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Circulation. 1995;92:518-525

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(Circulation. 1995;92:518-525.)
© 1995 American Heart Association, Inc.

Articles

Longitudinal Gradients for Endothelium-Dependent and -Independent Vascular Responses in the Coronary Microcirculation

Lih Kuo, PhD; Michael J. Davis, PhD; William M. Chilian, PhD

From the Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station.

Correspondence to Dr Lih Kuo, Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station, TX 77843-1114.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background Coronary microvessels (<300 µm in diameter) have been demonstrated to be important in the regulation of local resistance and flow. Recent studies also suggest that these microvessels are more responsive to physiological and pharmacological stimuli than conduit vessels. However, little is known regarding the relative sensitivity of different microvascular segments in response to flow (shear stress) and agonists. The goal of this study was to test the hypothesis that a longitudinal gradient for shear stress– and agonist-induced dilation exists in the coronary microcirculation.

Methods and Results Experiments were performed in four different sizes of porcine subepicardial coronary arterial microvessels: small arterioles (40±1-µm ID with resting tone); intermediate arterioles (60±1 µm); large arterioles (106±4 µm); and small arteries (179±9 µm). Vessels were isolated and cannulated to allow luminal pressure and flow to be independently controlled. All vessels developed active tone (to {approx}65% to 75% of maximum diameter) at their control luminal pressures and showed graded dilations to stepwise increases in shear stress (0 to 10 dynes/cm2). For arterioles, the magnitude of the dilations increased as vessel size increased. The highest shear stress produced 21±3%, 32±2%, and 52±5% increases in diameter in small, intermediate, and large arterioles, respectively. Small arteries dilated only 22±6%. The endothelium-dependent vasodilator substance P (SP) produced dose-dependent dilation of all vessels with a threshold at 10-16 mol/L. Arterioles were maximally dilated at 10-9 mol/L SP. However, this dose produced only 80% dilation in small arteries. The ED50 for SP was shifted to the right by two orders of magnitude in small arteries compared with the arterioles. Adenosine preferentially dilated small arterioles, and the dose-response curves shifted to the right for larger vessels. The thresholds for adenosine-induced dilation were 10-12, 10-11, and 10-9 mol/L for small, intermediate, and large arterioles, respectively. The endothelium-independent vasodilator nitroprusside produced identical dose-dependent dilations in all vessel segments.

Conclusions The results indicate that the pig coronary circulation exhibits a heterogeneity in physiological and pharmacological responses along the microvascular network. Small arterioles are more sensitive to adenosine, but large arterioles are more responsive to shear-stress stimulation. We speculate that site-specific preferential responses may play a crucial role in coordinating overall vascular function in the coronary microvascular network.


Key Words: endothelium-derived factors • vessels • microcirculation • substance P • adenosine


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The vasodilatory response of femoral arteries to an augmentation of blood flow was first observed by Schretzenmayr in 1933.1 Mechanistic and quantitative aspects of this phenomenon, now called flow-induced vasodilation, have been examined in various organ systems of different species,2 3 4 5 6 7 including human subjects.8 In conduit arteries, flow-induced dilation is caused by a local mechanism,9 and selective removal or destruction of the endothelium abolished the response.2 9 10 Recently, flow-induced responses have been observed in resistance vessels from mesentery,4 skeletal-muscle,11 12 cerebral,13 and coronary microcirculation.7 14 It has been suggested both for conduit arteries5 and for microvessels6 that an increase in wall shear stress, secondary to an increase in flow, is the physical force that initiates vasodilation via production and/or release of endogenous vascular smooth muscle relaxing factor(s) from endothelial cells. In the coronary circulation, endothelial release of nitric oxide has been suggested to be responsible for this vasodilation.15 16 17

Although flow-induced vasodilation has been found in both the macrocirculation and the microcirculation, a significant difference in the magnitude of the response appears to exist. Studies of canine conduit arteries indicate that the magnitude of flow-induced vasodilation is a 9% increase in diameter in the femoral artery (diameter, 5.0 mm) and a 15% increase in diameter in the smaller, downstream saphenous artery (diameter, 2.6 mm) in response to a 10-fold increase in flow.2 Recent studies in the mesenteric microcirculation indicate that flow-induced dilation is much more pronounced in resistance vessels: 68-µm arterioles dilated approximately 70% to a sevenfold increase in flow velocity.4 Similarly, in the coronary circulation, we recently found a 30% dilation of arterioles with resting diameters of 65 µm during flow augmentation,7 in comparison to only a 3% to 10% dilation found in large coronary arteries.8 15 18 These observations suggest that the microcirculation is a major site for flow-induced responses and that a longitudinal gradient for flow-induced responsiveness may exist within the coronary microcirculation. However, the size of coronary microvessels that dominate in these responses is not clear. In addition, a longitudinal response gradient to agonists, ie, dilation or constriction that varies inversely with vessel size, has been shown in arteriolar networks of several different tissues other than the heart.19 Whether the coronary microvascular network also exhibits this pharmacological response gradient has not been unequivocally demonstrated. Since flow-induced dilation17 20 and the local release of adenosine21 have been suggested to play an important role in maximizing blood flow to tissue during periods of increased metabolic demand and the majority of coronary resistance (>90%) resides in microvessels <300 µm in diameter, it is important to quantitatively evaluate the regulatory properties of coronary microvessels.

The purpose of the present study was to systematically examine the relative responsiveness of coronary arterial microvessels to physiological (ie, flow) as well as to pharmacological (substance P, adenosine, and nitroprusside) stimuli. To achieve these goals, the changes in vascular diameter in response to different levels of flow and agonist concentration were studied in four different sizes (25 to 45, 50 to 70, 80 to 130, and 140 to 280 µm) of subepicardial coronary microvessels in vitro. The microvessels were isolated and cannulated to allow flow and intraluminal pressure to be independently controlled. Thus, the magnitudes of flow-induced vasodilation and pharmacological responses were evaluated at a constant intraluminal pressure and without the confounding influence of the myogenic response.


*    Methods
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 up arrowIntroduction
 *Methods
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General Preparation
Pigs (8 to 12 weeks old, of either sex) were sedated with intramuscular injection of ketamine (2.5 mg/kg) and Rompun (2.25 mg/kg), then anesthetized and heparinized with an intravenous injection of pentobarbital sodium (20 mg/kg) and heparin (1000 U/kg), respectively, via marginal ear vein. Pigs were intubated and ventilated with room air. After a left thoracotomy was performed, hearts were electrically fibrillated, excised, and immediately placed in cold (4°C) saline solution.

Isolation and Cannulation of Microvessels
The techniques for identification and isolation of coronary microvessels were described previously.22 In brief, a mixture of india ink and gelatin in physiological salt solution (PSS) containing (in mmol/L) NaCl 145.0, KCl 4.7, CaCl2 2.0, MgSO4 1.17, NaH2PO4 1.2, glucose 5.0, pyruvate 2.0, EDTA 0.02, and MOPS buffer 3.0 was perfused under low pressure (20 to 40 cm H2O) into the left anterior descending artery (0.5 mL) and the circumflex artery (0.5 mL) to enable visualization of the coronary microvessels. At 4°C, four consecutive branches of coronary arterial microvessels were selected and dissected for in vitro studies. The left anterior descending and circumflex arteries were considered first-order arteries. The small arteries (140- to 300-µm ID) branching from left anterior descending and circumflex arteries were designated second- or third-order vessels. Their downstream large arterioles (90 to 130 µm) were designated third- or fourth-order vessels. Intermediate (50 to 80 µm) and small (25 to 45 µm) arterioles further downstream corresponded to the fifth and six generations of microvessels, respectively. These vessels were selected and dissected from the surrounding cardiac tissue and transferred for further dissection to a dish (4°C) containing filtered PSS-albumin (BSA, 1 g/100 mL PSS; US Biochemical Corp) solution at pH 7.4. After careful removal of any remaining cardiac tissue, each microvessel was transferred for cannulation to a Lucite vessel chamber containing PSS-albumin solution equilibrated with room air at ambient temperature. One end of the microvessel was cannulated with a glass micropipette filled with filtered PSS-albumin solution, and the outside of the microvessel was securely tied to the pipette with 11-0 ophthalmic suture (Alcon). The ink-gelatin column inside the vessel was flushed out at low perfusion pressure (<20 cm H2O). The other end of the vessel was cannulated with a second micropipette and secured with suture. In this study, four sets of micropipettes with different tip diameters were used for cannulating different sizes of vessels. For example, micropipettes with 20-, 30-, and 40-µm tip ID were used for cannulation of small, intermediate, and large arterioles, respectively. Small arteries were cannulated with micropipettes with 60-µm tip diameter. Electrical resistances (measured by LCR Bridge Circuit, model LCR-740, Leader Electronics) of each micropipette pair were matched (±0.5%).

Instrumentation
After a vessel was cannulated, the preparation was transferred to the stage of an inverted microscope (model IM35, Carl Zeiss) coupled to a Dage-MTI camera (model 67M, Newvicon), video micrometer (Microcirculation Research Institute, Texas A&M University), and video recorder (Panasonic). IDs of the vessel were measured manually throughout the experiment by videomicroscopic techniques.22 To study flow-induced responses without interference from possible myogenic responses, a dual-reservoir system was used to maintain a constant intraluminal pressure over a wide range of flows.7 In brief, the micropipettes were connected to independent reservoir systems, and intraluminal pressures were measured through side arms of the two reservoir lines by low-volume-displacement strain-gauge transducers (Statham P23 Db, Gould). The isolated vessels were pressurized without flow by setting both reservoirs at the same hydrostatic level. The recorded intraluminal pressure of the vessel was equivalent to the actual hydrostatic pressure of the reservoirs if there were no leaks. Preparations with leaks were excluded from further study. Flow was initiated by simultaneously moving the reservoirs in equal but opposite directions, thus generating a pressure gradient ({Delta}P, inflow pressure minus outflow pressure). Because the resistances of both cannulation pipettes were equivalent, movement of the reservoirs in this manner did not alter luminal pressure.22 Thus, flow-induced responses could be studied by perfusing the vessel at different flow rates, ie, at various pressure gradients, without changing intraluminal pressure.

Calculation of Shear Stress
Shear stress ({tau}) at each level of {Delta}P was calculated as follows: {tau}=4{eta}Q/{pi}r3, where {eta} is viscosity (0.8 cp for PSS-albumin solution at 37°C), Q is the volumetric flow with respect to {Delta}P, and r is steady-state vessel radius before flow. The relationship between {Delta}P and flow rate was calibrated in each pair of micropipettes according to techniques described previously.7 Specifically, flow rates for micropipettes of 20-µm ID were determined in arterioles between 30 and 45 µm (maximally dilated with 10-4 mol/L nitroprusside, 41±3 µm, n=3) at {Delta}P=2, 4, 10, 20, 40, and 60 cm H2O. Similar flow calibrations in paired micropipettes (30-, 40-, and 60-µm ID) were made in different sizes of vessels (65 to 250 µm, n=6) at the same pressure gradients. In this system, flow was determined primarily by the caliber of the tip of the micropipette and increased linearly with increases in {Delta}P.7 In each pair of resistance-matched micropipettes, the increase in flow was independent of size of vessel within the range of {Delta}P studied. In paired 20-, 30-, 40-, and 60-µm micropipettes, the ranges of mean volumetric flows for {Delta}P between 0 and 60 cm H2O were 0 to 8.9, 0 to 34.8, 0 to 112.5, and 0 to 211.2 nL/s, respectively.

Experimental Protocols
To study flow-induced responses, each cannulated vessel was bathed in PSS-albumin solution, and the temperature was maintained at 36°C to 37°C by an external heat exchanger. The vessel was set to its in situ length22 and allowed to develop active tone at 50, 60, or 70 cm H2O intraluminal pressure without flow for small, intermediate, and large arterioles, respectively. Small arteries were pressurized to 80 cm H2O. These internal pressures were selected on the basis of in vivo micropressure measurements.23 After the vessel developed active tone, the relation between flow and vessel diameter was examined. Diameter was measured at each level of flow corresponding to a {Delta}P of 4, 10, 20, 40, and 60 cm H2O, and shear stress was calculated as described above.

To study the response gradient for pharmacological agonists, the cannulated microvessels were set to their corresponding intraluminal pressures and allowed to develop active tone without flow at 36°C to 37°C. After a steady diameter was established, the dose-dependent vasomotor responses to substance P, sodium nitroprusside, and adenosine were evaluated by construction of cumulative dose-response curves at a constant luminal pressure (no flow). At the end of each experiment, each vessel was relaxed with nitroprusside (10-4 mol/L) in PSS-albumin solution to obtain the maximum diameter at its corresponding intraluminal pressure.

Drugs were obtained from Sigma Chemical Co except as specifically stated. All drugs were dissolved in PSS-albumin solution and administered to the bath surrounding the vessel.

Data Analysis
To analyze the level of vascular tone in different sizes of microvessels, all diameters were normalized to the maximum diameter in the presence of nitroprusside (10-4 mol/L). To analyze vascular responses to shear stress, vessel diameters were normalized to their resting levels and increases in diameter were expressed as percent vasodilation. To analyze pharmacological responses, all diameter changes were normalized to the maximum dilation in the presence of nitroprusside (10-4 mol/L). Normalized diameters were averaged at each flow step or each dose of drug. All data are reported as mean±SEM. In this study, only vessels with relatively stable resting tone (±5%) between interventions were analyzed. Statistical comparisons of vasodilation at different levels of shear stress or at different doses of a specific drug among four sizes of vessels were made with two-way ANOVA and tested with Fisher's least-significant-difference multiple-range tests. The dose-response curves of each vessel were linearized by the Hill transformation, and the ED50s were determined by the y intercept and slope according to the equation: ED50=10-(y intercept/slope). Because ED50 is a logarithmic value, analysis was performed on the -(y intercept/slope). The statistical comparison of ED50s among different sizes of vessels were made by one-way ANOVA and tested with Fisher's least-significant-difference multiple-range tests. Significance was accepted at P<=.05.


*    Results
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 up arrowIntroduction
 up arrowMethods
*Results
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Spontaneous Microvascular Tone
In the present study, approximately 90% of cannulated subepicardial arterioles and small arteries developed spontaneous (active) tone within 45 minutes at their corresponding luminal pressures. Only vessels with active tone were used for further study. In the TableDown, the average active and passive diameters (in the presence of nitroprusside 10-4 mol/L) of four different sizes of vessels at their corresponding luminal pressures are listed. All arterioles (40 to 106 µm) developed similar levels of active tone (63% to 67% of maximum passive diameter), but small arteries exhibited slightly less vascular tone (74% of maximum passive diameter) than arterioles (P<.05) (TableDown).


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  		Table 1. Active and Passive IDs of Subepicardial Coronary Microvessels at Their Corresponding Luminal Pressures

Segmental Gradient for Flow-Induced Responses
Flow-induced vasodilation in four different sizes of microvessels was studied under constant luminal pressure. A graded vasodilation was observed in these vessels when {Delta}P, and thus flow, was increased in a stepwise manner. The corresponding shear stresses that initiated vascular dilation in different vascular segments are shown in Fig 1Down. The magnitude of the vasodilatory response increased as the size of the arterioles increased. Maximum vasodilations were observed at all vessel segments when shear stress was >4 dynes/cm2. The highest shear stress produced 21±3%, 32±2%, and 52±5% increases in diameter in small, intermediate, and large arterioles, respectively (P<.05). In small arteries, only 22±6% dilation was observed in response to the highest shear stress (Fig 1Down).



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  		Figure 1. Graph showing segmental coronary microvascular dilation to increased flow (shear stress). Diameter–shear stress relations were constructed under constant luminal pressure in physiological salt–albumin solution (see text for details). Luminal diameters were normalized to resting diameters at zero flow conditions. After increases in shear stress, all diameters were significantly different from those at zero shear stress (P<.05). The hierarchy of shear stress–induced response was large arterioles > intermediate arterioles > small arterioles = small arteries. Vertical and horizontal bars denote mean±SEM. *P<.05 between groups.

To estimate the degree of regulation of shear stress in different vascular segments, secondary changes in shear stress resulting from vessel dilation are shown in Fig 2Down. Shear stress was calculated at steady-state diameters after each flow step. This value was defined as "regulated shear stress" because it was determined by the degree of dilation of the vessel in response to the increased flow. This regulated shear stress was plotted against the "theoretical shear stress," which was calculated from the flow rate generated in a rigid tube with same ID as the vessel at zero flow. The line of identity shows how wall shear stress would relate directly to flow in a rigid tube. It should be noted that perfect regulation of shear stress would be reflected by a slope of zero. As shown in Fig 2Down, shear stress was partially regulated in all vascular segments, ie, slopes were less than the line of identity but greater than zero. However, large arterioles showed the best regulation of shear stress among these groups of vessels as indicated by the smallest slope (P<.05). In contrast, the small and intermediate-size arterioles as well as the small arteries exhibited similar degrees of shear-stress regulation (Fig 2Down).



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  		Figure 2. Graph showing calculated shear stress at steady-state dilation after each step change in flow (regulated shear stress) was plotted against shear stress calculated in a rigid tube with the same diameter as the microvessel (theoretical shear stress). The slope for each vessel segment was <1 (line of identity for rigid tube), indicating that shear stress was regulated during flow augmentation. The slope of the data set for the large arterioles (98±5 µm) was significantly smaller than for the other vessel segments (*P<.05), suggesting a better regulation of wall shear stress in large arterioles.

Segmental Gradient for Pharmacological Responses
We tested whether other endothelium-dependent mechanisms exhibited segmental response gradients. The endothelium-dependent vasodilator substance P17 produced dose-dependent dilation in all vessels with a threshold at 10-16 mol/L (Fig 3Down). The ED50 for substance P was shifted to the right by two orders of magnitude in small arteries (2.4x10-12 mol/L; CI, 8.2x10-12 to 7.2x10-13 mol/L) compared with the small arterioles (1.8x10-14 mol/L; CI, 6.3x10-14 to 4.9x10-15 mol/L). There was no statistical difference in ED50s among three different sizes of arterioles. Arterioles (40 to 100 µm) were maximally dilated at 10-9 mol/L. However, this dose produced only 80% dilation in small arteries (Fig 3Down).



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  		Figure 3. Graph showing dose-dependent responses of different coronary microvascular segments to substance P. There was no significant difference for substance P–induced dilation among small, intermediate, and large arterioles. In contrast, the magnitude of the dilation was significantly less in small arteries than in downstream arterioles (*P<.05 at concentrations >=10-14 mol/L).

Vasodilatory responses to adenosine are shown in Fig 4Down. The sensitivity and magnitude of vasodilation in response to adenosine decreased as the size of the vessels increased. Small arterioles exhibited the lowest threshold (10-12 mol/L) for dilation (P<.05) and were maximally dilated at 10-5 mol/L. In comparison with the small arterioles, intermediate arterioles were maximally dilated at 10-5 mol/L, but the ED50 and threshold shifted to the right by one and two order(s) of magnitude, respectively (Fig 4Down). Large arterioles and small arteries exhibited identical dose-response relations with the same threshold (10-9 mol/L), ED50 (3.0x10-7 mol/L versus 2.5x10-7 mol/L, respectively), and maximum dilation (10-4 mol/L) (Fig 4Down).



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  		Figure 4. Graph showing dose-dependent responses of different coronary microvascular segments to adenosine. Small arterioles had the lowest threshold for adenosine (P<.05). The dose-response curves to adenosine shifted significantly to the right in larger vessel segments. The statistical comparison was performed with factorial one-way ANOVA tested with Fisher's least-significant-difference multiple-range tests. *P<.05 between small and intermediate arterioles. {dagger}P<.05 between intermediate and large arterioles. There was no statistical difference in the dilation between large arterioles and small arteries.

The dose-dependent responses to the endothelium-independent vasodilator nitroprusside are shown in Fig 5Down. Nitroprusside produced identical dose-dependent dilations in all groups of vessels with thresholds at 10-10 mol/L, ED50 at 9.2x10-8 mol/L, and maximum dilations at 10-4 mol/L. There were no statistical differences in threshold, ED50, and maximum dilation of the different vessel segments in response to nitroprusside.



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  		Figure 5. Graph showing dose-dependent responses of different coronary microvascular segments to nitroprusside. There were no differences in the threshold or magnitude for nitroprusside-induced vasodilation among the vessel segments.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The major findings of this study are that the coronary microvascular network (1) exhibits a longitudinal gradient for flow-induced dilation, with the magnitude of dilation being large arterioles > intermediate arterioles > small arterioles = small arteries; (2) exhibits a heterogeneous response to endothelium-dependent and -independent pharmacological stimuli; and (3) has vasoactive responses to the nitric oxide donor nitroprusside that are similar in all groups of microvessels. We speculate that these inherent properties of coronary microvessels may be important in the normal regulation of myocardial blood flow. To provide a perspective for our results, critical aspects of our study, including methodological considerations such as the viability of the preparation and the functional integrity of endothelium and smooth muscle, will be discussed. In addition, the differential vascular responses to shear stress and pharmacological agonists and the possible physiological significance of our findings will be addressed.

Methodological Considerations
There are two key advantages of the isolated arteriole preparation over in vivo microcirculatory techniques. These are important for quantitative evaluation of functional heterogeneity in the microvascular network. First, in the in vitro preparation, luminal pressure and flow can be independently and precisely controlled with the double-reservoir system previously developed in our laboratory.7 Second, due to the nature of isolated vessel preparations, confounding effects of neurohumoral and metabolic interferences are eliminated. In contrast, most in vivo studies cannot precisely and quantitatively evaluate segmental reactivity of coronary microvessels because local changes in pressure and flow are always associated with application of physiological and pharmacological stimuli. We previously demonstrated that coronary microvessels are sensitive to local pressure (myogenic responses) and flow (flow-induced responses) changes.7 24 These two factors also interact with each other to influence vascular tone.17 It is conceivable that this would be a particular problem in the study of vascular heterogeneity due to the confounding influences generated by local changes in hemodynamics and tissue metabolites. In the present study, the experiments were conducted under constant luminal pressure during flow variations.7 Therefore, the differential responsiveness to flow and agonist stimulation among vessel segments most likely reflects inherent differences in vascular reactivity.

Isolated arteriolar segments are potentially susceptible to trauma as a result of dissection and cannulation procedures. The amount of trauma may potentially increase as vessel size decreases because smaller vessels have thinner walls and fewer vascular smooth muscle cell layers and are also more difficult to cannulate. This might artifactually generate an apparent response gradient. Thus, great care was taken to minimize possible damage to the vessels during isolation and cannulation. Lack of damage is supported by the fact that the smallest arterioles (1) developed a level of active tone comparable to that of larger arterioles (TableUp), (2) dilated equally in comparison with larger arterioles to substance P (Fig 3Up), and (3) exhibited the greatest sensitivity to adenosine (Fig 4Up). Taken together, these findings indicate that the endothelial and vascular smooth muscle cell function in small arterioles was preserved.

An increase in shear stress has been shown to be responsible for the dilation during flow augmentation.5 In addition to the increase in flow rate, the increase in fluid viscosity (under constant flow) also initiates vascular dilation because of the increase in shear stress.5 In our studies, the fluid viscosity was relatively low (0.8 cp) in comparison with those in vivo studies.5 11 Under the conditions of our experiments, pig coronary arterioles began to dilate at a pressure gradient of only 4 cm H2O. If we used solutions with a higher viscosity, the dilation would probably have occurred at an even lower {Delta}P. This would have made precise diameter-flow relations difficult to determine because small pressure differences (<1 cm H2O) would have been difficult to precisely control. Because of this technical problem, we were not able to study the flow-dependent vascular responses under higher-viscosity conditions. To the best of our knowledge, normal ranges of shear stress in coronary microvessels are not known. However, the average value of shear stress in the dog left circumflex coronary artery is approximately 25 dynes/cm225 and in the left main coronary bifurcation of humans is between 2.3 and 19.7 dynes/cm2.26 Our results indicate that coronary microvessels actively respond to this range of shear stress (0 to 10 dynes/cm2, Fig 1Up). Interestingly, the same range of shear stress correlates well with the opening of endothelial potassium channels,27 with increases in endothelial cell calcium,28 and with nitric oxide production by cultured porcine endothelial cells.29 It is worth noting that a mean red cell velocity between 2 and 3 mm/s was found in dog subepicardial coronary arterioles between 10 and 30 µm in diameter.30 31 Thus, flow velocities between 0 and 35 mm/s in 40- to 180-µm vessels for the present study can be considered to extend over a large portion of the physiological range. In contrast with our results, isolated rat cremaster muscle arterioles (80 µm in diameter) were maximally dilated at a relatively high shear stress (50 dynes/cm2).11 These disparate findings may be related to factors such as differences in animal species (pigs versus rats), vascular bed (cremaster muscle versus coronary), and/or differences in the mechanism of flow-induced dilation (eg, release of a prostaglandin11 versus nitric oxide17 ).

Segmental Gradient for Flow-Induced Responses
The present study, using an in vitro approach, is the first to systematically and quantitatively evaluate flow-induced responsiveness in vessels from a single vascular network (the coronary microcirculation). When our results are compared with data from large coronary arteries8 15 18 and coronary venules,14 a clear segmental gradient for flow-induced responses in the coronary circulation became apparent. Large coronary arterioles ({approx}100 µm in diameter) appeared to dominate these responses, and the magnitude of the dilations progressively decreased in larger and smaller vessels. In a separate study, we showed that coronary venules (100 µm in diameter) also exhibited flow-induced dilation of a magnitude ({approx}15% increase in diameter) comparable to those observed in small arterioles and arteries.14 In contrast, the magnitude of flow-induced dilations of large conduit arteries (eg, left anterior descending and circumflex arteries) was minimal ({approx}3% to 10% increase in diameter). These observations appear to fit together even though those studies were performed in different species under varied experimental conditions using dissimilar techniques.8 15 32

It has been suggested that vasodilation in response to an increase in flow is a physiological mechanism that will maintain wall shear stress relatively constant.33 Our results support this idea, because increases in wall shear stress were limited during flow augmentation (Fig 2Up). The effectiveness of maintaining a constant shear stress was greatest in large arterioles. This is consistent with the fact that the largest magnitude of dilation was observed in these vessels (Fig 1Up). We therefore propose that the inherent properties of segmental flow-induced responsiveness in the coronary microcirculation may play an important role in the regulation of myocardial blood flow under physiological conditions.

Segmental Gradient for Endothelium-Dependent Receptor-Mediated Vasodilation
Recent experiments indicate that heterogeneity exists among different sizes of vessels in the amount of endothelium-derived relaxing factor (EDRF) released under basal conditions and in response to various stimuli.19 34 35 It has been shown in denuded canine coronary arteries that relaxation caused by basal release of EDRF (from a femoral artery) is greater in distal than in proximal arteries.35 In addition, a gradual increase in acetylcholine-induced endothelium-dependent vasodilation with decreasing initial arterial diameter was found in rabbit ear.19 Recent studies in pig coronary circulation also indicate that basal release of EDRF appears to be more pronounced in small arteries (300-µm ID) than in large conduit arteries.34 These findings suggest that a heterogeneous, agonist-induced, endothelium-dependent response may exist in the coronary circulation. Our data support this point of view because substance P–induced vascular dilation mediated by the endothelial release of nitric oxide was greater in arterioles (40 to 100 µm) than in small arteries (175±18 µm) (Fig 3Up). However, the pattern of vascular responsiveness to substance P was different from flow-induced dilation in arteriolar segments (Figs 1Up and 3Up). Therefore, the differential synthesis and release of nitric oxide in response to flow seems unlikely to be the major mechanism responsible for segmental responsiveness.

Interestingly, recent studies in the coronary circulation of conscious dogs indicated that cGMP-mediated vasodilation mechanisms vary according to vessel size.36 This suggests that a differential sensitivity of guanylyl cyclase–mediated vasodilation may also exist in the coronary microcirculation. However, the vasodilation induced by sodium nitroprusside, a nitrovasodilator that exerts its relaxant effect through direct activation of soluble guanylate cyclase, appeared to be identical in all microvascular segments (Fig 5Up). Thus, it is unlikely that a difference in the sensitivity of soluble guanylyl cyclase can explain the gradient for flow-induced responsiveness.

Another possible explanation for differences in the pattern of responsiveness to flow and other endothelium-dependent stimuli may be that fundamental regulatory differences exist between flow- and agonist-induced nitric oxide biosynthesis. This is supported by a recent study in cultured endothelial cells showing that shear stress and pharmacological agonists stimulate different metabolic pathways for nitric oxide synthesis.37 Conversely, the differences in the distribution of pharmacological receptors and shear-stress mechanoreceptors along the microvascular network could explain the inherent differences in endothelium-dependent responses.

Segmental Gradient for Adenosine- Induced Vasodilation
In vivo studies in dogs indicate that adenosine preferentially dilates coronary microvessels smaller than 150 µm and that the magnitude of dilation increases with decreasing vessel size.38 39 This vasodilatory pattern, ie, greater dilation in the smaller coronary arterioles, is similar to the microvascular dilation during graded ischemia,40 increased metabolic activity,38 and decreased perfusion39 of the heart. This suggests that adenosine may play a role in the regulation of microvascular activity during increased metabolic demand and in coronary autoregulation. However, a major deficiency of the in vivo studies described above is that the investigators could not exclude local arteriolar pressure and flow changes during the experimental interventions. It is conceivable that the preferential increase in downstream arteriolar diameter may be due to a passive distension of the vascular wall during upstream arteriolar dilation to adenosine. In addition, the interaction of other local regulatory mechanisms, such as myogenic and flow-dependent responses, may also alter the metabolic vasodilatory responses in the coronary microcirculation. Moreover, the above-mentioned studies38 39 did not extend to the analysis of dose-response relations in different-size coronary microvessels. In the present study, without interference of myogenic and flow-induced responses, we demonstrated a segmental gradient for adenosine-induced vasodilation in the coronary microcirculation (ie, the vasodilatory responsiveness varies inversely with vessel size). In a porcine model,41 adenosine relaxes preconstricted left anterior descending and circumflex coronary arteries at a threshold of 10-6 mol/L, which is about six orders of magnitude greater than our present finding in small arterioles (10-12 mol/L) (Fig 4Up). This may support the idea that endogenous release of adenosine from cardiac tissue during metabolic activation may significantly influence flow perfusion by dilation of small coronary arterioles.

In the present study, we did not examine the endothelial dependence of adenosine-induced dilation. Isolated vascular ring studies have shown that the relaxation induced by adenosine is partially dependent on the presence of an intact endothelium.42 43 In contrast, an endothelium-independent response has also been reported.44 45 Furthermore, adenosine may cause vasodilation through activation of ATP-sensitive potassium channels in addition to activation of vascular smooth muscle adenylyl cyclase.46 Although the mechanisms of adenosine-induced vasodilation in coronary microvessels are not clear, our study confirms the apparent longitudinal gradient for adenosine responses in the coronary microvascular network found in previous in vivo studies; most importantly, our study provides quantitative dose-response information for four consecutive coronary vascular segments. Furthermore, we have shown that the response gradient to adenosine was different from that for shear stress and substance P. The difference in the response pattern between shear stress and agonists may be essential for integrating and coordinating blood flow regulation in response to physiological stimuli.

Physiological Considerations
Segmental distribution of local regulatory mechanisms may be a general feature of most microvascular systems. Recent in vivo studies in cat skeletal muscle indicate that slight activation of metabolic demands causes inhibition of intrinsic tone and decreases vascular resistance selectively in the small arteriolar segment.47 The dilation of proximal arterial resistance vessels occurs only at increasing workloads47 and may be initiated by endothelium-dependent flow-induced dilation mechanisms.48 These results suggest a segmental response pattern to metabolic and flow-induced dilation. In addition, in the rabbit ear microcirculation, shear stress–induced dilation of larger feeding arterioles has been shown to play an important role in coordinating the behavior of vascular resistance and optimizing perfusion characteristics over a wide range of flow rates.12

We previously proposed an integrative hypothesis for metabolic, myogenic, and flow-induced control of coronary blood flow during an increase in metabolic demand by the myocardium.7 In that model, different elements of the microvasculature would be governed predominantly by different regulatory mechanisms. First, an increase in metabolic demand by the myocardium would preferentially dilate small arterioles through the release of a metabolic vasodilator, presumably adenosine. This dilation would then result in a decreased pressure in upstream intermediate sizes of arterioles, which would in turn elicit myogenic dilation of these vessels. The dilation would decrease arteriolar resistance and hence increase flow. The increased flow would recruit larger upstream vessels to dilate because of endothelium-dependent flow-induced responses. The additive interaction of myogenic and flow-mediated responses would increase tissue perfusion and optimize oxygen delivery. This integrative flow control mechanism is supported by our finding that small coronary arterioles indeed were more sensitive to adenosine than larger arterioles and that flow-induced dilation operated predominantly in upstream larger arterioles. Furthermore, we also found a greater myogenic responsiveness in intermediate sizes of coronary arterioles (54±4 µm)17 than in upstream larger arterioles (70 to 100 µm)22 24 in the same species. Segmental heterogeneity would help to coordinate the overall vascular response of the microvasculature during physiological stress.

The segmental gradient for flow-induced responsiveness may also be beneficial in maintaining a constant flow in the microvascular network via interactions with other local regulatory mechanisms. For example, an increase in local flow could preferentially dilate large feeding arterioles (flow-sensitive segments) and also preferentially constrict downstream small arterioles (metabolite-sensitive segments) as a result of washout of local metabolic vasodilators. These vascular changes would facilitate the increase in pressure in intermediate-size arterioles, which exhibit a greater myogenic responsiveness (pressure-sensitive segments). It is worth noting that the myogenic constriction effectively counteracts flow-induced dilation in these vessel segments.17 Therefore, the constriction of arterioles downstream from feeding vessels would increase local resistance and thus limit the increase in flow. Thus, the preferential dilation of feeding arterioles in response to flow (shear stress) could participate in the regulation of resistance and blood flow in the microcirculation.


*    Acknowledgments
 
This study was supported by National Heart, Lung, and Blood Institute awards HL-48179 to Dr Kuo, HL-32788 to Dr Chilian, and HL-46502 for Dr Davis.

Received November 10, 1994; revision received January 9, 1995; accepted January 22, 1995.


*    References
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*References
 

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