We compared the effects of the converting enzyme inhibitor perindopril on components of the renin-angiotensin system in plasma and kidney of male Sprague-Dawley rats administered perindopril in their drinking water at two doses (1.4 and 4.2 mg/kg) over 7 days. Eight angiotensin peptides were measured in plasma and kidney: angiotensin-(l-7), angiotensin II, angiotensin-(l-9), angiotensin I, angiotensin-(2-7), angiotensin III, angiotensin-(2-9), and angiotensin-(2-10). In addition, angiotensin converting enzyme activity, renin, and angiotensinogen were measured in plasma, and renin, angiotensinogen, and their respective messenger RNAs were measured in kidney; angiotensinogen messenger RNA was also measured in liver. In plasma, the highest dose of perindopril reduced angiotensin converting enzyme activity to 11% of control, increased renin 200-fold, reduced angiotensinogen to 11% of control, increased angiotensin-(l-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels 25-, 9-, 10-, and 13-fold, respectively; angiotensin II levels were not significantly different from control. By contrast, for the kidney, angiotensin-(l-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels did not increase; angiotensin II levels fell to 14% of control, and angiotensinogen fell to 12% of control. Kidney renin messenger RNA levels increased 12-fold, but renal renin content and angiotensinogen messenger RNA levels in kidney and liver were not influenced by perindopril treatment. These results demonstrate a differential regulation of angiotensin peptides in plasma and kidney and provide direct support for the proposal that the cardiovascular effects of converting enzyme inhibitors depend on modulation of tissue angiotensin systems. Moreover, the failure of kidney angiotensin I levels to increase with perindopril treatment, taken together with the fall in kidney angiotensinogen levels, suggests that angiotensinogen may be a major rate-limiting determinant of angiotensin peptide levels in the kidney. {Hypertension 1991;18:763-773)A ngiotensin II (Ang II) plays a major role in the / \ regulation of blood pressure and fluid and J. X . electrolyte homeostasis. The major pathway of Ang II formation is by the action of renin (EC 3.4.99.19) to cleave the decapeptide angiotensin I (Ang I) from angiotensinogen, 12 with subsequent cleavage of the C-terminal dipeptide from Ang V by angiotensin converting enzyme (ACE) (dipeptidyl carboxypeptidase, peptidyldipeptide hydrolase; EC 3A.IDA).

No abstract

No abstract

Studies were undertaken to characterize angiotensin peptides in hypophysial-portal blood of conscious sheep and to determine whether the median eminence (ME) secretes angiotensin peptides into the hypophysial-portal circulation. Simultaneous measurements of angiotensin peptides in jugular and hypophysial-portal plasma were performed in 6 sheep. Cerebrospinal fluid (CSF) was collected and data for hypophysial-portal plasma were corrected for CSF contamination. Angiotensin peptides were also measured in extracts of sheep ME. In a separate group of 4 sheep, simultaneous measurements of angiotensin peptides in arterial and jugular plasma were performed. Using high performance liquid chromatography-based radioimmunoassays, 8 angiotensin peptides were measured: Ang-(1–7), Ang II, Ang-(1–9), Ang I, Ang-(2–7), Ang III, Ang-(2–9), and Ang-(2-10). Renin, angiotensinogen and prolyl endopeptidase were also measured. No differences in angiotensin peptide levels in arterial and jugular plasma were observed. Angiotensin peptide levels in hypophysial-portal plasma were similar to those in jugular plasma, except for Ang-(1–7), the levels of which were 5-fold higher in hypophysial-portal plasma, and Ang I, for which the levels in hypophysial-portal plasma were 46% of the jugular levels. Renin and angiotensinogen levels were similar in arterial, jugular, and hypophysial-portal plasma. Angiotensin peptide contents of sheep ME were < 16 fmol/ME. However, the prolyl endopeptidase content of sheep ME was 430-fold higher than plasma levels. The low levels of angiotensin peptides in sheep ME indicate that it does not secrete these peptides into the hypophysial-portal circulation. Rather, the high level of prolyl endopeptidase in ME is consistent with region-specific metabolism of Ang I delivered to the ME by arterial blood, generating increased levels of Ang-(1–7) in hypophysial portal plasma. The increased levels of Ang-(1–7) in hypophysial-portal plasma may play a role in regulation of pituitary function.

Several lines of evidence indicate that angiotensin peptides may be formed in the brain, where angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) may function as neurotransmitters. However, there is considerable controversy concerning the identity and levels of angiotensin peptides in the brain. We have used a novel high performance liquid chromatography-based radioimmunoassay to measure Ang-(1-7), Ang II, Ang-(1-9) and Ang I in various brain regions and in the pituitary of the rat and sheep. We also studied the effect of different methods of tissue extraction, and the effect of the converting enzyme inhibitor ramipril, on angiotensin peptide levels in the rat hypothalamus. The levels of Ang-(1-7), Ang II, Ang-(1-9) and Ang I were low (<25 fmol/g) in all brain regions examined, except for the sheep median eminence and cerebellar cortex where Ang II levels were 385±116 and 193±37 fmol/g (mean ± SEM, n = 6), respectively. Pituitary Ang II levels were 103±13 fmol/g in the rat and 63±18 fmol/g in the sheep. The levels of Ang-(1-7), Ang-(1-9) and Ang I were much lower than those of Ang II in brain and pituitary. Ang-(1-7) levels in the rat hypothalamus were low (<6 fmol/g) but methods of extraction which involved freezing and thawing of the tissue resulted in substantially higher levels of this peptide. Ang II levels in the rat hypothalamus (18±3 fmol/g) were reduced to undetectable levels (<6 fmol/g) by ramipril administration. The low levels of angiotensin peptides in the hypothalamus and brainstem indicate that if these peptides function as neurotransmitters in these regions, then they are of particularly low abundance. Moreover, our results indicate that the high levels of Ang-(1-7) reported previously for rat hypothalamus may be artefactual, due to the method of tissue extraction.