The peptide hormone angiotensin II (AII) has been implicated not only in blood pressure homeostasis, but also in numerous other biological control mechanisms extending from regulation of thirst, ADH production, modulation of catecholamine release to auto regulation of renal function. It has been a widely accepted concept that tissue AII responses are regulated by AII derived from the peripheral circulation. However, it is now apparent that certain AII target tissues, linked to blood pressure regulation, contain locally synthesized renin and renin substrate which may generate AII at specific receptors, despite normal or even low plasma levels of this hormone. The recent observations, that tissues can produce AII, independent of the plasma renin system, has confirmed the postulate that AII in tissue may be regulated locally. However, the majority of evidence in support of the hypothesis for local generation has been gained indirectly by observing the physiological responses to pharmacological blockade of the renin system when plasma renin was low. Elucidation of mechanisms which control the activity of renin within AII target tissues such as the aorta and adrenal gland, particularly as this enzyme is related to hypertensive disease, remain to be determined and are long term objectives of this research. Specifically, this proposal is designed to delineate the interaction of the dopaminergic system to mediate tissue renin activity. Inhibition of dopamine by specific antagonists significantly and acutely increases tissue renin activity independent of the plasma renin system. Although the association between dopamine and the plasma renin angiotensin aldosterone system has been extensively investigated, our new information on the actions of dopamine antagonist to acutely increase tissue renin, may be central to the local mechanism by which angiotensin may mediate aldosterone secretion. The interactions between the dopamine and angiotensin systems may be pivotal in our ultimate delineation of mechanisms related to the interactions of dopaminergic agonists (which depress) and angiotensin II (which facilitate) catecholamine actions within arterial tissue to mediate blood pressure. The goals of the present study are to (i) describe the subtype of dopamine receptor responsible for modulating tissue renin by the use of specific receptor agonists and antagonists in vivo, (ii) determine the mechanism by which dopamine receptor antagonists increase tissue renin (activation of an inactive tissue renin or changes in renin synthesis by measurement of renin specific mRNA), (iii) investigate the correlation between increased renin in the adrenal gland and aldosterone secretion in vitro, and (iv) evaluate the antihypertensive effectiveness of dopamine agonists and their interactions with converting enzyme inhibitors to reduce blood pressure in experimental hypertensive animals in which blood pressure elevation is attributable to increased levels of tissue renin.
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| Eggena, P; Zhu, J H; Clegg, K et al. (1993) Nuclear angiotensin receptors induce transcription of renin and angiotensinogen mRNA. Hypertension 22:496-501 |
| Barrett, J D; Eggena, P (1991) Trypsin activation of inactive renin: plasma blanks and angiotensin I radioimmunoassay. Can J Physiol Pharmacol 69:1315-20 |
