Wilhelm Vetter

TREATMENT OF RENOVASCULAR HYPERTENSION WITH PERCUTANEOUS TRANSLUMINAL DILATATION OF A RENAL-ARTERY STENOSIS

Percutaneous transluminal dilatation of a left-sided renal-artery stenosis was done in a 61-year-old patient with hypertension. Shortly after dilatation blood-pressure fell to normal and renal plasma flow increased. Dilatation might be an alternative to renal vascular surgery in severe renal hypertension.

Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane receptor gene expression.

Objectives Vasoconstrictor prostanoids have been implicated in abnormal vasomotion in atherosclerosis and hypertension. Method Using lean and diet-induced obese mice, we investigated whether obesity affects vascular function or expression of genes involved in prostanoid action. Results In lean C57BL/6J mice, at high concentrations acetylcholine caused endothelium-dependent contractions in the carotid artery but not in the aorta. Endothelium-dependent contractions to acetylcholine were blocked by the non-selective cyclooxygenase (COX) inhibitors indomethacin and meclofenamate, or a prostaglandin H2/thromboxane A2 receptor antagonist, but not by inhibitors of COX-2, thromboxane synthase or cytochrome P450 monooxygenase. Obesity increased endothelium-dependent contractions to acetylcholine in the carotid artery, and prostanoid-mediated vasoconstriction was now present in the aorta. Similarly, contractions to endothelin-1 were largely blocked by meclofenamate and were increased in the aorta of obese mice. Real-time quantitative polymerase chain reaction analysis of the thromboxane receptor gene in the carotid artery revealed a robust upregulation in obese animals (18-fold, P < 0.05); in comparison, obesity had a less pronounced effect on thromboxane synthase (2.1-fold increase, P < 0.05), or preproendothelin-1 gene expression (4.2-fold increase, P < 0.05). Conclusions These data demonstrate that obesity augments prostanoid-dependent vasoconstriction and markedly increases vascular thromboxane receptor gene expression. These changes are likely to promote the development of vascular disease, hypertension and thrombosis associated with obesity.

Interrelations between age and plasma renin, aldosterone and cortisol, urinary catecholamines, and the body sodium/volume state in normal man

ZusammenfassungUntersuchungen bei 28 jungen (19–29 Jahre), 16 mittel-alten (32–58 Jahre) und 15 älteren (60–74 Jahre) Normalpersonen zeigten eine mit zunehmendem Alter progressive Abnahme der Plasmareninaktivität und -aldosteronkonzentration sowie eine Zunahme der Noradrenalinexkretionsrate. Mit Ausnahme der im Stehen gemessen Plasmaaldosteronspiegel waren die Korrelationen dieser Parameter mit dem Alter (r≥0,34;p<0.05) sowie die Unterschiede der Mittelwerte zwischen jungen und älteren Personen (p<0,02) signifikant. Die Plasmacortisolkonzentration blieb beim Aufstehen bei jungen und mittel-alten Personen im Mittel unverändert (−10 und −8%), stieg jedoch bei älteren Menschen um 50% an (p<0,02). Der Blutdruck korrelierte (p<0,05) bei Analyse der gesamten Studienpopulation mit dem Alter (r=0,35) und der Noradrenalinexkretionsrate (r=0,34), bei den älteren Personen fand sich auch eine signifikante Beziehung zum Blutvolumen (r=0,68). Austauschbares Körpernatrium, Plasma- und Blutvolumina und Adrenalinexkretionsrate zeigten keine signifikanten altersbezogenen Variationen. Plasmarenin- und -aldosteronspiegel korrelierten weder mit diesen letzteren Parametern noch mit dem Blutdruck. Es wird gefolgert, daß der Einfluß des Alters auf Plasmarenin- und -aldosteronwerte, das freie periphere Noradrenalin und die Stimulierbarkeit von Plasmacortisol durch Orthostase in Betracht gezogen werden sollte, wenn immer diese Faktoren bei Patienten mit arterieller Hypertonie oder anderen klinischen Störungen interpretiert werden müssen. Diese Resultate sind außerdem mit der Möglichkeit vereinbar, daß die altersbezogene Zunahme des Liegendblutdrucks beim normalen Menschen zumindest teilweise auf dem parallelen Anstieg des freien peripheren Noradrenalins beruhen könnte.SummaryInterrelations between age and plasma renin, aldosterone and cortisol levels, urinary catecholamines, plasma and blood volumes, exchangeable body sodium and blood pressure were studied in 28 young (19 to 29 years), 16 middle-aged (32 to 58 years) and 15 elderly (60 to 74 years) healthy subjects. Supine and upright plasma renin and supine aldosterone levels decreased while urinary noradrenaline excretion rate increased progressively with aging (r≥0.34;p<0.05), with significant differences in mean values between young and elderly subjects (p<0.02). There was also an age-related decrease in upright plasma aldosterone concentration, although this was not statistically significant. Furthermore, mean plasma cortisol concentrations increased in response to upright posture in elderly (+50%;p<0.02), but not in young (−10%) or middle-aged (−8%) subjects. Blood pressure correlated with age (r=0.35;p<0.05) or noradrenaline excretion rate (r=0.34) in the entire study population and with blood volume in the elderly (r=0.68), but not in the young or middle-aged study groups. There were no significant age-related differences in the body sodium/volume state, basal plasma cortisol levels or urinary adrenaline excretion rate, and plasma renin or aldosterone levels did not correlate with these parameters or with blood pressure. It is concluded that the influence of age on plasma renin or aldosterone levels, plasma cortisol responsiveness to upright posture, and urinary noradrenaline excretion should be taken into consideration, whenever these factors have to be interpreted in patients with arterial hypertension or other clinical disorders. Furthermore, these data are consistent with the possibility that in normal man increases in supine blood pressure with aging may be related at least partly to concomitant changes in free peripheral noradrenaline.

Is there a Role for the ob Gene Product Leptin in Essential Hypertension

In this study we wanted to evaluate the relationship between the ob gene product leptin and blood pressure, as well as plasma renin activity and plasma aldosterone levels. We studied 139 subjects with a mean+/-SD age of 50 +/-14 years and a body mass index of 26.5+/-5.3 kg/m2; 110 subjects had essential hypertension and 29 were healthy nonhypertensive controls. Blood pressure was measured in resting conditions in the morning and blood was drawn for the determination of the plasma renin activity, aldosterone, and leptin levels. The mean blood pressure of the population was 155/97 mm Hg. The relationship between these parameters was studied by univariate regression analysis according to gender and, whenever indicated, adjusted for age and body mass. The mean+/-SEM plasma leptin level in the whole population was 9.5+/-0.6 ng/mL (range, 1.1-43.3). Subjects with stage I hypertension had significantly higher plasma leptin levels than normotensive subjects. Systolic blood pressure correlated with the plasma leptin levels and the leptin levels adjusted for body weight in women (r = 0.422, P < .01) and nonhypertensive men (r = 0.644, P = .03) only. Plasma renin activity (r = 0.329, P = .03) and aldosterone levels (r = 0.342, P = .026) correlated with the leptin concentration. A significant relationship between the peripheral expression of the ob gene product leptin and systolic blood pressure was found in women and nonhypertensive men. In view of the multiple functions of leptin a causal relationship is postulated and potential mechanisms may involve modulatory effects of leptin on neuropeptide Y, angiotensinogen gene expression, the modulation of the autonomous nervous system, or effects on the pituitary adrenal axis. Direct relationships between both plasma renin activity and aldosterone levels and leptin support the potential importance of the relationship between leptin and blood pressure. Our observation may be of future importance for the understanding of the link between the increase in blood pressure and increasing body weight.

Fibromuscular Hyperplasia: Extension of the Disease and Therapeutic Outcome

92 patients with fibromuscular hyperplasia (FMH) seen at the University Hospital Zurich were studied. Renovascular FMH was the most frequent manifestation of the disease (89%). FMH of the cerebral arteries was seen in 26%. The intestinal and subclavian arteries were involved in 9% each and the iliac arteries in 5% of the patients. In 2 patients each FMH of the abdominal aorta or the coronary arteries, respectively, was found. 26% of the patients had systemic disease with involvement of 2 or more arteries. Half of the patients with bilateral renovascular disease showed additional extrarenal FMH. All patients with renovascular FMH were hypertensive (mean blood pressure 194 +/- 34/119 +/- 18 mm Hg). Surgery, percutaneous transluminal angioplasty (PTA) and medical therapy were equally effective in controlling blood pressure. The cure rates were 52% in patients undergoing surgery and 50% in those treated with PTA. The complication rate, however, was higher with surgery (11%) than with PTA (3%). 62% of the patients treated medically were normotensive. Major side effects occurred in 4.8%. The outcome of curative interventions (surgery or PTA) was influenced by the extension of FMH. In unilateral disease the cure rate was significantly higher (62%) than in systemic FMH (28%; p less than 0.03). Patients with strict bilateral disease were cured in 50%. We conclude: (a) PTA seems to be the treatment of choice in renovascular FMH because of a high cure and a low complication rate and (b) the outcome of curative interventions seems markedly influenced by the extension of FMH in these patients.

Roxithromycin Treatment Prevents Progression of Peripheral Arterial Occlusive Disease in Chlamydia pneumoniae Seropositive Men A Randomized, Double-Blind, Placebo-Controlled Trial

Background—Evidence has been provided that the atherosclerotic process may be associated with chronic infection with Chlamydia pneumoniae. The effect of antibiotic treatment on peripheral arterial occlusive disease has not been investigated yet. Methods and Results—Forty C pneumoniae seropositive men suffering from peripheral arterial occlusive disease were randomly assigned to receive either roxithromycin (300 mg daily) or placebo for 28 days. During the 2.7-year follow-up, the number of invasive revascularizations per patient, the walking distance before intervention (in patients without intervention at study end), and the change of carotid plaque size were assessed. Five interventions were performed on 4 patients (20%) in the roxithromycin group, and 29 interventions were performed on 9 patients (45%) in the placebo group. Limitation of walking distance to 200 m or less was observed in 4 patients (20%) in the roxithromycin group and in 13 patients (65%) in the placebo group. The effect of macrolide treatment on the number of interventions per patient and on preinterventional walking distance was significant. Possible confounding variables such as classical vascular risk factors were excluded by multiple regression analyses. Carotid plaque areas monitored over 6 months decreased in the roxithromycin group (mean relative value, 94.4%) but remained constant in the placebo group (100.2%). Regression of carotid plaque size observed in roxithromycin-treated patients was significant for soft plaques. Conclusions—This study indicates that macrolide treatment for 1 month is effective in preventing C pneumoniae seropositive men from progression of lower limb atherosclerosis for several years.

The use of self-measured blood pressure determinations in assessing dynamics of drug compliance in a study with amlodipine once a day, morning versus evening.

Objective: To test whether the time of administration influences the therapeutic response to a calcium antagonist taken once a day. Also, the dynamics of drug compliance and its impact on blood pressure control were investigated Design: Twenty outpatients with mild-to-moderate hypertension were included in a randomized, placebo-controlled open study. In a crossover design, all of the patients received 5 mg amlodipine, either in the morning or in the evening, during two consecutive 4-week treatment periods Methods: Blood pressure was taken by casual measurement, ambulatory 24-h monitoring (SpaceLabs 90202) and self-measurement at home, performed with a semi-automatic oscillometric device during the whole study period. Compliance was assessed using the Medication-Event-Monitoring System (MEMS) Results: Neither casual nor ambulatory day- or night-time readings detected a significant difference between morning and evening administration. However, self-measurement documented significantly greater blood pressure reductions for morning than for evening administration. The MEMS showed different compliance on the days of ambulatory monitoring (100% with both drug regimens) compared with the whole treatment period. The number of days with missed medication was thus significantly higher for the evening dosing regimen. The difference in self-measured blood pressure between the two regimens was lost if the days with missed medication were removed from the statistical analysis Conclusions: Time of once-a-day amlodipine administration does not influence its efficacy for 24-h blood pressure control. Furthermore, the use of self-measurement and the MEMS may provide useful additional information on the pharmacodynamic impact of different dosing patterns in hypertensive patients

Long-term experience in percutaneous transluminal dilatation of renal artery stenosis

Percutaneous transluminal dilatation was attempted in 65 patients with renovascular hypertension. In five cases (8 percent), percutaneous transluminal dilatation could not be performed for technical reasons. In the remaining 60 patients (35 with atherosclerotic stenosis and 25 with fibromuscular dysplasia), both mean systolic and diastolic pressure fell immediately after percutaneous transluminal dilatation and remained significantly lower for a period of up to five years. Cure rates after a mean control period of 21.6 months were higher in patients with fibromuscular dysplasia (50 percent) than in those with atherosclerotic stenosis (29 percent). Improvement of blood pressure was observed in 32 percent of patients with fibromuscular dysplasia and in 48 percent of patients with atherosclerotic stenosis. Follow-up angiography in 33 cases showed occlusion of the dilated artery in two patients and recurrence of slight renal artery stenosis in nine patients. Successful redilatation could be performed in five of these cases. Furthermore, renal vein renin determinations were only of limited diagnostic or prognostic value. These results document the good long-term effect of percutaneous transluminal dilatation in patients with renal artery stenosis. Percutaneous transluminal dilatation should, therefore, be the favored procedure in patients with renovascular hypertension.

Acute and Chronic Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Severe Hypertension

Abstract In this study the acute and chronic effect of the converting enzyme inhibitor captopril was investigated in a relatively large number of patients (acute: n = 78, chronic: n = 67) with various forms of severe hypertension, the majority of cases being resistant to a standardized triple therapy (100 mg of hydrochlorothiazide or 80 to 500 mg of furosemide, 320 mg of propranolol and 200 mg of hydralazine). Up to an observed period of 240 minutes, a single oral dose of 25 mg of captopril led to a significant and marked decrease in systolic and diastolic blood pressure. The acute antihypertensive effect of captopril was more pronounced in patients with renovascular than in those with essential or renal parenchymal hypertension. Similar differences among the three groups of patients were also observed during chronic treatment. Over a period of 18 months, patients with renovascular hypertension showed both a more pronounced decrease in mean diastolic blood pressure values and a significantly higher percentage of cases with excellent blood pressure control (diastolic blood pressure 95 mm Hg or less). Under long-term conditions, about 90 percent of all patients required a diuretic and a substantial percentage also needed propranolol as a third drug. Positive correlations between pretreatment plasma renin activity levels and captopril-induced blood pressure reduction were found under acute conditions only. The most frequent side effects were skin manifestations, taste disturbances, dizziness and unproductive cough. Serious adverse effects were rare and included one case of leukopenia and one of the nephrotic syndrome, both being reversible after withdrawal of captopril. Our results demonstrate that captopril is a very potent blood pressure lowering agent in severe hypertension especially in cases of renovascular hypertension. However, currently the potential risk of serious side effects should induce the physician to reserve this drug for those patients with truly resistant hypertension.

Novel cellular activities for low density lipoprotein in vascular smooth muscle cells.

Hyperlipidemia and hypertension play important roles in the pathogenesis of atherosclerosis. To investigate the underlying intraceiiular mechanisms, we studied the effect of various concentrations of low density lipoprotein from normolipidemic subjects on concentrations of free intracellular calcium, intraceiiular pH, DNA synthesis, and vascular tone in vascular smooth muscle cells and rings from rat aortas. Low density lipoprotein in the range of 1–15 μg/ml induced a dose-dependent increase of concentration of free intraceiiular calcium and a biphasic change of the intraceiiular pH. Similar concentrations of low density lipoprotein led to an enhanced DNA synthesis. Furthermore, cumulative addition of 1–15 μg/ml low density lipoprotein produced a dose-dependent increase in contractile tension of thoracic aortic rings from rats. The maximal low density lipoprotein-induced contractile response was approximately 70% of that induced by 40 mM KCI. These findings indicate that low concentrations of low density lipoprotein occurring, for example, in the extravascular fluid might contribute to the pathogenesis of cardiovascular diseases by enhancing cell proliferation and vasoconstriction by changing intraceiiular calcium and intracellular pH.