Comparative carcinogenicity in Sprague-Dawley rats of the polychlorinated biphenyl mixtures Aroclors 1016, 1242, 1254, and 1260.

A comprehensive chronic toxicity and carcinogenicity study was conducted on a series of Aroclors (1016, 1242, 1254, and 1260). Each Aroclor was assessed at multiple dietary concentrations, ranging from 25 to 200 ppm, for 24 months in male and female Sprague-Dawley rats. Liver toxicity was indicated by elevated serum enzyme activity (AST, ALT, and GGT), elevated serum cholesterol concentration, decreases in hematologic parameters (RBC, Hb, and Hct), hepatocellular hypertrophy, an increased incidence of altered hepatocellular foci, and an increased incidence of hepatocellular neoplasms (primarily adenomas). Liver toxicity was distinctly more severe in females than in males. The incidence of hepatocellular neoplasms was highly sex-dependent (females >> males), differed between Aroclor mixtures and, for females, increased with dose and followed the general incidence pattern of Aroclor 1254 > Aroclor 1260 approximately Aroclor 1242 > Aroclor 1016. A significant response (p < 0.05) in males was seen only for the high dose of Aroclor 1260. A small increase in the incidence of thyroid gland follicular cell adenomas was noted in males for Aroclors 1242, 1254, and 1260, with the incidence being uniform across dose groups and Aroclor mixtures. For females, increased survival relative to controls was observed for all Aroclor treatment groups. A significantly decreased trend in the incidence of mammary gland neoplasms compared to control was also noted for females receiving Aroclors 1242, 1254, and 1260.

Nitric oxide mediates fluid accumulation during cardiopulmonary bypass.

Fluid accumulation during cardiopulmonary bypass may be related to the production of endogenous vasoactive substances. We investigated the role of nitric oxide in mediating fluid accumulation during cardiopulmonary bypass. Normothermic cardiopulmonary bypass was carried out for 3 hours in male Sprague-Dawley rats with constant, nonpulsatile flow and hemodilution. Fluid accumulation (rate of change of external reservoir volume) was measured under three experimental conditions: saline solution control (n = 8), L-arginine infusion (n = 6), and N-nitro-L-arginine methyl ester infusion (n = 6). At the end of the experiments, body weight and organ wet/dry ratios were examined. Percentage weight gain was 77% greater in the N-nitro-L-arginine methyl ester group and 23% less in the L-arginine group compared with control values. Fluid accumulation was increased with N-nitro-L-arginine methyl ester after 30 minutes (p < 0.01) and reduced with L-arginine after 120 minutes (p < 0.01) compared with control animals. Water content was significantly decreased in the heart, lung, skin, muscle and peritoneum in rats receiving L-arginine. These data suggest that endogenous nitric oxide plays an important role in minimizing fluid accumulation during cardiopulmonary bypass.

Alpha- and beta-adrenergic mechanisms in the control of vascular capacitance by the carotid sinus baroreflex system.

We examined the active and passive contributions of the alpha- and beta-adrenergic receptor mechanisms to the changes in systemic vascular capacitance caused by the carotid sinus baroreflex system in anesthetized, vagotomized dogs. The carotid sinuses were isolated from the systemic circulation and perfused with controlled pressures. To determine the changes in vascular capacitance, a constant flow, constant venous pressure cardiopulmonary bypass was used. The changes in unstressed vascular volume were calculated when carotid sinus pressure was reduced from 200 to 50 mmHg without any adrenergic receptor antagonist, with either an alpha- (phentolamine) or a beta- (propranolol) antagonist and then with both. The reflex change in unstressed vascular volume in the systemic circulation (22.6 +/- 9.0 ml/kg without any antagonist) was reduced by 72% with phentolamine, by 35% with propranolol, and by 73% with both antagonists. Our results suggest that the alpha-adrenergic mechanisms contribute significantly to active changes in systemic venous capacity. In addition, the beta-adrenergic system has very little effect on active changes in venous vessels but does contribute to the overall capacity changes by dilating the hepatic outflow resistance when the carotid sinus baroreflex system is activated.

Exogenous arginine vasopressin does not enhance carotid baroreflex control in the conscious dog.

Arginine vasopressin (AVP) has profound effects on the cardiovascular system, yet has minimal pressor activity at physiological levels in intact subjects. We designed an investigation to delineate the effects of AVP on open-loop carotid baroreflex control of mean arterial pressure (MAP), total peripheral resistance (TPR), and cardiac output (CO) in conscious, chronically instrumented dogs. During graded infusions of AVP (0.5-2.0 ng.kg-1.min-1), the open-loop hemodynamic responses to controlled changes in isolated carotid sinus pressure (CSP) were determined. Increasing levels of AVP infusion led to significant increases in plasma AVP levels (P < 0.01). Increasing doses of AVP led to significant increases in TPR at all levels of CSP (P < 0.01). The overall range and gain of the response were not significantly different at any level of AVP infusion. Despite this increase in systemic resistance, there was no significant change in the MAP-CSP relationship. Infusion of AVP led to a dose-dependent depression in CO (P < 0.01) and heart rate (HR; P < 0.05) at all levels of CSP with no significant effect on open-loop baroreflex control. We conclude that although exogenous AVP induces profound changes in cardiovascular function, it does not alter carotid baroreflex control of MAP, TPR, CO, and HR.

Extravascular fluid uptake during cardiopulmonary bypass in hypertensive dogs.

We investigated the effects of increases in central venous pressure (CVP) and carotid baroreceptor-induced vasodilation on the rate of extravascular fluid uptake during cardiopulmonary bypass in normotensive and Goldblatt hypertensive dogs. Carotid sinus baroreceptors were selectively perfused to control the level of vasodilation. Central venous pressure was controlled by changing the height of the venous outflow cannula. Extravascular fluid uptake was determined from the rate of change in reservoir volume. After 3 hours of bypass, total fluid accumulation was 56.11 +/- 14.16 mL/kg in normotensive dogs, significantly less than in hypertensive dogs (110.90 +/- 23.20 mL/kg) (p < 0.05). Raising CVP from 1 to 5 mm Hg increased the rate of extravascular fluid uptake in both normotensive (from 0.05 +/- 0.25 to 0.85 +/- 0.22 mL.kg-1.min-1; p < 0.05) and hypertensive dogs (from 0.68 +/- 0.28 to 2.57 +/- 0.46 mL.kg-1.min-1; p < 0.01)). At a constant CVP, baroreceptor-induced vasodilation increased the rate of extravascular fluid uptake in normotensive (from 0.25 +/- .15 to 0.81 +/- .22 mL.kg-1.min-1) and in hypertensive dogs (from 0.84 +/- .12 to 1.72 +/- .32 mL.kg-1.min-1; p < 0.05). Hypertensive dogs were more sensitive to changes in CVP and to baroreceptor-induced vasodilation. The results of this study imply that elevations in CVP or the use of vasodilators may lead to increased extravascular fluid uptake during bypass; this effect may be exacerbated in the hypertensive state.

Arterial pressure-flow relationships in hypertensive dogs: effect of carotid sinus baroreflex.

The effect of the carotid sinus baroreflex reflex on arterial pressure-flow relationships was studied in Goldblatt hypertensive and normotensive dogs on cardiopulmonary bypass. Dogs were anesthetized with pentobarbital sodium, vagotomized, and the carotid sinuses were isolated at controlled carotid sinus pressures (CSP). The mean arterial pressure-flow relationships were measured at different levels of CSP. The arterial pressure-flow relationship was found to be linear except at extreme levels of flow. The slopes derived from the linear regression of the pressure-flow relationships [total peripheral resistance (TPR)] were 1.466 +/- 0.111 and 0.786 +/- 0.13 mmHg.ml-1 x min.kg at CSP of 50 and 200 mmHg in the normotensive group and 1.758 +/- 0.183 and 0.937 +/- 0.114 mmHg.ml-1 x min.kg at CSP of 50 and 250 mmHg in the hypertensive group. The increases in slope measured when CSP was decreased from saturation to threshold were 0.68 mmHg.ml-1 x min.kg (187% increase) in the normotensive group and 0.82 mmHg.ml-1 x min.kg (188% increase) in the hypertensive group. Zero-flow arterial pressures at CSP of 50, 125, and 200 mmHg were found to be 23.1 +/- 2.9, 21.7 +/- 2.2, and 17.1 +/- 1.8 mmHg in the normotensive group and 28.4 +/- 2.2, 23.8 +/- 1.5, and 20.0 +/- 1.2 mmHg in the hypertensive group. A nonlinear model fit was found to give a significantly better fit [coefficient of determination (r2) = 0.932 linear, 0.956 nonlinear] of the arterial pressure-flow relationships. We conclude that, in experimental hypertension, carotid baroreflex control of TPR is shifted to a higher operating point without any reduction in overall reflex gain.

Arterial compliance and its control by the baroreflex in hypertensive dogs.

The effect of the carotid baroreflex on systemic arterial compliance was tested in normotensive and Goldblatt hypertensive dogs. After the development of experimental hypertension, dogs were acutely anesthetized with pentobarbital sodium and vagotomized. The carotid sinuses were then isolated and held at controlled carotid sinus pressures (CSP) of 50, 125, and 200 mmHg. The dogs were placed on constant flow, constant venous pressure, cardiopulmonary bypass. Arterial compliance was determined from the time constant of the exponential fall in arterial pressure, which occurred when the flow was stopped at three different levels of CSP. The reflex characteristic curve (mean arterial pressure vs. CSP) was shifted upward and to the right in the hypertensive group. Arterial compliance significantly decreased with decreasing CSP, but at any given level of CSP, arterial compliance was not different in the normotensive and hypertensive groups. A nonlinear analysis revealed that the arterial compliance-arterial pressure relationship was not altered by Goldblatt experimental hypertension. The results of this study indicate that the arterial compliance is primarily a function of the absolute level of arterial pressure. Baroreflex control of arterial compliance is important at lower levels of arterial pressure.

Baroreflex control of arterial and venous compliances and vascular capacity in hypertensive dogs.

The ability of the carotid sinus baroreflex to elicit reflex changes in vascular capacity was studied in chronically hypertensive (one-kidney, one-clip) and sham-operated normotensive dogs under pentobarbital sodium anesthesia. Vascular compliances and reflex-induced changes in external reservoir volume were measured in response to changes in isolated carotid sinus pressure (CSP). The mean arterial pressure-CSP reflex characteristic curve was shifted to a higher arterial pressure with hypertension with no change in maximum reflex gains. Arterial compliance in both groups increased significantly (P < 0.01) when CSP was increased from 50 to 200 mmHg. Total, arterial, and venous vascular compliances were not different in normotensive and hypertensive groups. Changes in CSP caused no significant changes in either total systemic vascular or calculated venous compliances. A decrease in CSP from 250 to 50 mmHg resulted in an increase in external reservoir volume of 8.02 +/- 1.03 and 7.44 +/- 1.33 ml/kg in normotensive and hypertensive groups, respectively, with changes in venous volume of 11.99 +/- 1.39 and 12.58 +/- 1.52 ml/kg (NS). We conclude that despite the increase in arterial resistance, Goldblatt hypertensive dogs retain the ability to make short-term reflex adjustments in both arterial pressure and venous blood volume.

Carotid baroreflex control during hemorrhage in conscious and anesthetized dogs.

The hypothesis was tested that carotid baroreflex gain is increased after 20% hemorrhage. The baroreceptor reflex responses to changes in carotid sinus pressure (CSP) were measured in control, 20% hemorrhage, and reinfusion conditions in three experimental groups: conscious intact (n = 7), anesthetized intact (n = 8), and anesthetized vagotomized (n = 8) dogs. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and calculated total peripheral resistance (TPR) responses to changes in CSP were measured. At any given CSP, MAP, CO, and SV all decreased significantly with the 20% hemorrhage, as reflected by a downward shift in the reflex characteristic curve with no change in overall reflex range or gain. In contrast, TPR and HR responses to CSP were not significantly altered by 20% hemorrhage; reflex curves and gains were comparable to control conditions. In the conscious intact dogs, the maximal reflex gain, Gmax, for the MAP response was -1.365 +/- 0.25, -1.298 +/- 0.33, and -1.324 +/- 0.25 in control, 20% hemorrhage, and reinfusion conditions, respectively, and was not significantly altered by hemorrhage. In the same group, the Gmax for the HR response was -1.792 +/- 0.65, -1.709 +/- 0.33, and -1.986 +/- 0.67 in control, 20% hemorrhage, and reinfusion conditions, respectively; baroreflex gain on HR was not increased with hemorrhage. Plasma arginine vasopressin (AVP), an increase in which has been proposed to augment baroreflex gain, increased from a control level of 0.98 +/- 0.27 to 9.66 +/- 2.67 pg/ml during 20% hemorrhage in the conscious intact dogs; despite the increase in plasma AVP during hemorrhage, augmentation of baroreflex gain was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and respiratory responses to carotid sinus pressure alteration in experimental hypertension.

The purpose of this study was to determine whether baroreflex control of respiratory responses is diminished in hypertension. Ten dogs were made chronically hypertensive with use of a bilateral renal wrap technique. Eight sham-operated dogs served as normotensive controls. After the development of experimental hypertension, carotid baroreflex control of arterial pressure, heart rate, respiratory frequency, tidal volume, and ventilation was acutely assessed. Under pentobarbital anesthesia and with bilateral vagotomy, the carotid sinuses were isolated and perfused at controlled pressures. Before the carotid sinus region was manipulated, the mean arterial pressure was significantly higher (P < 0.005) in the hypertensive group (146.4 +/- 2.3 mmHg) than in the normotensive group (124.7 +/- 2.6 mmHg). The mean arterial pressures and heart rates measured at every level of carotid sinus pressure were significantly higher in the hypertensive group. Reflex gain of heart rate, but not mean arterial pressure, was significantly reduced in the hypertensive group. Respiratory frequency, tidal volume, and ventilatory responses to changes in carotid sinus pressure were significant and resulted in an approximately 40% reflex change in ventilation. These responses were not diminished in the hypertensive group. We conclude that respiratory baroreflex responses are preserved in experimental hypertension.

Jugular venous vasopressin increases during carotid endarterectomy after cerebral reperfusion.

Several recent reports have suggested that pressor hormones may be released during and after carotid endarterectomy and that release of these factors may be associated with postoperative hypertension and other postoperative morbidity. We measured vasopressin, adrenocorticotropic hormone, and cortisol in jugular venous blood during carotid endarterectomy under general anesthesia in 43 patients with routine carotid shunting. Jugular venous vasopressin increased significantly after the second period of carotid occlusion for shunt removal and remained increased at closure. Vasopressin did not change during the initial carotid occlusion for shunt placement or during the endarterectomy itself, and neither ACTH nor cortisol changed at any sample time. Greater resting vasopressin and cortisol and larger responses of vasopressin were observed in patients receiving phenylephrine to correct intraoperative hypotension. There were no correlations between postoperative hypertension or postoperative complications and intraoperative hormone values. These results suggest (1) basal intraoperative vasopressin values reflect the blood volume of the patient, (2) increased vasopressin was not related to postoperative morbidity, and (3) intraoperative increases in pressor hormones are most likely physiologic responses to specific stimuli such as hypovolemia or hypotension rather than pathologic phenomena. We speculate that the increase of vasopressin after the second carotid occlusion and reperfusion of the brain may be due to the action of humoral factors released into the carotid circulation from the endarterectomy site.

Rapid resetting of baroreflexes in hypertensive dogs.

The hypothesis tested was that the rapid resetting of the arterial baroreflex control of arterial pressure in normotension could be demonstrated in experimental hypertension. After the development of experimental hypertension (using a bilateral renal wrap technique), rapid resetting of arterial pressure and heart rate (HR) was acutely assessed under pentobarbital sodium anesthesia in hypertensive and normotensive vagotomized dogs. The carotid sinus area was isolated and perfused at controlled carotid sinus pressures (CSPs). Baroreflex response [mean arterial pressure (MAP) and HR] curves were measured after three carotid sinus conditioning pressures (50, 125, and 200 mmHg) were applied. For the MAP response, the CSPo (CSP at point of maximum reflex gain) increased significantly to the same extent in both groups with increasing conditioning pressures (with 22.2 and 16.7% resetting in the normotensive group, and 20.3 and 14.2% resetting in the hypertensive group). We conclude that short-term adjustments to changes in prevailing pressure (rapid resetting) occur in the arterial pressure response in experimental hypertension to the same extent seen in normotension.

Carotid baroreceptor control of right atrial mechanics in dogs.

To investigate the influence of the carotid arterial baroreceptors on right atrial mechanics, the carotid sinus region was isolated surgically in eight dogs prepared acutely under pentobarbital. Right atrial pressure and conductance volume were measured with a strain-gauge tip catheter and a conductance catheter, respectively. Reduction of carotid sinus pressure from 225 to 50 mmHg elicited significant increases in the a wave in right atrial pressure, in atrial stroke volume, in atrial stroke work (2.5-fold), and in atrial stroke power (4-fold). Mean central venous pressure and atrial volume at the onset of each beat did not change. These responses were unchanged after bilateral cervical vagotomy. Head-up tilt was applied at carotid sinus pressures less than or equal to 150 mmHg in four dogs to oppose any contribution of decreased systemic venous capacity to the responses through increased atrial filling. Tilt did not change atrial stroke work or atrial filling during late ventricular systole before vagotomy but inhibited these variables significantly after vagotomy. The slope of the relationship between right atrial stroke work and atrial volume at the onset of contraction increased significantly with reduction of carotid sinus pressure. This response was unaffected by either vagotomy or tilt. Carotid arterial hypotension appears to augment right atrial stroke work and stroke volume through an increase in atrial contractility. A decrease in venous capacity may contribute to this response especially after vagotomy.

Comparison of carotid baroreflex control of plasma AVP concentration in conscious and anesthetized dogs.

We compared carotid sinus baroreflex control of endogenous plasma arginine vasopressin (AVP) in chronically prepared conscious and acutely prepared anesthetized dogs. The carotid sinuses of both conscious and pentobarbital-anesthetized dogs were isolated bilaterally and perfused at constant pressures. Carotid sinus pressure (CSP) was changed between 200 and 50 mmHg in 25-mmHg steps in intact conscious and anesthetized dogs. Similar runs were repeated after vagotomy. Mean arterial pressure (MAP) and heart rate (HR) were monitored. At each interval of CSP, blood was withdrawn for AVP analysis by radioimmunoassay. MAP responses to changes in CSP were not different in the four experimental groups. Both anesthesia and vagotomy increased the HR responses to changes in CSP. With vagi intact, AVP increased at high CSP in conscious but not in anesthetized dogs. After vagotomy, low CSP led to an increase in plasma AVP that did not differ between conscious and anesthetized dogs. The results suggest that the release of AVP is modulated by the action of the carotid baroreflex as a normal component of an integrated efferent response. The response is similar in conscious and pentobarbital-anesthetized dogs and is normally buffered by reflexes with vagal afferents.

Carotid sinus compliance and baroreflex responses in hypertensive dogs.

The hypothesis that changes in baroreflex function seen in hypertension could be explained by a decreased vascular compliance in the carotid sinus region itself was tested. Six dogs were made chronically hypertensive (MAP = 146.0 +/- 3.3 mm Hg) using a bilateral renal wrap technique, while six other dogs were sham operated and served as normotensive controls (MAP = 125.8 +/- 4.7 mm Hg). Six weeks after the procedure, compliance of the carotid sinus region was measured, and carotid baroreflex control of arterial pressure and heart rate was assessed acutely. Dogs were anesthetized with sodium pentobarbital and the carotid sinus was isolated and perfused at controlled pressures. Vagotomy was performed to eliminate aortic and cardiopulmonary reflex buffering. The carotid sinus pressure (CSP) was changed from 25 to 250 mm Hg in a stepwise fashion, and the corresponding arterial pressure, heart rate and volume changes were recorded. Compliance was determined as the change in volume infused divided by the changes in pressure achieved. Significant differences between the normotensive and hypertensive groups were found in the reflex responses of arterial pressure and heart rate to changes in CSP. Carotid sinus compliance decreased with increasing CSP, but was not different in the two groups. Changes in baroreflex responses seen in mild hypertension occur without significant changes in carotid sinus compliance, and cannot be explained solely by a decreased compliance in the receptor wall.

Carotid sinus baroreflex control of beta-endorphin release in anesthetized dogs.

A quantitative assessment of the carotid sinus baroreflex release of endogenous plasma beta-endorphin-like immunoreactive material has been established. The carotid sinuses of 12 pentobarbital sodium-anesthetized dogs were isolated bilaterally and perfused with a constant pressure maintained by infusion or withdrawal of normal saline. Mean arterial pressure (MAP) and heart rate (HR) were monitored. Carotid sinus pressure (CSP) was changed from 200 to 50 mmHg in 25 mmHg steps before and after vagotomy. At each interval of CSP, 10 ml mixed venous blood were collected, and beta-endorphin-like peptides were extracted from plasma and assayed. Concentrations of plasma beta-endorphin-like material were determined by radioimmunoassay. Sigmoidal responses of MAP and HR were revealed during changes in CSP. No significant differences in beta-endorphin-like immunoreactivity (beta-END-L-I) were measured at CSP of 200 and 50 in the intact condition (35.9 +/- 3.9 and 35.0 +/- 6.4 fm/ml, respectively). However, after vagotomy, beta-END-L-I measured at 50 mmHg CSP was significantly elevated to 53.3 +/- 5.2 fm/ml compared with the value of 35.5 +/- 7.2 fm/ml at CSP of 200 mmHg. The results suggest that the release of beta-endorphin is modulated by the action of the carotid baroreflex as a normal component of an integrated efferent response. However, this response is normally buffered by reflexes with vagal afferents.

Carotid sinus baroreceptor control of splanchnic resistance and capacity.

The contribution of the splanchnic vascular bed in the carotid sinus baroreceptor reflex control of vascular resistance and capacity was studied in nine pentobarbital-anesthetized dogs. The splanchnic circulation was vascularly isolated in an unopened abdomen and perfused at constant flow and venous pressure. Decreasing carotid sinus pressure from 200 to 50 mmHg resulted in a 72% increase in splanchnic vascular resistance and a decrease in splanchnic blood volume of 4.7 ml/kg. Changes in splanchnic inflow from 0 to 70 ml.min-1.kg-1 resulted in linear changes in splanchnic arterial pressure. Increasing carotid sinus pressure significantly decreased the slope (P less than 0.005) and intercept (P less than 0.025) of the splanchnic pressure-flow relationship. It is concluded that in the dog, the splanchnic vascular bed contributes a major portion of blood volume mobilized by the carotid sinus reflex.

Concerning reflex summation.

A simple, linear, noninteractive model of the reflex control of blood pressure was developed to demonstrate that simple linear addition of the responses of the baroreceptor reflexes can produce observations that appear to have resulted from a redundant control system. Our analysis indicated that common experimental paradigms such as hemorrhage with sequential reflex ablation, which are often used to evaluate reflex interactions, can be simply interpreted. Complex nonlinear interactions need not be postulated to explain data that appear to indicate a redundant control system.

Pulsatile vs. mean component of baroreflex compensation for posthemorrhage hypotension.

We studied the influence of pulsatile pressure and mean arterial pressure signals on the restoration of arterial pressure after 10% hemorrhage in seven anesthetized dogs. After transection of the aortic nerve, a quick 10% hemorrhage was repeated under four different sinus conditions: condition 1, carotid sinus pressure depulsated and fixed at a level equal to the prehemorrhage level (no feedback); condition 2, pulsatile component of aortic pressure fed back to the carotid sinus with a fixed mean pressure (pulsatile feedback); condition 3, depulsated mean aortic pressure fed back (mean pressure feedback); condition 4, both pulsatile and mean pressure fed back (pulsatile plus mean component feedback). The restoration of arterial pressure in condition 2 was not significantly different from that in condition 1, but there was greater restoration in conditions 3 and 4. At 1.5 min posthemorrhage, the open-loop gains calculated from the restoration values were nearly zero for the pulsatile feedback only, 2.8 +/- 0.8 for mean arterial pressure feedback, and 1.5 +/- 0.3 for pulsatile and mean pressure feedback. These results indicate that the pulsatile component of the carotid baroreflex contributes minimally to the restoration of arterial pressure after 10% hemorrhage in the anesthetized dog.

Interaction of carotid chemoreceptor and baroreceptor reflexes in anesthetized dogs.

Interaction between baroreceptors and chemoreceptors during simultaneous activation of the reflexes was studied in eight pentobarbital sodium-anesthetized vagotomized dogs. The carotid sinus reflexogenic area was isolated and perfused at controlled carotid sinus pressure (CSP), PO2, and PCO2. Random combinations of CSP, PO2, and PCO2 were delivered to the carotid sinus. Results were analyzed by multiple linear regression. For the arterial pressure response, increasing CO2 resulted in an upward shift of the baroreceptor reflex response curve and an increased slope of the linear portion of the curve. The heart rate-CSP curve was also shifted upward by CO2, with the effect being greatest at high levels of CSP. The respiratory frequency-CO2 relationship had an increased slope and was shifted upward when CSP was decreased. The responses of tidal volume and ventilation (VE) depended on all three inputs. At any level of PO2, decreasing CSP resulted in a parallel shift of the VE-CO2 relationship. The results indicate that there is a significant interaction between chemoreceptor and baroreceptor reflex sensitivities.