DIFFERENTIAL REGULATION OF KALLIKREIN, KININOGEN, AND KALLIKREIN-BINDING PROTEIN IN ARTERIAL HYPERTENSIVE RATS

This study was designed to determine whether the kallikrein-kinin syst em exerts a protective action in hypertension induced by chronic inhib ition of nitric oxide synthase. N-omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/100 mi water) was given orally to Sprague-Dawley rats, while controls received regular tap water. Hepatic kininogen mRNA leve ls in the L-NAME-treated group were 2.9- and 2.5-fold higher at 3 and 4 wk, respectively, compared with control rats, whereas kallikrein-bin ding protein (KBP) mRNA levels were 82% and 45% of the values found in control rats at 3 and 4 wk, respectively. There was no significant ch ange in hepatic alpha(1)-antitrypsin mRNA level under the same conditi ons. At 3 and 4 n lr post L-NAME treatment, renal kallikrein mRNA leve ls were 2.5- and 3.4-fold higher than in controls, whereas renal beta- actin mRNA level were similar between groups. Changes in the transcrip t levels of renal kallikrein, kininogen, and KBP were consistent with their protein levels. Immunoreactive total kininogen and low-M(r) kini nogen levels in sera and tissue kallikrein levels in kidney were signi ficantly higher in the L-NAME-treated group, whereas SCBP levels in th e circulation were lower compared with controls. Systolic blood pressu re was increased by 58 +/- 4 mmHg after 4 wk of L-NAME treatment. This effect was enhanced in rats given L-NAME in combination with HOE-140, a bradykinin B-2-receptor antagonist, at the dose of 100 mu g/day ip (79 +/- 5 vs. 58 +/- 4 mmHg, P < 0.05). This difference was confirmed by direct measurement of mean blood pressure (MBP). An intra-arterial bolus injection of 200 ng bradykinin significantly decreased MBP of L- NAME-treated rats, and this effect was blunted in the group treated wi th the bradykinin antagonist(-29 +/- 3 vs. -9 +/- 2 mmHg, P < 0.01). T hese results suggest that enhanced kallikrein and kininogen synthesis may have a protective role against the cardiovascular effects induced by chronic inhibition of nitric oxide synthesis.