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In a duplicate study during 1987-1991, 478 24-h duplicate samples from 14 homes for elderly people and 10 homes for youth were investigated for their contents of selected harmful substances. The analyses covered 45 active substances of pesticides, 17 PCB-congeners as well as lead, cadmium, and nitrate contents. Pesticides could be detected only in 15% of the investigated samples. The pesticide contents reached max. 8% of the respective FAO/WHO-limits. As the mean intake of the three most important PCB-congeners (sum of the congeners 138, 153, and 180) values of 0.9 and 1.1 micrograms per day and ration or person, respectively, were found. Also in the worst case the daily PCB intake was below the recommended ADI value of the FDA of 1 microgram/kg of body weight. The daily nutritional intake of lead and cadmium via the investigated daily rations reached about 5.6% and 20% of the Provisionally Tolerably Weekly Intake values of the FAO/WHO. The mean nitrate content of the duplicate portions was 101 mg per day and person (median: 79 mg per day and person). Referred to the median value the WHO limit (3.65 mg/kg body weight and day) was exhausted to about 36%.

The identification of nitric oxide (NO) as an endothelium derived relaxing factor (EDRF) has allowed a thorough investigation of the effects of organic nitrate esters as well as other nitrogen containing vasodilators such as nitrites, nitrosothioles, sydnonimines and nitroprusside. These substances can release NO or mediators derived from it, and have thus received annotation as NO donors. The pharmacokinetic characteristics of NO donors as well as the reactions which might mediate their bioactivation shall be reviewed. For organic nitrates this is of particular interest, since clinical tolerance arises because mechanisms involved in their bioactivation become exhausted. In contrast however, both the molsidomine metabolite SIN-1 as well as nitroprusside are considered to act as direct NO donors since their biological activity is not limited by the mode of their bioactivation. The principles of NO¿s actions as well as the related biological activities of NO donors will be covered in this article. The vascular selectivity and dose dependency of the haemodynamic nitrate effects shall also be described as well as the potential interactions of nitrates with endothelium, thrombocytes and leukocytes. The significance of specific tolerance to nitrates and the loss of responsiveness due to neurohormonal counter-regulation, which has also been observed with molsidomine, shall be discussed. Newly acquired knowledge therefore justifies consideration of NO donors as therapeutic substitutes for the protective autacoid NO, which is the basis for further pharmacological and clinical development of NO donors.

Although organic nitrates have been used in the treatment of patients with angina pectoris for more than 100 years, their mechanism of action was only disclosed during the last years. In the seventies it became already clear that nitrates act via the intracellular messenger cyclic 3,5'-guanosine-monophosphate (cGMP). Later on, S-nitrosothiols were suggested as possible intermediary messengers arising during metabolism of the nitrates. In parallel with the discovery of the endothelium-derived relaxing factor (EDRF) and its biochemical identification as nitric oxide (NO), it became clear that organic nitrates act via the release of NO in the vascular wall and thus by using metabolic pathways identical to those of endogenous EDRF. The target-enzyme for nitrates or for the NO released by them, respectively, thus is the soluble guanylylcyclase. The rate of enzymic stimulation induced by a given nitrate correlates closely with the rate of measured NO production from the nitrate molecule. The highest NO production was detected with nitroglycerin, followed by the group of dinitrates and mononitrates. In the vessel wall both endothelial cells as well as vascular smooth muscle cells can transform nitrates into NO. This might explain, why the antiaggregatory effect of nitrates is more pronounced in the presence of these cells or in vivo than it is in the absence of vascular cells in vitro. In spite of some differences in metabolism, nitrates are thus closely related by their end-product to the endothelium-derived relaxing factor and represent, therefore, an adequate substitution for NO missing in diseased blood vessels.

Nitrates belong to the most potent drugs for treatment of angina pectoris. Patients with this disease always show arteriosclerotic changes in their coronary arteries. In arteriosclerotic vessels endothelium-dependent relaxation induced by the endogenous vasodilator nitric oxide (NO) is markedly reduced. This article introduces a theory, whereby NO production is not reduced in arteriosclerotic vessels (in the arteriosclerotic aorta of the rabbit it is even enhanced) but that the activity of superoxide dismutase, which normally metabolizes free oxygen-radicals (O2-) is reduced and that NO is metabolized by accumulating superoxides. It is interesting that only endogenous nitrate (NO) can be metabolized by this pathway, whereas in arteriosclerotic vessels exogenous nitro-vasodilatators remain fully effective. For the clinical use of nitrates it is of particular importance that these exhibit different potencies for epicardial coronary vessels and the myocardial microcirculation. Nitroglycerin causes extensive relaxation in isolated large coronary arteries but has only a limited effect on middle-sized vessels and almost none on arteries in the microcirculation. These differences in efficacy of nitroglycerin in the coronary micro- and macrocirculation is probably due to the inability of microvessels to transform nitroglycerin into active metabolites such as S-nitroso-L-cysteine. Comparing vascular and clinical effects of nitroglycerin (in particular dilatation of coronary vessels) and of adenosine (acting in particular on the coronary microcirculation) discloses the great importance of the aforementioned effects on epicardial coronary vessels for treatment of angina pectoris. In this context a vasodilatating effect on the coronary microcirculation might not only be disadvantageous but could even trigger angina pectoris itself.

Analytical possibilities for nitrate determination in milk on the base of photometric methods are discussed. An automated method, similar to Nijhuis u. a. (1979), is proposed using flow stream analyser ADM 300. Natrium nitrate (5 g and 10 g/kg live weight resp.) was given to two dairy cows after morning feeding on the 1st and on the 3rd day of experiment. The increase of nitrate content in the milk was very quick, maximal concentrations after 2 h were found as 5.6 mg/l (animal 1) and 3.2 mg nitrate-N/l (animal 2). But nitrate also disappeared relatively quickly, after 24 h there only values were observed corresponding to normal range of 1 mg/l.

Small differences in nitrate intake with the drinking water are not reflected in nitrate contents of saliva and urine of test persons. A correlation of nitrate concentration in body fluids and cancer incidence can be expected hardly. Inflammatory diseases of the gut are frequently accompanied by enhanced endogenous nitrate synthesis and have an essential influence on total nitrate load of the human organism. Nitrate contents in saliva and/or urine are not general indicators of inflammatory processes. As the role of the nitrate ion in humans is not yet understood, the claim remains for a nitrate intake being as low as possible.

Nitrate tolerance is defined as an attenuation or even loss of hemodynamic and anti-ischemic effects during continuous nitrate medication. The blunted response may be due to the development of pseudotolerance and true pharmacologic tolerance. Pseudotolerance is the result of volume and salt retention, as well as the stimulation of counter-regulatory mechanisms which may alter the baseline hemodynamics of a patient during nitrate therapy. Far less important are changes in nitrate pharmacokinetics. True pharmacological tolerance may also be of practical importance. Diminished uptake of nitrates into the vascular smooth muscle cell, a decrease in intracellular SH groups, inhibition of the guanylate-cyclase, and stimulation of a specific phosphodiesterase may result in a decrease of cyclic GMP formation and hence to a decrease in nitrate induced vasodilatation. Tolerance development may be prevented by intermittent nitrate administration providing intervals with low plasma and tissue nitrate levels. In consequence, nitrates should be used predominantly for treatment of ischemic episodes, but 24-hour anti-ischemic action for the prevention of ischemia can be better achieved by treatment with a beta-blocker and/or a calcium antagonist. Nitrates should be added in times of maximum susceptibility to ischemia, while allowing nitrate levels to fall at other times.

Nitrate and nitrite contents were determined in urine, saliva, and blood of 298 patients suffering from urological diseases. Crude values of nitrate and nitrite in morning urine without any correction due to density and creatinine are sufficient for epidemiological purposes. Significant correlations exist with vegetables intake and bacteriuria, but not with age, sex, disease, smoking, and medicaments. Neither nitrate nor nitrite may be considered to be general indicators of inflammatory processes in the urogenital tract. According to recent investigations nitrite formation during bacterial infections must be seen in connection with simultaneously occurring macrophage activation, as the latter one is catalyzing the formation of carcinogenic N-nitroso compounds from nitrite and secondary amines.