The therapeutic use of angiotensin converting enzyme (ACE) inhibitors, at a large scale, in arterial hypertension has showed that these molecules can exert beneficial effects on insulin sensitivity and may reduce the occurrence of type 2 diabetes mellitus. One hypothesis explaining these effects of ACE inhibitors may relate to their capacity to interfere with bradykinin (BK) metabolism and action. BK may participate in the regulation of substrate utilization by several tissues by improving blood flow and substrate delivery to the tissues and also by promoting translocation of glucose transporters. Moreover, BK has been shown to increase phosphorylation of insulin receptor and its cell substrates. BK also appears to improve the release of insulin. Furthermore, insulin may activate the kallikrein-kinin system, which consequently may increase its metabolic effects. However, in experimental diabetes mellitus, BK can participate to the inflammatory reaction leading to Langerhans islets destruction. In diabetes, whereas tissue kallikrein mRNA levels were reduced in several organs, an overexpression of kinin receptors, an increase in plasma levels of kininogens and kallikrein and an activation of the kinin system have all been reported. Lastly, kinins may be involved in the development of diabetic nephropathy. Reduction of kinin metabolism by ACE inhibitors might be involved in the beneficial effects exerted by these compounds in diabetic kidney functions.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

Purification and characterization of plasma T-kininogen from Wistar and brown Norway rats.

A rapid and convenient three-step purification scheme has been developed for the purification of T-kininogen (alpha 1-cysteine proteinase inhibitor) from rat plasma. The purification process includes chromatography on hydroxyapatite, immunoaffinity chromatography and gel filtration. This procedure is applied to plasma from the brown Norway rat which is known to be deficient in high and low molecular weight kininogens. The method furnished large amounts of T-kininogen from turpentine-treated Wistar rats as well as from untreated and turpentine-treated deficient brown Norway rats. The amino acid and hexose content of the three T-kininogens has been determined. While the composition of the molecules isolated from both injured rats was similar, the neutral sugar content of T-kininogen purified from untreated brown Norway rats was lower and its amino acid composition showed slight differences. The three molecules have identical behaviour and similar physicochemical and immunological properties when analysed by SDS electrophoresis, isoelectrofocusing and two-dimensional immunoelectrophoresis.

Amino Acids↗

PubMedDate not supplied

Water losses induced by heat exposure and the kinin system in the rat.

Normal Wistar rats, normal and kininogen-deficient Brown Norway rats were kept at ambiant temperatures of 26 degrees C, 36 degrees C or 40 degrees C for 3 to 5 hours. Their colonic temperatures and body weights were measured. At 26 degrees C, the changes in these parameters were similar in the three strains. At 36 degrees C, body weight loss was increased more in normal rats than in kininogen-deficient rats. At 40 degrees C, body temperature increased more quickly and body weight loss was less enhanced in kininogen-deficient rats than in normal rats. The water content of muscles was less reduced in kininogen-deficient rats than in normal rats. HOE 140, a bradykinin antagonist, reduced the weight loss of Wistar rats kept at 36 degrees C and 40 degrees C. Atropine or removal of submaxillary glands increased colonic temperature and reduced the weight loss of Wistar rats at 36 degrees C and 40 degrees C. HOE 140 did not modify the reduction of weight loss induced by atropine but increased colonic temperatures and decreased thermal tolerance of atropinized Wistar rats at 36 degrees C. These results indicate that the kallikrein-kinin system plays a role in salivary secretion and in heat exchange during a heat exposure.

Animals↗

PubMedDate not supplied

Pilocarpine-induced salivary secretion, kinin system and nitric oxide in rats.

In anaesthetized rats, intraperitoneal injection of pilocarpine (0.1 to 1 mg.Kg-1) induced a dose-dependent flow of saliva. During salivation by pilocarpine (0.5 mg.Kg-1), the blood content of submaxillary glands was not significantly increased but the blood volume of the animals was reduced. The salivary flow rate induced by pilocarpine was similar in normal and kininogen-deficient rats. L-NG-nitro-arginine (L-NOARG, 35 mg.Kg-1), a nitric oxide synthesis inhibitor, increased the salivary flow elicited by pilocarpine (0.5 mg.Kg-1). L-NOARG did not modify the blood volume loss but decreased the blood content of the submaxillary glands. The volume of salivary secretion induced by isoproterenol (250 mg.Kg-1) was lower in kininogen-deficient rats than in normal rats. It was significantly reduced by HOE 140 (2 mg.Kg-1), a bradykinin antagonist. L-NOARG increased the salivary flow induced by isoproterenol during the ten first minutes of collection but suppressed it thereafter. We concluded that kinins are not involved in the stimulating effect of pilocarpine on rat salivary glands but these peptides would participate to the development of the salivation induced by isoproterenol in rats. Nitric oxide contributes to the control of the vascular tone in rat salivary glands. The influence of L-NOARG on salivation would be explained by its effects on blood pressure and vascular resistances.

Amino Acid Oxidoreductases↗

PubMedDate not supplied

Kallikrein, nitric oxide and the vascular responses of the submaxillary glands in rats exposed to heat.

During exposure of normal rats to an ambient temperature of 36 degrees C or 40 degrees C, body temperature increases; thermolytic processes are set up and saliva is spread on the skin. In Wistar rats, thermolytic salivation started when body temperature was above 39 degrees C. This water loss was associated with a loss of body weight. A 10% reduction of plasma volume was observed in animals exposed to 40 degrees C but no change was observed in those exposed to 36 degrees C. Body weight loss was reduced by hexamethonium, atropine, prazosin, HOE 140, a bradykinin-antagonist, and NG-nitro-L-arginine (NOARG), a NO synthase inhibitor. The weight and blood content of the submaxillary glands, which are the main effectors of the thermolytic processes, increased as a function of the ambient temperature. The increase of blood content was enhanced by hexamethonium but reduced by atropine and NOARG. The weight increase was inhibited by hexamethonium, prazosin, HOE 140 and NOARG. At an ambient temperature of 40 degrees C, a large swelling developed around the submaxillary glands, resulting in a distention of the surrounding soft tissues. This local oedema fluid contained low levels of endogenous proteins but accumulated exogenous labelled albumin. This swelling was enhanced by atropine but decreased by hexamethonium, trasylol, HOE 140, NOARG, ketoprofen, a cyclooxygenase inhibitor, and prazosin. In kininogen deficient rats, the blood content of submaxillary glands increased as a function of ambient temperature. No increase in glandular weight and no swelling of the of the soft tissues were observed. After atropine, the weight of the glands increased and a swelling of the soft tissues appeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMedDate not supplied

The release of glandular kallikrein from submaxillary glands of rats exposed to heat.

The salivary flow elicited by phenylephrine was reduced in kininogen-deficient rats or by pretreatment of normal Wistar rats with HOE 140, a bradykinin antagonist. Salivary flow induced by substance P was similar in normal and kininogen-deficient rats. Phenylephrine released large amounts of kallikrein in saliva. Isoproterenol was less active while pilocarpine and substance P induced a small secretion of kallikrein. The saliva produced by anaesthetized rats in response to heat stress contained low levels of kallikrein. However a large depletion of the kallikrein content of submaxillary glands was observed in awake animals exposed to 36 degrees C and 40 degrees C for one hour. This depletion was suppressed by prazosin administered with a beta-adrenergic antagonist. Administered alone, these drugs had no effect, whereas atropine increased the depletion. The presence of kallikrein was observed in the oedema fluid which developed around the submaxillary glands in rats pretreated with atropine or exposed to 40 degrees C. A consumption of plasma kininogens occurred during heat exposure. The reflex-induced release of kallikrein during heat exposure is mainly controlled by sympathetic nerves through activation of both alpha and beta-adrenoreceptors. This release induces the formation of kinins which participate to the thermolytic salivation.

Animals↗

PubMedDate not supplied

BM 144: an original thromboxane A2 receptor antagonist derived from torasemide.

Torasemide, a new sulfonylurea high ceiling loop diuretic, has been demonstrated to induce a concentration dependent relaxation of canine coronary precontracted with thromboxane A2 (TXA2). With the aim to develop more potent TXA2 receptor antagonists, we investigated a series of torasemide derivatives. This pharmacomodulation led to the discovery of a sulfonyl-cyanoguanidine (BM 144) which presents the same pharmacological profile as sulotroban, a TXA2 receptor antagonist used as reference.

Humans↗