Cerebral vasculopathy in HIV infection revealed by transcranial Doppler: A pilot study.
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BACKGROUND AND PURPOSE: There is growing evidence for affection of cerebral vessels during human immunodeficiency virus (HIV) infection. We prospectively evaluated cerebrovascular reserve capacity (CRC) in HIV-seropositive patients by transcranial Doppler sonography (TCD) after systemic administration of acetazolamide. We hypothesized that a disturbed vasoreactivity would reflect the cerebral arteries' involvement in HIV infection. METHODS: We assessed the mean blood flow velocity (BFV) of the middle cerebral artery and its increase after intravenous administration of 1 g acetazolamide (CRC) in 31 HIV-infected individuals without symptoms of cerebrovascular disease (mean+/-SD age, 39+/-11 years). Stenotic or occlusive lesions of the large brain-supplying arteries were excluded by color-coded duplex and transcranial imaging. BFV and CRC were also measured in an age-matched group of 10 healthy control subjects. Patients were classified according to clinical, laboratory, and neurophysiological parameters. We also performed cerebral MRI (n=25) and rheumatological blood tests (n=26). RESULTS: Baseline BFV and CRC both were significantly reduced in HIV-infected patients as compared with control subjects (P<0.05, Student's t test). These findings did not correlate with duration of seropositivity, helper cell count, or other clinical, rheumatological, and neuroradiological findings. CONCLUSIONS: Our findings support the hypothesis of a cerebral vasculopathy etiologically associated with HIV infection. (+info)
Natriuretic and diuretic actions of a highly selective adenosine A1 receptor antagonist.
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The natriuretic and diuretic action of a highly selective adenosine A1 receptor (A1AdoR) antagonist, 1,3-dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine (CVT-124), was investigated in anesthetized rats. CVT-124 (0.1 to 1 mg/kg) caused dose-dependent increases in urine flow and fractional and absolute sodium excretion of by six- to 10-fold and, at 0.1 mg/kg, increased the GFR (1.6+/-0.1 to 2.5+/-0.2 ml/min; P<0.01). There were no changes in BP or heart rate. CVT-124 reduced absolute proximal reabsorption (26+/-3 to 20+/-2 nl/min; P<0.05) despite unchanged proximally measured, single-nephron GFR (SNGFR) (42+/-5 to 44+/-4 nl/min; NS) and thereby decreased fractional proximal reabsorption (60+/-3 to 46+/-4%; P<0.05). Despite increasing distal tubular fluid flow rate (5.4+/-0.7 to 9.7+/-0.9 nl/min; P<0.001), it reduced the proximal-distal difference in SNGFR (before: 9.4+/-1.0 versus during CVT-124: 4.6+/-1.5 nl/min; P<0.01), suggesting that it had blunted the effects of the macula densa on SNGFR. Direct measurements of maximal tubuloglomerular feedback (TGF) responses were made from proximal stop flow pressure (PSF) during orthograde loop perfusion from the proximal tubule with artificial tubular fluid at 40 nl/min. TGF was blunted by intravenous CVT-124 (0.5 mg/kg; deltaPSF with vehicle: 8.3+/-0.6 versus CVT-124: 6.5+/-0.3 mm Hg; n = 9; P<0.01). In conclusion, A1AdoR blockade reduces proximal reabsorption and uncouples it from glomerular filtration. It increases distal delivery of fluid yet does not activate a macula densa-dependent fall in SNGFR because it blunts the TGF response. Natriuresis accompanied by blockade of proximal glomerulotubular balance and TGF characterizes a new class of diuretic drugs. (+info)
Enhanced natriuretic response to neutral endopeptidase inhibition in heart-transplant recipients.
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Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension. To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes. Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups. NEP-I increased plasma ANP (Htx, 20.6+/-2.3 to 33.2+/-5.9 pmol/L, P<0.01; controls, 7.7+/-1. 2 to 10.6+/-2.6 pmol/L) and cGMP, but not BNP. Renin decreased similarly in both groups, whereas aldosterone decreased significantly only in Htx. Enhanced urinary sodium (1650+/-370% versus 450+/-150%, P=0.01), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects. Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (6.9+/-2.0% versus 7.4+/-2.8% in controls and Htx). Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx. These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation. (+info)
Inhibition of carbonic anhydrase accounts for the direct vascular effects of hydrochlorothiazide.
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Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (KCa) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because KCa channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pHi) were measured simultaneously with 2', 7'-bis(2-carboxyethyl)-5(6)'-carboxyfluorescein (BCECF-AM). Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16+/-8% relaxation) compared with hydrochlorothiazide (74+/-12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of KCa channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Hydrochlorothiazide and the inhibitors of carbonic anhydrase failed to relax tone induced by a depolarizing potassium solution. Acetazolamide and hydrochlorothiazide increased pHi by 0.27+/-0.07 and 0.21+/-0.04, respectively, whereas bendroflumethiazide had a much smaller effect: 0.06+/-0.03. The rise in pHi induced by any agent was not inhibited by charybdotoxin. The vasorelaxant effect of hydrochlorothiazide is shared by other inhibitors of carbonic anhydrase. Inhibitors of carbonic anhydrase, but not bendroflumethiazide, cause intracellular alkalinization, which is associated with KCa channel opening. These data suggest that the vasodilator effect of thiazide diuretics results primarily from inhibition of vascular smooth muscle cell carbonic anhydrase, which results in a rise in pHI, leading to KCa channel activation and vasorelaxation. (+info)
Differences in drug treatment of chronic heart failure between European countries.
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AIMS: A large number of drugs are currently used for the treatment of chronic heart failure. Treatment for other cardiovascular disorders has been shown to differ between countries. In this study we examined whether this would also be true in heart failure. METHODS AND RESULTS: We studied patients with moderate to severe heart failure, who were enrolled in an international survival study, and compared patterns of drug use between the nine countries that each included >50 patients in the study. The results were analysed to determine whether observed differences between countries could be explained by differences in the patients recruited. 1825 patients were studied (range 81-427 per country). By trial protocol, most patients were treated with angiotensin converting enzyme (ACE) inhibitors (92%) and all with diuretics, but the proportion of patients taking high doses of these drugs was markedly different between countries. Large differences were also observed in the use of digoxin (overall 64%, 39% in the U.K. to 87% in Germany) and antiarrhythmics (overall 25%, with the highest use 44% in France). The use of beta-blockers and calcium antagonists was low (overall 6% and 8%, respectively), but also different between countries. Anticoagulants (overall 43%) were used in many patients in the Netherlands and Switzerland (around 70%), while antiplatelets (overall use 30%) were most often prescribed in Denmark (51%). CONCLUSIONS: Large differences in drug use and dosing for patients with advanced heart failure are observed between (European) countries. None of these differences could be explained by differences in patient characteristics, and whether they are related to factors such as tradition, economic circumstances and national guidelines, etc. is unknown. (+info)
Trends in antihypertensive drug advertising, 1985-1996.
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BACKGROUND: Over the past decade, calcium channel blockers (CCBs) and ACE inhibitors have been used increasingly in the treatment of hypertension. In contrast, beta-blocker and diuretic use has decreased. It has been suggested that pharmaceutical marketing has influenced these prescribing patterns. No objective analysis of advertising for antihypertensive therapies exists, however. METHODS AND RESULTS: We reviewed the January, April, July, and October issues of the New England Journal of Medicine from 1985 to 1996 (210 issues). The intensity of drug promotion was measured as the proportion of advertising pages used to promote a given medication. Statistical analyses used the chi2 test for trend. Advertising for CCBs increased from 4.6% of advertising pages in 1985 to 26.9% in 1996, while advertising for beta-blockers (12.4% in 1985 to 0% in 1996) and diuretics (4.2% to 0%) decreased (all P<0.0001). A nonsignificant increase was observed in advertising for ACE inhibitors (3.5% to 4.3%, P=0.17). Although the total number of drug advertising pages per issue decreased from 60 pages in 1985 to 42 pages in 1996 (P<0.001), the number of pages devoted to calcium channel blocker advertisements nearly quadrupled. CONCLUSIONS: Increasing promotion of CCBs has mirrored trends in physician prescribing. An association between advertising and prescribing patterns could explain why CCBs have supplanted better-substantiated therapies for hypertension. (+info)
beta blocker treatment and other prognostic variables in patients with clinical evidence of heart failure after acute myocardial infarction: evidence from the AIRE study.
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OBJECTIVES: To examine clinical outcomes associated with optional beta blockade in a population of patients with evidence of heart failure after myocardial infarction. DESIGN AND PATIENTS: Data from the acute infarction ramipril efficacy (AIRE) study were analysed retrospectively. At baseline 22.3% of the patients were receiving a beta blocker. To minimise confounding, beta blocker and diuretic treatments, presence of clinical signs of heart failure, left ventricular ejection fraction, and 16 other baseline clinical variables were simultaneously entered in a multivariate Cox regression model. In addition, the same analysis was repeated separately within a high and a low risk group of patients, as defined according to the need for diuretic treatment. RESULTS: beta Blocker treatment was an independent predictor of reduced risk of total mortality (hazard ratio 0.66, 95% confidence interval (CI) 0. 48 to 0.90) and progression to severe heart failure (0.58, 95% CI 0.40 to 0.83) for the entire study population. There were similar findings in high risk patients requiring diuretics (0.59, 95% CI 0.40 to 0.86; and 0.58, 95% CI 0.38 to 0.89). CONCLUSIONS: beta Blocker treatment is associated with improved outcomes in patients with clinical evidence of mild to moderate heart failure after myocardial infarction. Most importantly, high risk patients with persistent heart failure appear to benefit at least as much as lower risk patients with transient heart failure. (+info)
Acute effects of combined administration of kanamycin and furosemide on the stria vascularis studied by distortion product otoacoustic emission and transmission electron microscopy.
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Acute effects of kanamycin and/or furosemide administration on the stria vascularis of the guinea pig cochlea were assessed by distortion product otoacoustic emission (DPOAE) and transmission electron microscopy. Kanamycin alone failed to affect the DPOAE levels and ultrastructural changes. Furosemide alone caused a rapid but reversible fall of the DPOAE levels. No remarkable pathological changes in the strial vascularis were observed after a complete recovery of the DPOAEs. On the other hand, furosemide injection following kanamycin with a 2 hour interval resulted in two patterns of significant changes in the DPOAEs, namely, a sudden drop in the DPOAE levels 2 to 3 hours after furosemide injection and a gradual fall in the DPOAE levels immediately after the incomplete recovery from the furosemide-induced decrease of the DPOAE levels. Ultrastructural changes in the stria vascularis included numerous vacuoles in the strial marginal cells and increased electron density of the intermediate and basal cells. These physiological and morphological changes in the stria vascularis may imply new ototoxic features induced by kanamycin potentiated by furosemide. (+info)