Effect of adriamycin on the polyribosome and messenger-RNA content of rat heart muscle.

The myocardial contents of DNA, protein, total and polyribosomal RNA, messenger RNA (mRNA) and polyribosomes were determined in normal and adriamycin-treated rats. While the myocardial contents of DNA and protein changed only little in adriamycin-treated rats, total and polyribosomal RNA decreased by 23.2% and 35%, mRNA and polyribosomes by 51.6% and 38.7%. Size distribution and protein synthetic activity of the polyribosome preparations obtained remained unchanged in the adriamycin-treated rats. We conclude that the reduced myocardial contents of RNA, mRNA and polyribosomes cause the previously observed impairment of myocardial protein synthesis in adriamycin-treated rats and might be important in the pathogenesis of the adriamycin-cardiomyopathy.

Carvedilol for prevention of restenosis after directional coronary atherectomy : final results of the European carvedilol atherectomy restenosis (EUROCARE) trial.

BACKGROUND: In addition to its known properties as a competitive, nonselective beta and alpha-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis. METHODS AND RESULTS: In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 hours before scheduled directional coronary atherectomy and continuing for 5 months after a successful procedure. The primary end point was the minimal luminal diameter as determined during follow-up angiography 26+/-2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 (88.9%), a

Percutaneous peripheral atherectomy: angiographic and clinical follow-up of 60 patients.

The Simpson atherectomy catheter was used to treat 60 patients with a total of 94 lesions comprising 63 stenoses (mean length 1.1 +/- 0.5 cm) and 31 occlusions (4.2 +/- 2.9 cm) of the superficial femoral (n = 77), popliteal (n = 8), iliac (n = 8) and anterior tibial (n = 1) arteries. The immediate angiographic success rate was 90% for both occlusions and stenoses, and clinical success was obtained in 82% of patients. The stenoses were reduced from 83 +/- 13% to 17 +/- 18% acutely and to 31 +/- 26% at 6 months; the occlusions were reduced from 100% to 9 +/- 9% initially and to 60 +/- 34% at 6 months. Angiographic restenosis was found in 24% of lesions: 23% in concentric and 11% in eccentric lesions and 47% in total occlusions. At 1 year, 72% of patients had clinically patent arteries with maintained Doppler index and walking distance. Three of four patients undergoing repeat atherectomy had a second restenosis. In summary, the procedure was found to be safe and effective in the treatment of peripheral vascular disease. It appears to be particularly beneficial in the treatment of eccentric stenoses and is not limited by the presence of calcification.

Adenosine: a sensitive marker of myocardial ischaemia in man.

OBJECTIVE: In the human heart, the significance of adenosine as an indicator of myocardial ischaemia is controversial. Since adenosine fulfils key functions in the regulation of cardiac metabolism, its sensitivity as a marker of tissue ischaemia was investigated in this study in relation to other metabolites such as hypoxanthine and lactate. METHODS: Cardiac metabolite production was studied in 18 patients with left coronary obstruction (> 90%) undergoing percutaneous transluminal coronary angioplasty (PTCA). Three balloon inflation procedures per patient were performed for 30, 60, and 90 s (+/- 5 s each) and coronary sinus adenosine, hypoxanthine, uric acid, and lactate were determined. RESULTS: Before PTCA, coronary sinus concentrations of adenosine and hypoxanthine were 176(SEM 34) and 723(73) nM, respectively, and the lactate concentration was 0.47(0.07) mM. Lactate was extracted by cardiac tissue during normoxia, and adenosine and hypoxanthine were in the physiological range of healthy volunteers. During reperfusion the concentrations of all myocardial metabolites were temporarily increased. In particular, adenosine was enhanced in close proportion to the duration of coronary occlusion. Moreover, coronary sinus adenosine, but not lactate, was significantly lowered during reperfusion when nifedipine (0.2 mg) was given by intracoronary injection before PTCA. CONCLUSIONS: With longer periods of coronary occlusion (> 30 s) the relative rank order of sensitivity indicating myocardial ischaemia was adenosine > lactate > hypoxanthine > uric acid. Coronary sinus concentrations of adenosine are quantitatively sufficient to be responsible for some of the changes in coronary blood flow occurring during reactive hyperaemia.

Restenosis in human vein bypass grafts.

The restenosis rate in vein bypass grafts is higher than in native coronary arteries, and both the cascade of regulatory factors and the vessel reaction may be altered. In this study, vein bypass atherectomy specimens were classified as primary (n = 10) or restenotic (n = 12). Immunohistochemistry with 11 primary antibodies showed low levels of proliferation in both tissues and similar amounts of extracellular matrix components in both primary and restenotic specimens at the time points at which tissue was removed for clinical reasons. Inflammation appeared increased in restenotic specimens. Using in situ hybridization, transforming growth factor-beta1 messenger RNA was detected in both primary and restenotic tissue, with a trend to higher expression in restenosis (8.4 +/- 5.3 vs. 9.4 +/- 7.4 grains/nucleus) and further increased expression in multiple compared with single restenoses (15.1 +/- 6.1 vs. 5.6 +/- 5.1 grains/nucleus, P < 0.05). Hence, there were no great differences in cell proliferation or extracellular matrix formation between primary and restenosis vein graft tissue, in contrast to previously described findings in arterial tissue. This suggests that primary vein graft tissue is already in a chronic 'restenosis-like' state and subsequent injury creates minimal additional upregulation.

Cell constitution and characteristics of human atherosclerotic plaques selectively removed by percutaneous atherectomy.

The Simpson atherectomy device used for the recanalization of severely stenosed peripheral arteries is able to collect plaque material which can be further characterized. This study reports histological, immunohistochemical and transmission electron microscopic findings on advanced human primary atherosclerotic plaques of peripheral arteries percutaneously removed by a Simpson atherectomy catheter. Material from stenosing plaques consisted of dense connective tissue with abundant amounts of concentrically arranged elastic fibers and lamellae. This meshwork contained numerous cells, often arranged in clusters and oriented with their longer axis parallel to the direction of blood flow. The vast majority of these cells could be easily identified as vimentin-positive and desmin-negative smooth muscle cells containing lipid deposits in the perinuclear region and numerous glycogen particles. Monocytes/macrophages were observed only very infrequently. Plaque tissue contained a range of smooth muscle cell phenotypes. Most of the cells were of an intermediate phenotype, i.e. sparsely filled with myofilament bundles at the cell periphery and a high amount of organelles such as mitochondria, rough endoplasmic reticulum and Golgi cisterns. An intact lining of pieces of intimal tissue with endothelial cells was not observed. Two-dimensional gel electrophoresis of plaque tissue showed the presence of alpha-, beta- and gamma-actin isoforms with a clear predominance of the beta-isoform.

Neointimal growth can be influenced by local adventitial gene manipulation via a needle injection catheter.

Revascularization by percutaneous transluminal coronary angioplasty is limited in the long-term by restenosis, which is luminal renarrowing in the first 6 months after the procedure. Smooth muscle cell proliferation is thought to be an important factor in restenosis; this leads to neointima formation and arterial lumen narrowing. Local therapy delivered perivascularly may have an effect on events in the neointima and reduce restenosis. The effect of delivering expression vector plasmids for senescent cell-derived inhibitor SDI-1, which regulates cell proliferation, and its antisense, into the perivascular tissue of injured arteries was investigated in a porcine arterial injury model using a needle injection catheter. Transfection efficiency, biological effect and plasmid dissemination were evaluated in arterial and organ tissue sections between 2 days and 4 months. A limited number of adventitial, medial and neointimal cells were transfected up to 4 months. sdi gene transfer did not result in a change in neointima. Transfer of antisense sdi resulted in an increase in neointima after 3 weeks. No DNA plasmid was detected in control tissues. Liposomally-mediated adventitial local gene delivery is feasible and safe using the needle injection catheter in a porcine model. A limited number of cells was transfected, with expression of transfected genes up to 4 months after delivery. A transient biological effect with increased neointima was observed after delivery of the antisense sdi gene.

Differential expression of nonmuscle myosin II isoforms in human atherosclerotic plaque.

Intimal proliferation and functional changes involving vascular smooth muscle cells are key events in the development of atherosclerosis, including restenosis after percutaneous transluminal angioplasty. Nonmuscle myosin (NMM) is required for cytokinesis and has been shown in cultures of vascular smooth muscle cells to undergo changes of isoform expression depending on the stage of proliferation and differentiation. The purpose of this study was to examine the differential expression of the two most recently identified nonmuscle myosin heavy chain isoform II (NMMHC-II) isoforms A and B in atherosclerotic plaque. Primary atherosclerotic and restenotic atherectomy specimens and non-atherosclerotic controls, were analyzed by Western Blot analysis, immunohistochemistry and in situ hybridization. Nonmuscle myosin heavy chain isoform IIA (NMMHC-IIA) was equally expressed in all types of tissue specimens both at the protein and mRNA levels. In contrast, NMMHC-IIB protein was found in restenotic specimens and normal artery but was at very low levels in primary atherosclerotic plaque. By in situ hybridization NMMHC-IIB mRNA levels were significantly greater in restenotic versus primary atherosclerotic lesions. NMMHC-IIB expression is associated with vascular restenosis but is downregulated in stable atherosclerotic lesions, whereas NMMHC-IIA is expressed in both. These results indicate that these new myosin isoforms have different functions and should be regarded separately with respect to smooth muscle proliferation and restenosis. They should prove to be useful molecular markers for the study of atherosclerosis and restenosis.

Role of angioscopy in the treatment of peripheral vascular disease with percutaneous atherectomy.

The role of adjunctive video angioscopy was evaluated in 43 patients with symptomatic peripheral vascular disease undergoing percutaneous atherectomy with the Simpson atherocath. There were 57 target lesions (superficial femoral, n = 46; popliteal, n = 11) of which 33 were stenotic (86 +/- 11%) and 24 were total occlusions of 0.5 to 10.6 cm in length, determined by angiography. Intraluminal inspection, with angioscopes of 0.85 to 1.5 mm in outer diameter housed within a guide catheter, could be performed in 55 of 57 lesions (96%) before atherectomy and in 39 of these 55 (71%) after atherectomy. Failure to obtain an adequate image was usually due to insufficient irrigation, especially in recanalized vessels. In 13 of 23 successfully recanalized arteries (54%) the occlusion could be crossed by the angioscope itself, whereas in 10 cases (42%) a guidewire or a sheath introducer was necessary. Angioscopic passage revealed that often long total occlusions, determined by angiography, consisted of greater than or equal to 1 discrete occlusion with interposed patent thrombus-free vascular segments. After atherectomy, in 15 instances with an acceptable angiographic result, angioscopy was helpful in identifying residual plaques and flaps which then selectively underwent atherectomy. In conclusion, angioscopy proved to be a useful adjunct to angiography in optimizing vascular recanalization with percutaneous atherectomy.

Analysis of atherectomy specimens.

Atherectomy specimens may be regarded as biopsy tissue excised from human vascular target lesions. Proceeding from contrary histologic findings that attribute focal hypercellularity to restenosis, and hypocellularity to chronic lesions, further analysis of atherectomy specimens was performed to study ultrastructural characteristics and functional aspects propagated by both lesion types. Transmission electron microscopy examination showed that intimal smooth muscle cells (SMCs) were the predominant cells in both primary and restenotic lesions. SMCs exhibited variable degrees of metabolic activation, typically higher in SMCs of restenotic lesions. This SMC phenotype was equally expressed when tissue samples were placed in a cell culture model. In an attempt to quantify SMC activity, proliferative as well as migratory activities of cultured cells were measured by growth curves and a computer-assisted motion analysis system, respectively. A 2- to 3-fold increase of both activity determinants was observed with SMCs cultivated from restenotic lesions compared with those from primary lesions, irrespective of their coronary or peripheral origin. Drug-induced interference of human SMC metabolic activation and antagonism to their proliferative and migratory activities may be helpful in evaluation of therapeutic concepts to prevent restenosis. The antitubulin colchicine was studied for its effect on the defined determinants. The data in vitro demonstrate that colchicine decreased proliferative and migratory activity of SMCs and caused disorganization of the cytoplasmic ultrastructure. In conclusion, electron microscopy and cell culture studies may help to shed more light on the structures and mechanisms underlying restenosis and plaque growth. Deliberate counteraction of any of the specific early events implicated in these complex pathobiologic processes may eventually become effective means to suppress restenosis and may thus result in a prophylactic as well as therapeutic treatment of the diseased vascular wall.

Accuracy of spiral computed tomography for identifying arterial and venous coronary graft patency.

Late outcome after coronary artery bypass grafting (CABG) mainly depends on the status of graft patency. The recent generation of spiral computed tomography (SCT) scanners may have potential in the long-term follow-up of CABG. In this study, graft patency in patients with internal mammary (IMA) and venous CABG was investigated using SCT and angiography. Forty-nine consecutive patients (age 61 +/- 8 years, 45 men) who had undergone CABG were examined by SCT and angiography 22 +/- 6 months after CABG. In total, 134 bypass grafts (42 IMA and 92 venous grafts) were analyzed. The angiographically determined patency rate of grafts was 86% for IMA (n = 36 of 42) and 74% for venous grafts (n = 68 of 92). By SCT, 32 IMA and 64 venous grafts were diagnosed correctly as patent. Sensitivity was 89% (IMA) and 94% (venous); overall sensitivity was 92%. None of the truly occluded venous grafts was diagnosed falsely patent by SCT (specificity 100%), whereas the specificity of IMA graft visualization was somewhat lower (88%, p = NS [overall 97%]). The accuracy for a patent graft was 88% (IMA) and 96% (venous CABG, p = NS). Compared with previous studies, these data suggest that SCT using one of the recent generation scanners (single scan time 0.75 second) is a highly accurate and relatively noninvasive approach for assessing not only saphenous vein graft patency, but also IMA graft patency. To date, this technique has only limited use in visualizing graft stenosis or distal anastomosis site patency.

Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia.

Low-density lipoprotein (LDL) apheresis is a potent treatment for patients with coronary heart disease and severe hereditary forms of LDL hypercholesterolemia not adequately responsive to drug treatment. Until now, the beneficial effect of aggressive reduction of LDL cholesterol by LDL apheresis on the course of coronary heart disease has been demonstrated in one 3-year study and several studies lasting 2 years. We now report on the clinical course, lipoprotein concentrations, coronary angiograms, and side effects in patients undergoing LDL apheresis for as long as 8.6 years. Thirty-four patients (21 men and 13 women) with coronary heart disease and heterozygous familial hypercholesterolemia (FH) not adequately responsive to lipid-lowering drugs received weekly (four patients biweekly) LDL apheresis for 4.6 +/- 2.6 years under diet and lipid-lowering drug therapy; after 0.5 to 3 years, simvastatin in the maximal tolerable dose was added. The baseline LDL cholesterol concentration was 6.9 +/- 1.6 mmol/L. Combined treatment in the steady state yielded a pretreatment and posttreatment LDL cholesterol concentration of 4.8 +/- 0.9 and 1.8 +/- 0.4 mmol/L, respectively. The calculated interval mean LDL cholesterol was 3.3 +/- 0.6 mmol/L. Evaluation of the coronary angiographies revealed a definite regression of coronary lesions in four patients (11.8%); in 19 patients, there was a cessation of progression. Two patients developed atheromatous lesions in bypass grafts (L.H., 60% stenosis; S.M., occlusion). Of 23 patients eligible for the scoring of anginal symptoms, five (21.7%) reported a reduction of the frequency and severity of angina pectoris. The mean coronary symptom score in 23 patients changed from 1.65 +/- 0.83 at baseline to 1.39 +/- 0.66 at the end of the study. During the whole observation period, we observed three sudden deaths, one nonfatal myocardial infarction, and five patients requiring hospital admission because of unstable angina pectoris, one of which was followed by a transluminal coronary angioplasty. Aggressive reduction of LDL cholesterol with combined LDL apheresis and drugs induced regression of coronary lesions in four of 34 patients and prevented progression in 29 patients for as long as 8.6 years. The effect on LDL and high-density lipoprotein (HDL) cholesterol and lipoprotein(a) [Lp(a)] was comparable with all three apheresis techniques. Therefore, no obvious difference between the three techniques was found regarding changes in coronary lesions.

Current biotechnological approaches to the prevention of restenosis.

No systemic pharmacological treatment has been convincingly shown to reduce the incidence of restenosis after angioplasty in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates post-angioplasty and following stent implantation, as documented in dozens of clinical trials, has encouraged the development of new biotechnological approaches to the treatment of restenosis. Gene therapy and other agents, including antibodies, fusion toxins and ribozymes, have the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation. Mechanical methods of preventing restenosis, for example sophisticated local drug delivery strategies and biodegradable stents using new materials, in combination with novel therapeutic agents or radiation, may also be of use.

Thromboxane receptor blockade versus cyclooxigenase inhibition: antiplatelet effects in patients.

In a randomized pilot study we compared the antiplatelet effects of aspirin and BM 13.177 in two groups of 7 patients each undergoing PTCA. As compared with the pretreatment values template bleeding time was prolonged and collagen induced aggregation was inhibited in PRP and WB in all patients. In the course of angiography and PTCA a rise in platelet factor 4 and beta thromboglobulin was observed in both groups, followed by a decrease below the baseline levels. Thromboxane B2 in plasma and serum decreased in the aspirin group but remained unchanged during BM 13.177 treatment. In PRP and WB aggregation induced by U 46 619 was inhibited after ingestion of BM 13.177 but not following ASA. After three months a control coronary angiography was done. There was no difference in regard to the degree of restenosis between both groups. Medication was well tolerated, compliance was good and no side effects were noted.

Acute negative inotropic effect of adriamycin (doxorubicin).

The muscle mechanical and haemodynamic effects of adriamycin were investigated in guinea pigs and rats by use of isolated myocardium (isometric contractions of papillary muscles of guinea pigs and rats) and in situ preparations (haemodynamic parameters in thoracotomized rats). 1. Adriamycin (10-6 to 10-3 M) produced a concentration-dependent negative inotropic effect in papillary muscles of 21 guinea pigs (decrease of T max and dT/dt max to 80% of control) and in papillary muscles of 15 rats (decrease of T max and dT/dt max to 25% of control for maximally effective concentrations). 2. The haemodynamic parameters left ventricular pressure (LVP), dLVP/dt max, arterial pressure and cardiac output of thoracotomized rats (N = 12) decreased dose-dependently following i.v. injections of adriamycin at doses of 2-30 mg/kg until a lethal haemodynamic shock occurred. 3. "Low-dose-effects" were reversible within min, whereas "high-dose-effects" were not up to an observation period of 1 h. 4. In the haemodynamic experiments, the ionized serum calcium fell excessively after adriamycin (from 2.1 mEq/l for controls to 0.5 mEq/l after doses of 25 mg/kg adriamycin). 5. An antagonistic interaction was seen between the cardio-depressant effect of adriamycin and the positive inotropic effect of calcium and vice versa. 6. It is concluded that the acute muscle mechanical and haemodynamic effects of adriamycin result from an interaction between adriamycin and calcium.

Local photodynamic therapy reduces tissue hyperplasia in an experimental restenosis model.

Local photodynamic therapy may have potential in preventing myointimal hyperplasia after angioplasty. In this study, the effect of photodynamic therapy was evaluated in an experimental model of restenosis. Standardized unidirectional arterial injury with a directional atherectomy catheter was performed in porcine arteries. Animals were randomly allocated to four groups: group 1, unidirectional injury only; group 2, injury followed by local delivery of photosensitizer; group 3, injury followed by local exposure to monochromatic light; and group 4, where injury was followed by local drug delivery of photosensitizer and subsequent exposure to light (photodynamic therapy). Seven, 14 or 21 days after treatment, all experimental vessels were excised, fixed and processed for histology. An inflammatory and myoproliferative response was observed after injury in vessels from groups 1, 2 and 3. In group 4, after injury followed by photodynamic therapy, the myoproliferative response was significantly reduced. Thus, in this study, tissue hyperplasia after unidirectional injury was effectively suppressed by photodynamic therapy.

A new catheter for prolonged local drug application.

BACKGROUND: Local drug delivery using a new 5F catheter with six small needles is described. The needles can be extended laterally into vascular tissue for drug deposition. METHODS: A fluorescent indicator (Photofrin) was injected with a new local drug delivery device into porcine carotid arteries. The vessels were explanted 15, 30, 60 min and 14 days after local drug delivery. Vascular segments were analyzed using semi-quantitative measurement of fluorescence (calculated in relation to a standard, 100% representing the maximum fluorescence achieved by systemic intravenous application of Photofrin). RESULTS: Maximum fluorescence was found in adventitia (15 min: 374%; 30 min: 388%; 60 min: 251%). In intimal tissue, the detected fluorescence was 107% after 15 min, 294% after 30 min, and 25% after 60 min. Media fluorescence was lower (15 min: 151%, 30 min: 102%, 60 min: 55%). No systemic drug content was measured. Fourteen days after local drug delivery, 15% of maximal fluorescence was still found in media but no adverse tissue hyperplasia was observed. CONCLUSIONS: These experiments demonstrate that high-dose perivascular local drug delivery is feasible and allows prolonged and selective application of drugs in a vessel segment without side effects.

Colchicine antagonizes the activity of human smooth muscle cells cultivated from arteriosclerotic lesions after atherectomy.

AIM: Proliferative, migratory, and secretory activities of vascular smooth muscle cells are functional determinants of human atherosclerotic plaque and restenosis formation. The present study was designed to examine the effects of interfering with these processes using drugs. MATERIALS AND METHODS: For in-vitro studies of smooth muscle cell activity, arterial smooth muscle cells were cultivated from human plaque tissue excised from 22 coronary and peripheral lesions and treated with the antitubulin colchicine. Smooth muscle cell migratory activity was analyzed by a standardized semi-automatic video system. Transmission electron microscopy was used to examine cytoplasmic structures. RESULTS: Colchicine caused a concentration-dependent decrease in smooth muscle cell proliferative activity at a half-maximal inhibitory concentration (IC50) of 5 nmol/l. Smooth muscle cell migratory activity was reduced by colchicine in a concentration-dependent manner (IC50, 3 nmol/l). Concordantly, transmission electron microscopy revealed severe disorganization of cytoplasmic structures, especially of organelles, indicating metabolic activation. CONCLUSIONS: In-vitro studies with human smooth muscle cells from arteriosclerotic lesions suggest that the antitubulin principle may be useful in producing anti-arteriosclerotic effects, since a pronounced antagonization of smooth muscle cell proliferative, migratory, and secretory processes, indirectly inferred from ultrastructural analysis, was demonstrated with low concentrations of colchicine.

Non-invasive coronary bypass graft imaging after multivessel revascularisation.

Non-invasive imaging techniques for the detection of graft patency after multivessel coronary revascularisation may be useful for follow-up after surgery. Forty consecutive asymptomatic patients (38 men, age 59.9+/-1.3 years) who had undergone coronary bypass surgery with at least three grafts were examined by spiral computed tomography or magnetic resonance angiography 24.9+/-0.3 months after surgery, using conventional angiography as reference. In total, 133 grafts (37 internal mammary artery, 96 venous grafts) were analysed. Spiral computed tomography studies were performed with a subsecond scanner; for magnetic resonance angiography, a three-dimensional contrast-enhanced gradient echo technique with ultrashort echo time during breath holding was used. For spiral computed tomography, sensitivities were 76% (internal mammary artery) and 100% (venous graft). This was compared with 100% (internal mammary artery) and 92% (venous graft) assessed by magnetic resonance angiography (P=ns). The positive predictive values were 100% for internal mammary artery and venous graft (spiral computed tomography) and 100% (internal mammary artery), 92% for venous grafts studied by magnetic resonance angiography (P=ns). Both subsecond spiral computed tomography and contrast-enhanced magnetic resonance angiography are highly accurate and relatively non-invasive approaches of assessing coronary graft patency after multivessel revascularisation and have potential for follow-up assessment in the long term.

Effects of different once-a-day medications on 24-hour blood pressure recordings in hypertensives.

Compliance with antihypertensive treatment can be increased by using medications that are taken only once daily. There is, however, concern as to whether the efficacy of such drugs is sufficient to cover 24 h. Ambulatory blood pressure monitoring (ABPM) is an ideal technique to assess the effect of this kind of drug and to determine over- or undertreatment. In this study three drugs were examined as once-a-day preparations. Thirty-six patients were treated with three different doses of bisoprolol, as an example of the beta 1-selective beta-blockers; 12 patients were treated with a combination of the AChE-inhibitor enalapril and hydrochlorothiazide; eight patients were treated with nifedipine once per day, a new galenic form of nifedipine, as an example of the calcium-channel blockers. In each group we saw a significant downward shift over the entire 24-h curve. Our results also show that using 24-h blood pressure monitoring devices can help establish an appropriate dose, avoid over- and undertreatment, and control the total burden of the patient.