Components of a tissue kallikrein-kinin system (i.e. kininogen substrate kallikrein enzyme and the biologically active kinin peptides) have been identified within the central nervous system. The functional role of this brain peptide system is unknown but there is evidence to suggest that it may participate in the central regulation of blood pressure. The long-tern objective of this proposal is to determine the role of the brain kallikrein-kinin system in the central control of blood pressure in the normal physiologic state and whether this kinin peptide system contributes to the pathophysiology of hypertension in models, and ultimately in man. In these proposed studies, the activity of the brain kallikrein-kinin system will be evaluated through continuous sequential measurements of cerebrospinal fluid concentration of kinin in an in situ model. The role of the C1 area in the medulla of the brain as a potential site in mediating the effects of endogenous brain kinin on arterial pressure will be investigated utilizing stereotaxic microinjection techniques, push-pull cannula techniques, autoradiography.
The specific aims are to determine 1) endogenous levels of kininogen, kallikrein and kinin in the cerebrospinal fluid (CSF) in the basal state and under circumstances where afferent baroreceptor activity into the brain is altered by hemorrhage or vasodilator or vasoconstrictor drugs; 2) whether interruption of the brain kallikrein-kinin system by kinin receptor antagonists or the kallikrein inhibitors, or activation of the system by administration of kallikrein causes changes in blood pressure and heart rate; 3) whether kininogen, kallikrein, kinin and specific kinin receptors are present in the C1 area; 4) the cardiovascular effects of microinjections in to the C1 area of bradykinin are blocked by kinin antagonists. Ultimately, such information could provide a basis for the development of improved drug therapy for the management of hypertension.
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| Privitera, P J; Yates, P (1995) Hypertensive effect of tissue kallikrein in rostral ventrolateral medulla is mediated by brain kinins. Brain Res 704:103-6 |
| Privitera, P J; Thibodeaux, H; Yates, P (1994) Rostral ventrolateral medulla as a site for the central hypertensive action of kinins. Hypertension 23:52-8 |
| Khan, I M; Yamaji, I; Miller, D H et al. (1993) Cerebrospinal fluid kallikrein in spontaneously hypertensive and desoxycorticosterone acetate-salt hypertensive rats. J Hypertens 11:1039-45 |
| Privitera, P J (1992) Brain kallikrein-kinin system in arterial pressure regulation. Agents Actions Suppl 38 ( Pt 3):39-46 |
| Privitera, P J; Daum, P R; Hill, D R et al. (1992) Autoradiographic visualization and characteristics of [125I]bradykinin binding sites in guinea pig brain. Brain Res 577:73-9 |
