2 and hormonal 2 " 4 actions of angiotensin il seem to be calcium-mediated, there is at least a theoretical basis for a possible interaction between captopril and nifedipine, a calcium channel inhibitor 3 with proved antihypertensive effect.6 Furthermore, besides any theoretical consideration, practical information could be derived on the usefulness of associating these two drugs in the treatment of hypertensive patients. MethodsNine outpatients, five men and four women aged 36 to 59 years, with mild to moderate uncomplicated essential hypertension, gave informed consent to the.From the Ospedale Umberto I, Siracusa, and the Clinica Medica I, University of Pisa, Pisa, Italy.Supported by Grant 82.02300.56 from CNR, Rome. Address for reprints: Dr. Antonio Salvetti, Clinica Medica I, University of Pisa, 56100, Pisa, Italy. study. After all drugs were discontinued for at least 3 weeks, patients received, according to a randomized sequence, captopril (25 mg t.i.d.), nifedipine (10 mg t.i.d.) and both drugs for 1 week, each active treatment period being preceded by 1 week of placebo administration. At the end of each period and at the same time of the day, 1 hour after the last dosing, body weight was measured, venous blood samples were obtained for measurement of plasma renin activity (PRA), sodium, potassium, and aldosterone, while blood pressure and heart rate were monitored every 10 minutes over a 2-hour period using...

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Arterial hypertension and proteinuric nephropathy are common features in diabetic patients. In streptozotocin-diabetic rats, it has been possible to reduce the blood pressure and proteinuria by converting enzyme inhibitors, and so slowing the decline of kidney function. These results have been confirmed in diabetic patients affected by arterial hypertension and persistent proteinuria. However, up to now it has not been clear if these favorable renal effects are related specifically to converting enzyme inhibition. In the attempt to clarify this last point, from a practical as well as from a speculative point of view, 12 type 2 diabetic outpatients affected by mild to moderate arterial hypertension and persistent macroalbuminuria (greater than 250 mg/daily, at least on three consecutive occasions) without any other signs of renal diseases were studied. In a randomized sequence and in a double blind fashion, after a washout period of 3 weeks, the patients underwent pharmacological treatment which consisted of enalapril 20 mg o.d., chlorthalidone 12.5 mg o.d., atenolol 50 mg o.d. and placebo o.d. Each treatment lasted 45 days. Kidney function, blood pressure and heart rate were checked at the beginning and at the end of each treatment, while urinary albumin excretion was measured at the end of the 4th, 5th, and 6th week of each treatment. Blood pressure significantly decreased in a similar fashion after each active treatment, while kidney function did not change significantly. Urinary albumin excretion rate significantly decreased after enalapril and atenolol, but did not change after chlorthalidone. According to these results we can hypothesize that the inhibition of tissue angiotensin formation and its related change on the glomerular permeability, rather than renal and systemic hemodynamic features, seem to be the common mechanisms by which both enalapril as well as atenolol decrease the albuminuria in our patients.

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