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CARDIOVASCULAR ANESTHESIA

Splanchnic Organ Blood Flow During Calcitonin Gene-Related Peptide-Induced Hypotension With or Without Propranolol in Dogs

Department of Anesthesiology, Showa University Fujigaoka Hospital, Yokohama, Japan

Address correspondence and reprint requests to Shohei Takeda, MD, Department of Anesthesiology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama 227-8501, Japan. Address e-mail to shohei.takeda{at}nifty.com

	Abstract

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Propranolol has been used to attenuate reflex tachycardia during induced hypotension. The purpose of the current study was to determine whether propranolol can modify splanchnic organ blood flow during calcitonin gene-related peptide (CGRP)-induced hypotension in dogs anesthetized with 1.3% isoflurane in oxygen. After surgical preparation and hemodynamic stabilization, saline as a control, 0.5 mg/kg and 2.0 mg/kg propranolol (n = 10, each) were administered in a bolus injection 20 min before hypotension was induced. Mean arterial pressure was reduced to 60 mm Hg during 60 min of CGRP infusion. Renal blood flow (RBF), hepatic blood flow (HBF), and pancreatic blood flow (PBF) were measured using the hydrogen clearance method. Cardiac index did not change in all three groups, and heart rate in the control group remained unchanged. In the propranolol groups, however, heart rate decreased (P < 0.01). Plasma norepinephrine (NE), but not epinephrine (E), increased (P < 0.05) after propranolol administration. The NE and E increased (P < 0.01) during induced hypotension in all three groups. NE was higher in the 0.5 mg/kg propranolol group than in the control group. RBF in the control group remained unchanged throughout observation. RBF, HBF, and PBF decreased (P < 0.01) after propranolol and remained decreased during and after induced hypotension. The degrees of decreased HBF and PBF in the control group were less than those in the 2.0 mg/kg propranolol group. In conclusion, pretreatment with propranolol decreases splanchnic organ blood flow further during CGRP-induced hypotension, due in part to increased plasma catecholamine concentrations.

Implications: The reductions in splanchnic organ blood flows during CGRP-induced hypotension with propranolol are due to a reflex augmentation in sympathetic vasoconstrictor tone caused by an increase in plasma catecholamine concentrations. These findings suggest that propranolol may impair splanchnic organ blood flow during CGRP-induced hypotension.

	Introduction

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Calcitonin gene-related peptide (CGRP), an endogenous peptide in several biological processes, causes vasodilation, hypotension, and tachycardia (1), and produces splanchnic vasodilation (2). Despite these properties, CGRP has not been accepted as a vasodilating agent of clinical significance because of nuisance tachycardia. Reflex tachycardia caused by CGRP is blunted by ß-adrenoceptor antagonists (3), indicating that this change is likely mediated primarily by baroreceptor reflex. Propranolol, a nonselective ß-adrenergic antagonist, has been widely used as an anesthetic adjuvant to treat arterial hypertension, arrythmias, and ischemic heart disease (4), and to prevent tachycardia in response to induced hypotension (5).

However, propranolol has been reported to cause an increase in plasma norepinephrine (NE) concentration in humans (6). Blocking the ß-receptor with propranolol is suggested to result in an increase in plasma NE concentrations, with a resultant augmentation in -adrenergic activity (7). Therefore, -adrenergic vasoconstrictor tone caused by propranolol is of concern in the blood flow regulation of splanchnic organs. Because propranolol-induced alterations in plasma NE concentrations might have important clinical implications, we investigated the effects of propranolol on hemodynamics, catecholamine concentrations, and splanchnic organ blood flow during CGRP-induced hypotension in isoflurane-anesthetized dogs.

	Methods

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The study was approved by our animal experimentation committee. Thirty mongrel dogs (18.0 ± 0.5 kg) of either sex were anesthetized with sodium pentobarbital (25 mg/kg IV). After tracheal intubation, the lungs were mechanically ventilated with a volume-cycled ventilator (Model 613; Harvard Respirator, South Natrick, MA) to maintain normocapnia. Anesthesia was maintained with 1.3% isoflurane in oxygen via an Ohmeda Vaporizer (BOC Health Care, Windlesham, UK). End-tidal isoflurane and CO₂ concentrations were measured continuously by an infrared analyzer (Capnomac Ultima; Datex, Helsinki, Finland). Catheters were placed into the left femoral artery for systemic blood pressure monitoring and blood sampling, and into the right femoral vein for drug administration. Normal saline was infused at a rate of 7 mL · kg^-1 · h^-1. A 7F flow-directed pulmonary artery catheter (Swan-Ganz thermodilution catheter; Baxter Healthcare, Irvine, CA) was advanced into the pulmonary artery via the right external jugular vein for measurement of right atrial pressure (RAP), pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output (CO). CO was measured by thermodilution using 5 mL of cold temperature-monitored normal saline in triplicate. Results were recorded in the computerized system (Model MTC6210; Nihon Kohden, Tokyo, Japan). Heart rate (HR) was calculated from lead II of the electrocardiogram using a cardiotachometer (Model AT601G; Nihon Kohden). Mean arterial pressure (MAP) was determined electronically. Arterial blood was analyzed for pHa, PaCO₂, PaO₂, and base excess using a blood-gas analyzer (Radiometer ABL505, Copenhagen, Denmark). Plasma catecholamine concentrations were determined by high-performance liquid chromatography as previously described (8).

Dogs were laparotomized with a midline incision. Platinum electrodes (standard needle type 100 µM diameter, UHE-100; Unique Medical, Tokyo, Japan) were placed in the cortex of the left kidney, the left lobe of the liver, and the body of the pancreas. After completion of these procedures, the abdomen was closed. Splanchnic organ blood flows were measured by using the hydrogen clearance methods previously described (9).

After at least 60 min of hemodynamic stabilization, 30 dogs were randomly assigned to receive a bolus IV dose of 2 mg/kg propranolol (P2.0 group, n = 10), 0.5 mg/kg propranolol (P0.5 group, n = 10), or 2 mL/kg normal saline (control group, n = 10) over 2 min. CGRP infusion was started to reduce MAP to 60 mm Hg for the 60-min hypotensive period. Human CGRP() 0.001% dissolved in normal saline was used. All variables were measured 15 min after propranolol or normal saline, 30 and 60 min during CGRP infusion, and 30 min after discontinuation of infusion. Additional measurements were performed on hemodymanic variables 10 min after termination of the CGRP infusion.

Values were expressed as mean ± SEM. Intragroup differences were analyzed by two-way analysis of variance from repeated measurements of the same variables followed post-hoc by Tukey’s test. Intergroup comparisons (control group versus treatment groups) were analyzed by two-way analysis of variance from repeated measurement of the same variables followed by Dunnett’s test where appropriate. P < 0.05 was considered statistically significant.

	Results

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A hypotensive state of MAP at 60 mm Hg was achieved less than 5 min in all three groups. The doses of CGRP required to maintain the hypotensive period were 112 ± 16 ng · kg^-1 · min^-1 in the control group, 120 ± 30 ng · kg^-1 · min^-1 in the P0.5 group, and 112 ± 35 ng · kg^-1 · min^-1 in the P2.0 group, respectively. There were no significant differences in the time to achieve predetermined MAP or in the dosage of CGRP in all three groups.

The time course changes of hemodynamic variables are shown in Table 1. The HR in the control group remained unchanged. In contrast, HR in the propranolol groups decreased (P < 0.01) throughout observation. The cardiac index in all three groups did not change during and after CGRP infusion. RAP in the propranolol groups increased after propranolol administration, and it was higher in the propranolol groups than in the control group throughout observation. Pulmonary capillary wedge pressure in the control group decreased (P < 0.01) during the hypotensive period. Systemic vascular resistance did not change after propranolol administration, but was reduced (P < 0.01) during and after induced hypotension in all three groups. The time course of arterial blood gas variables are shown in Table 2. The PaO₂ in all three groups remained unchanged throughout observation. The base excess in all three groups decreased (P < 0.01) during and after induced hypotension. However, base excess values remained within normal limit.

View larger version (20K): [in this window] [in a new window]   Figure 1. Plasma norepinephrine concentration and plasma epinephrine concentration at baseline value, 15 min after drug (propranolol or saline) administration, 30 and 60 min during hypotension, and 30 min after hypotension in the control group (open circles, n = 10), in the propranolol 0.5 mg/kg group (open squares, n = 10), and in the propranolol 2.0 mg/kg group (solid squares, n = 10). Values are mean ± SEM. * P < 0.05 versus baseline; ** P < 0.01 versus baseline; P < 0.05 versus control.

View larger version (18K): [in this window] [in a new window]   Figure 2. Renal blood flow, hepatic blood flow, and pancreatic blood flow at baseline value, 15 min after drug (propranolol or saline) administration, 30 and 60 min during hypotension, and 30 min after hypotension in the control group (open circles, n = 10), in the propranolol 0.5 mg/kg group (open squares, n = 10), and in the propranolol 2.0 mg/kg group (solid squares, n = 10). Values are mean ± SEM. ** P < 0.01 versus baseline; P < 0.05 versus control; P < 0.01 versus control.

	Discussion

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Earlier studies reported that the hemodynamic effects of CGRP were not affected by propranolol in conscious rats (10) and dogs (11) as we observed in the current study of anesthetized dogs. In addition, muscarinic, histamine, platelet activating factor, and substance P antagonists and prostaglandin synthesis inhibitor also have no effects on the hemodynamic responses elicited by CGRP, suggesting that vasodilation induced by CGRP is mediated by direct peripheral interaction with CGRP receptors on vascular smooth muscle (10).

Prehypotensive values of hemodynamic variables (HR and RAP) and plasma NE concentrations in both propranolol groups were different from those of the control group. These findings indicate alterations of the hemodynamic and sympathetic environments by propranolol. In accordance with another study (6), the current study demonstrated increases in plasma NE after propranolol administration. Blocking the ß-adrenergic receptors with propranolol induces a reflex increase in the rate of release of NE from sympathetic neurons, with a resultant augmentation in -adrenergic activity (7). However, some investigators (12,13) have reported that the rate of NE spillover into plasma was unaffected by propranolol, suggesting that the increases in NE during propranolol administration was primarily the result of a decrease in the plasma NE clearance rate. Consequently, augmentation of -adrenergic activity caused by the increase in plasma NE in the current study appears sufficient in part to modulate the hemodynamic alterations and to contribute to the reductions in splanchnic organ blood flows.

RBF was maintained during CGRP-induced hypotension without propranolol, but reduced CGRP with propranolol pretreatment in this study. Hypotension was below the normal lower limit of autoregulation of the renal vasculature in dogs, because RBF intrinsically autoregulates with change in MAP from 80 to 180 mm Hg (14). Mechanisms responsible for the preservation of RBF may result in a direct vasodilating effect on renal vasculature, because CGRP has been reported to induce a dose-dependent increase in RBF and a dose-dependent decrease in renal vascular resistance (10,15). Prehypotensive values of RBF in the propranolol groups were different from those in the control group. In addition, no changes in RBF or plasma NE concentration caused by administration of an equivalent volume of normal saline (2 mL/kg) were observed in the control group. Alterations in plasma NE concentration may be more attributable to the changes in RBF.

HBF is maintained by both hepatic arterial and portal venous flows; this hepatic circulation is regulated by the hepatic arterial buffer response (16). The decreases in systemic blood pressure leads to decreased portal venous flow and consequently to decreased HBF. The small but significant decreases in HBF during hypotension in the control group may reflect primarily a redistribution of blood flows to the vital organs secondary to arterial hypotension, because the decrease in HBF was associated with a reduction in MAP, but with no significant alterations in CO or splanchnic vascular resistance (17). In the propranolol groups, the mechanisms of HBF reduction may be mediated by increases in NE and epinephrine concentrations, because NE infusion into the hepatic artery or portal vein increases hepatic arterial and portal resistance and decreases flow (18). Hence, propranolol may intensify hepatic arterial or portal venous vasoconstrictor effects of mixed - and ß-adrenoceptors caused by increased plasma epinephrine and NE concentrations.

Time course changes of PBF in all three groups were similar to those of HBF. The results of the current study, which showed significant increases in RAP in the propranolol groups—compared with the control group corresponding to the decreases in PBF—may be explained because autoregulation of the splanchnic vasculature is controlled by the intrinsic myogenic factor that regulates local blood flow in proportion to venous pressure elevation (19). Therefore, propranolol-induced alterations in RAP may have contributed, in part, to PBF reduction. The decrease in PBF caused by vasoconstriction could also be the result of reflex-increased sympathetic activity and circulating plasma catecholamines, because epinephrine and NE—when infused directly into the superior mesentric artery—decrease superior mesentic artery and portal venous flows, but can increase hepatic arterial flow (20). Ross and Kurrasch (21) reported that ß-adrenergic receptors are present in the hepatic arterial bed and that the changes in portal vein flow induced by catecholamines depend more on changes in the flow of blood through the intestines and spleen than on vascular changes within the liver. This indicates that the mesenteric artery is primarily responsible for liver circulation. Therefore, this suggests that the liver blood flow reduction in the current study may be caused, in part, by a decrease in PBF.

CGRP-induced hypotension, with or without propranolol, is associated with a decrease in splanchnic blood flow, but CGRP-induced hypotension may not increase risks for ischemic damage to the liver. This occurs because the hepatic blood flow, though decreased, was able to provide sufficient hepatic circulation to meet the oxygen supply and demand, as demonstrated by arterial blood-gas analysis. Moreover, alterations in circulating plasma catecholamines induced by propranolol may alter reflex control of splanchnic venous tone and thereby interfere with regulation and maintenance of venous return and CO. Splanchnic venous tone greatly contributes to the mobilization of blood volume by sympathetic nervous stimulation (22), and alterations in venous capacitance are a major component of the control of CO by affecting the filling of the right side of the heart (23). These findings in the propranolol groups may indicate that splanchnic organs may be at risk of hypoperfusion, but not ischemic damage, during hypotension, whereas redistribution of blood volume from the splanchnic organs appear to be attributable to hemodynamic stability.

CGRP is the most potent endogenous vasodilator studied in humans to date. Despite these properties, it has not been accepted as a vasodilating agent for clinical use. The lack of acceptance may be attributable, in part, to the tachycardia caused by CGRP. However, CGRP-induced tachycardia can be suppressed by volatile anesthetics (8). These hemodynamic profiles of CGRP during volatile anesthesia imply that it may be a safe vasodilating agent suitable for perioperative use, including induced hypotension and treatment of hypertension. The results in the current study are applicable to anesthesia using 1.3% isoflurane in oxygen with pentobarbital used as the anesthetic induction. But, it may not be applicable to other situations—such as isoflurane–N₂O in oxygen supplemented with ultra short-acting IV anesthetics, thiamylal, or propofol—because pentobarbital has a long elimination half-life. The different anesthetic action of these anesthetics may have intensified anesthetic depth and modified the splanchnic organ blood flow, because anesthetics differ in their effects on hepatic circulation (24). However, Greenway and Stark (25) analyzed many studies and concluded that HBF in dogs with pentobarbital was essentially the same as in conscious dogs. Hepatic arterial flow was increased at 1 and 2 minimum alveolar anesthetic concentrations of isoflurane-anesthetized dogs (26). Therefore, the interaction between pentobarbital and isoflurane on the hepatic circulation may not be defined exactly in the current study, but both anesthetics may affect the hepatic circulation only slightly. Our data nevertheless imply that CGRP-induced hypotension with propranolol should not be selected as the anesthetic tool when a decrease in HBF and a deterioration in hepatic oxygenation, or right ventricular dysfunction, are anticipated.

In conclusion, our results show that splanchnic organ blood flow responses induced by CGRP primarily result from a redistribution to the vital organs due to hypotension. Hemodynamic changes and reductions in splanchnic organ blood flow during CGRP-induced hypotension with propranolol are intensified because of a reflex augmentation in sympathetic vasoconstrictor tone caused by propranolol-induced alterations in circulating plasma NE concentrations. These findings suggest that a large dose of propranolol may impair the maintenance or adjustment of splanchnic organ blood flow during CGRP-induced hypotension.

	Acknowledgments

 
This study was supported, in part, by a grant from Showa University.

The authors thank Yoshie Hirakawa for excellent secretarial assistance. Human CGRP() was provided by Asahi Chemical Industry, Tokyo, Japan.

	Footnotes

 
This research was presented, in part, at the Annual Meeting of the American Society of Anesthesiologists, Orlando, FL, 1998 and Dallas, TX, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 1982;298:240–4.[Medline]
2. Mulholland MW, Sarpa MS, Delvalle J, Messina LM. Splanchnic and cerebral vasodilatory effects of calcitonin gene-related peptide I in humans. Ann Surg 1991;214:440–7.[Web of Science][Medline]
3. Lappe RW, Slivjak MJ, Todt JA, Wendt RL. Hemodynamic effects of calcitonin gene-related peptide in conscious rats. Regul Pept 1987;19:307–12.[Web of Science][Medline]
4. Foëx P. Alpha- and beta-adrenoceptor antagonists. Br J Anaesth 1984;56:751–65.[Free Full Text]
5. Bedford RF, Berry FA Jr, Longnecker DE. Impact of propranolol on hemodynamic response and blood cyanide levels during nitroprusside infusion: a prospective study in anesthetized man. Anesth Analg 1979;58:466–9.[Abstract/Free Full Text]
6. Lijnen PJ, Amery AK, Fagard RH, et al. The effects of ß-adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise. Br J Clin Pharmacol 1979;7:175–81.[Web of Science][Medline]
7. Cryer PE, Rizza RA, Haymond MW, Gerich JE. Epinephrine and norepinephrine are cleared through beta-adrenergic, but not alpha-adrenergic, mechanisms in man. Metabolism 1980;29:1114–8.[Web of Science][Medline]
8. Takeda S, Tomaru T, Inada Y. Haemodynamic and catecholamine responses to calcitonin gene-related peptide during volatile anaesthesia. Can J Anaesth 1998;45:1116–22.[Web of Science][Medline]
9. Takeda S, Tomaru T, Inada Y. The effect of CGRP-induced hypotension on organ blood flow during halothane anesthesia in dogs: a comparison with trimethaphan. J Anesth 1997;11:202–7.
10. Sirén A-L, Feuerstein G. Cardiovascular effects of rat calcitonin gene-related peptide in the conscious rat. J Pharmacol Exp Ther 1988;247:69–78.[Abstract/Free Full Text]
11. Wang BC, Bie P, Leadley RJ Jr, Goetz KL. Cardiovascular effects of calcitonin gene-related peptide in conscious dogs. Am J Physiol 1989;257 (Regul Integr Comp Physiol 26):R726–31.[Abstract/Free Full Text]
12. Rosen SG, Supiano MA, Perry TJ, et al. ß-Adrenergic blockade decreases norepinephrine release in humans. Am J Physiol 1990;258 (Endocrinol Metab 21):E999–1005.[Abstract/Free Full Text]
13. Best JD, Halter JB. Blood pressure and norepinephrine spillover during propranolol infusion in humans. Am J Physiol 1985;248 (Regul Integr Comp Physiol 17):R400–6.
14. Waugh WH, Shanks RG. Cause of genuine autoregulation of the renal circulation. Circ Res 1960;8:871–88.[Abstract/Free Full Text]
15. Villarreal D, Freeman RH, Verburg KM, Brands MW. Effects of calcitonin gene-related peptide on renal blood flow in the rat. Proc Soc Exp Biol Med 1988;188:316–22.[Medline]
16. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol 1985;249 (Gastrointest Liver Physiol 12):G549–56.
17. Kennedy WF Jr, Everett GB, Cobb LA, Allen GD. Simultaneous systemic and hepatic hemodynamic measurements during high spinal anesthesia in normal man. Anesth Analg 1970;49:1016–24.[Free Full Text]
18. Greenway CV, Lawson AE, Mellander S. The effects of stimulation of the hepatic nerves, infusion of noradrenaline and occlusion of the carotid arteries on liver blood flow in the anaesthetized cat. J Physiol 1967;192:21–41.[Abstract/Free Full Text]
19. Granger DN, Richardson PDI, Kvietys PR, Mortillano NA. Intestinal blood flow. Gastroenterology 1980;78:837–63.[Web of Science][Medline]
20. Hirsch LJ, Ayabe T, Glick G. Direct effects of various catecholamines on liver circulation in dogs. Am J Physiol 1976;230:1394–9.[Abstract/Free Full Text]
21. Ross G, Kurrasch M. Adrenergic responses of the hepatic circulation. Am J Physiol 1969;216:1380–5.[Free Full Text]
22. Rothe CF. Reflex control of veins and vascular capacitance. Physiol Rev 1983;63:1281–342.[Free Full Text]
23. Rothe CF. Reflex control of the veins in cardiovascular function. Physiologist 1979;22:28–35.[Medline]
24. Gelman S. General anesthesia and hepatic circulation. Can J Physiol Pharmacol 1987;65:1762–79.[Web of Science][Medline]
25. Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev 1971;51:23–65.[Free Full Text]
26. Gelman S, Fowler KC, Smith LR. Liver circulation and function during isoflurane and halothane anesthesia. Anesthesiology 1984;61:726–30.[Web of Science][Medline]

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