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Effect of Vasopressors on Atrial Natriuretic Factor and Hemodynamic Function in Humans

Effect of Vasopressors on Atrial Natriuretic Factor and Hemodynamic Function in Humans YORAM SHENKER, ERIC R. BATES, BRENT H. EGAN, JAMALHAMMOUD, AND ROGER J. GREKIN ; SUMMARY To assess the effects of
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Effect of Vasopressors on Atrial Natriuretic Factor and Hemodynamic Function in Humans YORAM SHENKER, ERIC R. BATES, BRENT H. EGAN, JAMALHAMMOUD, AND ROGER J. GREKIN ; SUMMARY To assess the effects of vasopressors on plasma levels of immunoreactive atrial natriuretk factor (ANF), 13 normal men were studied on two occasions. On the experimental day, subjects received sequential 15-minute intravenous infusions of angiotensin II in doses of 4, 8, and 16 pmol/kg/min. Following a 30-minute recovery period, subjects received sequential 15-minute infusions of phenylephrine in doses of 0.4 and 0.8 /tg/kg/min. Right atrial pressure, mean pulmonary capillary wedge pressure, pulmonary artery pressure, mean systemic arterial pressure, and plasma levels of renin activity, aldosterone, angiotensin II, and immunoreactive ANF were obtained sequentially throughout the protocol. During the control day, vehicle was infused and plasma samples were obtained for hormone measurements. Infusion of angiotensin II and phenylephrine increased mean systemic arterial pressure in a stepwise fashion. Both right atrial pressure and pulmonary capillary wedge pressure increased significantly during both doses of phenylephrine, but only the highest dose of angiotensin II significantly increased atrial pressures. Plasma levels of immunoreactive ANF increased in parallel with the changes in right atrial pressure and pulmonary capillary wedge pressure, with significant increases occurring only at the highest dose of both pressors. Angiotensin II and aldosterone levels increased and renin activity decreased during infusion of angiotensin II. There were no significant changes in plasma levels of immunoreactive ANF during the control day. These studies demonstrate that infusion of vasopressors increases plasma levels of ANF, but only when the vasopressor effect is associated with significant increases in right atrial and pulmonary capillary wedge pressures. Atrial stretch is the most likely mediator of the Increase in plasma levels of immunoreactive ANF during vasoconstriction. (Hypertension 12: 20-25, 1988) KEY WORDS atrial natriuretic factor * angiotensin II vasopressors * atrial pressure THE regulation of atrial natriuretic factor (ANF) secretion appears to be achieved primarily by changes in atrial pressure, presumably mediated through direct alterations in the stretch of the atrial tissues. 1 Conditions such as congestive heart failure 2-4 and chronic renal failure 5-6 are associated with increased plasma levels of immunoreactive ANF (iranf), probably due to increased atrial pressures. Previous studies have shown that plasma levels of iranf in patients with cardiac failure correlate closely with right atrial From the Department of Internal Medicine, Divisions of Endocrinology and Metabolism, Cardiology, and Hypertension, Veterans Administration Medical Center and the University of Michigan, Ann Arbor, Michigan. Supported in part by Grant from the American Heart Association, Grant HL from the National Heart, Lung, and Blood Institute, Grant 5M0I RR-42 from the Division of Research Resources, and by a grant from the Research Service of the Veterans Administration. Address for reprints: Dr. Yoram Shenker, Endocrinology Section, Medical Service, William S. Middleton Memorial Veterans Hospital, 2500 Overtook Terrace, Madison, WI Received October 15, 1987; accepted February 10, pressure and left atrial pressure as represented by pulmonary capillary wedge pressure. 7 Rapid saline infusion or atrial distention in rats 8-9 and saline infusion in humans 10 cause increases in plasma levels of iranf, which also correlate with increases in atrial pressure. 10 Infusion of vasopressors in rats has been reported to increase plasma iranf levels, apparently by increasing atrial stretch Studies in humans have also shown stimulatory effects of pressors on ANF secretion, but the role of atrial distention has not been explored in these studies. l3-14 In the present report, we describe the hemodynamic and hormonal effects of intravenous infusion of two vasopressors, angiotensin II (Ang II) and phenylephrine. The study was undertaken to examine the mechanisms of the stimulatory effects of vasopressors on the secretion of ANF in humans. Subjects and Methods Thirteen normal men aged 20 to 36 years were studied. All were within 10% of their ideal body weight and were found to be normotensive (supine 20 VASOPRESSORS AND ANF/Shenker et al. 21 blood pressure 135/85 mm Hg) on at least two occasions. None were taking any medication at the time of the study. Protocol Each volunteer was studied twice. Before each study, the subjects collected urine for 24 hours. On the day of the study, they ate breakfast as usual but did not eat lunch. AH studies were performed between 1300 and The experimental study was performed in the cardiac catheterization laboratory. Under fluoroscopic guidance, a thermodilution pulmonary artery catheter was inserted percutaneously through the femoral vein. Heart rate, right atrial pressure, pulmonary capillary wedge pressure, and mean pulmonary artery pressure were measured sequentially throughout the study. Blood pressure was measured using a sphygmomanometer, and cardiac output was measured using the thermodilution method. 15 Forty-five minutes after the subject had assumed the recumbent position, and 15 minutes after placement of the catheter, Ang II, diluted in saline, was infused through an antecubital vein at a rate of 4 pmol/kg/min. After 15 minutes, the rate was increased to 8 pmol/kg/min, and after an additional 15 minutes, to 16 pmol/kg/min. At the end of this dose, the infusion of Ang II was discontinued and the intravenous catheter was kept open with a small amount of saline for the next 30 minutes. Following this recovery period, phenylephrine, diluted in saline, was infused at 0.4 /ig/kg/min for 15 minutes and then at 0.8 /ng/kg/min for 15 minutes. The infusion of phenylephrine was discontinued, and the pulmonary artery catheter was removed. The subjects were observed for 30 minutes after removal of the catheter. Serum electrolytes were measured at the start of the study. Femoral blood was drawn for iranf, aldosterone, and plasma renin activity before beginning the Ang II infusion, at the end of each 15- minute infusion period, and following each recovery period. Samples were drawn for measurement of plasma levels of Ang II before, during, and after Ang II infusion. Hemodynamic measurements were obtained at the same times as blood sampling. The control study was performed 1 to 14 days after the experimental study. During this study blood sampling and volume infusion with normal saline were performed in the same fashion as during the experimental day. Antecubital veins in both arms were used for saline infusion and blood sampling. Blood pressure and heart rate were monitored throughout. Following 45 minutes of recumbency, an initial blood sample for serum electrolytes was obtained and samples were drawn throughout the study for plasma iranf levels. The total volume of saline infused, including 30 to 50 ml of saline for each determination of cardiac output, was approximately 300 ml for each day of the study. The total volume of blood drawn was 240 ml for the experimental day and 120 ml for the control day. No side effects of any kind were observed. The study was approved by the Human Studies Committees of the University of Michigan and the Veterans Administration Medical Center (Ann Arbor, MI, USA), and informed consent was obtained from each subject. Assays Urinary and serum electrolytes were measured by flame photometry (Klina-A, Beckman Instruments, Fullerton, CA, USA), and urinary creatinine was measured by autoanalyzer (Astra-8, Beckman Instruments). Plasma levels of aldosterone, renin activity, and Ang II were measured by radioimmunoassay Plasma iranf levels were measured by radioimmunoassay following an extraction step as previously described. 3 Intra-assay and interassay variations for immunoreactive human ANF were 8.5 and 12.6%, respectively. The lower limit of detectability of the assay was 3.4 pmol/l. Statistical Analysis Results are expressed as means ± SE. The data were analyzed using repeated-measures analysis of variance (ANOVA). A two-tailed paired t test with Bonferroni protection was used to compare individual measurements during the experimental day with corresponding control measurements. Fisher's modified least significant difference test was used to compare individual measurements with basal levels. For urinary excretion and serum electrolyte data, a two-tailed paired / test was used to compare the experimental and control measurements. The data were stored, processed, and analyzed using the CLINFO computer system at the Clinical Research Center of the University of Michigan Hospitals. Results Urinary measurements and serum electrolytes are shown in Table 1. Urinary volume, urinary creatinine, urinary electrolytes, and serum electrolytes were similar during the experimental and the control studies, and there were no significant differences for any of these data. The high urinary sodium excretion of 167 and 180 meq/24 hr is compatible with the high sodium diet typical for the United States. Figure 1 shows the results of mean arterial pressure and heart rate monitoring. Mean arterial pressure increased significantly during the lowest infusion rate of Ang II and continued to increase in response to the higher infusion rates. After infusion of Ang II, 16 pmol/kg/min, for 15 minutes, arterial pressure was 23 mm Hg higher than basal pressure. Mean arterial pressure returned to the basal level after the 30-minute recovery period and responded to phenylephrine infusion with progressive, significant increases, which reached 18 mm Hg following the higher infusion rates. Thirty minutes after the 22 HYPERTENSION TABLE 1. Urinary Measurements and Serum Electrolytes Urine Group Experimental Control Volume (ml/24 hr) 1131± Values are means + SE. Creatinine (g/24hr) 1.7± Sodium (meq/24 hr) Potassium (meq/24 hr) VOL 12, No 1, JULY 1988 Sodium (meq/l) 143 ± Serum Potassium (meq/l) termination of the protocol, the arterial pressure was still slightly but significantly elevated (98 ± 1 mm Hg; data not shown). There was a significant decrease in heart rate during the lowest infusion rate of both vasopressors and further significant slowing with the higher doses. Following the highest dose of both Ang II and phenylephrine, heart rate was decreased by 9 beats/ min compared with basal or recovery values (see Figure 1). During the infusion of both vasopressors, mean arterial pressure was significantly higher than at corresponding times during the control day. Neither arterial pressure nor heart rate changed significantly during the control day (see Figure 1). Figure 2 represents the results of mean levels of aldosterone, Ang II, and renin activity. As expected, Ang II levels rose sharply following increasing infusion rates of Ang II and returned to basal levels after 30 minutes of recovery. Aldosterone levels increased by almost 100% during infusion of the highest dose of Ang II. Following the recovery period, aldosterone decreased to levels close to Anglotensin II Control day MAP - HR * -* Phenylephrine Baial 4 fl 16 Recovery (pmo4/kg/mln) (ug/kg/mtn) -so -70 I O (Z I -50 FIGURE 1. Mean arterial pressure (MAP) and heart rate (HR) during experimental and control days (ANOVA for the experimental day: p for HR, p for MAP; ANOVA not significant for the control day). Asterisk indicates significant difference (a = 0.05, by Fisher's test) compared with basal levels. Double asterisk indicates significant difference (a = 0.05, by Fisher's test) compared with recovery values. Dagger indicates significant difference (p 0.05, by paired t test with Bonferroni protection) compared with corresponding timepoint during the experimental stage. basal and continued to decrease during phenylephrine infusion. Basal renin activity was low and decreased even further during the Ang II infusion. Renin activity remained stable during recovery and phenylephrine infusion. The systemic and pulmonary vasoconstriction achieved by both vasopressors resulted in concomitant decreases in cardiac output (Table 2). Calculated values for systemic and pulmonary vascular resistance increased sharply following both vasopressor infusions. Figure 3 shows right atrial pressure and pulmonary capillary wedge pressures as well as plasma iranf levels during pressor infusions. The increases in both pressures were nearly parallel and reached statistical significance following the highest dose of Ang II. Right atrial and pulmonary capillary wedge pressures were also significantly increased following the low dose infusion of phenylephrine and increased even further during the higher infusion rate. The maximal increases in both pressures were 3 and 4 mm Hg during phenylephrine infusion and only 2 mm Hg during Ang II infusion. Levels of iranf increased significantly following the highest infusion rate of both Ang II and phenylephrine (from 9.1 ± 2.1 to 17.1 ± 3.1 pmol/lfor Ang II and from 10 ± 2 to 14 ± 2 pmol/l for phenylephrine). During the control period, the levels did not change (Table 3). Basal levels during the control day were higher than basal levels during the experimental day (p 0.05). Discussion During these studies, the volunteers maintained their usual dietary habits. Sodium and potassium 0- V * 16- B C 12 - OJ 6- ROI P- O Q 4 - o J AngJoteneln II Ptienylaphrlne Basal 4 s 16 Recovery 0 4 OS (pmolag/min) (ug/kg/min) FIGURE 2. Ang II, aldosterone, and plasma renin activity (PRA) during the experimental day. (ANOVA: p for all variables). Single and double asterisks indicate significant difference (a = 0.05, by Fisher's test) compared with basal and recovery values, respectively. VASOPRESSORS AND ANF/Shenker et al. 23 TABLE 2. Cardiac Output, Pulmonary Artery Pressure, and Systemic and Pulmonary Vascular Resistances During the Experimental Day of Study Ang 11 (pmol/kg/min) Phenylephrine (/tg/kg/min) Variable Basal Recovery CO (L/min) PAP (mm Hg) SVR (dyn-sec-cm 5 ) PVR (dyn-sec-cm 5 ) 7.6±0.4 18±1 866±43 45±5 6.3±0.3* 17± ±86* ±0.3* ±110* 62 ±6' 6.0±0.3* 20±l 1383 ±65* 61 ±12* ±1 917±60 67±6 6.6±0.4t 21 + lt 1107±85t 76±7 6.0±0.3t 23±lt 1311±81t 93±7t Values are means ± SE. CO = cardiac output; PAP = pulmonary artery pressure; SVR = systemic vascular resistance; PVR = pulmonary vascular resistance. ANOVA for all the variables: p *a = 0.05, compared with basal values (Fisher's test). ta = 0.05, compared with recovery values (Fisher's test). intake, as reflected by urinary excretion data, did not change from the experimental to the control day. A relatively high sodium intake, as reflected by urinary sodium measurements, probably explains the low basal renin levels. Both Ang II and phenylephrine are potent vasoconstrictors, each acting by different mechanisms. Phenylephrine primarily activates vascular a,- adrenergic receptors, whereas Ang II acts through the angiotensin receptor. Both directly constrict vascular smooth muscle. As a result of these mechanisms, both agents cause a rapid and prominent elevation of blood pressure, as shown in Figure 1. The blood pressureelevating effects of Ang II are more prominent under sodium-replete conditions, which apply to our volunteers. 19 The significant decrease in heart rate observed after infusion of both pressors was expected on the basis of baroreceptor reflex brady- FIGURE 3. Right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), and immunoreactive ANF (iranf) levels during the experimental day. (ANOVA: p for RAP and PCWP, p for iranf). Single and double asterisks indicate significant difference (a = 0.05, by Fisher's test) compared with basal and recovery values, respectively. cardia. During the control stage both blood pressure and heart rate remained stable. Infusion of Ang II caused a rapid increase in circulating plasma levels of Ang II (see Figure 2), and the two higher infusion rates (8 and 16 pmol/ kg/min) caused significant increases in plasma aldosterone levels. The stimulation of aldosterone secretion was quite modest: The levels doubled following the highest infusion rate. This limited increase probably occurred because glomerulosa cells are relatively resistant to Ang II in sodium-replete subjects. l9 The decrease in renin activity during Ang II infusion is probably a result of direct suppressive effects of Ang II on renin secretion. 20 As expected, both pressor agents caused increases in systemic and pulmonary vascular resistance associated with elevations in mean arterial and pulmonary artery pressures. The effects of both pressor agents on right atrial and pulmonary capillary wedge pressures were very similar (see Figure 3). In each instance, the changes in atrial pressures were almost completely parallel. The highest infusion rate of angiotensin was needed to cause significant increases in atria! pressures, but both the low and the high infusion rates of phenylephrine caused significant increases. The plasma level of Ang II required to significantly increase atrial pressures was above the normal range for healthy subjects (20-83 pg/ml), but well within the range seen during diuretic therapy or in patients with congestive heart failure. 18-2I - 22 The highest infusion rate of Ang II caused almost a doubling of iranf levels, whereas the higher TABLE 3. Plasma Immunoreactive ANF Levels During the Control Day of Study Time (min) iranf (pmol/l) Basal ANOVA not significant 14.7± ± ± ± ± ±2.7 24 HYPERTENSION VOL 12, No 1, JULY 1988 infusion rate of phenylephrine caused an increase of 40% (see Figure 3). During the control day, iranf levels were stable throughout the study. The increase in iranf levels during the experimental day cannot be attributed to the modest volume infusion because the same volume was infused during the control day. Our own and other studies with hemodynamic monitoring during saline infusion 10 ' 23 suggest that much greater volumes and much more rapid infusions of saline are needed to increase levels of iranf. In rat studies, infusion of pressors including Ang II caused a prominent increase in iranf levels This increase seems to be closely related to changes in right atrial pressure. 12 Other studies have reported similar effects of Ang II on ANF levels in humans. Anderson et al. 24 found that doses of 10 ng/kg/min did not increase ANF levels. Using infusion rates of Ang II similar to those in the present study, Anderson and Miller 25 showed comparable increases in iranf levels. In that study, the effects of angiotensin were also evaluated following administration of the calcium channel blocker nifedipine. Pretreatment with nifedipine attenuated but did not abolish the increase in blood pressure, but it did abolish the Ang II-induced augmentation of plasma iranf levels. The authors postulated that Ang II stimulation of ANF is not dependent on the pressor action of Ang II but may be related to calcium movements blocked by nifedipine. These conclusions must be considered speculative since atrial pressure measurements were not obtained as part of the study. The results of the present study suggest that changes in iranf levels following pressor infusions are closely associated with changes in right atrial and pulmonary capillary wedge pressures. Increases in arterial pressure that did not result in increased atrial pressure did not affect plasma iranf levels. When increases in atrial pressure did occur, they were temporally associated with increased hormone levels in both instances. Both in vitro and in vivo studies provide evidence that atrial stretch is a direct stimulus for ANF secretion. 9 ' Catheterization studies in patients with cardiac disease have demonstrated a significant correlation between atrial pressure and plasma iranf levels, * and isolated increases in either right
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