We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive rats. A subdepressor dose of purified rat urinary kallikrein (700 ng/d IV) was infused by osmotic minipump for 4 weeks in male Dahl salt-sensitive rats fed a high salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure; however, urinary protein excretion was significantly decreased, and glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl salt-sensitive rats. Kallikrein infusion increased urinary A ngiotensin-converting enzyme (ACE) inhibitors affect both the renin-angiotensin and kallikrein-kinin-prostaglandin systems, inhibiting different catalytic sites on the same ACE. The cardiovascular protection induced by ACE inhibitors is primarily due to inhibition of the renin-angiotensin system. Recent advances in vascular biology suggest that the vasodepressor system participates in the progression or regression of cardiovascular injury.12 Vasodepressor eicosanoid directly delays the transition from the resting G0/G1 to DNA-synthetic (S) period progression in the proliferative cycle of vascular smooth muscle cells. 3 Moreover, enhancement of the endogenous production of prostacyclin attenuates vascular and renal injury in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats, a genetic model for salt-induced hypertension in humans. 4 Kinins stimulate the formation of nitric oxide, which also retards vascular smooth muscle cell proliferation. 56 The activity of the kallikrein-kinin-prostaglandin system is reduced in the kidneys of Dahl S rats. "9 Recently, kallikrein-like activity and its corresponding mRNAs have been found in the vascular wall.1012 More intriguingly, it has been reported that blood pressure cosegregates with a kallikrein gene restrictive fragment length polymorphism.13 These data Correspondence to Yoshio Uehara, MD, The Second Department of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.© 1994 American Heart Association, Inc.excretion of bradykinin and stimulated excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by rat urinary kallikrein infusion. The alterations induced by kallikrein infusion were potentiated by the concomitant administration of the angiotensin-converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl salt-sensitive rats. (Hypertension. 1994;24:770-778.) Key Words • kallikrein • renin-angiotensin system • rats, inbred Dahl • angiotensin-converting enzyme inhibitor • prostaglandins • kallikrein-kinin system clearly suggest that dysfunction of the kallikrein-kininprostaglandin system is involved in the genesis of saltinduced hypertension of Dahl S rats.We have ...
Aims: We investigated whether kallikrein infusion attenuates renal injury in Dahl salt-sensitive rats with hypertension and assessed the role of bradykinin-nitric oxide axis in the renal protection using HOE-140, the bradykinin type-2 (B2) receptor specific antagonist. Methods: Subdepressor dose of purified rat urinary kallikrein (RUK) (400 ng/day) was continuously infused through the jugular vein by an osmotic mini-pump for 4 weeks in Dahl salt-sensitive (Dahl S) rats fed a high-salt (2% NaCl) diet. Results: Blood pressure increased in a time-dependent manner in Dahl S rats fed a high-salt diet. The RUK infusion did not influence the elevation of blood pressure in Dahl S rats. However, the RUK infusion significantly decreased urinary protein excretion, and increased glomerular filtration rate, as compared with untreated high-salt Dahl S rats. Morphological investigation disclosed that the RUK infusion significantly attenuated glomerulosclerosis and arterial and tubular injuries in the kidney of hypertensive Dahl S rats. The RUK infusion produced an increase in urinary excretions of nitric oxide and cyclic guanosine monophosphate. In addition, the RUK infusion enhanced the generation of nitric oxide from the kidney slices. The functional and morphological effects of the RUK infusion on the kidney were completely lessened by co-administration of the bradykinin B2-receptor antagonist, HOE-140. Conclusion: Long-term infusion of subdepressor dose of rat urinary kallikrein attenuates functionally and morphologically the progression of renal injury in Dahl rats susceptible to salt-induced hypertension, and that the protection is mediated by stimulation of bradykinin B2 receptor.
The localization of tissue kallikrein in the pituitary gland of rats was investigated by an immunohistochemical technique using antiserum against rat urinary kallikrein. Kallikrein-positive cells were detected in the anterior lobe of the pituitary of both male and female rats, but were not observed in the posterior lobe of the pituitary in either sex. The kallikrein-positive cells in the anterior pituitary of female rats in oestrus were found to correspond to the prolactin-producing cells, whereas the cells producing GH, LH and ACTH were negative for kallikrein. It is possible, therefore, that the tissue kallikrein may be involved in the production of prolactin and not that of the other anterior pituitary hormones, such as GH, LH, FSH, ACTH and TSH.
Kallikrein-positive cells in the anterior pituitary of female rats were identified to be the same as prolactin-producing cells by using an immunoelectron microscopic method. The kallikrein immunoreactivity was localized at the Golgi apparatus, the rough endoplasmic reticulum, and secretory granules, suggesting that kallikrein is synthesized in the prolactin-producing cells and also may be secreted into the blood vessels.
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