Adenosine, NO, opening of the KATP channels, and H2O2 are the key factors among these agents. Their contributions and interactions are significant under both basal conditions and during increased myocardial activity. The relationship between myocardial oxygen consumption and coronary blood flow is depicted in Figure 17.33. Various interventions that either increase or decrease the myocardial metabolic rate affect this relationship. The imbalance in the O2 supply-O2 demand ratio alters coronary blood flow by affecting the rate of release of a vasodilator metabolite from cardiomyocytes. A decrease in the ratio leads to an increase in vasodilator release, while an increase in the ratio has the opposite effect, as illustrated in Figure 17.34.

Figure 17.35 provides a schematic representation of factors that increase or decrease coronary vascular resistance. Intravascular pressure, KATP channels, NO, PCO2, and PO2 are among the factors involved. Myocardial contractile activity, autonomic control, oxygen supply, myogenic mechanism, and metabolism also play significant roles in coronary vascular resistance.

The complex effects of myocardial contractile activity on vascular smooth muscle include a reduction in oxidative metabolism, which reduces ATP synthesis. This reduction in ATP opens KATP channels, leading to hyperpolarization and relaxation of coronary vascular smooth muscle, resulting in increased flow. ATP reduction also opens KATP channels in cardiac muscle, generating an outward current that reduces action potential duration and limits calcium entry during phase 2 of the action potential. This action is protective during periods of O2 supply-demand imbalance. Additionally, increased cardiac work stimulates H2O2 production, activating Kv1.5 channels, which causes hyperpolarization of muscle membrane and relaxation of vascular smooth muscle. The release of NO and adenosine dilates arterioles, adjusting O2 supply to O2 demand. Adenosine appears to activate endothelial KATP channels and enhance NO release at low concentrations. However, at higher concentrations, adenosine directly activates KATP channels in vascular smooth muscle. Decreased O2 demand maintains ATP levels, reduces the release of vasodilator substances, and allows for greater expression of basal tone. Inhibition of the production of all these agents leads to reduced coronary blood flow at rest and during exercise, along with contractile dysfunction and signs of myocardial ischemia.
Of these agents, the key factors appear to be adenosine, NO, opening of the KATP channels, and H2O2. The contributions of each of these agents and their interaction under basal conditions and during increased myocardial •Fig. 17.33 RelationshipbetweenmyocardialO2consumptionandcoronarybloodflowduringavarietyofinterventionsthatincreaseordecreasethemyocardialmetabolicrate.(FromBerneRM,RubioR:Coronarycirculation.InPageE,ed.Handbook of Physiology: Section 2: The Cardiovascular System: The Heart. Vol1.Bethesda,MD:AmericanPhysiologicalSociety;1979.)18 16 14 12 10 8 6 4 2 20 30 40 50 60 70 80 90 100 110 120 Coronary blood flow (mL/min/100 g) Myocardial oxygen consumption(mL/min/100 g) •Fig. 17.34 ImbalanceintheO2supply–O2demandratioalterscoronarybloodflowbytherateofreleaseofavasodilatormetabolitefromcardiomyocytes.Adecreaseintheratioelicitsanincreaseinvasodilatorrelease,whereasanincreaseintheratiohastheoppositeeffect.
372 SECTION4Berne & Levy Physiology •Fig. 17.35 Schematic Representation of Factors That Increase (+) or Decrease (−) Coronary Vascular Resistance. Intravascularpressure(arterialbloodpressure)stretchesthevesselwall.KATPchannels,adenosinetriphosphate–sensitivepotassiumchannels;NO,nitricoxide;PCO2,partialpressureofcarbondioxide;PO2,partialpressureofoxygen.˜ Myocardial contractile activity Autonomic control Sympathetic nerves: °-Receptors ˛-Receptors Vagus nerves Oxygen supply Myogenic mechanism ˜ Metabolism ˝ Myocardial PO2 KATP channels H2O2 NO Adenosine – + +± + – – – Other metabolic factors PO2, PCO2, H+, K+ Systolic compression activity are complex. A reduction in oxidative metabolism in vascular smooth muscle reduces ATP synthesis, which in turn opens KATP channels and causes hyperpolarization. This change in potential reduces entry of Ca++ and relaxes coronary vascular smooth muscle to increase flow. A reduction in ATP also opens KATP channels in cardiac muscle and generates an outward current that reduces action potential duration and limits Ca++ entry during phase 2 of the action potential. This action may be protective during periods of imbalance between O2 supply and demand. In addition, as cardiac work increases, H2O2 production rises, which activates Kv1.5 channels and thereby causes hyperpolarization of muscle membrane and relaxation of vascular smooth muscle. Moreover, the release of NO and adenosine dilates the arterioles and thereby adjusts the O2 supply to the O2 demand. At low concentrations, adenosine appears to activate endothelial KATP channels and to enhance release of NO. Conversely, at higher concentrations, adenosine acts directly on vascular smooth muscle by activating KATP channels. Decreased O2 demand would sustain the ATP level, as well as reduce the amount of vasodilator substances released, and allows greater expression of basal tone. If production of all these agents is inhibited, coronary blood flow is reduced, both at rest and during exercise. Furthermore, contractile dysfunction and signs of myocardial ischemia become evident.