SUMMARY. The cardiovascular actions of the synthetic natriuretic peptide, atriopeptin II, were examined in conscious unrestrained spontaneously hypertensive rats and normotensive WistarKyoto rats. The animals were chronically instrumented with miniaturized pulsed Doppler flow probes to allow measurement of regional blood flow, or with an electromagnetic flow probe on the ascending aorta to facilitate the measurement of cardiac output in the conscious rat. Intravenous infusion of increasing doses of atriopeptin II (0.25-4 MgAg P e r min) caused a dose-dependent fall in mean arterial pressure in the hypertensive and normotensive rats. Blood flow in the renal, mesenteric, and hindquarters vascular beds was markedly decreased during the infusion of atriopeptin II, and regional vascular resistance was significantly increased in both groups of rats. Heart rate was significantly elevated (47 ± 14 beats/min) in the spontaneously hypertensive rats during atriopeptin II infusion, but no change in heart rate was observed in the Wistar rats. In the hypertensive rats, atriopeptin II caused a marked dose-dependent decrease in cardiac output (maximal decrease = -39 ± 4%) and stroke volume (maximal decrease = -48 ± 4%). Central venous pressure and left atrial pressure were also significantly reduced during atriopeptin II infusion. Total peripheral resistance was increased over the infusion protocol by 26 ± 3%. These data suggest that atriopeptin II infusion markedly attenuated cardiac output in the conscious spontaneously hypertensive rats. Total and regional vascular resistances were increased, possibly through reflex compensatory mechanisms, to maintain arterial pressure in the face of decreased cardiac output. Also, similar changes in regional vascular resistance were observed in normotensive and hypertensive rats, suggesting that these responses were not confined to the spontaneously hypertensive rat. (Circ Res 56: 606-612, 1985)

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1-(3-Mercapto-2-methyl-1-oxopropyl)indoline-2-carboxylic acids (7b) and related compounds were synthesized in order to examine their ability to inhibit angiotensin converting enzyme (ACE) and to reduce the systolic blood pressure of spontaneously hypertensive rats (SHR). All four possible stereoisomers of the precursor 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]indoline-2-carboxylic acid (6b) were characterized with absolute stereochemical assignment. The removal of the benzoyl group of the precursor to give 7b was conveniently carried out by treatment with 2-methoxyethylamine. Three of the four stereoisomers of the benzoyl derivative 6 showed in vitro ACE inhibitory activity in the following order: 6b(S,S) greater than 6b(S,R) greater than 6b(R,S). The stereoisomer having the R,R configuration was essentially inactive. The substitution at the C5 of the indoline nucleus with the Et or OMe group caused only marginal changes in the inhibitory activity. The mercaptan 7b(S,S) was the most active ACE inhibitor synthesized in this study, showing in vitro potency 3 times that of captopril. The augmentation of the potency may be due to the increased hydrophobicity of 7b(S,S) compared with captopril and suggests the presence of a hydrophobic pocket at the active site of ACE. When tested in spontaneously hypertensive rats, 7b(S,S) exhibited oral antihypertensive activity 27 times that of captopril. The corresponding benzoyl derivative 6b(S,S) was 24 times as potent as captopril. The thio lactone 10 obtained by cyclization of 7b(S,S) as a potential prodrug was less potent than the parent compound, 7b(S,S), in the ACE inhibitory and antihypertensive tests.

A series of tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines were synthesized and tested for their ability to relax K+-depolarized aortic smooth muscle and antihypertensive activity. It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity. Those compounds that were the most effective hypotensive agents (6a,7,8,9-tetrahydro-5-(phenylmethyl)pyrido[3,2-a]pyrrolo[1,2-a]++ +pyrazin- 6(5H)-one and 6a,7,8,9-tetrahydro-5-(4-pyridinylmethyl)pyrido[3,2-e]pyrrolo [1,2-a]pyrazin-6(5H)-one, 12 and 13, respectively) displayed little vascular smooth muscle relaxant activity.

Previous studies have demonstrated that infusion of synthetic atriopeptin II (AP II) lowered arterial pressure, reduced regional blood flow, and increased total peripheral and regional vascular resistances in conscious spontaneously hypertensive rats (SHR). This study was designed to examine the mechanism(s) involved in regional vasoconstrictor responses to AP II. In these experiments, hemodynamic actions of AP II were examined in control, 6-hydroxydopamine-treated (chemically sympathectomized), and renal-denervated groups of instrumented conscious SHR. Infusion of AP II (1 microgram X kg-1 X min-1) caused similar reductions in mean arterial pressure in control (-22 +/- 2 mmHg), chemically sympathectomized (-23 +/- 2 mmHg), and renal-denervated (-23 +/- 3 mmHg) SHR. In control SHR, AP II infusion reduced renal (-20 +/- 3%), mesenteric (-26 +/- 2%), and hindquarters (-18 +/- 10%) blood flow and increased regional vascular resistance in all three beds. Chemical sympathectomy prevented the fall in renal blood flow (RBF) and significantly abolished the regional vasoconstrictor responses to AP II infusion. In unilateral renal-denervated groups of SHR, AP II reduced renal vascular resistance (RVR) -11 +/- 3% but failed to alter RBF (-3 +/- 1%) in denervated kidneys. In contrast, RVR increased (20 +/- 7%) and RBF was significantly reduced (-29 +/- 3%) in contralateral-innervated kidneys. This study demonstrated that chemical or surgical destruction of renal sympathetic nerves abolished AP II-induced increases in RVR. These data further indicate that in conscious SHR the regional vasoconstrictor responses to AP II infusion appear to be mediated by increases in sympathetic tone rather than through direct vascular actions of AP II.