Comprehensive Physiology Wiley Online Library

Regulation of Coronary Microvascular Resistance in Health and Disease

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Introduction and Background
2 Endothelial and Myogenic Mechanisms of Coronary Regulation
2.1 Endothelium‐dependent vasodilation
2.2 Flow‐ or shear stress‐dependent dilation
2.3 Myogenic control mechanisms
2.4 Interaction of pressure‐ and flow‐dependent control
3 Metabolic Regulation of Coronary Microvascular Resistance
3.1 General concepts
3.2 Parallel vs. redundant pathways
3.3 Measurement of metabolic control in vivo‐myocardial oxygen balance
3.4 Measurement of metabolic control in vitro
3.5 Putative mediators of metabolic regulation
4 Neurohumoral Control
4.1 General concepts
4.2 Sympathetic control
4.3 Parasympathetic control
4.4 Non‐adrenergic, non‐cholinergic control
4.5 Humoral control
5 Pathophysiological Disturbances
5.1 Impact of microvascular disease on the heart
5.2 Pathophysiology of endothelial dysfunction
5.3 Role of vasoconstrictors
6 Summary, Conclusions, Directions
Figure 1. Figure 1.

Distribution of pressures in the coronary microcirculation of the beating heart under control conditions and during intense vasodilation with dipyridamole. Dipyridamole produced a 5 to 6‐fold increase in flow, and despite this huge increase in flow, the pressure drop across the small arteries and arterioles decreased by half. This implies that resistance decreased by 10 to 12‐fold during dypridamole‐induced vasodilation.

Adapted from Ref.
Figure 2. Figure 2.

Pressure diameter relations of subepicardial arterioles before (closed circle) and after (open circle) mechanical denudation of endothelium. There is no statistical difference in myogenic response before and after mechanical denudation. Lumen diameters were normalized to diameter at a pressure of 60cmH2O in presence of nitroprusside(10−4M). Average luminal diameter(d) inphysiological saline‐albumin solution at 60cmH2O is shown. Vertical bars denote mean ± SEM. *Significantly different from diameter at 60cmH2O pressure with or without endothelium.

Adapted from Ref.
Figure 3. Figure 3.

Example of interaction between pressure‐induced myogenic responses and flow‐dependent dilation in isolated subepicardial arterioles. (A) Myogenic constriction was inhibited by an increase in flow. (B) Myogenic dilation was potentiated by flow. (C) Flow‐induced dilation was attenuated by elevating pressure. (D) Flow‐induced dilation was potentiated by lowering pressure. With permission from Ref. .

Figure 4. Figure 4.

Hypothetical scheme illustrating the interaction of pressure‐. flow‐ and metabolic control mechanisms during a rise in coronary perfusion pressure during sympathetic adrenal activation. Myogenic arteriolar constriction serves to limit the increase in coronary blood flow and the rise in pressure in coronary exchange vessels, perhaps thus protecting the myocardium from edema. Each of the interactions shown may be subject to neurohumoral influences. MVO2, myocardial oxygen consumption.

Figure 5. Figure 5.

Regulation of myocardial oxygen balance during changes in myocardial oxygen consumption. (See page 12 in colour section at the back of the book)

Figure 6. Figure 6.

Effects of endothelin receptor blockade (Tezosentan: ETA/ETB; EMD 122946: ETA) on coronary oxygen extraction and venous oxygen saturation during exercise under control conditions and during endothelin receptor blockade. Note, that endothelin blockade significantly affected the relationships suggesting the during the sympathoadrenal excitation with exercise, endothelin exerts a constrictor effect on coronary blood flow.

Adapted from Ref. . (See page 13 in colour section at the back of the book)
Figure 7. Figure 7.

Constriction of isolated coronary arterioles exposed to supernatant from cardiac myocytes stimulated with increasing concentrations of phenylephrine. Addition of the ETa antagonist, FR 139317 to the arteriolar tissue bath abolished the constrictor response that was observed following administration of 8‐para‐sulfaphenyltheophylline (8‐PSPT) to block adenosine A1 and A2 receptors. Adminstration of the α1‐adrenergic antagonist prazosin to the isolated myocytes prevented the production of the vasoconstrictor compound by the cardiac myocytes and had no effect when administered to the vessels (not shown), indicating that α‐adrenergic coronary constriction is mediated by the production of a myocyte‐derived vasoconstrictor, and not due to direct actions on smooth muscle. With permission from Teifenbacher el al. (1998).

Figure 8. Figure 8.

Responses of coronary microvessels 50–250μm in diameter to the α‐adrenergic agonist BHT‐933 under control conditions (Di) with autoregulatory mechanisms intact (left) and during hypoperfusion at 40mm Hg (D40) to prevent autoregulatory responses (right). Percent change in diameter is plotted as a function of control diameter. Under control conditions, small arterioles dilated as seen by a positive change in diameter while large arterioles constricted. Prevention of autoregulatory responses resulted in vasoconstriction of all arterioles.

Adapted from Chilian
Figure 9. Figure 9.

Blockade of feedforward β‐adrenergic dilation of the coronary microcirculation reduces the myocardial oxygen supply‐to‐consumption ratio in exercising dogs. With permission from Gorman el al. (2000).

Figure 10. Figure 10.

Schematic for the regulation of NO production and the influences of atherosclerosis. risk factors, and angiotensin on NO metabolism. (See page 13 in colour section at the back of the book)

Figure 11. Figure 11.

The metabolism of L‐arginine into NO and degradation of NO into nitrites and nitrates.

Figure 12. Figure 12.

Responses of isolated coronary arterioles removed from the ischemic region after ischemia‐reperfusion. The data presented were obtained from arterioles (n = 3 to n = 5) during initial conditions after ischemia/reperfusion (I/R), during incubation with 10μmol/L MH4 (I/R + MH4), a synthetic cell‐permeable tetrahydrobiopterin, and after washout of MH4 (I/R + MH4 + Wash). Data are expressed as mean±SEM. *p < 0.05 vs. ischemia/reperfusion.

Adapted from Ref.
Figure 13. Figure 13.

Responses of isolated human coronary arterioles from patients with significant atherosclerosis. Results were obtained from arterioles (n = 10) during baseline conditions and after incubation with 1 μM sepiapterin to restore endogenous pools of BH4. Data are expressed as mean±SEM. *p < 0.05 vs. baseline.

Adapted from Ref.


Figure 1.

Distribution of pressures in the coronary microcirculation of the beating heart under control conditions and during intense vasodilation with dipyridamole. Dipyridamole produced a 5 to 6‐fold increase in flow, and despite this huge increase in flow, the pressure drop across the small arteries and arterioles decreased by half. This implies that resistance decreased by 10 to 12‐fold during dypridamole‐induced vasodilation.

Adapted from Ref.


Figure 2.

Pressure diameter relations of subepicardial arterioles before (closed circle) and after (open circle) mechanical denudation of endothelium. There is no statistical difference in myogenic response before and after mechanical denudation. Lumen diameters were normalized to diameter at a pressure of 60cmH2O in presence of nitroprusside(10−4M). Average luminal diameter(d) inphysiological saline‐albumin solution at 60cmH2O is shown. Vertical bars denote mean ± SEM. *Significantly different from diameter at 60cmH2O pressure with or without endothelium.

Adapted from Ref.


Figure 3.

Example of interaction between pressure‐induced myogenic responses and flow‐dependent dilation in isolated subepicardial arterioles. (A) Myogenic constriction was inhibited by an increase in flow. (B) Myogenic dilation was potentiated by flow. (C) Flow‐induced dilation was attenuated by elevating pressure. (D) Flow‐induced dilation was potentiated by lowering pressure. With permission from Ref. .



Figure 4.

Hypothetical scheme illustrating the interaction of pressure‐. flow‐ and metabolic control mechanisms during a rise in coronary perfusion pressure during sympathetic adrenal activation. Myogenic arteriolar constriction serves to limit the increase in coronary blood flow and the rise in pressure in coronary exchange vessels, perhaps thus protecting the myocardium from edema. Each of the interactions shown may be subject to neurohumoral influences. MVO2, myocardial oxygen consumption.



Figure 5.

Regulation of myocardial oxygen balance during changes in myocardial oxygen consumption. (See page 12 in colour section at the back of the book)



Figure 6.

Effects of endothelin receptor blockade (Tezosentan: ETA/ETB; EMD 122946: ETA) on coronary oxygen extraction and venous oxygen saturation during exercise under control conditions and during endothelin receptor blockade. Note, that endothelin blockade significantly affected the relationships suggesting the during the sympathoadrenal excitation with exercise, endothelin exerts a constrictor effect on coronary blood flow.

Adapted from Ref. . (See page 13 in colour section at the back of the book)


Figure 7.

Constriction of isolated coronary arterioles exposed to supernatant from cardiac myocytes stimulated with increasing concentrations of phenylephrine. Addition of the ETa antagonist, FR 139317 to the arteriolar tissue bath abolished the constrictor response that was observed following administration of 8‐para‐sulfaphenyltheophylline (8‐PSPT) to block adenosine A1 and A2 receptors. Adminstration of the α1‐adrenergic antagonist prazosin to the isolated myocytes prevented the production of the vasoconstrictor compound by the cardiac myocytes and had no effect when administered to the vessels (not shown), indicating that α‐adrenergic coronary constriction is mediated by the production of a myocyte‐derived vasoconstrictor, and not due to direct actions on smooth muscle. With permission from Teifenbacher el al. (1998).



Figure 8.

Responses of coronary microvessels 50–250μm in diameter to the α‐adrenergic agonist BHT‐933 under control conditions (Di) with autoregulatory mechanisms intact (left) and during hypoperfusion at 40mm Hg (D40) to prevent autoregulatory responses (right). Percent change in diameter is plotted as a function of control diameter. Under control conditions, small arterioles dilated as seen by a positive change in diameter while large arterioles constricted. Prevention of autoregulatory responses resulted in vasoconstriction of all arterioles.

Adapted from Chilian


Figure 9.

Blockade of feedforward β‐adrenergic dilation of the coronary microcirculation reduces the myocardial oxygen supply‐to‐consumption ratio in exercising dogs. With permission from Gorman el al. (2000).



Figure 10.

Schematic for the regulation of NO production and the influences of atherosclerosis. risk factors, and angiotensin on NO metabolism. (See page 13 in colour section at the back of the book)



Figure 11.

The metabolism of L‐arginine into NO and degradation of NO into nitrites and nitrates.



Figure 12.

Responses of isolated coronary arterioles removed from the ischemic region after ischemia‐reperfusion. The data presented were obtained from arterioles (n = 3 to n = 5) during initial conditions after ischemia/reperfusion (I/R), during incubation with 10μmol/L MH4 (I/R + MH4), a synthetic cell‐permeable tetrahydrobiopterin, and after washout of MH4 (I/R + MH4 + Wash). Data are expressed as mean±SEM. *p < 0.05 vs. ischemia/reperfusion.

Adapted from Ref.


Figure 13.

Responses of isolated human coronary arterioles from patients with significant atherosclerosis. Results were obtained from arterioles (n = 10) during baseline conditions and after incubation with 1 μM sepiapterin to restore endogenous pools of BH4. Data are expressed as mean±SEM. *p < 0.05 vs. baseline.

Adapted from Ref.
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How to Cite

Cuihua Zhang, Paul A Rogers, Daphne Merkus, Judy M Muller‐Delp, Christiane P Tiefenbacher, Barry Potter, Jarrod D Knudson, Petra Rocic, William M Chilian. Regulation of Coronary Microvascular Resistance in Health and Disease. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 521-549. First published in print 2008. doi: 10.1002/cphy.cp020412