(Circulation. 1996;94:2201-2209.)
© 1996 American Heart Association, Inc.
Articles |
Reflex Coronary Vasoconstriction Caused by Gallbladder Distension in Anesthetized Pigs
the Laboratorio di Fisiologia, Dipartimento di Scienze Mediche, Facolta di Medicina e Chirurgia di Novara, Universita di Torino, Novara, Italy.
Correspondence to Prof G. Vacca, Facolta di Medicina e Chirurgia, via Solaroli 17, I-28100 Novara, Italy.
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Abstract |
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Background Gallbladder distension in anesthetized pigs reflexly increases heart rate and arterial pressure by means of afferent vagal pathways and efferent sympathetic mechanisms. The effect of such distension on the coronary circulation is unknown. The present study was undertaken to determine whether gallbladder distension primarily causes reflex changes in left circumflex blood flow.
Methods and Results In 21 pigs anesthetized with sodium pentobarbitone (16) or 
-chloralose (5), left circumflex blood flow was measured with an electromagnetic flowmeter. A balloon positioned within the gallbladder was distended with volumes of Ringer's solution equal to the volumes of bile previously withdrawn (mean vol: 62 mL; mean gallbladder pressure: 12 mm Hg). Heart rate and arterial pressure were kept constant by atrial pacing and by a pressurized reservoir connected to the left femoral artery. Gallbladder distension always caused a decrease in circumflex blood flow. In 6 of the 16 sodium pentobarbitone–anesthetized pigs, this decrease was graded by step increments of distension. In 5 of these 16 pigs, the decrease in circumflex blood flow was not affected by atropine. In 10 of these 16 pigs, including those given atropine, the response was not affected by propranolol but was abolished by subsequently giving phentolamine. Cervical vagotomy abolished the coronary vasoconstriction in the remaining 6 pigs. In the 5 -chloralose–anesthetized pigs, the response was not significantly affected by cutting the splanchnic nerves but was abolished by subsequent cervical vagotomy.
Conclusions The present study showed that innocuous distension of the gallbladder in anesthetized pigs caused a reflex coronary vasoconstriction that involved efferent sympathetic mechanisms related to -adrenoceptors and afferent vagal pathways.
Key Words: blood flow • gallbladder • reflex • vagus nerve
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Introduction |
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Distension of hollow viscera has been shown to stimulate mechanoreceptors located in their walls.1 2 3 Such stimulation in anesthetized animals causes reflex responses that involve the coronary circulation. For instance, distension of the urinary bladder, descending colon, or stomach has been reported to elicit reflex increases in heart rate and arterial blood pressure, which in turn lead to increases in left ventricular dP/dtmax and coronary blood flow.4 5 6 7 8 9 10 11 When these hemodynamic responses were prevented, the same distension primarily caused coronary vasoconstriction,6 8 9 11 accompanied by either small increases or no changes in left ventricular dP/dtmax.5 7 10
The walls of the gallbladder contain mechanoreceptors that respond to distension by discharging into afferent vagal or splanchnic nerve fibers; the latter pathway is believed to subserve nociception or reflexes related to gastrointestinal function.1 12 13 14 Recently, distension of the gallbladder by using physiological values of transmural pressure in anesthetized pigs has been shown to cause reflex increases in heart rate and arterial blood pressure that involved afferent vagal pathways and efferent sympathetic mechanisms.15 16 The effect of such a distension of the gallbladder on coronary blood flow is unknown.
The present study was planned to determine in anesthetized pigs the primary reflex effects of innocuous distension of the gallbladder on coronary blood flow and the reflex mechanisms involved. In addition, the effects of graded distensions of the viscus on the same flow were investigated.
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Methods |
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The experiments were carried out in a total of 21 pigs, weighing 65 to 84 kg, which were supplied by an accredited dealer (Azienda Cornelia srl, San Pietro Mosezzo, Novara, Italy). Food was withheld from all animals on the morning of the experiment. Sixteen pigs were anesthetized with intramuscular ketamine (20 mg/kg, Parke-Davis) followed after about 15 minutes by intravenous sodium pentobarbitone (15 mg/kg, Siegfried). The remaining five pigs were anesthetized with ketamine followed after about 15 minutes by intravenous bolus of
-chloralose (100 mg/kg, Sigma). All the animals were artificially ventilated with oxygen-enriched air by using a respiratory pump (Harvard 613, Harvard Apparatus). Anesthesia was maintained throughout the experiments in the 16-pig group by a continuous intravenous infusion of sodium pentobarbitone (7 mg·kg-1·h-1) and in the 5-pig group by a continuous intravenous infusion (0.5 to 1.0 mg·kg-1·min-1) of 1% -chloralose in saline solution. The experiments were carried out in accordance with the "Decreto legislativo 27 gennaio 1992, n. 116 (Attuazione della direttiva n. 86/609/CEE in materia di protezione degli animali utilizzati a fini sperimentali o ad altri fini scientifici)." The blood pressure in the ascending aorta and the right atrium was recorded by using two catheters connected to pressure transducers (Statham P23 XL, Gould) inserted into the right femoral artery and the right external jugular vein, respectively. The chest was opened in the left fourth intercostal space and the pericardium was cut. A catheter was inserted into the left ventricle through the left atrium and connected to a pressure transducer (Gould) to record left ventricular pressure. An electromagnetic flowmeter probe (model BL 613, Biotronex Laboratory Inc) was positioned around the proximal part of the left circumflex coronary artery to record coronary blood flow. Each probe was calibrated in vitro at the end of each experiment. Distal to the probe, a plastic snare was placed around the artery for the assessment of zero blood flow. To pace the heart, electrodes were sewn on the left atrial appendage and connected to a stimulator (model S8800, Grass Instruments), which delivered pulses of 3 to 5 V for 2 milliseconds' duration at the required frequency.
The gallbladder was exposed through a midline abdominal incision, the bile was withdrawn with a syringe, and a balloon catheter was introduced through a purse-string suture in the viscus and used to perform the distension experiments. Before emptying the gallbladder in the five pigs anesthetized with -chloralose, the pressure inside the viscus was 9.2±3.8 (range, 5 to 15) mm Hg. The volume of withdrawn bile was measured for use in the subsequent experiments. The exposed part of the cannula comprised two sections, one for the injection of warm Ringer's solution and one for the measurement of the pressure in the balloon. The solution was kept in a reservoir maintained at 38°C and was slowly injected into the intravisceral balloon with a syringe. To obtain the effective distending pressure, in each animal, the balloon was distended in vitro outside the gallbladder with the same volumes of Ringer's solution planned for subsequent experiments of distension. Gallbladder transmural pressure during the distension experiments was calculated as the difference between the values of pressure measured in the balloon inside the gallbladder (intravisceral balloon) and the values of intraballoon pressure previously obtained outside the gallbladder.
In some animals, the cervical vagal nerves or the splanchnic nerves immediately below the diaphragm were exposed. Arterial blood samples were used to measure the pH, PO2, PCO2 (with a gas analyzer; IL 1304, IL Instrumentation Laboratory), and hematocrit. The acid-base status of the animals was kept within normal limits as previously reported.17 The rectal temperature of the pigs was monitored and kept between 38°C and 40°C.
To prevent changes in aortic blood pressure during the experiments, a large-bore cannula was introduced into the abdominal aorta through the left femoral artery and connected to a reservoir primed with Ringer's solution and kept at 38°C. The reservoir was pressurized using compressed air, which was controlled using a Starling resistance, and pressure within the reservoir was measured by a mercury manometer. This procedure has been shown to allow the aortic blood pressure to be maintained at steady levels without significant changes in left ventricular pressures or hematocrit.6 10 11 Coagulation of the blood was avoided by the intravenous injection of heparin (Parke-Davis; initial dose of 500 IU/kg and subsequent doses of 50 IU/kg every 30 minutes).
Mean aortic and right atrial blood pressures, left ventricular pressure, pressure in the intravisceral balloon, and mean and phasic coronary blood flow were monitored and recorded, together with heart rate and left ventricular dP/dtmax, by using an electrostatic strip chart recorder (Gould ES 2000, Gould). The heart rate was obtained from the electrocardiogram.
At the end of the experiments, each animal was killed by intravenous injection of 90 mg/kg of sodium pentobarbitone.
Experimental Protocol
The experiments were performed after a steady state had been attained for at least 30 minutes with respect to heart rate, mean aortic blood pressure, mean right atrial pressure, mean coronary blood flow, left ventricular pressures, and dP/dtmax.
In each pig, distensions of the gallbladder were performed by injecting into the intravisceral balloon a volume of Ringer's solution equal to the volume of bile previously withdrawn. This method was used to ensure near physiological levels of distending volumes. Each distension lasted for a period of 1 minute. After the release of the distension, observations were continued for a further 2 minutes. The test period was during the last 15 seconds of distension, when a steady state in all measured variables had been attained. The response to each distension was calculated as the difference between means of variables during the test period and their average during two 15-second steady-state control periods taken immediately before the distension and 2 minutes after its release. Any change in measured hemodynamic variables caused by gallbladder distension was considered as a response only when it was reversed by the release of the distension. Zero flow in the coronary artery was checked before and after each experiment, and only the experiments in which it did not show any shift were considered.
In each pig, the initial distension experiment was performed without any attempt to control cardiovascular parameters. The distension experiments were then repeated while preventing changes in aortic blood pressure to determine the increase in heart rate in the absence of changes of arterial baroreceptor activity. The effect of distension on coronary blood flow was studied by repeating the distension experiments while preventing changes in heart rate and aortic blood pressure. The heart rate was kept constant by atrial pacing to a cardiac frequency faster than that noted beforehand during the distension in each animal.
To examine the reflex nature of the coronary blood flow response to distension of the gallbladder, the experiments were repeated when a steady state was attained after the intravenous administration of atropine sulfate (0.5 mg/kg; Sigma), propranolol (0.5 mg/kg; Sigma), or phentolamine (1 mg/kg; Ciba-Geigy) and after bilateral section of the cervical vagal nerves or the splanchnic nerves. Atropine was administered to 5 of the 16 pigs anesthetized with sodium pentobarbitone and propranolol to 10 of these pigs, which included the 5 pigs that had already received atropine. Phentolamine was given to the 10 pigs that had previously received propranolol. Bilateral cervical vagotomy was performed in the remaining 6 of the 16 pigs. In the 5 pigs anesthetized with -chloralose, the experiments of distension were repeated after cutting the splanchnic nerves and subsequently after additional cervical vagotomy.
Statistical Analyses
Student's paired t test was used to examine changes in measured variables caused by gallbladder distension. The relationship between gallbladder transmural pressure and changes in coronary blood flow was examined by using the least-squares procedures for linear correlation analysis. Analysis of variance and Student-Newman-Keuls test were used to examine the effect of successive procedures on coronary blood flow. A value of P<.05 was considered statistically significant. Group data are presented as mean±SD (range).
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Results |
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In all 21 pigs, recordings commenced
5 hours after the induction of anesthesia. The mean pH, PO2, and PCO2 of arterial blood were 7.40 (7.35 to 7.43), 120 (102 to 142) mm Hg, and 39 (37 to 43) mm Hg, respectively, and the hematocrit was 37% (31% to 42%). In the 16 animals anesthetized with sodium pentobarbitone, a total of 94 distensions of the gallbladder were performed, and the mean volume of Ringer's solution injected into the intravisceral balloon during the experiments of distension was 69.1±19.8 (30 to 120) mL. In the other 5 animals, which were anesthetized with -chloralose, a total of 35 distensions of the gallbladder were performed, and the mean volume of Ringer's solution injected into the intravisceral balloon was 48±13 (30 to 60) mL. During the preliminary experiments of distension, in all 21 animals, the resulting transmural pressure was 11.7±5.5 (5 to 33) mm Hg. Values of transmural pressure obtained in the 5 pigs anesthetized with -chloralose were not significantly different (P>.15) from values of pressure measured inside the gallbladder before emptying it. In the 16 pigs anesthetized with sodium pentobarbitone, control values of mean aortic blood pressure, heart rate, left ventricular dP/dtmax, and mean coronary blood flow, respectively, were 94.2±10.7 (80 to 111) mm Hg, 106.5±14.4 (85 to 132) bpm, 2196±354 (1813 to 2779) mm Hg/s, and 43.2±10.9 (24.1 to 63.1) mL/min. During the test period of gallbladder distensions without controlling hemodynamic variables, an increase in mean aortic blood pressure of 7.1±2.8 (4 to 15, P<.0005) mm Hg and a small group increase in heart rate of 1.8±1.9 (-1 to 6, P<.0025) bpm were obtained. These increases were accompanied by increases in left ventricular dP/dtmax and mean coronary blood flow, which respectively amounted to 101±53 (18 to 188, P<.0005) mm Hg/s and 2.5±2.5 (-0.5 to 7.9, P<.0025) mL/min. In the same animals, gallbladder distension while preventing changes in aortic blood pressure caused an increase in heart rate of 7.7±2.7 (2 to 12, P<.0005) bpm, which was accompanied by an increase in left ventricular dP/dtmax of 114±44 (26 to 192, P<.0005) mm Hg/s and by a group increase in mean coronary blood flow of 2±1.9 (-0.8 to 6.3, P<.0005) mL/min. During these experiments, changes in mean right atrial pressure and left ventricular end-diastolic pressure were insignificant (at least P>.20).
In the five pigs anesthetized with -chloralose, control values of mean aortic blood pressure, heart rate, left ventricular dP/dtmax, and mean coronary blood flow, respectively, were 91±17.3 (70 to 112) mm Hg, 102.4±10.2 (90 to 118) bpm, 2291±242 (1975 to 2612) mm Hg/s, and 48.1±9.6 (35 to 60) mL/min. In these animals, gallbladder distension without controlling hemodynamic variables caused increases in mean aortic blood pressure and heart rate of 11.6±2.9 (9 to 16, P<.0005) mm Hg and 5.6±1.5 (4 to 8, P<.0025) bpm, which were accompanied by increases in left ventricular dP/dtmax and mean coronary blood flow of 197±49 (119 to 252, P<.0005) mm Hg/s and 2.5±2.5 (-0.9 to 6.1, P<.05) mL/min. In the same animals, gallbladder distension while preventing changes in aortic blood pressure caused an increase in heart rate of 10.4±2.1 (8 to 13, P<.0005) bpm, accompanied by an increase in left ventricular dP/dtmax of 183±46 (123 to 230, P<.0005) mm Hg/s and by a group increase in mean coronary blood flow of 1.2±3 (-3.2 to 5, P>.20) mL/min. During these experiments, changes in mean right atrial pressure and left ventricular end-diastolic pressure were insignificant (at least P>.25).
The animals used for the present investigation were responsive to gallbladder distension in a manner similar to that previously observed,15 16 which allowed the determination of responses of heart rate and arterial blood pressure to be controlled in the present investigation.
Response of Coronary Blood Flow
The group increases in mean coronary blood flow obtained during the first two sets of experiments in the 21 pigs accompanied the increases in heart rate, arterial blood pressure, and left ventricular dP/dtmax; these increases can influence coronary blood flow by increasing myocardial demand for oxygen.18 However, despite the concomitant increases in hemodynamic variables, the increase in coronary blood flow did not occur in all pigs examined; in 5 pigs, this flow decreased and in the remaining 16 pigs, it increased. To avoid the secondary interference, the primary effects of gallbladder distension on coronary blood flow were examined with experiments performed while preventing changes in heart rate and arterial blood pressure. Such distension has been shown previously not to cause significant changes in left ventricular dP/dtmax.15 During this study, gallbladder transmural pressure was 11.7±5.4 (6 to 29) mm Hg.
An example of the hemodynamic changes caused by gallbladder distension in one pig is shown in Fig 1
. Group values of data in all experiments and individual changes in mean coronary blood flow are shown in the Table and Fig 2, respectively. As expected, distension of the gallbladder at constant heart rate and arterial blood pressure did not cause any significant change in left ventricular dP/dtmax. The same distension caused a decrease in mean coronary blood flow in each pig. Changes in left ventricular end-diastolic pressure and mean right atrial pressure were insignificant (Table). Considering all the animals, the decrease in mean coronary blood flow amounted to 9.1±4.8% (1.9% to 22.2%) of the control values. These findings indicate that distension of the gallbladder primarily caused coronary vasoconstriction.
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) and the 5 pigs anesthetized with 
). The values obtained during the test period of distension are plotted on the ordinate against the control values on the abscissa. The continuous line is the line of equality.
Response to Graded Distension
To examine the effect of graded distension on coronary blood flow, the gallbladder was distended in 6 of the 16 pigs anesthetized with sodium pentobarbitone in three steps by volumes of 45±10.5 (30 to 60), 60.8±22.5 (35 to 90), and 73.3±28.1 (40 to 120) mL. These distensions respectively resulted in transmural pressures of 5.5±2.3 (3 to 9), 9.2±2.5 (6 to 13), and 12.3±4.3 (8 to 20) mm Hg. The highest distending volume used in each pig was the same used in the initial experiments, as being equivalent to the aspirated volume of bile.
In each of the six animals, incrementing the distending volume augmented the responses of decrease in coronary blood flow (Fig 3). Group decreases in mean coronary blood flow for the three levels of distension were 2.3±1.1 (0.9 to 3.9, P<.0025), 3.7±1.2 (1.7 to 5, P<.0005), and 4.8±1.5 (2.4 to 7, P<.0005) mL/min, respectively. The response of mean coronary blood flow to the highest distending volume was significantly greater (P<.0025) than the response to the middle distending volume, which in turn was significantly greater (P<.0025) than the response caused by the lowest distending volume. Considering all the animals, there was a significant linear relationship (r=.62, P<.003) between the decrease in mean coronary blood flow and the gallbladder transmural pressure.
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Experiments With Atropine
In 5 of the 16 pigs anesthetized with sodium pentobarbitone, the administration of atropine caused an increase in heart rate of 10.2±3.8 (7 to 17, P<.0025) bpm in the absence of significant changes in mean aortic blood pressure, ie, -1.8±4.3 (-7 to 5, P>.20) mm Hg. These effects were accompanied by increases in left ventricular dP/dtmax and mean coronary blood flow of 95±54 (37 to 156, P<.01) mm Hg/s and 2.5±1.8 (-0.5 to 4, P<.025) mL/min, respectively. During the experiments performed after the administration of the drug, mean gallbladder transmural pressure was 10.8±1.9 (8 to 13) mm Hg.
The administration of atropine did not affect the response of coronary blood flow to gallbladder distension. The decrease in mean coronary blood flow during the experiments performed in these five pigs was 4.3±1.1 (2.7 to 5.2, P<.0005) mL/min, from a control value of 53.6±7.6 (44.3 to 60.8) mL/min. The difference between this response and the response obtained before the administration of atropine in the same five pigs was insignificant (P>.15). Changes in the other hemodynamic variables during the experiments were insignificant (at least P>.20).
Experiments With Propranolol
In 10 of the 16 pigs anesthetized with sodium pentobarbitone (which included the 5 pigs given atropine), the administration of propranolol caused a decrease in heart rate of 16.2±7.4 (6 to 30, P<.0005) bpm and an increase in mean aortic blood pressure of 6.9±5.3 (1 to 17, P<.0025) mm Hg. These changes were accompanied by decreases in left ventricular dP/dtmax and mean coronary blood flow of 322±300 (75 to 875, P<.005) mm Hg/s and 5.5±5 (0.4 to 13.7, P<.005) mL/min, respectively. During the experiments performed after the administration of the drug, mean transmural pressure was 13±5.3 (7 to 25) mm Hg.
The administration of propranolol did not affect the response of coronary blood flow to distension of the gallbladder. The decrease in mean coronary blood flow during the experiments performed in the 10 pigs amounted to 4.1±1.6 (2 to 7.5, P<.0005) mL/min, from a control value of 48.6±10.3 (26.5 to 60) mL/min. The difference between this response and the response obtained before the administration of propranolol in the same 10 pigs was insignificant (P>.47). Changes in the other hemodynamic variables during the experiments were insignificant (at least P>.15).
Experiments With Phentolamine
In the 10 of 16 pigs anesthetized with sodium pentobarbitone that were given propranolol, the subsequent administration of phentolamine caused a decrease in mean aortic blood pressure of 15±3.1 (10 to 20, P<.0005) mm Hg, which was accompanied by decreases in heart rate, left ventricular dP/dtmax, and mean coronary blood flow of 4.3±7.2 (-11 to 11, P<.05) bpm, 226±125 (75 to 468, P<.0005) mm Hg/s, and 3.4±5.8 (-10.7 to 7.4, P<.05) mL/min. The lack of increase in heart rate expected after reducing arterial blood pressure was due to the fact that 5 of the 10 pigs had received atropine in addition to propranolol. During the experiments performed after the administration of the drug, mean transmural pressure was 13.5±5.2 (7 to 25) mm Hg.
The administration of phentolamine completely abolished the decrease in mean coronary blood flow previously elicited by gallbladder distension. Changes in mean coronary blood flow during the experiments performed after giving the blocking agent amounted to 0.1±0.4 (-0.5 to 1, P>.20) mL/min, from a control value of 44.1±10.9 (25.9 to 57.8) mL/min. Changes in the other hemodynamic variables during the experiments were insignificant (at least P>.15). Analysis of variance for repeated measurements showed a significant difference in the responses of coronary blood flow to distension before and after the administration of phentolamine (F=69.6, P<.0005). The Student-Newman-Keuls test indicated that the response obtained after giving phentolamine was significantly different from those obtained before and after giving propranolol. A comparison between the individual responses of mean coronary blood flow before and after the administration of phentolamine is illustrated in Fig 4.
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Experiments After Cutting the Vagus or Splanchnic Nerves
Cervical vagotomy in 6 of the 16 pigs anesthetized with sodium pentobarbitone caused an increase in heart rate of 11.4±3.4 (6 to 16, P<.0005) bpm. This increase was accompanied by group decreases in mean aortic blood pressure, left ventricular dP/dtmax, and mean coronary blood flow of 5.3±8.5 (-15 to 3, P>.05) mm Hg, 42±96 (-144 to 143, P>.15) mm Hg/s, and 2.6±2.6 (-5 to 1.8, P<.05) mL/min, respectively. During the experiments performed after the intervention, mean transmural pressure was 9.3±1.8 (7 to 12) mm Hg.
Bilateral vagotomy completely abolished the response of coronary blood flow to distension of the gallbladder. In these six pigs, changes in mean coronary blood flow during the experiments performed after the intervention were 0.1±0.4 (-0.4 to 0.7, P>.25) mL/min, from a control value of 39.9±4.8 (34.5 to 47.3) mL/min. Changes in the other hemodynamic variables during the experiments were insignificant (at least P>.20). Analysis of variance for repeated measurements showed a significant difference in the responses of coronary blood flow to distension before and after vagotomy (F=33.2, P<.003). A comparison between individual responses of mean coronary blood flow before and after vagotomy is illustrated in Fig 5.
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In the five pigs anesthetized with -chloralose, the section of the splanchnic nerves did not have consistent effects on arterial blood pressure, heart rate, left ventricular dP/dtmax, and mean coronary blood flow. Group variations in these hemodynamic variables respectively amounted to -2.6±3.6 (-8 to 2, P>.05) mm Hg, -0.4±3.9 (-5 to 5, P>.40) bpm, -70±72 (-160 to 10, P<.05) mm Hg/s, and -0.6±2 (-3.2 to 1.7, P>.25) mL/min. The subsequent section of the vagus nerves caused an increase in heart rate of 15±4.7 (13 to 22, P<.0025) bpm, which was accompanied by small changes in mean aortic blood pressure, left ventricular dP/dtmax, and mean coronary blood flow that respectively amounted to 1.2±3.9 (-5 to 5, P>.25) mm Hg, 42±33 (-13 to 71, P<.025) mm Hg/s, and 1±2.5 (-4.1 to 2.1, P>.20) mL/min.
In each of the five animals, cutting the splanchnic nerves did not affect the increases in mean aortic blood pressure and heart rate at constant arterial blood pressure previously caused by gallbladder distension. These increases respectively amounted to 11.4±2 (10 to 14, P<.0005) mm Hg and 10.2±2.7 (8 to 14, P<.0025) bpm and were not significantly different from those obtained in the same animals before the intervention (P>.35 and P>.30). Similarly, in each of the five pigs, the section of the splanchnic nerves did not affect the response of decrease in mean coronary blood flow at constant heart rate and arterial blood pressure to gallbladder distension (Fig 6). The group decrease in this flow amounted to 7.8±1.8 (-9.7 to -5.1, P<.0005) mL/min and was not significantly different (P>.30) from that obtained during distension before the intervention. In each of the same five pigs, cutting the vagus nerves abolished the response of coronary blood flow to gallbladder distension (Fig 6). Changes in mean coronary blood flow during the experiments performed after the intervention amounted to -0.1±0.3 (-0.5 to 0.3, P>.20) mL/min. Changes in the other hemodynamic variables during the experiments performed in the five pigs after section of the splanchnic or the vagus nerves were insignificant (at least P>.20). Analysis of variance for repeated measurements showed a significant difference in the responses of coronary blood flow to distension before and after vagotomy (F=49.9, P<.0005). The Student-Newman-Keuls test indicated that the response obtained after vagotomy was significantly different from those obtained before and after section of the splanchnic nerves.
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Discussion |
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The major finding of this investigation was that distension of the gallbladder in anesthetized pigs primarily caused a reflex decrease in mean coronary blood flow that involved vagal afferent pathways and sympathetic efferent mechanisms. This response could be unraveled only after controlling responses of and changes in hemodynamic variables that secondarily could mask the response of coronary blood flow. These reflex coronary responses to distension of the gallbladder were similar to those that occur during distension of the stomach, colon, and urinary bladder.
Reflex Potentials
There is previously reported evidence indicating that the gallbladder and the biliary ducts are innervated by afferent vagal and splanchnic nerve fibers.19 The mechanoreceptors that discharge in the splanchnic nerves are believed to play a role in nociception or reflexes related to gastrointestinal function.1 12 13 14 The function of the mechanoreceptors that discharge into the vagus nerves is not known, although it is not thought to involve the process of nociception.1
Previous reports on models of distension of the gallbladder designed to stimulate mechanoreceptors have indicated variable changes in hemodynamic factors. However, this variability could be explained by differences in responses observed and secondary interference by concomitant hemodynamic changes. For instance, during distension of the gallbladder or biliary tract in patients with biliary tract disease, variable changes in heart rate and electrocardiogram accompanied increases in arterial blood pressure.20 21 Distension of the biliary tract in anesthetized dogs was reported to decrease arterial blood pressure and cause variable changes in heart rate that were associated with electrocardiographic changes after ligation of one or more coronary arteries.22 Gallbladder distension in anesthetized cats was reported to cause an increase in arterial blood pressure23 or inconsistent changes in hemodynamic variables,24 and distension of the biliary system in anesthetized ferrets was reported to increase arterial blood pressure.12 The effect of distension of the gallbladder on the coronary circulation is unknown. Therefore, it may be concluded from these variable reports that gallbladder distension can increase arterial blood pressure. However, this increase can interfere with other possible responses, including heart rate and coronary blood flow.
In pigs anesthetized with sodium pentobarbitone, gallbladder distension has been shown to elicit reflex increases in heart rate and aortic blood pressure without primarily affecting left ventricular inotropic state.15 16 These findings were enabled by avoiding secondary interferences. For instance, the increase in heart rate was obtained after preventing changes in arterial blood pressure, and the absence of changes in left ventricular inotropic state was shown after preventing the increases in heart rate and arterial blood pressure. In these reports, it was shown that the reflex responses involved afferent vagal pathways and efferent sympathetic mechanisms.15 16 These previous reports have made it possible to develop a model to test whether or not distension of the gallbladder primarily affects coronary blood flow by preventing changes in heart rate and arterial blood pressure and in the absence of changes in left ventricular dP/dtmax, which have been reported to affect coronary blood flow.18
Responses to Gallbladder Distension
In the present experiments, in 16 pigs we used the same anesthetic (sodium pentobarbitone) and experimental techniques. Distension of the gallbladder primarily caused an increase in heart rate and mean aortic blood pressure without affecting left ventricular dP/dtmax. Despite these increases, gallbladder distension caused a decrease in mean coronary blood flow in 4 of the 16 pigs, but group changes were not statistically significant. However, a consistent decrease in mean coronary blood flow in response to this distension in each of the 16 pigs was shown after preventing the increases in heart rate and aortic blood pressure and in the absence of changes in left ventricular contractility. In addition, in the present investigation, we examined the effect of gallbladder distension in 5 pigs anesthetized with -chloralose by an otherwise identical experimental protocol. Although our plan was to extend previous experience in pigs anesthetized with sodium pentobarbitone,15 16 it has been found that this anesthetic could impair reflex transmission.25 In the experiments with -chloralose, we found that gallbladder distension caused qualitatively the same response of an increase in heart rate and arterial blood pressure without affecting left ventricular dP/dtmax. The magnitude of the two responses showed marked overlap compared with those obtained in pigs anesthetized with sodium pentobarbitone. As with sodium pentobarbitone anesthesia, distension of the gallbladder under -chloralose anesthesia caused a primary decrease in mean coronary blood flow at constant heart rate and arterial blood pressure and in the absence of changes in left ventricular dP/dtmax. This decrease of coronary blood flow (about 15% of the control values) was somewhat greater than that observed in the 16 pigs under barbiturate anesthesia (about 7%). These findings suggest that gallbladder distension caused a primary response of coronary vasoconstriction, since it occurred in the absence of changes in heart rate, arterial blood pressure, left ventricular contractility, and filling pressures of the right and left sides of the heart. That this coronary vasoconstriction was primarily related to distension of the gallbladder was supported by the ability to grade the magnitude of this response by incrementing the level of gallbladder distension.
Reflex Mechanisms
A further finding in the present investigation was the demonstration that the coronary vasoconstriction in response to distension of the gallbladder was reflex in nature. The afferent pathway of this reflex response was shown to involve the vagus nerves, and the efferent pathway was shown to involve sympathetic mechanisms. Bilateral cervical vagotomy in pigs anesthetized with either sodium pentobarbitone or -chloralose always abolished the reflex response of coronary vasoconstriction at a time when cutting the splanchnic nerves did not have this effect. It has previously been shown that the results of reflex responses to distension of the stomach after bilateral cervical vagotomy were the same as those obtained after bilateral vagotomy performed at the level of the diaphragm.10 11 A further finding was that in the pigs anesthetized with -chloralose, cutting the splanchnic nerves did not affect the magnitude of responses of increased heart rate or arterial blood pressure. These results support our previous findings that responses of increased heart rate and arterial blood pressure15 16 and coronary vasoconstriction in the present investigation involved only afferent vagal pathways and occurred whether pigs were anesthetized with sodium pentobarbitone or -chloralose.
The present findings of obtaining reflex cardiovascular changes in response to stimulation of abdominal visceral afferents are consistent with previous reports in anesthetized cats showing that distension of the stomach elicited an increase in mean aortic blood pressure and heart rate accompanied by coronary vasoconstriction.26 27 28 Similar hemodynamic responses were obtained in the same experimental model after the application of capsaicin or bradykinin to the gallbladder or stomach.24 29 In these studies, it has been shown that the afferent limb of the reflex hemodynamic responses observed involved the splanchnic nerves.24 26 The reason for the difference in the afferent pathway of the present investigation and that previously reported is unknown. However, the involvement of a vagal afferent pathway in the present study suggests that mechanoreceptors in the gallbladder play a role in the reflex control of the coronary circulation.
Although the coronary vessels are innervated by both sympathetic and vagal nerve fibers, the latter did not contribute to the reflex coronary vasoconstriction elicited by gallbladder distension. This response was not affected by atropine, despite a decrease in the baseline values of coronary blood flow caused by the drug. The sympathetic effects leading to reductions in coronary blood flow involved -adrenergic mechanisms; the administration of propranolol did not affect this response, which was eventually abolished by phentolamine. It is of interest that other models that used capsaicin or bradykinin to stimulate visceral afferents from the gallbladder or the stomach in anesthetized cats showed a reflex coronary vasoconstriction that was also mediated by -adrenergic effects.29 In addition, in another report in anesthetized cats, a relative reflex -adrenergic coronary vasoconstriction and a more marked vasoconstriction in several other regional vascular beds have been observed when using the microspheres technique in response to gastric distension.28 In the present investigation, we did not observe potentiation of the reflex coronary vasoconstriction following ß-blockade, which hypothetically could result in unmasking -adrenergic vasoconstriction. It is notable that pigs have been reported to have little or no coronary -adrenergic receptors.30 31
Distension of other viscera, such as the urinary bladder, stomach, or descending colon, has been shown to primarily cause reflex coronary vasoconstriction similar to that obtained with distension of the gallbladder.6 8 9 11 The reflex coronary vasoconstriction in response to distension of the urinary bladder involved efferent vagal and sympathetic pathways.6 In common with the gallbladder, however, the coronary response to distension of the stomach and the descending colon involved only efferent sympathetic mechanisms.9 11
Clinical Implications
These findings suggest that distension of the viscera affects the coronary circulation and may be involved in some clinical conditions. Distension of the stomach has been related to the occurrence of postprandial angina; the response of coronary vasoconstriction may limit the increase in coronary blood flow that accompanies increases in heart rate and aortic blood pressure.11 28 Gallbladder disease has been associated with coronary artery disease and angina pectoris.32 33 The present results suggest that distension during gallbladder disease may limit increases in coronary blood flow and play a role in precipitating or aggravating angina pectoris. The decreases in coronary blood flow observed in the animals anesthetized with sodium pentobarbitone may have been small but were predominant in some of the pigs despite the influence of increases in heart rate, aortic blood pressure, and myocardial contractility that normally would have masked the reflex decrease in coronary blood flow. A greater coronary vasoconstriction was in fact observed in the pigs anesthetized with -chloralose. In addition, at the end of the experiments, we did not find a significant amount of bile in the gallbladder when it was examined postmortem. We therefore believe that our present results provide the foundation for involvement of gallbladder mechanoreceptors and their reflexes in the control of the coronary circulation. They also offer explanations for the association between gallbladder disease and myocardial ischemia. Also, we were able to increase the coronary vasoconstrictive response by increasing the degree of gallbladder distension, although we used a distending volume of Ringer's solution that was essentially equal to the volume of bile present in the gallbladder, a technique of distension that resulted in values of transmural pressure similar to those measured in the gallbladder before emptying the viscus and that are considered unlikely to evoke nociceptive responses.12
Conclusions
The present investigation has shown that distension of the gallbladder by a volume of Ringer's solution equal to its content of bile reflexly caused coronary vasoconstriction. The afferent pathway of the reflex was in the vagus nerves, and the efferent pathway involved sympathetic mechanisms related to coronary -adrenoceptors.
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Acknowledgments |
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This research has received generous sponsorship by the University of Turin and Banca Popolare di Novara.
Received March 25, 1996; revision received May 28, 1996; accepted May 30, 1996.
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