Basal Coronary Vascular Tone Research Articles

Role of K+ATP channels in local metabolic coronary vasodilation.

ATP-sensitive potassium (K+ATP) channels have been shown to play a role in the maintenance of basal coronary vascular tone in vivo. K+ATP channels are also involved in the coronary vasodilator response to adenosine. The aim of this study was to determine the role of K+ATP channels in local metabolically mediated increases in coronary blood flow during cardiac electrical paired pacing without catecholamine effects. In 10 anesthetized closed-chest dogs, coronary blood flow was measured in the left circumflex coronary artery, and myocardial O2 consumption was calculated using the arteriovenous O2 difference. Cardiac interstitial adenosine concentration was estimated from coronary venous and arterial plasma adenosine measurements using a previously described, multicompartmental, axially distributed, mathematical model. Paired stimulation increased heart rate from 57 to 120 beats/min, myocardial O2 consumption 88%, and coronary blood flow 76%. During K+ATP channel blockade with glibenclamide, baseline coronary blood flow decreased in relation to myocardial O2 consumption and thus coronary sinus O2 tension fell. Paired-pulse pacing with glibenclamide resulted in increases in myocardial O2 consumption and coronary blood flow similar to those during control pacing. Coronary venous and estimated interstitial adenosine concentration did not increase sufficiently to overcome the glibenclamide blockade. In conclusion, K+ATP channels are not required for locally mediated metabolic increases in coronary blood flow that accompany myocardial O2 consumption during pacing tachycardia without catecholamines, and adenosine levels do not increase sufficiently to overcome the glibenclamide blockade.

Coronary hemodynamics in endothelial NO synthase knockout mice.

For the specific analysis of endothelial NO synthase (eNOS) function in the coronary vasculature, we generated a mouse homozygous for a defective eNOS gene (eNOS-/-). Western blot as well as immunohistochemical staining revealed the absence of eNOS protein in eNOS-/- mice. Aortic endothelial cells derived from eNOS-/- mice displayed only background levels of NOx formation compared with wild-type (WT) cells (88 versus 1990 pmol NOx x h-1/mg protein-1). eNOS-/- mice were hypertensive (mean arterial pressure, 135 +/- 15 versus 107 +/- 8 mm Hg in WT) without the development of cardiac hypertrophy. Coronary hemodynamics, analyzed in Langendorff-perfused hearts, showed no differences either in basal coronary flow or in maximal and repayment flow of reactive hyperemia. Acute NOS inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME) in WT hearts substantially reduced basal flow and reactive hyperemia. The coronary response to acetylcholine (ACh) (500 nmol/L) was biphasic: An initial vasoconstriction (flow, -35%) in WT hearts was followed by sustained vasodilation (+190%). L-NAME significantly reduced vasodilation in WT hearts (+125%) but did not alter the initial vasoconstriction. In eNOS-/- hearts, the initial vasoconstriction was augmented (-70%), whereas the ACh-induced vasodilation was not affected. Inhibition of cyclooxygenase with diclofenac converted the ACh-induced vasodilation into vasoconstriction (-49% decrease of basal flow). This effect was even more pronounced in eNOS-/- hearts (-71%). Our results demonstrate that (1) acute inhibition of eNOS reveals a role for NO in setting the basal coronary vascular tone as well as participation in reactive hyperemia and the response to ACh; (2) chronic inhibition of NO formation in eNOS-/- mutant mice induces no changes in basal coronary flow and reactive hyperemia, suggesting the activation of important compensatory mechanisms; and (3) prostaglandins are the main mediators of the ACh-induced vasodilation in both WT and eNOS-/- mice.

Glibenclamide, a specific inhibitor of ATP-sensitive K+ channels, inhibits coronary vasodilation induced by angiotensin II-receptor antagonists.

The purpose of our study was test the hypothesis that endogenous angiotensin II contributes to the basal coronary artery tone by acting at vascular ATP-sensitive K+ (K+ATP) channels. Coronary blood flow (CBF) and other hemodynamic parameters were measured in anesthetized dogs. Intracoronary infusion of the selective antagonists of angiotensin II AT1 receptors (L-158,809 and E4177) increased CHF without affecting other hemodynamic parameters, indicating that endogenous angiotensin II caused coronary vaso-constriction through the AT1 subtype receptors. Coronary vasodilation in response to AT1 receptor antagonists was blunted by pretreatment with glibenclamide (a specific inhibitor of K+ATP channels; p < 0.01) but not by either an adenosine-receptor antagonist or an inhibitor of nitric oxide synthesis. Coronary vasodilation in response to AT1-receptor antagonists was partly reduced (p < 0.01) by PD-123319 (the AT2-receptor antagonist). Glibenclamide had no effect on coronary vasodilation induced by sodium nitroprusside. These results indicate that in dogs in vivo, coronary vasodilation in response to AT 1-receptor antagonists inhibited markedly by glibenclamide and partly by PD-123319, suggesting that endogenous angiotensin II contributes to the maintenance of basal coronary vascular tone by acting at K+ATP channels through its receptors.

Influence of basal release of nitric oxide on systolic and diastolic function of both ventricles

Nitric oxide is continuously released by coronary artery endothelium under basal conditions; it maintains vascular tone and regulates coronary blood flow. The objective of this study was to investigate the influence of this basal release of nitric oxide on right and left ventricular systolic and diastolic function. Isolated pig hearts perfused at a constant pressure with enriched autologous blood were used. Systolic and diastolic pressure-volume relationships of isovolumically contracting hearts were studied in the control setting and after addition of 1 mmol/L l-N G-monomethyl-arginine followed by 5 mmol/L l-arginine to the perfusate. Addition of l-N G-monomethyl-arginine caused an acute rise in coronary vascular resistance and a reduction in right and left ventricular systolic function as evaluated by the slope values of the pressure-volume curves, but had little effect on the diastolic function of either ventricle. l-Arginine restored the systolic function to the control level. This alteration in ventricular function was not a result of ischemia because myocardial oxygen consumption was not significantly affected by the acute increase in coronary vascular resistance induced by l-N G-monomethyl-arginine. We conclude that basal release of nitric oxide has no direct negative inotropic effect, but in fact plays an important role in preserving right and left ventricular systolic function and maintains the basal coronary vascular tone. (J Thorac Cardiovasc Surg 1997;113:770-6)

Pulse pressure-related changes in coronary flow in vivo are modulated by nitric oxide and adenosine.

Acute increases in arterial pulsatile load imposed on the left ventricle can increase coronary flow without commensurate changes in myocardial oxygen consumption. One explanation is that augmenting pulsatile perfusion at the same mean pressure itself stimulates flow by releasing endothelium-mediated vasorelaxant factors such as NO. The present study tested this hypothesis and determined whether NO and adenosine modulate this response. In open-chest anesthetized dogs, the distal left anterior descending coronary artery (LAD) was whole-blood-perfused by a novel servopump system to control mean and pulsatile perfusion pressure within the isolated vascular bed. Central aortic pressure was measured, stored to computer memory, and then digitally modified (varying the pulse pressure [PP]) to generate a real-time servocommand that was still synchronous with ventricular contraction. Left heart workload was unchanged. LAD flow was measured before and after increasing the PP (to 60 to 100 mm Hg) from baselines of either 0 or 40 mm Hg. With normal basal coronary vascular tone, raising the PP increased flow (+9 +/- 2% at a PP of 100 mm Hg). This response was markedly amplified (+39 +/- 8%) when basal tone was first partially reduced by adenosine. Competitive inhibition of NO synthase by N omega-monomethyl-L-arginine reduced acetylcholine and PP-dependent flow responses by 50%. Thus, enhanced pulsatile perfusion increases in vivo coronary flow in part by triggering NO release. The marked augmentation of the PP response with reduced basal coronary tone from adenosine suggests that this mechanism may play a role in improving myocardial perfusion during exercise.

Role for the endogenous natriuretic peptide system in the control of basal coronary vascular tone in dogs.

1. While the natriuretic peptides (atrial, brain and C-type) mediate potent endothelium-independent vasorelaxing actions in vitro, the role of the endogenous natriuretic peptide system in vascular regulation in vivo remains unclear. 2. HS-142-1 is a novel natriuretic peptide receptor antagonist derived from a fungus named Aureobasidium sp. which selectively blocks particulate guanylate cyclase-linked natriuretic peptide A and B receptors that bind atrial, brain and C-type natriuretic peptide, and thus attenuates the generation of cGMP. 3. To characterize the vascular actions of the endogenous natriuretic peptide system in the control of basal coronary and systemic haemodynamics, six normal male mongrel anaesthetized dogs were studied while a second group of five dogs served as a control. HS-142-1 was given as an intravenous bolus at 3 mg/kg and was studied over five 20 min periods. 4. No significant difference after HS-142-1 was observed in mean arterial pressure, heart rate, cardiac output, right atrial pressure, pulmonary capillary wedge pressure or systemic vascular resistance compared with control. In contrast, a significant increase in coronary vascular resistance and decrease in coronary blood flow were observed which were different from the baseline values and the responses of the control group. 5. These studies demonstrate that HS-142-1 produces vasoconstriction in the coronary circulation. We conclude that the endogenous natriuretic peptide system, which is of cardiac and endothelial cell origin, is an important regulator of basal coronary vascular tone.

Coronary vascular ATP-sensitive potassium channels are activated to a greater extent in spontaneously hypertensive rats than in Wistar-Kyoto rats.

To determine whether opening of coronary vascular adenosine 5'-triphosphate (ATP)-sensitive potassium (KATP) channels is involved in the maintenance of resting coronary flow in hypertrophied hearts. We examined the effects of glibenclamide, a selective inhibitor of KATP channels, on basal coronary vascular tone in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Using a Langendorff system, the hearts from WKY rats and SHRs were isolated and perfused with oxygenated Krebs-Henseleit solution at a constant perfusion pressure of 60 and 100 mmHg respectively. Basal coronary flow and myocardial oxygen consumption (MV02) were similar in SHRs and WKY rats. The percentage decreases in coronary flow with glibenclamide at graded doses were greater (P < 0.01) in SHRs than in WKY rats (n = 8), whereas the percentage decreases in MV02 with glibenclamide were similar in the two groups. The decreases in coronary flow caused by U46619 (a thromboxane A2-mimetic agent) were similar in SHRs and WKY rats (n = 4). The increase in coronary flow caused by pinacidil (a KATP opener) was greater in SHRs than in WKY rats; glibenclamide prevented the pinacidil-induced increase in coronary flow in both SHRs and WKY rats. There was a significant positive correlation between the glibenclamide-induced decrease in coronary flow and the degree of left ventricular hypertrophy (r = 0.54, P < 0.05). Our results suggest that the basal opening state of coronary vascular KATP channels is activated to a greater extent in SHRs than WKY rats, which may contribute to the maintenance of basal myocardial perfusion in hypertrophied hearts.

Inhibition of nitric oxide synthesis reduces coronary blood flow response but does not increase cardiac contractile response to beta-adrenergic stimulation in normal dogs.

Whether the nitric oxide (NO) system constitutively present in the normal myocardium and resistance coronary vessels regulates basal cardiac contractility and coronary blood flow (CBF), as well as their responses to beta-adrenergic stimulation in intact heart, remains controversial. We examined the effects of low and high doses of NG-nitro-L-arginine methyl ester (L-NAME) (10 and 100 mu g/kg/min for 10 min), an NO synthase inhibitor, as well as D-enantiomer administered into left circumflex (LCX) artery on responses of left ventricular (LV) dP/dt, regional wall thickening in LCX region and LCX blood flow to graded intracoronary doses of isoproterenol (ISO 0.002-0.016 mu g/kg/min) in normal dogs. Intracoronary L-NAME, which was associated with dose-related reductions in acetylcholine (ACh)-induced coronary vasodilation, significantly reduced baseline LCX blood flow and its response to ISO. However, L-NAME did not change baseline LV contractility as assessed by LV dP/dt and regional wall thickening, nor did it increase its response to ISO. D-Enantiomer was ineffective in reducing baseline LCX blood flow as well as its response to ISO. These results indicate that constitutive NO formation in the vasculature contributes to basal coronary vascular tone as well as resistance adjustments during beta-adrenergic stimulation. However, NO formation in the normal myocardium did not influence basal cardiac contractility; nor did it increase cardiac response to beta-adrenergic stimulation.

1030-12 The Action of a Specific Natriuretic Peptide Receptor Antagonist (HS142-1) Upon Basal Coronary and Renal Vascular Resistances

While the natriuretic peptides, ANP (atrial), BNP (brain). and CNP (C-type), mediate potent endothelial-independent vasorelaxing actions in vitro, the role of the endogenous natriuretic peptide system in vascular regulation in vivo remains unclear. HS142-1 is a novel natriuretic-peptide receptor antagonist derived from a fungus named Aureobasidium sp. which selectively blocks particulate guanylate cyclase-linked natriuretic peptide A and B receptors which bind ANP, BNP and CNP and thus attenuates the generation of cGMP. To characterize the vascular actions of the endogenous natriuretic peptide system in the control of basal coronary and renal vascular tone, six normal male mongrel anesthetized dogs were studied while a second group of six dogs served as control. HS142-1 was given as an intravenous bolus at 3 mg/kg and five 20 minute periods were studied. No significant change after HS142-1 was observed in MAP, HR, CO, PAP, PCWP, renal blood flow (RBF) or renal vascular resistance (RVR) compared to baseline. In contrast, a significant increase in coronary vascular resistance (CVR) and decrease in coronary blood flow (CBF) was observed which was different from the control group. C1 (base line) C2 (20 min) C3 (40 min) C4 (60 min) C5 (80 min) C6 (210 min) CBF 52 ± 10 41 ± 10 41 ± 9 37 ± 9 * 33 ± 10 * 32 ± 10 * RBF 258 ± 40 266 ± 46 251 ± 42 249 ± 40 242 ± 37 241 ± 38 CVR 2.1 ± 0.5 3.0 ± 0.7 * 2.9 ± 0.5 * 3.5 ± 0.8 * 3.9 ± 0.8 * 4.0 ± 0.9 * RVR 0.4 ± 0.1 0.4 ± 0.1 0.4 ± 01 0.4 ± 0.1 0.4 ± 0.1 0.4 ± 0.1 CBF, RBF = ml/min, CVR and RVR = RU. Data are Mean ± SE. * denotes p &lt; 0.05 These studies demonstrate that HS142-1 produces potent vasoconstriction in the coronary but not renal vascular circulation. We therefore conclude that the endogenous natriuretic peptide system which is of cardiac and endothelial cell origin is an important regulator of basal coronary vascular tone.

KATP channels and basal coronary vascular tone

After reviewing recent experimental work from various laboratories we have come to the following conclusions. (1) An increase in transmural pressure causes depolarisation of coronary arterioles, which increases smooth muscle tone. Under these conditions the opening of KATP channels can induce a much larger change in membrane potential than in relaxed arteries. Furthermore, the rate of ATP hydrolysis by contractile proteins, and thus the submembrane nucleotide concentrations, might also be changed in the presence of myogenic tone. Therefore care should be taken when extrapolating patch clamp results from isolated coronary smooth muscle cells to the function of KATP channels in vivo. (2) The opening of KATP channels is increased in situations related to energy imbalance, such as hypoxia, adenosine release, intracellular acidification, and lactate accumulation. However, there is increasing evidence that KATP channels also contribute to the setting of the membrane potentials of coronary smooth muscle cells under normoxic conditions. Thus the modulation of KATP channels by intracellular metabolites and by vasoactive autacoids may play an important role in the regulation of coronary blood flow even in the presence of normal intracellular ATP concentrations. (3) The smooth muscle cells of coronary terminal arterioles form an electrical syncytium. The opening of a new KATP channels in smooth muscle cells of a terminal arterioles might induce a spatially homogeneous hyperpolarisation of the entire arteriole. The resulting homogeneous decrease in the tone of the coronary smooth muscle cells of the arteriole may induce a considerable change in vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP-sensitive potassium channel is essential to maintain basal coronary vascular tone in vivo.

Glibenclamide, a known selective inhibitor of ATP-sensitive potassium channels, was infused into the coronary vasculature of anesthetized dogs and of isolated perfused rabbit hearts to assess the role of this channel in the maintenance of basal coronary resistance. Infusion of glibenclamide at a concentration of 55-80 microM in the dogs resulted in a twofold steady-state increase in coronary resistance with resultant tissue ischemia. Infusion of 1 microM glibenclamide in the isolated hearts resulted in a 67% increase in coronary resistance with resultant tissue ischemia. The ischemic changes were reversible upon removal of the drug. These findings indicate that the ATP-sensitive K+ channel plays a significant role in the maintenance of basal coronary resistance in vivo. Higher concentrations of glibenclamide (80-100 microM) in the in vivo dog heart consistently gave rise to an oscillating pattern of coronary flow. These oscillations were either eliminated or decreased in amplitude and frequency by the infusion of 8-phenyltheophylline, a specific competitive inhibitor of adenosine receptors. 31P-nuclear magnetic resonance spectroscopy performed at the peaks and troughs of these oscillations revealed oscillation of the phosphorylation potential at the same frequency. Thus adenosine release caused by tissue ischemia appears to play a major role in creating the oscillating pattern of coronary blood flow, that occurs during the inhibition of ATP-sensitive K+ channels by glibenclamide.

Importance of basal nitric oxide synthesis in regulation of myocardial blood flow

The aim was to investigate whether basal coronary vascular tone and myocardial perfusion depend upon endothelial nitric oxide (NO) synthesis. Myocardial blood flow and vascular resistance of the left and right ventricles were studied before and after intravenous infusions of either NG-nitro-L-arginine (L-NA), a specific inhibitor of NO synthase, or L-arginine, the precursor of NO synthesis. Radiolabelled microspheres were used to study myocardial blood flow in small tissue sections. 14 anaesthetised male cats, weight 2.1-3.5 kg, were used. Measurements were made before and 15 and 40 min after L-NA treatment (30 mg.kg-1 bolus followed by 1 mg.kg-1.min-1 infusion; n = 8), and before and 15 min after L-arginine treatment (30 mg.kg-1 bolus followed by 10 mg.kg-1.min-1 infusion; n = 6). L-NA significantly reduced coronary blood flow to the left and right ventricle, by 30(SEM 9) and 48(6)% respectively, after 15 min, but only to the right ventricle, by 45(8)%, after 40 min. Mean arterial pressure and myocardial vascular resistance were raised during the L-NA infusion. In contrast, L-arginine did not elicit any change in the variables studied. The conductance of the coronary vascular bed and the resting myocardial blood flow is regulated by L-arginine derived nitric oxide, and exogenous L-arginine availability is not a limiting factor in this NO generation.

Cholinergic regulation of resting coronary blood flow in domestic swine

Cholinergic vasoconstriction in vivo and the influence of resting cholinergic activity on basal coronary tone were investigated by measuring coronary blood flow, cardiac function, and blood gases during either acetylcholine injection, muscarinic receptor blockade, or vagal ligation, in open-chest chloralose-urethan-anesthetized swine. Intracoronary injections of acetylcholine (0.5-3.0 micrograms) caused significant (P less than 0.05) dose-dependent reductions in coronary blood flow (19.0-75.5%) and conductance (14.3-78.2%). Atropine (200 micrograms) completely blocked these responses. Cholinergic mediation of basal coronary tone was initially evaluated by determining the effects of muscarinic blockade with intracoronary injection of atropine (200 micrograms). Intracoronary injection of atropine had no significant effects on coronary blood flow or conductance. Finally, to ensure that parasympathetically released acetylcholine was not overcoming the muscarinic blockade, vagal ligation was performed during pacing. Neither coronary blood flow nor conductance was significantly altered by vagal ligation. The present studies demonstrate that acetylcholine induces a muscarinic vasoconstriction of coronary arteries in the domestic swine. However, these studies do not support a role for parasympathetic mediation of basal coronary vascular tone.

Effect of atenolol and pindolol on the phorbol ester‐induced coronary vasoconstriction in the isolated perfused heart of the rat

1. The effects of atenolol (beta 1-adrenoceptor antagonist without partial agonistic activity) and pindolol (beta 1- and beta 2-antagonist with partial agonistic activity) were studied on basal coronary vascular tone and on the phorbol ester-induced coronary vasoconstriction in the rat perfused heart. 2. The addition of the phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate (TPA; 1.8 X 10(-8)-1.6 X 10(-7) M) into the perfusion fluid during perfusion of rat heart at constant flow caused a dose-dependent, sustained increase in perfusion pressure. The vasoconstrictor response in hearts of reserpine-treated rats to infusion of TPA was similar to that of non-reserpine treated hearts. 3. Infusion of a calcium channel agonist Bay K 8644 at a concentration of 4 X 10(-7) M enhanced, whereas isoprenaline (1 X 10(-5) M), dibuturyl-cyclic AMP (1.6 X 10(-4) M) and forskolin (1 X 10(-6) M), which elevate intracellular concentrations of cyclic AMP, all inhibited the coronary vasoconstriction induced by TPA. 4. Pindolol, in doses which produced comparable inhibition of isoprenaline-induced tachycardia, dose-dependently attenuated the phorbol ester-induced increase in perfusion pressure, whereas atenolol had no effect. The inhibitory action of pindolol (2 X 10(-5) M) on TPA-induced vasoconstriction was blocked by addition of 2.2 X 10(-5) M propranolol into the perfusion fluid. When infused alone, atenolol (2 X 10(-4) M) significantly increased coronary vascular tone, but pindolol had no effect. 5. The present results indicate that pindolol has coronary vasodilator properties due to stimulation of vascular beta-adrenoceptors. If stenosis dilatation of coronary artery spasm is an important component of the anti-anginal effect of beta-blocking drugs, the possession of partial agonistic property by a beta-blocking drug may be of importance in maintaining coronary flow.

Metabolic modulation of cardiac neurosympathetic activity in vivo: effects of potassium and adenosine.

The effects of intracoronary (LAD) infusion of potassium and adenosine on changes in coronary vascular resistance and regional cardiac noradrenaline overflow during graded cardiac sympathetic stimulation were assessed in non-ischaemic myocardium in the open chest anaesthetised dog. Intracoronary potassium at three concentration (10, 25, 75 mmol.litre-1) progressively increased the potassium content of local venous effluent from 3.6 to 9.4 mmol.litre-1 and produced biphasic effects on nerve stimulated regional noradrenaline overflow. At low dose it was inhibitory (peak overflow at 20 Hz stimulation being reduced from (mean(SEM)) 10.2(2.6) to 2.9(1.8) pmol.ml-1 with 10 mmol.litre-1 potassium chloride; p less than 0.01). At high dose, overflow was potentiated to 13.3(2.7) pmol.ml-1 with 75 mmol.litre-1 potassium chloride (p less than 0.05). Noradrenaline overflow from and the potassium content of circumflex territory venous effluent was unchanged. Intracoronary adenosine at high concentration (10(-3) and 10(-2) mol.litre-1) potentiated basal noradrenaline overflow from the heart producing a small negative arteriovenous concentration difference of 0.6(0.7) and 1.0(0.6) pmol.ml-1 respectively. However, noradrenaline overflow during maximal sympathetic stimulation was inhibited from 3.8(1.4) to 0.4(0.7) pmol.ml-1 with 10(-3) mol.litre-1 adenosine and to 0.7(0.6) pmol.ml-1 with 10(-2) mol.litre-1 adenosine (p less than 0.05). The changes in blood flow and coronary vascular resistance seen with sympathetic stimulation were not modified by adenosine, despite major alteration in basal coronary vascular tone. Thus both metabolites may potentially alter local neurosympathetic activity in ischaemic myocardium and act diversely to determine noradrenaline release at the nerve terminal.