Ramipril dose-dependently increases nitric oxide availability in the radial artery of essential hypertension patients

DESIGN AND PARTICIPANTS: A double-blind, crossover, randomized study was designed to evaluate the effect of 3-month treatment with a lower versus a higher antihypertensive dosage of ramipril (5 or 10 mg/day) on nitric oxide (NO)-dependent vasodilation in 46 untreated patients with essential hypertension. Radial artery flow-mediated dilation (FMD), before and after the intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA), to block NO synthase, and the response to sublingual glyceril trinitrate (GTN, 25 microg) were measured at baseline and after the two treatment periods as a change in artery diameter (computerized system from ultrasound scans). Plasma angiotensin II and oxidative stress markers were also assessed. RESULTS: FMD was significantly (P < 0.01) lower in hypertensive patients (4.6 +/- 1.8%) than in normotensive subjects (7.1 +/- 2.6%), whereas the response to GTN was similar. L-NMMA significantly (P < 0.001) inhibited FMD in normotensive but not in hypertensive subjects. Mean 24-h ambulatory blood pressure, plasma angiotensin II and oxidative stress marker levels were similarly reduced at the end of the two treatment periods. Both dosages of ramipril significantly (P < 0.001) increased FMD (5 mg: 5.9 +/- 2.1%; 10 mg: 6.3 +/- 2.4%) without modifying the response to GTN. However, compared with baseline (11 +/- 19%), the inhibiting effect of L-NMMA on FMD (NO-dependent FMD) was significantly (P < 0.01) greater with ramipril 10 mg (49 +/- 12%) than 5 mg per day (38 +/- 15%). The improvement in FMD and NO-dependent FMD was not related to changes in plasma levels of angiotensin II or markers of oxidative stress. CONCLUSION: Treatment with ramipril at a higher dosage induced a greater improvement in NO-dependent vasodilation compared with the lower antihypertensive dosage in hypertensive patients.     

Relationship between bladder dysfunction and brain MRI in multiple sclerosis.

We studied 70 consecutive patients with definite multiple sclerosis (MS) to examine the relationship between magnetic resonance imaging (MRI) cerebral findings and urinary disturbances. Thirty-two subjects (46%) had urinary symptoms and 38 (54%) were asymptomatic. Patients with urinary symptoms exhibited greater overall functional disability. A significant correlation between the presence of midbrain lesions and urinary dysfunctions was found which may indicate an important role of the mesencephalic formation to preserve continence.     

Acetylcholine receptor-specific T-lymphocyte clones in the normal human immune repertoire: target epitopes, HLA restriction, and membrane phenotypes.

Potentially autoimmune T-lymphocyte lines specific for the nicotinic acetylcholine receptor of the neuromuscular junction have been isolated previously from patients with myasthenia gravis. We report on the isolation and expansion of T cells specific for the acetylcholine receptor of Torpedo californica or for a recombinant mammalian acetylcholine receptor alpha chain peptide (X4), from the peripheral blood of 11 healthy donors. Two major T-cell epitopes, located between amino acid positions 44-104 and 141-172, were identified using a panel of overlapping mammalian alpha chain fusion proteins. Most T lines recognized the acetylcholine receptor epitopes in the molecular context of HLA-DR molecules. Unexpectedly, all the T. californica acetylcholine receptor-specific T lines obtained from one DR4 (DRw53), DQw3 donor and two DR4, w8 (DRw53), DQw3 donors were restricted by DRw53 product(s). Using DR gene-transfected L cells as antigen presenters, in 4 lines, a close relationship between the recognized epitope and the restricting DR element was revealed. The membrane phenotype of the T. californica acetylcholine receptor-and X4-specific T lines was predominantly CD4+CD8-, with some CD4+CD8+ components. It did not significantly differ from that of control, tuberculin purified protein derivate-specific T lines raised from the same donors. These findings are in harmony with previous ones demonstrating the presence of potentially autoimmune T-lymphocyte clones within normal immune repertoires.     

Adenosine and the vascular tissue renin-angiotensin system in the forearm of essential hypertensive patients

The present study was designed to evaluate whether adenosine can activate a vascular tissue renin-angiotensin system in the forearm of essential hypertensive patients. In a group of 6 patients, we infused adenosine at cumulative increasing doses into the brachial artery and collected simultaneous arterovenous samples for angiotensin II determinations (by radioimmunoassay). Forearm blood flow was evaluated by strain-gauge plethysmography. Adenosine caused a dose-dependent increment in forearm blood flow and in venous angiotensin II, whereas it did not affect arterial angiotensin II. When repeated in the presence of the antagonist, theophylline, the adenosine effect was blunted. Moreover, in the forearm of another group of 6 hypertensives ischemia was applied for 7 min to induce the production of endogenous adenosine while active renin (by radioimmunometric assay) and angiotensin II were measured. During the reactive hyperemia, venous active renin and angiotensin II increased, while arterial values did not change. This effect was also blunted by theophylline. Taken together these data indicate that either exogenous or endogenous adenosine can activate a vascular tissue renin-angiotensin system in the forearm of essential hypertensive patients. © 1993 Wiley-Liss, Inc.     

Dipyridamole echocardiography in essential hypertensive patients with chest pain

The exercise-electrocardiography test shows limited feasibility and diagnostic accuracy for the noninvasive detection of coronary artery disease in hypertensive patients. Recently, the dipyridamole-echocardiography test (two-dimensional echocardiographic monitoring with dipyridamole infusion, up to 0.84 mg/kg over 10 minutes) has been proposed as an exercise-independent method for the diagnosis of coronary artery disease. The diagnostic usefulness of the exercise-electrocardiography test and the dipyridamole-echocardiography test was evaluated in 63 consecutive inpatients with history of chest pain, essential hypertension, and no previous myocardial infarction. The criterion of positivity for the exercise-electrocardiography test was a horizontal or downsloping ST segment shift exceeding 0.1 mV and for the dipyridamole-echocardiography test, a transient dyssynergy of contraction. Fifteen patients could not perform a diagnostic exercise-electrocardiography test because of an inability to exercise adequately (two patients), severe hypertension in spite of full antihypertensive therapy (six patients), or excessive blood pressure rise at the first step of the exercise-electrocardiography test (seven patients). Five patients could not perform the dipyridamole-echocardiography test because of a poor acoustic window. The overall feasibility was 76% for the exercise-electrocardiography test and 92% for the dipyridamole-echocardiography test (p less than 0.05). All 43 patients who performed both tests underwent coronary angiography; 30 had significant coronary artery disease (greater than 70% lumen reduction of at least 1 major coronary vessel). Sensitivity was 67% for both the exercise-electrocardiography test and the dipyridamole-echocardiography test (p = NS); specificity was 46% for the exercise-electrocardiography test and 92% for the dipyridamole-echocardiography test (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

THE EFFECT OF PHENTOLAMINE ON ACTIVE AND INACTIVE RENIN RELEASE IN HUMAN RENOVASCULAR HYPERTENSION

1. Phentolamine was infused at low increasing doses (0.2, 0.3, 0.4 and 0.5 mg/min) in five patients with unilateral renal artery stenosis measuring active and inactive (cryoactivable) renin in the renal veins from the stenosed and nonstenosed kidney and in a peripheral vein. 2. PRA values from the stenosed kidney (11.59, s.e.m. = 5.79 pmol ang I/ml per h) were higher than those in the peripheral vein (5.19, s.e.m. =2.64) while these latter were similar to those from the contralateral kidney (5.09, s.e.m. =2.93). Phentolamine significantly increased PRA from the stenosed kidney and in the peripheral vein in a dose-related manner. PRA changes were unrelated both to blood pressure decrements and to heart rate increments induced by the drug. 3. Before phentolamine, inactive renin from the stenosed kidney (5.19, s.e.m. = 2.84 pmol ang I/ml per h) did not differ significantly from that on the contralateral side (3.15, s.e.m. = 1.96) and in the peripheral vein (4.40, s.e.m. = 1.96). Phentolamine induced significant (P < 0.005) increments of inactive renin only from the stenosed kidney at the doses of 0.3, 0.4 and 0.5 mg/min. Inactive renin from the contralateral kidney was unchanged and it tended to increase, but not to a significant extent, in the peripheral vein. A highly significant relationship was found between active and inactive renin from the stenosed kidney (r = 0.79, P < 0.001, n= 25) and in peripheral blood (r = 0.71, P < 0.001, n= 25) but not from the stenosed kidney (r = 0.29, n= 25). 4. These results suggest that phentolamine, infused at low increasing doses causes an increase of PRA only in the stenosed kidney, an action which does not seem to be wholly explained by either sympathetic nervous system activation or decrease of renal perfusion pressure, and which suggests an action on intrarenal a-adrenoreceptors. Furthermore, phentolamine stimulated inactive renin release only from the stenosed kidney without evidence of intrarenal conversion of the inactive into the active form.     

Further evidence for the existence of alpha2-mediated adrenergic vasoconstriction in human vessels

Summary To confirm the presence of alpha₂-mediated vasoconstriction in human vasculature, the effect of selective alpha₁- and alpha₂-agonists (methoxamine and B-HT 933) and antagonists (indoramin and Yohimbine) was studied in fourteen patients with mild, uncomplicated, essential hypertension. Drugs were infused, into the brachial artery at systemically ineffective rates, and concomitant changes in forearm blood flow were measured by strain gauge venous plethysmography.During control conditions, cumulative infusions either of methoxamine or B-HT 933 caused dose-related vasoconstriction, while both indoramin and yohimbine doubled forearm blood flow.Subsequently, the alpha₁-adrenoceptor mediated vasoconstriction produced by methoxamine was shown to be completely blocked by indoramin pretreatment, and to be left unchanged by yohimbine. The alpha₂-vascular stimulation by B-HT 933 was antagonized by previous yohimbine but not by indoramin pretreatment, thus fulfilling the pharmacological requirements for identification of distinct alpha-adrenoceptor mediated excitation-contraction pathways.The data provide further evidence of the existence of alpha₂-mediated vasoconstriction in human forearm vessels.     

Dipyridamole decreases circulating renin-angiotensin system activity in hypertensive patients.

To study the effect of adenosine on renin release, n = 6 hypertensive patients, while on a constant 80 to 100 mEq/24 h Na+ diet, received oral 150 mg dipyridamole (an adenosine uptake inhibitor) three times daily for 3 days while upright plasma renin activity (PRA) and plasma aldosterone, urinary aldosterone, plasma and urinary Na+,K+, and creatinine clearance were monitored the day before (basal) the first and third day of the treatment and the day after the withdrawal (recovery). As compared to basal and to recovery, dipyridamole significantly decreased PRA, and plasma and urinary aldosterone without affecting plasma and urinary Na+ and K+, creatinine clearance, blood pressure, and heart rate. These data, showing that dipyridamole decreases PRA and aldosterone, confirm also in hypertensives that endogenous adenosine inhibits the circulating renin-angiotensin-aldosterone system.