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Cardiovascular Research 1997 35(2):377-383; doi:10.1016/S0008-6363(97)00112-0
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Copyright © 1997, European Society of Cardiology

Response of coronary microvascular collaterals to activation of ATP-sensitive K+ channels

Kathryn G Lamping*, Daniel W Nuno, Leonard A Brooks and Mikio Fujii

Department of Internal Medicine and The Cardiovascular Center, College of Medicine, University of Iowa, E314-4 GH, Iowa City, IA 52242, USA

* Corresponding author. Tel.: +1 (319) 356-2881; fax: +1 (319) 353-6343; e-mail: kathryn-lamping@uiowa.edu

Received 30 December 1996; accepted 14 April 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Studies have suggested that collateral vessels of the coronary and hind-limb circulations are more sensitive to activation of ATP-sensitive K+ channels than are non-collateral vessels. The objective of the present study was to compare responses of microvascular non-collaterals, native collaterals and stimulated collaterals in the heart to three vasodilators which act through different mechanisms: activation of ATP-sensitive K+ channels with aprikalim, release of nitric oxide with acetylcholine, and endothelium-independent activation of soluble guanylate cyclase with nitroglycerin. Methods: Collateral growth was stimulated by placing an Ameroid occluder on the proximal left circumflex artery in dogs. Non-collaterals, native collaterals and stimulated collaterals (100–220 µm in diameter) were isolated, cannulated on micropipettes and pressurized in vitro. Vessel diameters were measured using videomicroscopy. Results: Dilation to aprikalim (10–8–10–5 M), acetylcholine (10–9–10–6 M) and nitroglycerin (10–8–3x10–4 M) were similar in non-collateral, native collateral and stimulated collaterals. Dilation of native collaterals to aprikalim and acetylcholine was attenuated by glibenclamide (10 µM), an inhibitor of ATP-sensitive K+ channels, but not by tetraethylammonium (1 mM), a non-selective inhibitor of K+ channels. Dilation of native collaterals to acetylcholine but not aprikalim was also inhibited by nitro-L-arginine (10 µM), an inhibitor of nitric oxide synthase. Conclusion: These findings suggest that microvascular native and stimulated collaterals respond to activation of ATP-sensitive K+ channels and acetylcholine similar to non-collaterals of similar size. Thus, changes in reactivity of collaterals to activation of ATP-sensitive K+ channels are not related to changes in the ability of the vessels to respond to vasodilators but may primarily be determined by a change in the distribution of collateral vessel size.

KEYWORDS Aprikalim; Tetraethylammonium; Acetylcholine; Nitric oxide; Nitroglycerin; Potassium channel opener; Potassium channel, ATP sensitive; Dog, arteries; Collateral circulation


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
During coronary occlusion, myocardium at risk for infarction is dependent upon flow through the collateral circulation to remain viable. Collateral vessels that develop in response to a gradual coronary occlusion appear histologically similar to native or non-collateral vessels following growth of smooth muscle in the vessel wall. However, there is evidence of endothelial proliferation, defects in the internal elastic membrane contributing to an increased tortuosity of the vessel, monocyte adherence and perivascular inflammation [1–3].

Because these alterations in vessel structure may affect vascular reactivity, several studies have examined reactivity of large collaterals in comparison to non-collateral vessel of similar size to endothelium-dependent agonists. Despite the alterations in vascular structure, responses of large collateral vessels to vasodilators generally are similar to non-collaterals. Dilation of large collaterals to the endothelium-dependent agonist, acetylcholine, the endothelium-independent agonist, nitroprusside, and activation of ATP-sensitive K+ channels with cromakalim were not different from large non-collateral arteries [4, 5]. However, constrictions to potassium chloride, endothelin and the thromboxane mimetic, U46619 [GenBank] , were reduced in large collaterals [4]. In contrast, dilation of isolated microvessels from collateral-dependent myocardium distal to a chronic occlusion was impaired compared to non-collaterals of similar size to the endothelium-dependent agents, acetylcholine and ADP, and enhanced to the endothelium-independent agent, nitroglycerin [6]. Responses of microvascular collaterals supplying collateral-dependent myocardium in comparison to microvascular non-collaterals have not been examined.

Preliminary studies in vivo measuring flow to collateral-dependent myocardium as an index of changes in collateral resistance have suggested that collateral vessels may be more sensitive to activation of ATP-sensitive K+ channels than are non-collateral vessels in non-ischemic myocardium. Activation of ATP-sensitive K+ channels preferentially increased flow to collateral-dependent myocardium [7]. The preferential increase in flow to collateral-dependent myocardium may represent an increased sensitivity of microvascular collaterals to activation of ATP-sensitive K+ channels. Collateral blood flow increases in skeletal muscle and the coronary circulation before flow increases in non-ischemic regions following activation of K+ channels with cromakalim, pinacidil, nicorandil [8]and bimakalim [7]. Although these studies suggest that collateral vessels may be more sensitive to activation of ATP-sensitive K+ channels than non-collateral vessels, they cannot separate direct effects on collateral vessels from effects on vessels at the source of the collaterals or in collateral-dependent myocardium. Generally, in vivo studies have been unable to demonstrate effects of pharmacological agents on collateral resistance after acute coronary occlusions [9].

The objective of the present study was to compare responses of native and stimulated microvascular collaterals to responses of non-collaterals to agents which produce dilation through three different mechanisms. First, dilation as a result of activation of ATP-sensitive K+ channels was compared using aprikalim. Second, dilation in response to release of EDRF was compared with acetylcholine. Last, responses to endothelium-independent activation of guanylate cyclase with nitroglycerin were compared


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Stimulation of collateral growth
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). Adult mongrel dogs of either sex (20–30 kg) were anesthetized with sodium pentothal (30 mg/kg i.v.) and halothane (0.75–1.5%). Dogs were intubated and ventilated with a respirator. Using sterile surgical procedures, the chest was opened in the left fourth intercostal space and the lungs retracted. The heart was suspended in a pericardial cradle and a segment (approximately 1.0–1.5 cm in length) of the proximal left circumflex coronary (LCx) artery was isolated. An ameroid constrictor (i.d. 2.0–3.0 mm) was placed around the vessel. The size of ameroid was chosen to fit snugly around the vessel without producing a visible stenosis. The chest was closed in layers and evacuated. Dogs were allowed to develop collaterals for 9–12 months.

2.2 Experimental preparation
On the day of study, normal dogs or dogs with mature collaterals were anesthetized with sodium pentothal and {alpha}-chloralose (100 mg/kg i.v.) and mechanically ventilated. Cannulas were placed in a femoral vein and artery for administration of anesthetic and measurement of arterial pressure. A thoracotomy was performed in the left fifth intercostal space and the pericardium was opened. To assess the extent of collateral development, coronary pressure in the LCx distal to the ameroid occluder was measured with a catheter inserted into the LCx distal to the ameroid. The dog was exsanguinated and the heart was rapidly excised and placed in cold Krebs' buffer (mM; NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25 and glucose 11.1) bubbled with 20% O2, 5% CO2 and balance N2. The ameroid occluder on the LCx was isolated and visually examined for complete closure.

2.3 Measurement of microvascular diameter
Measurements of microvascular diameters were made with a video microscopy system [10–12]. Briefly, microvessels were isolated under a 40x dissecting microscope. Segments of non-collateral arteries (100–220 µm in diameter, 1.5–2.0 mm in length) were isolated from the perfusion region of the left anterior descending coronary artery (LAD) and native or stimulated collaterals were identified visually between the LCx and LAD in acute dogs (Native Collaterals) and ameroid dogs (Stimulated Collaterals). Vessels were placed in a plexiglas organ chamber filled with cold Krebs' solution, cannulated with dual glass micropipettes measuring 20–30 µm in diameter and secured with 10-0 nylon monofilament suture. Krebs' buffer aerated with 20%O2, 5% CO2 and balance N2 was continuously circulated through the organ chamber. In preliminary studies the response of arterioles to KCl (100 mM) was measured at increasing distending pressures from 5 to 100 mmHg. Maximal contractions to KCl were obtained at approximately 20 mmHg of distending pressure similar to the results of Sellke et al. [6]. Thus, subsequent studies were performed in vessels pressurized to 20 mmHg under no-flow conditions using two burettes filled with Krebs' solution. Using a Leitz microscope (100x) connected to a Hitachi camera, images of microvessels were displayed on a video monitor. An electronic video dimension analyzer (Living Systems Instrumentation, Burlington, VT) continuously measured lumen diameter which was recorded on a strip-chart recorder [12]. Distending pressure of the microvessels was measured with a pressure transducer connected to a side arm of the cannula on one of the micropipettes. Vessels were allowed to equilibrate in the organ bath for 45–60 min before study. Viability of the microvessel was defined as a minimum of 50–70% contraction from basal diameter to the addition of 100 mM of KCl. Endothelial function was tested in all vessels with a single dose of acetylcholine (10–5 M). Relaxation to acetylcholine less than 80% was considered abnormal.

2.4 Protocols
Microvessels were preconstricted with endothelin (0.1–0.15 nM) to 30–60% of the resting diameter. Dose–response curves to one or two vasodilators were performed in each vessel. Three groups of vessels were studied: non-collaterals, native collaterals and stimulated collaterals. Increasing concentrations of acetylcholine (10–9 to 10–6 M), nitroglycerin (10–8 to 3x10–4 M) or aprikalim (RP52891, 10–8 to 10–5 M) were added to the bath. To examine the role of nitric oxide containing compounds in responses to acetylcholine and aprikalim in native collaterals, vessels were incubated with N{omega}-nitro-L-arginine (10 µM) for 10-20 min before performing dose–response curves to acetylcholine or aprikalim. To examine the role of ATP-sensitive K+ channels in responses to acetylcholine and aprikalim in native collaterals, the vessels were incubated with glibenclamide (10 µM) for 10–20 min before performing dose–response curves to acetylcholine or aprikalim. To determine the role of calcium-activated K+ channels in responses to acetylcholine and aprikalim, vessels were incubated with tetraethylammonium (1 mM) before performing dose–response curves to acetylcholine or aprikalim.

2.5 Statistical analysis
Dilation was calculated as percent change in diameter from the preconstricted diameter. Data are presented as mean±standard error of the mean. Numbers represent number of dogs. When more than one vessel per dog was studied, responses were averaged. Dose–response curves were compared using an analysis of variance. For comparisons between individual concentrations, paired t-tests were performed corrected for multiple comparisons using Bonferroni. Statistical significance was considered at the P<0.05 level.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
In dogs in which an ameroid constrictor was placed around the LCx the mean arterial pressure was 124±3 mmHg. Coronary pressure in the LCx distal to the ameroid constrictor was 112±3 mmHg, a 10±1% drop from arterial pressure suggesting that collateral development was stimulated.

3.1 Responses to aprikalim
Baseline diameters of non-collaterals (n = 8, 133±14 µm), native collaterals (n = 9, 144±12 µm) and stimulated collaterals (n = 8, 150±15 µm) were similar. Following preconstriction with endothelin, diameters of non-collaterals (68±8 µm), native collaterals (78±9 µm) and stimulated collaterals (81±10 µm) were similar. Aprikalim produced dose-dependent dilation in non-collateral, native collaterals and stimulated collaterals that was not different among the groups (Fig. 1). Dilation in response to aprikalim was maximal at 10–6 M in all vessels. Dilation of native collaterals in response to aprikalim was significantly inhibited by glibenclamide (10 µM, n = 6, Fig. 2A), but not by nitro-L-arginine (10 µM, n = 6, Fig. 2B) or tetraethylammonium (1 mM, n = 4, Fig. 2A). Thus, in native collaterals, dilation to aprikalim is mediated by activation of ATP-sensitive K+ channels and does not stimulate release of nitric oxide.


Figure 1
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  		Fig. 1 Dilation of non-collateral, native collateral and stimulated collateral vessels to activation of ATP-sensitive K+ channels with aprikalim. There were no differences in dilation to aprikalim among the vessel types.

 

Figure 2
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  		Fig. 2 Dilation of native collaterals to activation of ATP-sensitive K+ channels with aprikalim before (Control) and after addition of glibenclamide (GLB, µM, A), tetraethylammonium (TEA, 1 mM, A) or nitro-L-arginine (L-NNA, 10 µM, B). Dilation to aprikalim was significantly attenuated by glibenclamide (*P<0.05 vs. Control) but not altered by TEA or L-NNA.

 
3.2 Responses to acetylcholine
Baseline diameters of non-collaterals (n = 6, 145±16 µm), native collaterals (n = 7, 152±13 µm) and stimulated collaterals (n = 8, 163±16 µm) were similar. Following preconstriction with endothelin, diameters of non-collaterals (78±10 µm), native collaterals (91±10 µm) and stimulated collaterals (91±12 µm) were similar. Dilation to acetylcholine was similar in all vessels (Fig. 3). In native collaterals, dilation to acetylcholine was attenuated by both glibenclamide (10 µM, n = 6, Fig. 4A) and nitro-L-arginine (10 µM, n = 6, Fig. 4B). Dilation of native collaterals to acetylcholine was not altered by tetraethylammonium (1 mM, n = 5, Fig. 4A). Thus, dilation of native collaterals to acetylcholine involves release of nitric oxide and activation of ATP-sensitive K+ channels.


Figure 3
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  		Fig. 3 Dilation of non-collateral, native collateral, and stimulated collateral vessels to acetylcholine. There were no differences in the dilation to acetylcholine among the vessel types.

 

Figure 4
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  		Fig. 4 Dilation of native collaterals to acetylcholine before (Control) and after addition of glibenclamide (GLB, 10 µM, A), tetraethylammonium (TEA, 1 mM, A) or nitro-L-arginine (L-NNA, 10 µM, B). Dilation to acetylcholine was significantly attenuated by glibenclamide and nitro-L-arginine (*P<0.05 vs. Control).

 
3.3 Responses to nitroglycerin
Baseline diameters of non-collateral (n = 7, 144±18 µm), native collateral (n = 7, 165±15 µm), and stimulated collateral vessels (n = 7, 167±13 µm) were similar. Following preconstriction with endothelin, diameters of non-collaterals (73±10 µm), native collaterals (94±9 µm) and stimulated collaterals (91±12 µm) were similar. In contrast to aprikalim and acetylcholine, nitroglycerin did not produce maximal dilation of coronary microvessels (Fig. 5). Maximal response of non-collateral vessels to nitroglycerin was 68±4% at 3x10–5 M. The response of non-collateral, native collateral and stimulated collaterals to nitroglycerin was similar in all groups.


Figure 5
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  		Fig. 5 Dilation of non-collaterals, native collaterals, and stimulated collaterals to nitroglycerin. Dilation to nitroglycerin was not different among the groups.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The important finding in the present study is that native and stimulated microvascular collaterals respond similarly to non-collateral vessels of similar size to activation of ATP-sensitive K+ channels with aprikalim, release of nitric oxide by acetylcholine, and activation of guanylate cyclase by nitroglycerin. Thus, selective increases in collateral-dependent flow by activation of ATP-sensitive K+ channels in previous studies does not appear to be related to a greater sensitivity of collateral vessels to activation of K+ATP channels compared to non-collaterals. In addition, these data suggest that native collaterals are vasoactive and can respond to acetylcholine and nitroglycerin similar to both non-collaterals and collaterals.

One unique aspect of this study is our ability to compare responses of microvascular native and stimulated collaterals to non-collateral vessels. Previous studies examining reactivity of the collateral circulation in the dog in vivo have not convincingly demonstrated that native collaterals are capable of responding to pharmacological or neurohumoral stimuli [1]. In the presence of stimulated collaterals pharmacological and neurohumoral agonists can increase flow to collateral-dependent myocardium, suggesting that reactivity of collaterals changes during development [1]. However, studies of native collaterals usually use measurements of blood flow to collateral-dependent myocardium, retrograde blood flow or coronary pressure in a collateral-dependent region as an index of changes in collateral resistance following acute coronary occlusion. Previous studies from our laboratory have demonstrated that following acute coronary occlusion, arteries and arterioles in the central ischemic region are maximally vasodilated [13]. Topical application of adenosine or EDTA had no effect on microvascular diameter. In contrast, following stenosis of the proximal large artery the vasodilator reserve of the microcirculation in the ischemic region was not exhausted because EDTA and/or adenosine produced further dilation. A similar effect of coronary occlusion may be occurring with microvascular collaterals at the border of the ischemic region. Following acute coronary occlusion microvascular collaterals progressively dilate for 15–30 min and are probably maximally vasodilated [14]. Thus, the inability of pharmacological agents to increase flow to collateral-dependent myocardium following an acute occlusion may be related to an exhausted vasodilator capacity and not to an inability of native collaterals to respond to pharmacological vasodilators. Our data demonstrate that native collaterals respond similarly to non-collaterals and stimulated collaterals to a variety of vasodilators.

In the present study, all isolated vessels were studied at 20 mmHg pressure following preconstriction with endothelin. Vessels were pressurized to 20 mmHg based on preliminary studies examining responses to KCl and acetylcholine. In isolated microvessels, maximal contractions to KCl were obtained at approximately 20 mmHg similar to the results of Sellke et al. [6]. In addition, we have compared responses of isolated microvessels to acetylcholine at distending pressures from 20 to 60 mmHg. Relaxation to acetylcholine was similar at all pressures (unpublished results). Lastly, all vessels were preconstricted with endothelin-1 since dog coronary microvessels do not routinely develop spontaneous tone and do not consistently constrict to other agonists such as the thromboxane mimetic, U46619 [GenBank] , {alpha}-adrenoceptor agonists, or PGF2{alpha}. These methodological aspects must be considered in evaluating these in vitro data in relationship to in vivo conditions where perfusion pressure and neural, humoral and tissue factors may be different and influence vascular reactivity.

Although the functional significance of coronary collaterals in humans has been controversial [1, 9], it has become clear that well-developed collaterals can contribute to the maintenance of normal myocardial perfusion in regions distal to a flow-limiting stenosis or coronary occlusion in the dog [9]. The contribution of native collaterals to maintenance of flow to collateral-dependent myocardium is substantially less. Native collaterals in the dog heart are relatively few in number and small in diameter (average 40 µm) [1]. Collateral arteries larger than 100 µm are seldom observed. After stimulation of collateral growth, collaterals can increase in diameter to an average of 650 µm. However, morphologically stimulated collaterals are different from non-collaterals since there is intimal thickening, a ruptured internal elastic lamina and monocyte infiltration. These alterations could lead to abnormal vascular reactivity of well-developed collaterals. The ability of vasoactive agents to increase collateral flow in the presence of well-developed collaterals, but not native collaterals, may be related to an alteration in the reactivity of the collateral vessels themselves or due to a difference in the distribution of collateral vessel size.

Microvascular collaterals have been described anatomically, but their physiological role is unclear. Although large collateral vessels that develop during chronic coronary occlusion are considered the primary source of flow to collateral-dependent myocardium, studies by Downey and co-workers [15, 16]suggest that microvascular collaterals contribute substantially to flow to collateral-dependent myocardium. During diversion of collateral flow from epicardial arteries, flow to collateral-dependent myocardium measured with radiolabeled microspheres was still approximately half of control. These studies suggested that the microscopic collaterals are uniformly distributed transmurally and make a significant contribution to maintaining flow to collateral-dependent tissue.

Recent studies on the coronary circulation have suggested that activation of ATP-sensitive K+ channels is important in the regulation of the vascular response to hypoxia [17], ischemia [14, 18], and during decreases in perfusion pressure within the autoregulatory range [18, 19]. Treatment with glibenclamide abolishes the autoregulatory response and microvascular dilation of non-collaterals during decreases in perfusion pressure [18, 19]. Dilation of native collaterals following coronary occlusion is also inhibited by glibenclamide [14]. Thus, dilation of the coronary microcirculation including microvascular collaterals during hypoxia or ischemia appears to be mediated through activation of ATP-sensitive K+ channels. The results of the present study suggest that activation of ATP-sensitive K+ channels with aprikalim is similar in native and well-developed collaterals compared to non-collateral vessels.

Dilation of native collaterals to aprikalim is primarily mediated by activation of ATP-sensitive K+ channels on smooth muscle since dilation to aprikalim was inhibited by glibenclamide, a specific blocker of the ATP-sensitive K+ channel. It is likely that aprikalim activates ATP-sensitive K+ channels in non-collaterals and stimulated collaterals as well. Recent studies suggest that activation of ATP-sensitive K+ channels also stimulates release of nitric oxide from endothelium. Inhibition of nitric oxide synthase attenuated increases in pulmonary blood flow following activation of ATP-sensitive K+ channels [20]. ATP-sensitive K+ channels are present on microvascular endothelium and activation of these channels may be involved in release of EDRF or endothelium-derived hyperpolarization factor [21]. However, in the present study dilation of native collaterals to aprikalim was not affected by nitro-arginine. Thus, activation of ATP-sensitive K+ channels does not stimulate release of nitric oxide in native collaterals.

Previous studies examining responses of non-collateral microvessels in collateral-dependent myocardium have demonstrated impaired dilation to endothelium-dependent agonists such as acetylcholine and ADP [6]. In contrast, dilation to nitroglycerin was enhanced. These studies did not examine responses of collaterals themselves. Dilation of native and stimulated collaterals to acetylcholine were not different from non-collaterals in the present study. Similar to our findings with microvascular collaterals, studies of large collateral arteries from dogs with Ameroid constrictors have demonstrated normal responses to both acetylcholine and nitroprusside [4]. Thus, during the development of collaterals synthesis and/or release of EDRF in endothelium of collaterals is normal in response to acetylcholine. Collateral vessels at the border of the ischemic region which supply blood flow to dependent myocardium may be spared from the effects of persistent ischemia and maintain normal endothelial function.

In contrast to previous studies, responses to nitroglycerin were not increased in stimulated collaterals. There was no change in sensitivity or maximal dilation to nitroglycerin in either native or stimulated microvascular collaterals compared to non-collaterals. Following an acute coronary occlusion nitroglycerin has little effect on collateral resistance as measured by collection of retrograde flow or measurement of flow to collateral-dependent myocardium with radiolabeled microspheres [22–24]. This is in marked contrast to the effects of nitroglycerin in the presence of well-developed collaterals. In the presence of well-developed collaterals nitroglycerin produces marked increases in collateral blood flow [25–27]. This difference in the effect of nitroglycerin on collateral blood depending upon the degree of collateral development is probably related to the distribution of collateral vessel size. The response of coronary arteries and arterioles to nitroglycerin is directly related to vessel size [10, 28, 29]. Larger arteries and arterioles dilate to nitroglycerin whereas arterioles less than 100 µm do not respond or respond minimally. Following decreases in coronary perfusion pressure nitroglycerin can still dilate large coronary arteries, but not affect diameter of arterioles less than 100 µm [28]. It is possible that the ability of nitroglycerin to increase flow to collateral-dependent myocardium only in the presence of well-developed collaterals is related to a shift in the distribution of collaterals to larger collaterals compared to small collaterals less than 100 µm and is not related to a difference in the response of the collaterals themselves.

In summary, the response of both native and stimulated microvascular collaterals to activation of ATP-sensitive K+ channels with aprikalim, release of EDRF with acetylcholine, and activation of guanylate cyclase with nitroglycerin is comparable to non-collaterals of similar size. These data demonstrate that during the development of collateral vessels, responses of endothelium and vascular smooth muscle to activation of ATP-sensitive K+ channels and nitric oxide are maintained.

Time for primary review 24 days.


   Acknowledgements
 
We thank Icilio Cavero, Ph.D., of Rhone-Poulenc Rorer for the generous supply of aprikalim (RP52891). These studies were supported by grants from the National Institute of Health (HL39050) and the American Heart Association. K.G.L. is an Established Investigator from the American Heart Association.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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