Effects of cyclooxygenase inhibitors on plasma and urinary kallikrein.

In vitro studies were performed to investigate the direct effects of the cyclooxygenase inhibitors (COI), meclofenamate, imidazol, acetylsalicylic acid (ASA), indomethacin, and acetaminophen on the plasma kallikrein system and on urinary kallikrein excretion. Biological (guinea pig ileum) and colorimetric (synthetic substrate) methods were used. Results showed that all COIs except ASA affected both the activation of pre-kallikrein in plasma and the direct activity of plasma kallikrein, but none of the COIs tested was able to alter the urinary kallikrein excretion. Additionally, in Wistar rats we studied the effects of chronic administration of ASA, meclofenamate, and indomethacin on the plasma kallikrein system and urinary kallikrein excretion. In contrast to the in vitro studies, administration of these COIs reduced the amount of total 24-hour urinary kallikrein excretion. Moreover, the pre-plasma kallikrein and total plasma kallikrein levels were diminished in all experimental groups. However, only ASA and meclofenamate increased the free-plasma kallikrein levels despite the fact the three COIs used reduced the high molecular weight kininogen. Thus, in vitro data suggest an important and direct effect of meclofenamate, imidazol, indomethacin, and acetaminophen on the plasma kallikrein system, without any effect on urinary secretion. ASA was the only COI that showed no direct effect in these experiments. Chronic COI administration in Wistar rats suggests that ASA, meclofenamate, and indomethacin affect both the plasma kallikrein-kinin system and kallikrein excretion. When these drugs are used to evaluate the interactions between prostaglandins and the kallikrein-kinin system, their possible effects through both mechanisms, directly or via prostaglandin inhibition, should be considered.

Malignant hypertension: a syndrome associated with low plasma kininogen and kinin potentiating factor.

Plasma levels of kininogen, kallikrein, and prekallikrein were determined in patients with malignant hypertension (MH) and compared to normotensive controls (NC) and patients with mild to moderate essential hypertension (EH). Also, a recently described kinin potentiating factor (KPF) was estimated by dividing the value of kininogen determined by trypsin (Kgn-Try) by that of kininogen determined by human urinary kallikrein (Kgn-HuUk). No significant alterations were detected among plasma values of pre-kallikrein and kallikrein of MH as compared to NC. However, Kgn-HuUK values were significantly lower in MH (1.9 +/- 0.3 micron gLBK/ml) as compared to EH and NC (2.7 +/- 0.1 micron gLBK/ml and 3.0 +/- 0.2 micron gLBK/ml respectively, p less than 0.05). Furthermore, KPF values were also low (p less than 0.05) in MH (1.6 +/- 0.3) when compared with similar values obtained in EH and NC (3.0 +/- 0.2 and 2.8 +/- 0.1, respectively). Adequate control of blood pressure levels for 90 days in MH group caused no significant alterations in plasma levels of kininogen and KPF. It is suggested that diminished kininogen levels as well as a decrease in a kinin potentiation KPF that is generated in plasma by trypsin may be involved in the pathogenesis of human malignant hypertension.

Malignant hypertension: a syndrome accompanied by plasmatic diminution of low and high molecular weight kininogens.

Total kininogen (Kgn), kallikrein, and prekallikrein were measured in patients with malignant hypertension (MH), essential hypertension (EH), normotensive control (NC), and hypertension and chronic renal failure (HRF). These components of the kallikrein-kinin system were related to the levels of creatinine and fibrinogen. High molecular weight Kgn and low molecular weight Kgn were also measured in blood samples from a peripheral vein, arterial blood, and suprahepatic vein in NC, EH, and MH. Results showed that total Kgn levels were diminished in MH and this diminution could not be ascribed to decreases in renal function, hematocrit, or fibrinogen levels. Appropriate antihypertensive treatment for over 1 year did not normalize Kgn levels in 10 of 11 patients. High molecular weight Kgn and low molecular weight Kgn were both diminished in MH (0.26 +/- 0.04 nmol bradykinin/ml and 0.93 +/- 0.12 nmol lysyl-bradykinin/ml, respectively) as compared to NC (0.39 +/- 0.07 and 1.92 +/- 0.16) and EH (0.51 +/- 0.07 and 1.65 +/- 0.13). Higher concentrations of high molecular weight Kgn were demonstrated in the suprahepatic vein as compared to arterial blood, demonstrating its synthesis by the liver. However, patients with MH had a diminished capacity to synthetize high molecular weight Kgn. A decrease in synthesis of high molecular weight Kgn may be a partial explanation for low levels of total Kgn. It is suggested that a lack of Kgn may play a role in the pathogenesis of MH.

Efeito do inibidor da enzima conversora da angiotensina sobre a funcao renal de caes com expansao do espaco extracelular. / Effect of a converting enzyme inhibitor of the renal function in dogs with expansion of the extracellular space

A maioria dos estudos com o SQ 14225(Squibb), um inibidor da enzima de conversao de angiotensina, foram feitos em animais e pacientes hipertensos. Tendo em vista a possibilidade de a droga ter uma acao farmacologica independente do seu efeito sobre a renina angiotensina, resolvemos estuda-la no seguinte protocolo experimental: Caes normais foram submetidos a uma expansao de 20% do espaco extracelular com solucao salina isotonica para inibir a atividade plasmatica do sistema renina, angiotensina, aldosteroma (S.R.A.A.).Nossas observacoes indicam que o SQ 14225 administrado a caes por via endovenosa, na dose de 7mg/kg e na vigencia de inibicao do S.R.A.A. por expansao com salina, apresentada uma acao hipotensora, assim como provoca proteinuria transitoria, provavelmente por aumentar a permeabilidade da membrana basal glomerular