Changes in the serum creatine kinase (CK) activity and the mechanism of its release after administration of two kinds of beta-blockers to rats were studied in order to determine the mechanism of the increase in serum CK accompanying administration of beta-blockers. When pindolol or propranolol was administered at a dose of more than 10 mg/kg of body weight, the serum CK activity was increased in proportion to the dose. Also when an alpha-stimulator or an alpha, beta-stimulator such as noradrenaline and adrenaline was administered, the serum CK activity was increased. When the beta-stimulator isoproterenol or the alpha 1-blocker prazosin was administered, there was no increase in the serum CK activity. In terms of consecutive administration of a combination of beta-blockers and adrenaline, the serum CK activity was not increased by the second and succeeding administrations. As for the use of adrenaline alone, on the other hand, the serum CK activity after the second administration was equal to that after the first administration. The increase in CK activity after administration of adrenaline as the second treatment following administration of a beta-blocker as the first treatment was approximately the same as that after single administration of adrenaline. From the fact that the serum CK activity in rats was increased by administration of an alpha-stimulator and of a beta-blocker, it is possible that CK release in the blood is due to the action of alpha-receptors rather than beta-receptors. In the case of consecutive administration of a beta-blocker, the serum CK activity was not increased after the second administration. However, the serum CK activity was increased by the administration of an alpha-stimulator. This finding suggests the possibility that CK release is due to the disturbance of the balance between alpha-receptor and beta-receptor. Most of the CK isoenzymes released in the blood after administration of a beta-blocker were of the MM type.
Recent clinical studies have established an important role of angiotensin converting enzyme inhibitors (ACE-I) as a tool for renal protection. Although angiotensin receptor antagonists (AII-A) share the common property with ACE-I with regard to blockade of angiotensin activity via angiotensin type 1 receptors (AT1), AII-A is also reported to stimulate AT2 that plausibly activates nitric oxide production within renal medulla and augments synthesis of vasodilatory P450-metabolites in renal afferent arterioles. In contrast, AII-A is reported to have no effect on bradykinin activity. Results obtained in experimental animals indicate that AII-A effectively prevents the progression of renal injury. Several clinical studies are in progress, and the preliminary results suggest that AII-A has potent renal protective action in a variety of renal disorders.
Short (2 weeks) and long (12 weeks) term effects of furosemide and chlorothiazide on blood pressure, plasma renin activity, and uric acid concentration were studied in 69 hypertensive patients. Both treatments caused significant reductions in blood pressure and increases in plasma renin activity and uric acid at 2 and 12 weeks in 6) normal renin patients; there was no difference between the effects of furosemide and that of chlorothiazide. Reduction in blood pressure in eight low renin patients who showed smaller changes in plasma renin activity and uric acid was not significant at 2 weeks but significant after 12 weeks of treatment.
Recently, we demonstrated that glucocorticoid potentiates inositol triphosphate production evoked by angiotensin II in vascular smooth muscle cells. To clarify this mechanism, we investigated the effects of dexamethasone on the modulation of angiotensin II type 1 receptor and on postreceptor mechanisms in vascular smooth muscle cells. The number of angiotensin II type 1 receptors began to increase after 12 hours' incubation with dexamethasone. After 48 hours, the Bmax value reached 27 +/- 3 fmol/mg protein in dexamethasone-treated cells and 15 +/- 3 fmol/mg protein in control cells. However, binding affinity did not change. A glucocorticoid antagonist, RU 38486, completely blocked these effects of dexamethasone. Also, to elucidate the effects of dexamethasone on postreceptor mechanisms, GTP analogue-induced inositol trisphosphate production in permeabilized cells was examined. Pretreatment with 1 mumol/L dexamethasone for 48 hours did not affect these inositol trisphosphate productions. Moreover, dexamethasone had no effect on the level of Gq alpha protein. Furthermore, steady-state levels of angiotensin II type 1 receptor messenger RNA were increased 2.2 +/- 0.3-fold after 30 minutes' exposure to 1 mumol/L dexamethasone and 7.8 +/- 0.4-fold after 24 hours. We conclude that glucocorticoid induced expression of the angiotensin II type 1 receptor gene and resulted in an increase in the number of angiotensin II type 1 receptors through the glucocorticoid-specific receptor, without significant effect on postreceptor systems in vascular smooth muscle cells.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)