Wolf-Dieter Busse

Influence of muzolimine on arterial wall elastin

Muzolimine, 3-amino-1-(3,4-dichloro-alpha-methylbenzyl)-2- pyrazolin -5-one, an antihypertensive and diuretic drug, accumulates in the arterial tissue of rats and dogs after oral administration. Two weeks after the administration of 3 mg [14C]muzolimine, the aorta of rats contained 60-300 times more 14C-radioactivity/weight unit than the skin or tail tendon. The 14C-radioactivity was exclusively bound to the isolated aortic elastin and corresponded to 0.04% of the applied muzolimine dose. Up to ca 250 ng bound muzolimine/mg elastin was found in the aorta of dogs treated with non-labelled muzolimine for 52 weeks. The elastin-bound [14C]muzolimine was not extractable by organic solvents or by weak acids or bases but was released in a soluble form by pancreatic elastase and extracted from the elastase digest by dichloromethane. In the dichloromethane extract muzolimine was detected by HPLC and HPTLC, and was identified by mass spectrometry. Muzolimine pretreatment of rats for 2 months did not influence the elastin content of arterial tissue or [3H]glycine incorporation into aortic elastin under organ culture conditions, but after labelling the elastin with [4,5-3H]lysine, the [3H]desmosine and [3H]-isodesmosine isolated from the elastin of muzolimine-pretreated rats and incorporated under organ culture conditions was lower than that of control animals. In addition, aortic elastin of rats pretreated for 2 months with 800 ppm muzolimine in the diet was more resistant to elastase degradation. This effect might give some implications for muzolimine in the therapy of cardiovascular disorders with impaired arterial elastin metabolism.

Experimental Hypertension and Therapeutic Progress: Vasodilation and Beyond

Inhibition of atrial natriuretic peptide (ANP) degradation by enkephalinase is known to increase endogenous ANP levels and to induce similar functional effects as administration of exogenous ANP. The influence of this principle on cardiac function in rats with hypertension-induced heart failure was investigated. We used 13-month-old male stroke-prone spontaneously hypertensive rats (SHR) with heart failure and hypertrophy. Groups of 12 rats were treated either with the enkephalinase inhibitor sinorphan (SIN; 31.5 mg/kg bj.d.), 50 ppm hydrochlorothiazide (HCTZ), in the feed or vehicle only for 14 days. SIN and HCTZ had similar acute natriuretic effects. Chronic treatment failed to affect natriuresis. SIN increased plasma and urinary cyclic guanosine monophosphate (cGMP). Unlike HCTZ, SIN reduced left ventricular enddiastolic pressure and heart weights. HCTZ failed to affect cardiac function or hypertrophy, but increased plasma renin activity. These reSults suggest that therapeutic use of ANP can improve cardiac function and structure in hypertension-induced cardiac failure. It was also shown that standard natriuretic treatment was ineffective.

Gentechnik und Molekularbiologie in der Arzneimittelforschung

Die Ursachen vieler Krankheiten liegen nach inzwischen gesicherter wissenschaftlicher Erkenntnis in der Fehlsteuerung auf der molekularen Ebene. Nur mit Hilfe der Gentechnik kann deshalb die Ursache vieler lebensbedrohender Krankheiten, wie z. B. Herz-/Kreislauferkrankungen, Krebs, AIDS und Erkrankungen des Zentralnervensystems, aufgeklart werden. Fur die pharmazeutische Industrie ist die Gentechnik somit unverzichtbar, und die Bewertung von Nutzen und Risiko dieser Schlusseltechnologie mus eindeutig positiv ausfallen.

Inhibition of the Antiaggregatory Activity of the Vessel Wall (Rat) by Acetylsalicylic Acid

The antiaggregatory activity of the vessel wall (rat) and its inhibition by acetylsalicylic acid (ASA) was tested under different experimental conditions (dose- and time related effects) in human platelet rich plasma (BORN-techn.)