Control Of Coronary Vascular Tone Research Articles

Endothelial Control of Coronary Vascular Tone is Altered After MI: Interactions of Nitric Oxide and Prostanoids with Endothelin

Nitric oxide (NO) and prostanoids induce coronary vasodilation directly, but also indirectly by modulating endothelin (ET)‐mediated vasoconstriction. We have shown that ET‐induced coronary vasoconstriction disappears after myocardial infarction (MI). We aimed to investigate the interactions between NO, prostanoids and ET in control of coronary tone after MI.Changes in coronary tone in response to ETAB blockade with Tezosentan alone and following inhibition of eNOS (LNNA) or cyclooxygenase (Indomethacin) were measured in chronically instrumented swine (27 normal; 14 MI), at rest and during exercise (EX).In normal swine, LNNA and Indo caused coronary vasoconstriction (decrease in cvSO2) at rest and during EX and increased the vasodilator effect of tezosentan, particularly during EX.In swine with MI, the vasoconstrictor effect of LNNA was decreased. A vasodilator effect of tezosentan was uncovered after LNNA, however this effect was decreased as compared to normal swine. Indo‐induced vasoconstriction was maintained after MI, while a vasodilator effect of tezosentan was unmasked at rest and during EX. This effect was increased compared to normal swine.Our results show that both NO and prostanoids exert their vasodilator influence on the coronary vasculature at least in part through suppression of the endogenous ET system, particularly after MI.Supported by Netherlands Heart Foundation (2000T042)

Phosphorylation of phospholamban correlates with relaxation of coronary artery induced by nitric oxide, adenosine, and prostacyclin in the pig.

The intracellular mechanisms underlying the action of the endogenous vasodilators such as NO/EDRF, adenosine, and prostacyclin acting through cGMP and cAMP, respectively, are not well understood. One important action of cyclic nucleotides in smooth muscle relaxation is to lower the cytosolic Ca2+ concentration by enhanced sequestration into the sarcoplasmic reticulum. The present study was undertaken to elucidate the potential role of phosphorylation of phospholamban, the regulator of sarcoplasmic reticulum Ca2+ pump, for the control of coronary vascular tone by NO/EDRF, adenosine, and prostacyclin. Phospholamban was identified in pig coronary artery preparations by immunofluorescence microscopy, Western blotting and in vitro phosphorylation. Segments of pig coronary artery, with either intact or denuded endothelium, were precontracted with prostaglandin F2alpha (PGF2alpha). In endothelium-denuded preparations 3-morpholinosydnonimine (SIN-1), 5'-N-ethylcarboxiamidoadenosine (NECA), and iloprost (ILO) caused both relaxation and phospholamban phosphorylation with the potency: SIN-1 > NECA > ILO. The regulatory myosin light chain was significantly dephosphorylated only by SIN-1. In endothelium-intact pig coronary artery, L-NAME caused additional vasoconstriction and a decrease in phospholamban phosphorylation, while phosphorylation of myosin light chain remained unchanged. An inverse relationship between phospholamban phosphorylation and vessel tone was obtained. Our findings demonstrate significant phospholamban phosphorylation during coronary artery relaxation evoked by NO, prostacyclin, and adenosine receptor activation. Because of the close correlation between phosphorylation of phospholamban and vessel relaxation, we propose that phospholamban phosphorylation is an important mechanism by which endogenous vasodilators, especially endothelial NO/EDRF, control coronary vascular smooth muscle tone.

Icodextrin with nitroprusside increases ultrafiltration and peritoneal transport during long CAPD dwells

Icodextrin with nitroprusside increases ultrafiltration and peritoneal transport during long CAPD dwells

Regulation of potassium channels in coronary arterial smooth muscle by endothelium-derived vasodilators.

Recent studies have suggested that coronary endothelial cells produce and release nitric oxide (NO), prostaglandin I2, and epoxyeicosatrienoic acids (EETs). These endothelium-derived vasodilators play an important role in the control of coronary vascular tone. However, the mechanism by which these endothelium-derived vasodilators cause relaxation of coronary arterial smooth muscle has yet to be determined. This study characterized and compared the effects of NO, prostaglandin I2, and 11,12-EET on the two main types of potassium channels in small bovine coronary arterial smooth muscle: the large conductance Ca(2+)-activated K+ channels (KCa) and 4-aminopyridine-sensitive delayed rectifier K+ channels (Kdrf). In cell-attached patches, nonoate, an NO donor, activated both KCa and Kdrf channels. The open probability of both KCa and Kdrf channels increased 10- to 25-fold when nonoate was added to the bath at concentrations of 10(-6) to 10(-4) mol/L. 11,12-EET (10(-8) to 10(-4) mol/L) also increased the activity of the KCa channels in a concentration-dependent manner, but it had no effect on the activity of the Kdrf channels, even in the highest concentration studied (10(-4) mol/L). In contrast to the effect of 11,12-EET, iloprost, a prostaglandin I2 analogue (10(-6) to 10(-4) mol/L), produced a concentration-dependent increase in the activity of Kdrf channels without affecting the KCa channels. In conclusion, all three endothelium-derived vasodilators act to open potassium channels; however, the channel types that they affect are different. NO activates both KCa and Kdrf channels; 11,12-EET activates only the KCa channels; and prostaglandin I2 activates only the Kdrf channels.

Metabolism and actions of ADP-riboses in coronary arterial smooth muscle.

The present study examined the metabolism of ADP-ribose (ADPR) and cyclic ADP-ribose (cADPR) in small bovine coronary arterial homogenates and characterized the effects of these nucleotides on the activity of potassium (K+) channels in coronary smooth muscle cells. ADPR and cADPR were produced from NAD+ (1mM) by homogenates from small bovine coronary arteries. The conversion rate was 2.81 +/- 0.19 nmol/min/100 micrograms protein for ADPR and 1.37 +/- 0.03 nmol/min/100 micrograms protein for cADPR. In patch clamp experiments, ADPR produced a concentration-dependent increase in the activity of a calcium activated K (Kca) channel in inside-out membrane patches of coronary arterial smooth muscle cells at concentrations of 0.1, 1 and 10 microM. The open state probability (NPo) of Kca channel was maximally increased 5-fold at a concentration of 10 microM. cADPR reduced the activity of Kca channel at concentrations of 1 and 10 microM. The NPo was decreased by 45% and 75%, respectively. The results indicate that there is an enzymatic pathway in the coronary arterial smooth muscle to produce ADPR and cADPR. These nucleotides may play a role in the control of coronary vascular tone by altering the activity of the Kca channel in vascular smooth muscle cells.

Endothelium-mediated control of coronary vascular tone after chronic exercise training

The purpose of this paper is to examine the role of endothelium-derived relaxing factors in the control of coronary vascular resistance in conditioned subjects (i.e., after exercise training for a period of time sufficient to complete adaptation processes). Results from studies with exercise trained (EX) dogs, miniature swine, and rats are summarized. Since the relative importance of vascular control mechanisms differ in various segments of the coronary arterial tree, the effects of EX on conduit arteries and the coronary arterial microcirculation are discussed separately. Results indicate that endothelium-mediated vasodilator responses are normal in conduit coronary arteries of EX dogs, miniature swine, and rats. It is proposed that endothelium-mediated vasodilation of conduit coronary arteries is enhanced early in the exercise-adaptive process but returns to normal as adaptation to EX is complete, when structural adaptations produce a relative decrease in coronary shear during exercise. EX miniature swine manifest enhanced endothelium-mediated vasodilation stimulated by bradykinin and flow in isolated coronary resistance arteries and appear to have increased expression of NO synthase (ecNOS). Brief training also appears to increase the expression of ecNOS. The role of endothelium-mediated vasodilation in regulation of coronary blood flow in EX animals remains uncertain.

The Role of Nitric Oxide in the Control of Coronary Vascular Tone in Relation to Partial Oxygen Pressure, Perfusion Pressure, and Flow

Isolated guinea pig hearts were used as a model to investigate the role of pO 2 , coronary perfusion pressure (CPP), and flow on the release of nitric oxide (NO) into the coronary circulation. The in vitro half-life of NO strongly depends on the pO 2 . Reduction of pO 2 from 700 and 50 mm Hg prolonges the NO half-life by 78%, from 3.6 to 6.4 s. Basal release of guansine-3', 5'-cyclic monophosphate (cyclic GMP) taken as an index of endogenous NO concentration, remained unaltered in isolated hearts perfused at normoxic (100% O 2 ) and hypoxic conditions (30% O 2 ).

The Role of Nitric Oxide in the Control of Coronary Vascular Tone in Relation to Partial Oxygen Pressure, Perfusion Pressure, and Flow

The Role of Nitric Oxide in the Control of Coronary Vascular Tone in Relation to Partial Oxygen Pressure, Perfusion Pressure, and Flow

Control of coronary vascular tone by nitric oxide.

A specific difference-spectrophotometric method was used to measure nitric oxide (NO) release into the coronary effluent perfusate of isolated, constant-flow-perfused guinea pig hearts. Authentic NO applied into the coronary circulation decreased vascular resistance dose dependently and enhanced coronary release of cyclic GMP (cGMP) fivefold. Increasing oxygen tension in aqueous solutions from 150 to 700 mm Hg decreased NO half-life (5.6 seconds) by 32%. During single passage through the intact coronary system, 86% of the infused NO was converted to nitrite ions. Oxidation of NO was more than 30 times faster within the heart than in aqueous solution. Endogenously formed NO was constantly released into the coronary effluent perfusate at a rate of 161 +/- 11 pmol/min. The NO scavenger oxyhemoglobin and methylene blue increased coronary resistance and decreased cGMP release (basal release, 342 +/- 4 fmol/min), whereas superoxide dismutase reduced coronary resistance. L-Arginine (10(-5) M) slightly decreased coronary perfusion pressure and enhanced release of cGMP. NG-Monomethyl L-arginine (10(-4) M) reduced basal release of NO and cGMP by 26% and 31%, respectively, paralleled by a coronary vasoconstriction. Bradykinin in the physiological range from 5 x 10(-11) M to 10(-7) M dilated coronary resistance vessels, which was paralleled by the release of NO and cGMP. Onset of NO release preceded onset of coronary vasodilation in all cases. Upon stimulation with bradykinin, amounts of endogenously formed NO were within the same range as the dose-response curves for exogenously applied NO both for changes in coronary resistance and cGMP release. Acetylcholine (10(-5) M), ATP (10(-5) M), and serotonin (10(-8) M) increased the rate of NO and cGMP release, resulting in coronary vasodilation. Our data suggest the following: 1) NO, the most rapidly acting vasodilator presently known, is metabolized within the heart mainly to nitrite and exhibits a half-life of only 0.1 second; 2) in the unstimulated heart, basal formation of NO may play an important role in setting the resting tone of coronary resistance vessels; 3) the kinetics and quantities of NO formation suggest that NO is causally involved in the bradykinin-induced coronary vasodilation; and 4) amounts of NO formed within the heart stimulated with ATP, acetylcholine, and serotonin are effective for vasodilation.

Reflex control of coronary vascular tone by cardiopulmonary receptors in humans

To examine whether cardiopulmonary receptors participate in the reflex control of coronary vascular resistance, systemic and coronary hemodynamics were assessed before and during -10 mm Hg lower body negative pressure in eight normal subjects and eight hypertensive patients with left ventricular hypertrophy. In both study groups, lower body negative pressure induced a significant decrease in right atrial pressure, left ventricular filling pressure and cardiac output, an increase in systemic vascular resistance and no change in mean arterial pressure and heart rate. In normal subjects, there was also a significant increase in plasma norepinephrine concentration (from 294 ± 39 to 421 ± 47 pg/ml, p < 0.01). This increase was accompanied by a reduction in coronary blood flow, assessed by the continuous thermodilution method (from 101 ± 5 to 79 ± 4 ml/min, p < 0.05). An increase in coronary vascular resistance (from 0.865 ± 0.1 to 1.107 ± 0.1 mm Hg/ml per min, p < 0.05) and in myocardial oxygen consumption was detected in normal subjects during cardiopulmonary baroreceptor unloading. In contrast, in hypertensive patients, −10 mm Hg lower body negative pressure failed to induce any change in plasma norepinephrine, coronary blood flow or vascular resistance.Intravenous propranolol administration caused no significant change in the systemic hemodynamic response to −10 mm Hg lower body negative pressure in either study group, but it did abolish the decrease in coronary flow and the increase in plasma norepinephrine, coronary vascular resistance and myocardial oxygen consumption observed in normal subjects in control conditions. Finally, propranolol did not modify the systemic and coronary hemodynamic responses either to lower body negative pressure in hypertensive patients or to a 60 mm Hg increase in neck tissue pressure in both groups of subjects.These results suggest that cardiopulmonary baroreceptors participate in the reflex control of coronary vascular tone in normal subjects and that this response is abolished in hypertensive patients with left ventricular hypertrophy as a result of an altered cardiopulmonary receptor function.

Endothelium-dependent relaxation in coronary arteries requires magnesium ions.

A great deal of interest has recently focused upon the mechanism(s) associated with the generation and action of endothelium-derived relaxant factors (EDRFs) in blood vessels. Since we have shown that extracellular magnesium ions ([Mg2+]o) are important in control of coronary vascular tone and reactivity, we wondered whether these divalent cations play any role in the generation or action of EDRF in coronary arterial smooth muscle. Using isolated canine coronary arterial rings, we have now found that removal of [Mg2+]o inhibits the ability of these vascular preparations to relax when challenged with acetylcholine; in the absence of [Mg2+]o, the relaxation concentration-response curves for acetylcholine are shifted markedly to higher concentrations with small maxima. It, thus, appears that [Mg2+]o is an important co-factor for acetylcholine-induced endothelium-dependent relaxation in canine coronary arteries. These findings support our previous hypothesis that dietary deficiency of Mg may be an important factor in aetiology of coronary vasospasm.

Evidence for direct control of coronary vascular tone by oxygen.

The interaction between the effects of oxygen and adenosine on acetylcholine-induced contractile tension was observed in helical coronary arterial strips suspended in physiological salt solution. It was found that (1) steady-state contractile tension was unaffected or depressed 5-20% when oxygen pressure (Po 2 ) was diminished to levels as low as 5-10 mm Hg, (2) contractile tension was markedly depressed at a Po 2 of 0 mm Hg, (3) adenosine-induced relaxation of contractile tension was inversely proportional to Po 2 in the tissue bath, and (4) in the presence of adenosine at a concentration just adequate to inhibit contractile tension at a Po 2 of 10 mm Hg, contractile tension was directly proportional to bath Po 2 . The latter two observations were usually most apparent at a Po 2 between 10 and 40 mm Hg. It is proposed that the vasodilating effect of adenosine on the intact coronary vasculature may be most effective during myocardial hypoxia and that physiological control of coronary vascular tone may be more closely related to variations in local Po 2 than to variations in local concentrations of adenosine.

Release of adenosine in reactive hyperemia of the dog heart.

Release of adenosine in reactive hyperemia of the dog heart.

REGULATION OF CORONARY BLOOD FLOW.

New approaches for coronary flow measurement neural control of coronary blood flow role of adenosine in regulation of coronary blood flow role of endothelial cells in coronary circulation ischemia and reperfusion injury in the experimental and clinical studies.