Metoprine-induced thirst and diuresis in Wistar rats

Abstract

In the present study, the renal responses to metoprine, a histamine-N-methyltransferase inhibitor, were studied in conscious rats. Metoprine (10-20 mg kg(-1)) or vehicle were administered i.p. to male Wistar rats and the effects were followed for the subsequent 24 h. It was found that as early as 3 h after the drug administration metoprine 20 mg kg(-1) had increased water consumption and urine flow approximately 6-8-fold. The treatment decreased urine osmolality and increased free water clearance, but caused no change in plasma renin activity or plasma vasopressin concentration. In addition, a metoprine-induced elevation in the systolic blood pressure was observed during the first few hours of the experiment. During the nocturnal period of the study, glomerular filtration rate and the excretion of electrolytes did not increase in metoprine-treated rats as they did in control rats. A decrease in the release of atrial natriuretic peptide was also found. The present results show that inhibition of histamine catabolism by metoprine causes massive changes in renal functions. It seems to promote water excretion by the kidneys but, on the other hand, to reduce the excretion of electrolytes. Although the exact mechanisms, especially the role of increased blood pressure and nocturnal suppression of atrial natriuretic peptide, require further clarification, the present data suggest that renin-angiotensin system and vasopressin were not involved in these renal responses to metoprine.

Cardiac and regional haemodynamic effects of histamine N-methyltransferase inhibitor metoprine in haemorrhage-shocked rats

“…Thus, the present study confirms earlier findings by Lecklin et al [15] that metoprine, by increasing central histamine concentrations, induces a rise in blood pressure in normotensive rats. Interestingly, however, increases in MAP and HR in haemorrhagic hypotension are significantly higher than in normovolaemia.…”

“…Metoprine is a generally accepted HNMT inhibitor previously used to study the influence of the histaminergic system on pain perception [14], regulation of body water balance [15], anxiety [16] and learning and memory processes [17]. The study by Hough et al demonstrates that metoprine (10 mg/kg; ip) inhibits HNMT activity in the rat brain by more than 80 % [18].…”

Involvement of arginine vasopressin in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats

“…Recent studies by the author confirm that it increases histamine levels in the hypothalamus and medulla oblongata 20 min after icv injection, which is associated with a longlasting pressor effect and improvement in survival at 2 h [13]. In contrast to normotensive animals in which metoprine also increases MAP [23], the pressor effect in haemorrhageshocked rats is significantly higher [13]. The possible explanation is that activation of the histaminergic system leads to mobilisation of compensatory mechanisms in critical hypotension.…”

“…Inhibition of HNMT activity with metoprine belongs to generally accepted pharmacological methods used to explore in vivo biological effects of the histaminergic system in, for example, pain perception [22], regulation of body water balance [23], anxiety [24], and learning and memory processes [25]. Recent studies by the author confirm that it increases histamine levels in the hypothalamus and medulla oblongata 20 min after icv injection, which is associated with a longlasting pressor effect and improvement in survival at 2 h [13].…”

Structural Basis for Inhibition of Histamine N-Methyltransferase by Diverse Drugs

“…H1-receptor antagonists (conventionally called anti-histamines) are useful for relieving the symptoms of an allergic reaction such as rhinitis, urticaria, and atopic dermatitis. 21 Besides antihistamines, several anti-malarial compounds 22,23 such as quinacrine and amodiaquine, 24-26 the antitumor agent metoprine, [27][28][29][30][31][32][33][34] and an early drug for Alzheimer's disease called tacrine [35][36][37] are among the most potent HNMT inhibitors known so far. Here, we describe the structure of the H1-receptor antagonist diphenhydramine in complex with HNMT and methyl donor analog S-adenosyl-L-homocysteine (AdoHcy).…”