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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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.

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SUMMARY The cardiovascular responses to intravenous bolus administration of several synthetic atrial natriuretic peptides were examined in conscious spontaneously hypertensive rats and compared with the hemodynamic effects of continuous infusions of the peptides. Rats were instrumented with pulsed Doppler flow probes to allow measurement of regional blood flow in the conscious, unrestrained hypertensive rat. Bolus administration of increasing doses (0.036-18 nmol/kg) of atriopeptin II, o-rat atrial natriuretic peptide, Wy-47,663, or a-human atrial natriuretic peptide caused shortlived, dose-dependent reductions in mean arterial pressure and renal vascular resistance. A marked but transient (10-40 seconds) increase in renal blood flow was observed after administration of the peptides. Mesenteric and hindquarter vasodilation also were observed after bolus injection of high doses of the atrial peptides. Infusion of a-rat atrial natriuretic peptide or Wy-47,663 (0.045-1.44 nmol/kg/min) resulted in sustained reductions in mean arterial pressure. The fall in arterial pressure was accompanied by significant reductions in regional blood flow in the renal, mesenteric, and hindquarter vascular beds. Dose-dependent increases in regional vascular resistances were observed in all three vascular beds during the peptide infusions. These data indicate that the hemodynamic responses to synthetic atrial peptides are greatly dependent on the mode of administration of the peptide in conscious spontaneously hypertensive rats. Stable, sustained responses were observed only during infusion steady state conditions. (Hypertension 8: 866-873, 1986) KEY WORDS • regional blood flow • conscious spontaneously hypertensive rats • renal vascular resistance • renal vasodilation • atriopeptin T HE family of synthetic atrial peptides, collectively referred to as atrial natriuretic factor (ANF), has been demonstrated to possess potent natriuretic and diuretic properties (for recent reviews, see References 1 through 3) and to inhibit the release of aldosterone, 4 "* renin, 67 and vasopressin. 8Atrial natriuretic factor has also been reported to exert a marked influence on cardiovascular function. The atrial peptides have been reported to reduce arterial pressure in many experimental animal models 1 " 3 and humans 9 ; however, the depressor mechanism of action of ANF remains quite controversial. Initial observations suggested that ANF was a peripheral vasodilator, reducing arterial pressure by lowering total peripheral resistance. Indeed, several investigators have reported that ANF was a potent relaxant of isolated vascular smooth muscle.10 " 12 Also, ANF was observed to reduceFrom the Department of Experimental Therapeutics, Wyeth Laboratories, Inc., Philadelphia, Pennsylvania.Address for reprints: Rodney W. Lappe, Ph.D., Department of Experimental Therapeutics, Wyeth Laboratories, Inc., P.O. Box 8299, Philadelphia, PA 19101. Received October 6, 1985; accepted April 8, 1986. arterial pressure and total peripheral resistance in conscious ra...