RESUMEN
Numerous in vitro studies indicate that endothelium-mediated relaxation is reduced with development of hypertension. Considering the role of protein kinases in many metabolic processes of phosphate transferring and its importance in the cell communication and function [in the physiological and pathological states] and also the absence of any reports on the effects of these enzymes in the mediating responses to vasodilators during hypertension, this study became of interest. The objectives of this study were to measure the vascular responses to acetylcholine [ACh] and sodium nitroprusside [SNP] in the isolated rat aorta and mesenteric bed removed either from hypertensive or control rats and also to investigate the role of protein kinase C in these responses. Hypertension was induced in the male Sprague-Dawley rats [200-250 g] by DOCA-salt injection [20 mg/kg, twice weekly, for 5 weeks, s.c.] and NaCl [1%] was added to their drinking water. Control rats received saline injection [0.5 ml/kg, twice weekly, for 5 weeks, s.c.]. 5 weeks later, animals were anaesthetized with thiopental [30 mg/kg, i.p.], and arterial blood pressure was directly measured. Mean arterial blood pressure in control and hypertensive rats were: 98+/-7.5, 163 +/- 3.5, mmHg, respectively [P < 0.0001]. In in vitro studies, rings of descending aorta were cut and mounted for isometric tension recording in an organ chamber containg Krebs solution. After 1 h of stabilization, rings were precontracted with phenylephrine [5 x or 1 0-6 or 10-6 M], then concentration response curve to acetylcholine [ACh,-10-6 - 10-3 M] and SNP -10-8 - 10-4 M] were constructed. There was a significant decrease in response to Ach and also a reduction in the maximal response in rings isolated from hypertensive rats. Mesenteric beds were also removed either from control or hypertensive rats and perhsed with Krebs solution. After 1 h of stabilization, tissue were precontracted with norademalin M], then concentration-response curve to ACh [l0-8 - 10-4 M] and SNP [l0-8 - 10-4 M] were constructed. Responses to ACh but not to SNP were significantly reduced in tissue removed from hypertensive rats [eg. in response to l0-6 M of ACh: control: 41.6 +/- 4.9 hypertensive: 17.2 +/- 3.6 mmHg, P < 0.05]. However, addition of chelerythrine [l0 micro M], a protein kinase C [PKC] inhibitor, to the organ bath significantly restored these impaired responses. These results suggest that protein kinase C is involved in the endothelial dysfunction induced by hypertension
RESUMEN
The effects of tyrosine kinases on acute and chronic inflammation during diabetes are not fully determined. Therefore, the present study focuses on investigating the effects of genistein, a tyrosine kinase inhibitor, on acute and chronic inflammation in diabetic mice. The mice either received normal saline [control, 0.1 ml, i.p., n=144] or were injected with streptozotocin [diabetic, STZ, 200 mg kg -1, i.p., n=144]. By injecting carrageenan and implanting 2 cotton pellets [a week after the injection of saline or STZ] we induced acute and chronic inflammation. Before injecting carrageenan or 5 day after implantation, 9 mice from each group [control or diabetic] received genistein [10 mg kg -1, i.p.], indomethacin [2 mg kg -1, i.p.] or L-NAME [0.1 mg kg -1, i.p.]. Paw edema and the weight of cotton pellets were significantly higher in diabetic mice. Pretreatment with either indomethacin or L NAME significantly reduced the acute and chronic inflammation in the diabetic group. Genistein reduced chronic inflammation significantly [P<0.0001]. These results suggest that activation of tyrosine kinases as well as prostaglandins and nitric oxide pathways are involved in the increased chronic inflammatory responses observed in the diabetic animals