Inflammation in atherosclerosis and psoriasis: common pathogenic mechanisms and the potential for an integrated treatment approach.

Inflammation plays a key role in the pathogenesis of a number of chronic inflammatory systemic diseases (CISDs), including psoriasis, rheumatoid arthritis, systemic lupus erythematosus and Crohn's disease, and also in the pathogenesis of atherosclerosis. CISDs and cardiovascular diseases, such as atherosclerosis, share common pathogenic features, and cardiovascular disease is an important cause of morbidity and mortality in patients with CISDs. Activated inflammatory cells and pro-inflammatory cytokines contribute to the development of psoriatic lesions and play an important role in the breakdown of atherosclerotic plaques. Psoriasis and atherosclerosis also have similar histological characteristics involving T cells, macrophages and monocytes. In particular, the extravasation of T cells through the epithelium is characteristic of both psoriatic and atherosclerotic plaques. Cardiovascular disease is an important cause of morbidity and mortality in patients with psoriasis, which is associated with an increased cardiovascular risk profile compared with the general population. Patients with psoriasis are at increased risk of arterial hypertension, coronary heart disease, hyperlipidaemia, obesity and type II diabetes, which are more prevalent than in control patients. This increased risk could be due to the effects of chronic inflammatory changes, particularly the infiltration of T cells and subsequent secretion of pro-inflammatory cytokines. Some drugs used in the treatment of cardiovascular disease, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors have anti-inflammatory activity. In addition, systemic treatments for psoriasis may, by decreasing inflammation, reduce the risk of cardiovascular disease. It is suggested, therefore, that an integrated approach to the treatment of the inflammatory processes underlying both psoriasis and atherosclerosis may be beneficial in reducing cardiovascular risk in patients with psoriasis. The newer targeted biological therapies, such as efalizumab and infliximab, which offer the potential for long-term disease control in psoriasis, may be of particular use in this setting.

[The symptomatic patient with pathologic coronary angiogram. "evidence-based" or "best-evidence medicine" in the interventional cardiology]. / Der symptomatische Patient mit pathologischem, interventionsbedürftigem Koronarogramm. "Evidence-based" oder "Best-Evidence Medicine" in der interventionellen Kardiologie.

Ischemic heart disease is the most frequent cause of death in industrialized countries. This is a result of persistent risk factors and aging of the population. Medical progress with application of conservative, surgical or interventional strategies indeed reduced the morbidity and mortality of arteriosclerotic diseases, but markedly increased the medical care costs. The result is a discussion about the optimal use of the different therapeutic measures under consideration of the evidence based medicine. This article reviews several recently published clinical trials and discusses, which patient with symptomatic coronary artery disease should undergo a conservative strategy, percutaneous or surgical revascularization.

Potential beneficial effects of urapidil in primary and secondary prevention of stroke.

Stroke is a partly preventable neurological disease associated with excessive economic cost. Adequate prevention of stroke and sufficient therapy in the acute phase will help to reduce the heavy burden of morbidity and severe economic impact. Hypertension as such, and even more so stroke itself, are known to influence cerebral autoregulation in a negative sense. With respect to the prevention of stroke, antihypertensive therapy should be accompanied by attempts to inhibit of atherogenesis, for instance via improvements of the lipid profile (lowering of LDL, elevation of HDL) or via inhibition of platelet aggregation. In conditions of acute stroke, a pharmacologically induced rise in intracranial pressure should be avoided, whereas cerebral perfusion pressure must be maintained. If possible, ischaemic tolerance should be increased. Also with respect to the secondary prevention of stroke, antihypertensive therapy should be aiming at maintaining cerebral blood flow, whereas the progression of atherosclerotic lesions should be impaired as much as possible. Urapidil may be characterised as a peripheral alpha 1-adrenoceptor blocker with additional sympathoinhibitory effect, triggered by the stimulation of central 5HT1A-receptors. Urapidil, well documented as an effective antihypertensive agent in short- and long-term trials, also showed beneficial influence in the acute phase of stroke. After 3 years of treatment with urapidil (60 mg b.i.d.), the total cardiovascular risk proved reduced by 26%. In addition, urapidil influenced lipid profile, glucose metabolism, and platelet aggregation favourably in hypertensive patients. In animal experiments, urapidil improved the ischaemic tolerance of the brain. Taken together it would seem worthwhile to investigate urapidil as a possibly beneficial agent in the treatment of acute stroke, as well as in secondary prevention of this condition.

Effects of single intravenous administration of urapidil and diltiazem in patients with nonfixed pulmonary hypertension secondary to chronic obstructive lung disease.

In patients with chronic obstructive lung disease (COLD), pulmonary hypertension (PH) often develops in addition over the course of years. In this study, the acute effects of urapidil and diltiazem in patients with mild PH secondary to COLD were investigated. Eighteen male and 2 female patients, aged 42-78 years, received in randomized, single-blind fashion single intravenous (i.v.) doses of either urapidil (35-50 mg, n = 10) or diltiazem (25 mg, n = 10). Mean pulmonary artery pressure (MPAP), pulmonary wedge pressure (PWP), mean arterial blood pressure (BP) (MAP), and arterial and central venous blood gases were determined at rest and during exercise (starting with 25 W with increases in 25-W steps) before and after drug administration. Urapidil caused a significant reduction in MPAP (from 19 +/- 7 to 15 +/- 4 mm Hg, p < 0.01), PWP (from 9 +/- 3 to 7 +/- 2 mm Hg, p < 0.05), but not significantly in MAP at rest, whereas with diltiazem only MAP was decreased (from 103 +/- 14 to 98 +/- 12 mm Hg, p < 0.05) and MPAP and PWP were not significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of hypertensive urgencies and emergencies with nitrendipine, nifedipine, and clonidine: effect on blood pressure and heart rate.

Nitrendipine is a new calcium antagonist of the 1,4-dihydropyridine group with strong vasodilating properties. In a randomized trial involving 45 patients, whose mean blood pressure was 236 +/- 24/129 +/- 21 mm Hg, 5 mg nitrendipine (given sublingually via a phiole) was compared with 20 mg nifedipine (given sublingually via two pierced 10-mg capsules) and 0.15 mg clonidine (given intravenously). Blood pressure and heart rate were assessed for 8 h after intake of the antihypertensive agents. Within 60 min, nitrendipine reduced blood pressure by an average of 78 +/- 17 mm Hg for the systolic and 42 +/- 12 mm Hg for the diastolic. Heart rate fell significantly from 106 +/- 17 to 87 +/- 11 beats/min. Nifedipine produced equivalent falls in systolic (-72 +/- 15 mm Hg) and diastolic (-41 +/- 11 mm Hg) blood pressure, but increased heart rate from 89 +/- 13 to 103 +/- 14 beats/min within 1 h. Intravenous administration of clonidine lowers systolic (-84 +/- 13 mm Hg) and diastolic (-35 +/- 10 mm Hg) blood pressure within 60 min. Heart rate decreased from 96 +/- 15 to 84 +/- 9 beats/min. The antihypertensive effect of each drug was maintained until 8 h after medication. Main side effects were observed in the nifedipine group (flush and reflex tachycardia) and in the clonidine group (dry mouth and drowsiness). In conclusion, nitrendipine, nifedipine, and clonidine show similar efficacy in the treatment of hypertensive urgencies and emergencies. However, sublingual application of the calcium antagonists is simple and safe; moreover, nitrendipine is better tolerated than nifedipine and clonidine.

Bioelectrical and mechanical effects of tiapamil (Ro 11-1781) on isolated guinea pig myocardium.

In isolated electrically stimulated guinea pig papillary muscles tiapamil exerts a negative inotropic action that corresponds to its presumptive inhibitory effects on the slow-channel-mediated transmembrane Ca2+ influx. However, contractile depression is always accompanied by marked alterations of the normal Na+-carried action potential. Thus Na+-dependent upstroke velocity (dV/dtmax) declines while the length of the plateau phase increases. These observations indicate that tiapamil, besides inhibiting Ca2+ inflow, also interferes with the fast inward Na+ current and possibly also reduces the repolarising K+ efflux. After partial depolarisation with a K+-rich tyrode solution (19 mmol X litre-1 K+). tiapamil lowers the Ca2+-dependent contractile force as it reduces the bioelectric parameters (upstroke velocity, amplitude, duration) of the Ca2+-mediated action potentials. Moreover, in partially depolarised myocardium, the Mg2+-induced bioelectric membrane activity is suppressed by tiapamil. Tiapamil probably operates as an agent with mixed Na+-, K+-, Ca2+- and Mg2+-antagonistic effects and, in this respect, differs considerably from the more specific Ca2+ antagonists such as verapamil, D 600 (gallopamil), nifedipine (and other 1,4-dihydropyridines) or diltiazem. However, tiapamil by virtue of its combined damping actions on both transmembrane Na+ and Ca2+ conductivities (together with prolongation of the action potential plateau), is a drug which exerts, simultaneously, the fundamental myocardial membrane effects of antiarrhythmic agents of group I, III and IV, according to the classification of Singh and Vaughan Williams. Thus these bioelectrical observations are in accordance with the results of clinical studies on tiapamil, which have demonstrated directly its antiarrhythmic efficacy.

Asocainol, a new antiarrhythmic drug with natrium- and calcium-antagonistic effects on ventricular myocardium.

In isolated guinea pig papillary muscles, asocainol, a new antiarrhythmic drug, and its optical isomers exert a concentration-dependent negative inotropic action that is due to an inhibitory influence on the slow Ca2+ influx. However, depression of contractility is always accompanied by marked alterations of normal Na+-carried action potentials; thus, overshoot and duration decline together with Na+-dependent upstroke velocity. These observations indicate that asocainol not only inhibits Ca2+ inflow, but interferes with the fast inward Na+ current. In partially depolarized ventricular muscle, asocainol lowers Ca2+-dependent contractile force as it reduces upstroke velocity, overshoot, and duration of Ca2+-mediated action potentials. Moreover, Mg2+-induced membrane activity is suppressed by asocainol. Ba2+-induced ventricular autorhythmicity, representing a model of a slow-channel-dependent ectopic pacemaker, is abolished by asocainol. We conclude that asocainol exerts mixed Na+-, Ca2+-, and Mg2+-antagonistic effects in mammalian ventricular myocardium. Thus, asocainol keeps an intermediate position between specific Ca2+ antagonists (verapamil) and predominantly Na+-antagonistic drugs such as certain local anesthetics. On the basis of this dual inhibitory action on both transmembrane Na+ and Ca2+ conductivities, it is easily understood that asocainol is a rather efficient antiarrhythmic agent that exerts in combination the particular effects of both class-I and class-IV antiarrhythmic drugs.

Forskolin, a new positive inotropic agent, and its influence on myocardial electrogenic cation movements.

Forskolin exerts concentration-dependent positive inotropic effects in guinea pig isolated papillary muscles; resting potential, overshoot, and upstroke velocity remain unchanged. It markedly potentiates Ca2+-mediated action potentials elicited in partially depolarized myocardial fibers (increases in upstroke velocity, height, and action potential duration) and restores slow-channel-mediated transmembrane Ca2+ influx and contractile force under conditions of external Ca2+ withdrawal or in the presence of the specific Ca2+ antagonist D 600. In partially depolarized ventricular muscle, the potentiation of transmembrane inward Ca2+ current by forskolin is correlated with a reciprocal inhibition of Mg2+-induced electrogenic membrane effects. In this respect, forskolin resembles other Ca2+ influx promoters such as beta-adrenoceptor agonists, histamine, and dibutyryl-cyclic AMP (cAMP). All these agents favor sarcolemmal Ca2+ accumulation through increases in intracellular cAMP and the subsequent formation of Ca2+-binding phosphorylated membrane proteins; Mg2+ ions seem to be displaced by Ca2+. These findings support the concept that the effects of forskolin result from an increase in intracellular cAMP.

[Comparative studies on the basic Ca2+ antagonistic activities of niludipine (Bay a 7168) and nifedipine (Bay a 1040) on the myocardium, myometrium and vessels of smooth muscles (author's transl)]. / Vergleichende Untersuchungen über die Ca++-antagonistischen Grundwirkungen von Niludipin (Bay a 7168) und Nifedipin (Bay a 1040) auf Myokard, Myometrium und glatte Gefässmuskulatur.

Niludipine (bis(2-propoxyethyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate; Bay a 7168) with respect to its specific actions on mammalian myocardium, sino-auricular or atrio-ventricular pacemakers, myometrium, and vascular smooth muscle has to be considered one of the most potent representatives of the new group of calcium antagonists. The pharmacodynamic effects of niludipine strikingly resemble those of nifedipine both qualitatively and quantitatively. Interestingly enough, niludipine is also a powerful coronary vasodilator. This is made particularly evident by the present experiments on potassium- or glycoside-contractured smooth musculature originating from large extramural coronary stem arteries.