Abstract The aims of this study were to elucidate the vasoconstrictor mechanism that mediates the changes in celiac and mesenteric vascular resistances during vasoconstriction and hypotension induced by ganglionic blockade and to explore the preferential mechanism that contributes to the elevation of arterial pressure in conscious spontaneously hypertensive rats (SHR). In conscious SHR and normotensive control rats, blood flow and arterial pressure were measured with an implanted electromagnetic flow probe and an indwelling arterial catheter. Peripheral vascular resistance was calculated as arterial pressure divided by regional flow. Celiac contribution to the hypertension in SHR was below average for the entire body and was smaller than that from the superior mesenteric bed. The increase of mesenteric resistance with arterial pressure elevation after ganglionic blockade suggests that mesenteric blood flow is regulated by a stretch-dependent myogenic mechanism, whereas celiac blood flow is regulated preferentially by the sympathetic neural mechanism. It is speculated that the flow superregulation in the mesenteric bed in SHR is due to the enhanced myogenic response and contributes to the early stage of hypertension.
Hypertensive arterioles maintain higher levels of active tension than normotensive arterioles. Increased myogenic response has been considered to potentiate hypertension by contributing to the increase in vascular resistance. The mechanisms of vasoconstriction responsible for the elevated peripheral resistance associated with the development and maintenance of hypertension have been a subject of intensive investigation. For the most part, the increased total peripheral resistance found in hypertension has been associated with the autonomic nervous system,1 the renin-angiotensin system,2 and hemodynamic events in the local myogenic mechanism.3 4 The change in the reactivity of the myogenic mechanism is most likely related to the process of autoregulation, whereby upstream arterioles attempt to maintain constant capillary pressure and blood flow.5 It has been hypothesized that the myogenic mechanism is due to changes in the cellular mechanism of vascular smooth muscle or endothelium underlying vascular smooth muscle contraction.6
We have previously reported that hypertension in conscious spontaneously hypertensive rats (SHR)7 is largely sustained by elevation of peripheral resistance in the superior mesenteric and hindquarter areas8 and that the elevated peripheral resistance in the hindquarters is for the most part ascribable to an abnormal sympathetic vasoconstrictor tone, whereas that in the superior mesenteric area is not.9 Recently, we have obtained results showing that the contribution of the celiac area to hypertension in SHR is quantitatively less than that of the mesenteric and hindquarter areas, but the elevated celiac resistance in SHR is maintained by the sympathetic neural mechanism.10 The splanchnic circulation makes an important hemodynamic contribution to the early development of hypertension, and the increase in vascular resistance is apparent in the stomach, small and large intestines, pancreas, and liver.11 Nevertheless, little information is available regarding the celiac blood flow, which perfuses the stomach, liver, spleen, and a part of the duodenum and pancreas, compared with the superior mesenteric flow.12 The celiac and mesenteric blood flows in the splanchnic circulation have been speculated to be maintained by a different vasoconstrictor mechanism.11 13 Presumably, the clarification of the mechanism of peripheral flow regulation must provide a useful indication of the potential mechanism that contributes to the development and maintenance of hypertension.
The purposes of this study are to elucidate the vasoconstrictor mechanism that mediates the changes in celiac and mesenteric vascular resistances during vasoconstriction and hypotension induced by ganglionic blockade and to explore the preferential mechanism that contributes to the elevation of arterial pressure in conscious SHR.
The degree of contribution of the peripheral vascular resistance to the hypertension in SHR was quantified by introducing α (resistance) and β (conductance) indexes. The magnitude of vascular compensatory response in peripheral vascular beds was further estimated by calculating the closed-loop gain (autoregulation index, G) in vascular beds and the change of regional wall tension (tension index, γ) during the change of arterial pressure.
Animals used in this study were maintained and used in accordance with the guidelines of the Animal Care Advisory Committee of the University of Hiroshima School of Medicine and the “Guiding Principles for Care and Use of Animals in the Field of Physiology Science” of the Physiological Society of Japan (1988).
Male SHR (n=28) and normotensive control Wistar rats (NCR) (n=28) 10 to 27 weeks of age were used in this study. They were anesthetized with thiamylal sodium (50 mg/kg IP). Fig 1⇓ illustrates the surgical preparation. The celiac (n=30) or mesenteric (n=26) artery was reached retroperitoneally by a left flank incision, and an electromagnetic flow probe (type FC, Nihon Kohden) with an internal diameter of 1 or 1.5 mm was implanted around it. The wire from the probe was passed under the skin and exteriorized at the dorsal neck. A polyethylene tube (PE-10 fused to PE-20) for pressure measurement was inserted into the terminal aorta from the right femoral artery. Another tube for drug administration was inserted into the left external jugular vein. The opposite end of each tube was also exteriorized at the neck. After the operation, the rat was housed separately in a white plastic cage measuring 35×30×17 (depth) cm and containing wood chips. Water and food pellets were given ad libitum.
Recording of Flow and Pressure
Three or 4 days after the operation, celiac or mesenteric blood flow and arterial pressure were measured in the rats in their home cage. The electromagnetic flowmeter used was a Nihon Kohden MFV-1100. Both flow and pressure were smoothed with a resistance and capacitance (RC) filter with a time constant of 1 second and recorded by a pen writer. After baseline values were obtained, hexamethonium bromide (90.5 mmol/L) was infused at a rate of 0.8 mg/min for a total dose of 25 mg/kg for ganglionic blockade. Celiac peripheral resistance or mesenteric peripheral resistance was calculated as arterial pressure divided by celiac or mesenteric blood flow, respectively. All flow-related variables were indexed to body weight. The dependency of vascular resistance and blood pressure on neurally mediated vasoconstrictor tone was estimated by the magnitude of the drop in these parameters after interruption of sympathetic transmission with the ganglionic blocking agent. The group t test was used to determine the significance of the difference between SHR and NCR and the paired t test for the significance of change on ganglionic blockade.
Computation of α, β, and γ Indexes
The degree of contribution of a vascular area to hypertension was quantified by two indexes: resistance index, α, and conductance index, β.14
The resistance index α is the contribution of the peripheral resistance (r) of the particular area to the changes in total peripheral resistance (R) and is calculated as
where Fo and Po are control values in NCR at the outset and indicate peripheral blood flow and arterial pressure, respectively. F and P indicate blood flow and arterial pressure, respectively, in SHR. Fw is cardiac output.
The conductance index β indicates what percentage of the change in total peripheral conductance, the inverse of total peripheral resistance, is contributed by a particular area and is calculated as
where 1/r is peripheral conductance, 1/R is total conductance, and Δ is the difference between the hypertensive and normotensive control rats. In the computation of β, cardiac index, Fw, was assumed to be 22 mL/min per 100 g body weight for both SHR and NCR15 and under the condition that cardiac output per body weight did not show any difference between SHR and NCR at rest.16 Total peripheral resistance (R) was calculated by dividing arterial pressure (P) by cardiac output (Fw).
Thus, α indicates how intensely the particular area participates in the hypertension. When α=1, the increase in the local peripheral resistance compared with normotensive controls is equal to that of total peripheral resistance, and the participation of the area is average over the entire body. Similarly, the participation is above average if α>1 and below average if α<1. On the other hand, β indicates the percentage of the total conductance decrease, compared with controls, that is contributed by the particular area.
The autoregulation index G denotes the fractional compensation of the flow regulation system and is given17 as
When G=0, the vascular bed behaves as a rigid system of tubes. If 0<G<1, the vascular system indicates autoregulatory behavior, but compensation for disturbance in perfusion pressure is incomplete. Perfect autoregulation is denoted by G=1. The vascular system indicates overcompensation (ie, superregulation) if G>1, and the vascular system indicates passive behavior for perfusion pressure changes (nonautoregulation) if G<0.
Furthermore, to estimate the compensatory strength of vascular wall tension (that is, the mechanical factor of flow autoregulation) against the arterial pressure changes, we attempted to theoretically derive the tension index γ as
by assuming that peripheral blood flow is Poiseuille’s flow and the vascular wall is characterized by Laplace’s law. Here, the percent change of wall tension, ΔT/To (=ΔP/Po+ΔD/Do), is derived from the differential equation (1+ΔT/To)=(1+ΔP/Po)(1+ΔD/Do) in Laplace’s law (To=PoDo/2, Do is vessel diameter). The percent change of vessel diameter, ΔD/Do [=1/(1+Δr/ro)1/4−1], is also computed from the percent change of vascular resistance, 1/(1+Δr/r)=(1+ΔD/D)4, derived from the differential equation in Poiseuille’s law [r=8ηL/π(D/2)4].
The tension index γ indicates how intensely the vascular wall tension of the particular vascular area compensates for the changes of arterial pressure. When γ=1, the percent change in the vascular wall tension is equal to that of total arterial pressure; that is, the vessel diameter remains nearly constant (isometric contraction). Similarly, the vascular wall tension increases passively during the increases of arterial pressure if γ>1. If 0<γ<1, the vascular wall tension is compensated actively by vasoconstrictor responses with the increases of arterial pressure. When γ=0, the vascular wall tension remains constant (isotonic contraction).
Effects of Ganglionic Blockade on Celiac and Mesenteric Vascular Beds
Fig 2⇓ shows simultaneous recordings of arterial pressure and celiac and superior mesenteric flows in single SHR and single NCR. The recordings show the changes that occurred in mean values of arterial pressure, celiac flow, and mesenteric flow on ganglionic blockade with hexamethonium bromide. Celiac flow in SHR (B) remarkably increased inversely with the reduction of arterial pressure during the infusion of hexamethonium bromide, whereas celiac flow in NCR (A) increased slightly. On the other hand, mesenteric flow in both NCR (C) and SHR (D) decreased consistently with the reduction of arterial pressure.
The Table⇓ summarizes changes of mean arterial pressure, celiac and mesenteric blood flows, and heart rate in response to sequential ganglionic blockade with hexamethonium bromide in both SHR and NCR. In this depressor response to ganglionic blockade, mean celiac flow increased significantly in SHR but not in NCR. The mean values of celiac resistance decreased significantly in both groups (P<.001 for SHR and P<.025 for NCR), but the percent decrease was significantly greater in SHR than in NCR (−40.2±11.9% versus −9.6±11.6%, P<.001). After blockade, the mean value of celiac resistance was even lower in SHR than in NCR. In contrast, mean mesenteric flow decreased significantly in both SHR and NCR (P<.001) after ganglionic blockade, and mean values of mesenteric resistance increased slightly in both groups. The difference between mesenteric resistances in SHR and NCR remained significant even after blockade. Mean heart rate was higher in NCR than in SHR and was not affected by the infusion of hexamethonium bromide.
Pressure-Resistance Relations in Celiac and Mesenteric Vascular Beds
Celiac and mesenteric resistances in both NCR and SHR increased consistently with the elevation of arterial pressure, as shown in Fig 3⇓. The changes of vascular resistance during the elevation of arterial pressure were given mathematically by the regression curves as y=28.6 e0.006x and y=12.4 e0.007x, for celiac and mesenteric beds, respectively. The pressure-dependent resistance curves demonstrated that celiac and mesenteric beds have autoregulatory ability to restore blood flow toward normal levels for arterial pressure elevation and that the intensity of autoregulation was increased in SHR (as indicated by exponential slopes of the regression curves).
After ganglionic blockade with hexamethonium bromide, however, the pressure-dependent resistance curves exhibited quite different changes in celiac and mesenteric vascular beds, as shown in Fig 4⇓. Celiac resistance decreased inversely with the elevation of arterial pressure, and the celiac vasoconstrictor response almost disappeared after ganglionic blockade. The changes of celiac resistance responsible for elevated arterial pressure were expressed by the regression curves as y=86.1 e−0.007x. The results suggest that celiac vasoconstrictor response is mediated by sympathetic vasoconstrictor activity. In contrast, mesenteric vasoconstrictor response was further potentiated in both NCR and SHR after ganglionic blockade. The mesenteric resistances in NCR and SHR increased positively with the elevation of arterial pressure (NCR: from 28.4±8.0 to 29.5±6.1 mm Hg · mL−1 · min−1 · 100 g; SHR: from 41.3±10.4 to 44.3±15.3 mm Hg · mL−1 · min−1 · 100 g). The regression curve for mesenteric resistance was obtained as y=8.36 e0.014x. The slope of the regression curve was twice that before ganglionic blockade. These facts suggest that the elevated mesenteric resistance after blockade is mediated by a few local mechanisms without a sympathetic neural mechanism.
Hemodynamic Responses of Hypertensive Celiac and Mesenteric Beds to Elevated Arterial Pressure
Fig 5⇓ shows the hemodynamic effects of elevated arterial pressure on peripheral resistance (α index, Fig 5A⇓), regional wall tension (γ index, Fig 5B⇓), and regional flow autoregulation (G index) in hypertensive celiac and mesenteric beds. These indexes were derived from Equations 1, 3, and 4 by calculating the difference in values between each SHR in reference to the mean value for NCR. In hypertensive celiac and mesenteric vascular beds, peripheral resistance increased (A, α>0) and regional wall tension decreased (B, γ<1), consistent with the increase of flow autoregulation (G>0) during the elevation of arterial pressure from the level of NCR to that of SHR. Peripheral blood flow in the mesenteric bed was superregulated over the upper limit of autoregulation (quadrant I, G>1), whereas blood flow in the celiac bed was almost regulated within the range of autoregulation (quadrant II, 1>G>0). The vasoconstrictor response of vascular wall to stretch stimuli was greater in the mesenteric than the celiac bed. The flow superregulation in the mesenteric bed may contribute to the early stage of hypertension.
On the other hand, the compensatory response in the hypertensive celiac bed disappeared almost completely (quadrant III, G<0) after ganglionic blockade, as shown in Fig 6⇓. The celiac resistance decreased (A, α<0) and the vascular wall tension increased (B, γ>1), consistent with the decline of celiac flow autoregulation (G<0) during the elevation of arterial pressure from the level of NCR to that of SHR. The contribution of the celiac bed to the hypertension in SHR was shown to be sustained preferentially by increased sympathetic activity. In contrast, mesenteric resistance further increased (A, α>0) after ganglionic blockade and wall tension decreased (B, γ<1), consistent with the enhancement of vasoconstrictor responses with the elevation of arterial pressure. The compensatory response in the hypertensive mesenteric bed was promoted more than at the preblockade level (G>1). Presumably, the increased superregulation in the mesenteric area must be due to the changes of the cellular mechanism of vascular smooth muscle caused by sympathetic denervation because the same phenomenon was also observed in the mesenteric bed in NCR.
Our criterion for the presence of sympathetic vasoconstrictor tone in a vascular area is whether or not the regional peripheral resistance decreases significantly after ganglionic blockade.18 According to this criterion, both SHR and NCR were judged to have a sympathetic vasoconstrictor tone in the celiac area (Fig 2⇑). The mean percent decrease in celiac resistance after ganglionic blockade was significantly greater in SHR than in NCR, and the mean celiac flow increased despite the decrease in mean arterial pressure, whereas the mean value of the flow in NCR decreased (see the Table⇑). Mean flow compensatory response (G) decreased from 0.76±0.57 to −2.00±3.39 after ganglionic blockade, and the tension strength of celiac vascular wall (γ) increased from 0.87±0.13 to 1.45±0.87. These findings suggest that the celiac blood flow is regulated positively by the sympathetic neural mechanism and the sympathetic tone may have been greater in SHR than in NCR at the outset.10 The participation of the celiac area to the hypertension of SHR was also estimated from α and β indexes. The mean value of the α index of 0.84±0.76 indicates that the participation was quantitatively below average. The β index value of 6.7±4.7% suggests that the contribution of the celiac area to the hypertension is far smaller than that of the superior mesenteric area (18.7±11.3%).
Unexpectedly, the contribution of the mesenteric area to hypertension increased more intensely after ganglionic blockade. The mean values of the α and β indexes further increased, respectively, from 1.47±1.25 to 2.74±2.98 and from 18.7±11.3% to 19.6±24.8%, and the tension strength of the vascular wall (γ) decreased inversely from 0.78±0.20 to 0.55±0.54. The flow compensatory response (G) increased from 1.17±0.80 to 1.89±2.17. These results suggest that the increased vasoconstrictor response in the mesenteric bed may be ascribable to the mechanical changes of the myogenic mechanism caused by sympathetic denervation.19 Denervation supersensitivity to circulating vasoconstrictor substances is a well-known occurrence after denervation at all ages.20 In addition to denervation supersensitivity, intrinsic stretch-dependent myogenic tone is also promoted more after denervation. Mangiarua et al21 have pointed out that it may be a change consequent to an altered cell membrane that is associated with the development of sensitivity, such as partial depolarization, impairment of the electrogenic Na+-K+ pump, or the disposition of Ca2+ ion. Bevan et al22 have also speculated that lowering of the membrane potential of denervated vascular smooth muscle might potentiate contractile effects and that flow contraction is associated with calcium entry into vascular smooth muscle cells.
Furthermore, Meininger et al11 have suggested that an autoregulatory vasoconstriction mediates a component of the increase in splanchnic vascular resistance and that the goal of the autoregulatory phenomenon is to minimize local disturbances in microvascular flow or pressure. However, by amplifying the effects of extrinsic vasoconstrictor mechanisms responsible for the initiation of the hypertension, autoregulation may potentiate the overall disturbance in blood pressure control, and as much as 74% to 64% of the increase in intestinal resistance for the fed and fasted rats is attributable to local pressure or flow-dependent autoregulatory mechanisms.11
Taken together, these data suggest that the mesenteric blood flow may be regulated by a stretch-dependent myogenic mechanism mediated by the cellular mechanism of vascular smooth muscle, whereas celiac blood flow is regulated preferentially by the sympathetic neural mechanism. Structural factors such as the wall-to-lumen ratio could not be responsible for the difference in mesenteric area in SHR23 24 because this interpretation does not explain the percent increase in mesenteric resistance in NCR after ganglionic blockade. It is unknown which of the three main tributaries of the celiac artery, ie, hepatic, gastric, or splenic, is responsible for each of the foregoing phenomena concerning the celiac blood flow. It would be important for the understanding of hypertension to determine which portion of the celiac bed causes sympathetic neural effects and to investigate the cellular mechanisms of vascular smooth muscle and endothelium underlying vascular smooth muscle contraction. However, hypertension in SHR appears to be partially mediated by variable components such as sympathetic nerve activity, elasticity of the blood vessel wall, lumen size, agonist sensitivity, smooth muscle proliferation, endothelial function, and small vessel number. It may be difficult to discuss the development and maintenance of hypertension by only a typical regulation mechanism.
In summary, the increase in mesenteric resistance with arterial pressure elevation after ganglionic blockade suggests that mesenteric blood flow is regulated by a stretch-dependent myogenic mechanism, whereas celiac blood flow is regulated preferentially by the sympathetic neural mechanism. It was speculated that the flow superregulation in the mesenteric bed in SHR is due to the enhanced myogenic response and contributes to the early stage of hypertension.
- Received February 16, 1994.
- Revision received March 9, 1994.
- Accepted October 17, 1994.
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