© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Nitric oxide causes dysfunction of coronary autoregulation in endotoxemic rats
aDepartment of Surgery, University Hospital Rotterdam, Erasmus University Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands
bDepartment of Anesthesiology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands
* Corresponding author. Tel.: +31 (10) 4639222; fax: +31 (10) 4635307.
Received 10 December 1996; accepted 12 May 1997
 |
Abstract |
|---|
 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Objective: This study tested the hypothesis that overproduction of endogenous nitric oxide (NO) during endotoxemia may modulate coronary autoregulation and myocardial reactive hyperemia. Methods: Hearts of endotoxin-pretreated rats and controls were isolated and arranged for perfusion in a Langendorff preparation. Autoregulation was studied by examining flow–pressure relations during stepwise changes in perfusion pressure. The contribution of nitric oxide was examined by perfusion with N
-nitro-L-arginine (NNLA), an inhibitor of nitric oxide synthesis and methylene blue (MB), an inhibitor of soluble guanylate-cyclase. Results: Endotoxin-treated hearts showed massive coronary vasodilatation and autoregulatory function was impaired at perfusion pressures from 20 to 60 mmHg. Both NNLA and MB reduced coronary flow, improved autoregulation and eliminated differences in coronary flow and autoregulation between the control and endotoxin-treated group. Vasoconstriction with vasopressin, a direct smooth muscle constrictor, could not eliminate differences in autoregulation between groups. Reactive hyperemia following coronary occlusion in endotoxin-treated hearts showed decreased duration, flow repayment and repayment ratio. In the presence of NNLA or MB, however, no significant differences in reactive hyperemic flow patterns were present. Conclusions: These observations suggest that massive coronary vasodilatation due to increased myocardial NO synthesis can result in autoregulatory dysfunction and altered myocardial reactive hyperemia during endotoxemia.
KEYWORDS Nitric oxide; Autoregulation; Reactive hyperemia; Sepsis; N-Nitro-L-arginine; Methylene blue; Rat, heart
|
1 Introduction |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Coronary autoregulation is the ability of the coronary vasculature to maintain blood flow relatively constant during changes in perfusion pressure [1, 2]. Among the physiological mechanisms that are known to influence autoregulation are metabolic factors (i.e., oxygen tension and/or tissue metabolites) and the so-called ‘myogenic response’, which mediates constriction in response to increased transmural pressure [3]. By increasing vascular tone in response to increasing perfusion pressure, the myogenic autoregulatory response may be an important mechanism in keeping capillary hydrostatic pressure relatively constant and preventing excess flow to the microcirculation [4, 5].
Nitric oxide (NO) is a major endothelium derived relaxing factor (EDRF), formed from the precursor amino acid, L-arginine, and stimulates the enzyme soluble guanylate-cyclase (GC) in the smooth muscle cell which converts GTP to cGMP resulting in vascular relaxation [6]. In the coronary vessels NO plays an important role in the regulation of vascular tone and myocardial blood flow both in vivo and in the isolated heart preparation [7, 8]. The increased release of NO is suggested to be responsible for the vascular relaxation and hypotension seen in states of sepsis and endotoxemia [6]. Recently it was found that endothelium-derived NO can counteract coronary autoregulation by opposing myogenic tone and that inhibition of NO synthesis results in improved coronary autoregulation in the isolated guinea pig heart and rabbit heart [9, 10]. Furthermore, NO plays a role in myocardial reactive hyperemia [11, 12]—i.e., the increase in flow following a period of coronary arterial occlusion.
During sepsis and endotoxemia the coronary circulation is often characterized by inappropriately high coronary flow rates secondary to coronary vasodilatation with uncoupling of flow from metabolic demand [13, 14]. This massive coronary dilatation may depend on accelerated cardiac production of NO [15, 16]. We recently showed that inhibition of this increased NO synthesis can result in focal myocardial ischemia [17]. Since the basal release of NO can attenuate coronary autoregulation [9, 10], it is feasible to hypothesize that increased synthesis of NO, as in sepsis and endotoxemia, can interfere with the physiological process of flow regulation leading to dysfunction of coronary autoregulation and altered reactive hyperemic response.
In this study, we investigated coronary myogenic autoregulatory function in response to step-wise changes in perfusion pressure and myocardial reactive hyperemia after a stop of coronary flow in isolated hearts of normal and endotoxin-treated rats. To investigate the role of NO, we used the L-arginine analogue N-nitro-L-arginine (NNLA) [18], to inhibit NO synthesis and methylene blue (MB) [19], to inhibit soluble guanylate-cyclase. To see if the effect of direct vasoconstriction was different from the effect of inhibition of NO synthesis, we used vasopressin, a direct smooth muscle constrictor that acts independently of the L-arginine/NO/cGMP pathway [20].
|
2 Methods |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
2.1 Experimental set-up
This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. The protocol was approved by the animal ethics board of our university. Male Wistar rats (300–360 g) received either a sublethal dose of 0.7 mg/kg body wt Escherichia coli endotoxin (LPS, 0127:B8, Sigma Chemical Co.) or saline by intraperitoneal injection 12 h before the initiation of the experiments. In vivo measurements of hemodynamic parameters and plasma metabolites have been previously presented [17]. Endotoxin-treated animals showed elevated rectal temperature, decreased mean arterial blood pressure, increased heart rate, and increased plasma levels of lactate. Serum nitrate+nitrite (NO2–+NO3–), the stable end-products of NO production, were elevated in endotoxin-treated animals as a sign of increased systemic release of NO. Rats were anesthetized with ether, heparinized (0.5 ml, 100 IU); the hearts were removed, immediately cooled in ice-cold perfusion medium, and rapidly arranged for constant pressure perfusion at 37°C according to Langendorff. The perfusion medium consisted of (mmol/l) NaCl 128, KCl 4.7, MgCl2 1, NaH2PO4 0.4, NaHCO3 20.3, CaCl2 1.3, glucose 5.0, pyruvate 2.0, and was oxygenated with 95%O2/5%CO2. All hearts were continuously paced at 5 Hz. To minimize the metabolic component of coronary autoregulation, the left ventricle was drained by a cannula in the apex so that no external work was performed. Flow rates (expressed as milliliters per minute per gram of ventricular wet weight) were measured by an electromagnetic flow probe (Skalar-Medical) in the aortic perfusion line. For the determination of effluent oxygen pressure the right pulmonary artery was cannulated and a constant fraction of the coronary effluent was led along a Clark-type electrode (YSI Biological Oxygen Monitor, model 5300, Yellow Springs Instruments). The coronary influent was similarly monitored for oxygen pressure via a side arm of the aortic cannula. Oxygen consumption (in micromoles per minute per gram of ventricular wet weight) was calculated from the product of influent–effluent oxygen concentration difference and coronary flow.
2.2 Autoregulatory function protocol
Autoregulatory function was investigated by studying adjustments in coronary flow in response to step-wise changes in perfusion pressure [21]. Following stabilization at 60 mmHg perfusion pressure, perfusion pressure was first lowered to 20 mmHg and subsequently increased by step-wise changes in perfusion pressure of 10 mmHg at 3-min intervals to a maximum of 100 mmHg. At the end of this series of pressure changes, perfusion pressure was set at the initial value of 60 mmHg. When the flow was stable, the perfusion medium was switched to one containing 100 µmol/l NNLA or 5 µmol/l MB. After a 30-min interval to reach a new steady state, the step-wise changes in perfusion pressure were repeated. Hearts were perfused for a total of 130 minutes. MB was used in a concentration of 5 µmol/l since higher concentrations (>20 µmol/l) caused a paradoxical increase in coronary flow in control hearts, probably by non-specific toxic effects [22].
In 5 hearts of the control and endotoxin-treated group, a supramaximum dose of nitroprusside (10 µmol/l), a nitrovasodilator that acts as an exogenous NO donor, was tested to obtain maximum vasodilatation. To see if the effect of direct vasoconstriction was different from the effect of inhibiting the release of the endogenous vasodilator NO, we repeated the protocol of pressure steps switching to vasopressin, a direct smooth muscle constrictor that acts independently of the L-arginine/NO/cGMP pathway [20], in a concentration of 1 nmol/l that caused approximately the same reduction in flow as NNLA did in 4 hearts of the control and endotoxin-treated group. In 4 separate hearts of the control group the effect of increasing flow similar to endotoxin-treated hearts with nitroprusside (0.1 µmol/l) was tested. NNLA, MB, vasopressin and nitroprusside were diluted in the perfusate in their final concentration.
2.3 Hyperemic flow response
Myocardial reactive hyperemia is the increase in coronary flow following a period of coronary artery occlusion [23, 24]. Reactive hyperemic flow response was investigated after a stop of coronary flow for 90 s in hearts of control and endotoxin-treated animals (n = 8 in both groups). To study the contribution of NO in reactive hyperemic response, the flow stop was repeated after the perfusion medium was switched to one containing 100 µmol/l NNLA or 5 µmol/l MB in 4 hearts each. In 4 separate hearts of the control group the effect of increasing flow similar to endotoxin-treated hearts on reactive hyperemic flow response was tested with nitroprusside (0.1 µmol/l). In 4 separate hearts of the endotoxin-treated group the effect of reducing flow similar to NNLA with vasopressin was tested.
2.4 Definitions and calculations
Autoregulatory function was quantified by an index (ArI) first described by Norris et al. [21]which compares the observed change in vascular conductance for a given change in pressure in relation to the calculated change in conductance assuming that flow remained constant:
|
|
F = Fi–F and P = Pi–P. If conductance is unchanged or increases when pressure is increased (passive vascular bed), then ArI
0 and there is no autoregulation. If conductance decreases when pressure increases, then ArI >0 with a maximum value for ArI of 1.0, where coronary flow remains constant irrespective of pressure changes indicating perfect autoregulation [1]. Quantitative analyses of features characterizing the myocardial reactive hyperemic flow response were performed according to the criteria described by Coffman and Gregg [23]where flow debt (ml) = control flow rate (ml/s) x occlusion time (s); flow repayment (ml) = total flow volume during reactive hyperemia (ml) – control flow rate (ml/s) x duration of reactive hyperemia (s); flow repayment ratio = flow repayment / flow debt.
2.5 Statistics
All values are expressed as mean±s.e.m. Student's t-test for group comparisons or paired t-test where appropriate were used to statistically compare values. Linear regression analysis was performed to determine the relation between myocardial oxygen consumption and coronary flow. P<0.05 was taken as statistically significant. NS is used to denote ‘not significant’.
2.6 Chemicals
NNLA, MB, vasopressin and nitroprusside were obtained from Sigma. All the other chemicals were obtained from Merck.
|
3 Results |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
3.1 Effect of endotoxemia on coronary flow, oxygen consumption and autoregulatory function at varying perfusion pressure
Fig. 1 shows representative tracings of coronary flow responses to step-wise changes in perfusion pressure. During the different perfusion pressures ranging from 20 to 100 mmHg, coronary flow (Fig. 2a) and oxygen consumption were significantly raised in hearts from endotoxin-treated animals at all perfusion pressures studied. At 60 mmHg perfusion pressure coronary flow was raised 58±3% (from 10.5±0.2 to 16.6±0.5 ml/min per gram wet weight) and oxygen consumption 23±3% (from 4.0±0.1 to 4.9±0.1 µmol/min per gram wet weight) in hearts from endotoxin-treated animals (n = 16) as compared to control (n = 15). As shown in Fig. 3, there was a linear relation between oxygen consumption and coronary flow in control (y = 0.130x+2.58, r2=0.76, P<0.001) and endotoxin-treated hearts (y = 0.125x+2.74, R2=0.78, P<0.001). The endotoxin-treated hearts showed significantly reduced autoregulatory function at perfusion pressures ranging from 20 to 60 mmHg (Fig. 4a). At perfusion pressures of 70 mmHg and higher autoregulatory function was not significantly different from control hearts. Attaining maximum coronary flow with a supra-maximum dose of nitroprusside (10 µmol/l) caused a rise of coronary flow of 9.4±0.5 ml/min per gram (89%) in control hearts (n = 5) and 3.5±0.7 ml/min per gram (21%) in endotoxin-treated hearts (n = 5), which resulted in similar flow rates (Fig. 2c) and absence of autoregulation (ArI<0 at all perfusion pressures studied) in control and endotoxin-treated hearts.
|
|
–) and (n = 16) endotoxin-treated (LPS) (–
–) hearts. Coronary flow following inhibition of NO synthesis with 100 µmol/l N
–) and (n = 8) endotoxin-treated (–
–) hearts. (b) Coronary flow following 5 µmol/l methylene blue (MB), an inhibitor of soluble guanylate-cyclase, in (n = 4) control (–
–) and (n = 4) endotoxin-treated (–
–) hearts and coronary flow in (n = 4) untreated hearts with 0.1 µmol/l nitroprusside (NP) (–+–). (c) Coronary flow in a ‘passive’ vascular bed following maximum vasodilatation with 10 µmol/l nitroprusside (NP) in (n = 5) control (–
–) and (n = 5) endotoxin-treated (–
–) hearts and with the direct smooth muscle constrictor, vasopressin (VP) 1 nmol/l, in (n = 4) control (–
–) and (n = 4) endotoxin-treated (–
–) hearts. Values are mean±s.e.m. *P<0.05 for LPS v. control.
|
|
3.2 Effect of nitroprusside (0.1 µmol/l) on coronary flow, oxygen consumption and autoregulatory function of control hearts
The effect of increasing flow in normal hearts similar to the flow level of endotoxin-treated hearts at 60 mmHg was tested using nitroprusside (0.1 µmol/l) (n = 4). Normal hearts with 0.1 µmol/l nitroprusside had increased coronary flows (Fig. 2b). Oxygen consumption increased parallel to the increase in flow (4.8±0.1 µmol/min per gram wet weight at 60 mmHg) with a linear relation between oxygen consumption and coronary flow (y = 0.127x+2.71, r2=0.74, P<0.001) (Fig. 3). Regression lines were not significantly different between groups with regard to slope and intercept (Fig. 3). Normal hearts with nitroprusside (0.1 µmol/l) showed decreased ArI at perfusion pressures from 20 to 60 mmHg (P<0.05 compared to control) similar to endotoxin-treated hearts (Fig. 4b).
3.3 Effect of NNLA, MB and vasopressin on coronary flow and autoregulation
Switching to perfusion medium containing 100 µmol/l NNLA reduced coronary flow at all perfusion pressures to similar levels in control and endotoxin-treated hearts (Fig. 1 and Fig. 2a). Parallel to the reduction in flow there was a reduction in oxygen consumption (per gram wet weight) to 3.1±0.1 µmol/min in control hearts and 3.2±0.1 µmol/min in endotoxin-treated hearts at 60 mmHg perfusion pressure, which is not significantly different between groups. With NNLA the autoregulation index was increased at all perfusion pressures in both control and endotoxin-treated hearts (P<0.05) to similar levels in both groups (Fig. 4c), resulting in a plateau of considerable autoregulation at perfusion pressures above 40 mmHg
Inhibition of soluble guanylate-cyclase with 5 µmol/l MB reduced coronary flow at all perfusion pressures to a similar level in both groups (Fig. 1 and Fig. 2b). Autoregulation index with MB (Fig. 4d) was increased at perfusion pressures from 20 to 40 mmHg and above 70 mmHg in control hearts (P<0.05) and at all perfusion pressures in endotoxin-treated hearts (P<0.05) to similar levels at all perfusion pressures. ArI following MB compared to before MB was not increased at 50 and 60 mmHg perfusion pressure (P = NS).
Direct smooth muscle constriction with vasopressin in a concentration of 1 nmol/l that reduced flow to a similar level as NNLA at 60 mmHg perfusion pressure (Figs. 1 and 2
c) increased ArI at 20 mmHg perfusion pressure and decreased ArI at perfusion pressures above 40 mmHg in control and endotoxin-treated hearts. Vasopressin could not eliminate differences in ArI between control and endotoxin-treated hearts in the pressure range between 30 and 70 mmHg (P<0.05 of LPS versus control) (Fig. 4e). In all hearts coronary flow returned to the baseline value, when at the end of the series of pressure step changes, perfusion pressure was set at the initial value of 60 mmHg.
3.4 Effect of endotoxemia on reactive hyperemic flow response
Endotoxemia resulted in a changed pattern of reactive hyperemia (Fig. 5a). As shown in Table 1, endotoxemia resulted in 59±7% increased basal flow and flow debt, 66±7% decreased duration of reactive hyperemia, 65±7% decreased flow repayment and 80±6% decreased repayment ratio (all P<0.01 compared to control). Maximum hyperemic flow was not significantly different from control hearts (Table 1). The changed pattern of reactive hyperemia could be mimicked in untreated hearts by increasing flow equally to endotoxin-treated hearts with 0.1 µmol/l nitroprusside (Fig. 5d). Quantitative analyses of reactive hyperemic response showed no significant differences of untreated hearts with 0.1 µmol/l nitroprusside versus endotoxin-treated hearts (P = NS, Table 1).
|
|
3.5 Effect of NNLA, MB and vasopressin on reactive hyperemic response.
Perfusion of the hearts with 100 µmol/l NNLA or 5 µmol/l MB resulted in similar reactive hyperemic flow patterns of control and endotoxin-treated hearts (Fig. 5b,c). In the presence of NNLA or MB reductions in basal flows, flow debt and maximum hyperemic flow were seen in control and endotoxin-treated animals (P<0.05, Table 1). NNLA reduced the duration of reactive hyperemia and flow repayment in control hearts and increased flow repayment in control and endotoxin-treated hearts (P<0.05, Table 1). NNLA did not change the duration of reactive hyperemia in endotoxin-treated hearts (P = NS, Table 1). MB reduced the duration of reactive hyperemia in control hearts but increased the duration of reactive hyperemia in endotoxin-treated hearts (P<0.05, Table 1). MB increased flow repayment in endotoxin-treated hearts (P<0.05) but did not change flow repayment in control hearts (P = NS, Table 1). Furthermore, MB resulted in increased flow repayment ratio in both control and endotoxin-treated hearts (P<0.05, Table 1).
In the presence of NNLA or MB no significant differences in basal flow, flow debt, maximal reactive flow, duration of hyperemia, flow repayment and repayment ratio were present between control and endotoxin-treated hearts (P = NS, Table 1).
In endotoxin-treated hearts, the presence of 1 nmol/l vasopressin caused a similar reduction in basal flow, flow debt and maximal reactive flow as was seen with NNLA (P = NS of NNLA versus vasopressin, Table 1) and increased duration of reactive hyperemic flow, flow repayment and repayment ratio (P<0.05 of NNLA versus vasopressin, Table 1).
|
4 Discussion |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
The main finding of this study is that the excessive myocardial production of NO in isolated hearts from endotoxemic rats leads to massive coronary vasodilatation that results in dysfunction of coronary autoregulation and attenuation of myocardial reactive hyperemia. Reduction of coronary flow by inhibition of the L-arginine/NO/cGMP pathway with NNLA or MB could restore this autoregulatory dysfunction, whereas direct smooth muscle constriction with vasopressin could not. These findings may bring some new insights into the pathophysiological processes leading to cardiovascular dysfunction in sepsis and septic shock.
Coronary flow autoregulation has been extensively studied both in vivo and in vitro in the isolated vessel preparation and isolated perfused heart preparation [1, 3]. The present study used an isolated perfused heart preparation. In this preparation, which does no external work, oxygen demand is low so that perfusion at low pressures is tolerated without causing severe ischemia. Furthermore, oxygen consumption is kept as constant as possible minimizing variations in flow through metabolic coronary vasodilatation. Compared to the isolated vessel preparation this whole-organ preparation has the advantage that it contains all consecutive vascular segments including larger coronary arteries and small arterioles, since autoregulation of blood flow can be spatially organized [25, 26]. However, some reservations must be made to extrapolate the findings of the present study to the in vivo situation. The isolated non-working heart preparation that was used misses the neurohumoral and metabolic input which are known to influence autoregulation in vivo [1]. Furthermore, changes in NO production may directly influence myocardial contractility [27], which was not measured in the preparation used. Therefore we cannot rule out that any changes in autoregulation that have been found during isolated perfusion may have been compensated for in the in vivo situation.
A hyperdynamic model of endotoxemia was used that showed increased coronary flow together with increased myocardial oxygen consumption. Although the origin of this high oxygen consumption in hearts of endotoxin-treated animals is still speculative, the increases in oxygen consumption could have directly resulted from increases in coronary flow, the so-called Gregg phenomenon [28, 29]. This is supported by the finding that isolated hearts showed a linear increase in oxygen consumption with increases in coronary flow and increased oxygen consumption following addition of the vasodilator, nitroprusside (Fig. 3). Parallel with these observations, reduction of coronary flow by NNLA resulted in decreased oxygen consumption. Similar findings were made by Pohl et al. [9]in the isolated rabbit heart where NNLA reduced oxygen consumption during constant pressure perfusion but was without effect during constant flow perfusion, excluding a direct inhibitory effect of NNLA on myocardial metabolism.
Coronary autoregulation depends on the balance between competing constricting and dilating influences [1]. Autoregulatory dysfunction in endotoxin-treated hearts could therefore have resulted from defective vasoconstrictive mechanisms or an overshoot of vasodilator mechanisms. The myogenic response mediates vasoconstriction in response to increased transmural pressure and is considered a major constricting force in the coronary vessels [3]. Myogenic dilation following a period of occlusion and myogenic constriction after restoration of flow is one of the mechanisms contributing to reactive hyperemia in the coronary vessels [24]. The mechanism responsible for the myogenic response is still incompletely understood but is probably located in the vascular smooth muscle cell itself, and mediated by an increase in intracellular calcium through influx via either stretch-activated or voltage-gated ion channels [30, 31]. Endotoxin could have induced defects in the myogenic response that may have resulted in a loss of vascular tone, autoregulatory dysfunction and altered reactive hyperemia. However, inhibition of the L-arginine/NO/cGMP pathway with NNLA or MB reduced basal coronary flow and prevented pressure-induced increases in coronary flow of endotoxin-treated hearts, resulting in similar levels of autoregulation to those in control hearts with NNLA or MB, whereas with vasopressin, a direct smooth muscle constrictor, differences in autoregulation between control and endotoxin-treated hearts remained. Furthermore, in endotoxin-treated hearts in the presence of NNLA or MB there was only a brief reactive hyperemic response following occlusion after which coronary flow returned to baseline levels. These results suggest that myogenic tone was well preserved following inhibition of the L-arginine/NO/cGMP pathway. An overshoot in NO mediated vasodilating influences, thus counteracting myogenic vascular tone, is more likely to have caused the autoregulatory dysfunction and altered reactive hyperemic response in endotoxin-treated hearts. This view is further supported by the present finding that vasodilation with the exogenous NO donor, nitroprusside, in control hearts resulted in autoregulatory dysfunction and altered reactive hyperemic response similar to that in endotoxin-treated hearts.
Earlier studies have shown that under normal (i.e., non-septic or non-endotoxemic) conditions the endogenous production of NO can attenuate autoregulation by opposing myogenic tone in the isolated perfused rabbit ear [32], guinea pig heart [10]and rabbit heart [9], and in the canine heart in vivo [33]. The present study is the first to show that autoregulatory dysfunction may exist in endotoxemia resulting from excessive production of NO. However, NO is not the only regulator of vascular tone. Other vasoactive factors, such as adenosine, prostaglandins, pO2 and pCO2, are known to influence vascular tone [1, 34]. To what extent one or more of these metabolites may have contributed to vasodilatation and derangements in autoregulation and reactive hyperemia in the endotoxin-treated hearts is unknown.
Under physiological conditions NO plays an important role in myocardial reactive hyperemia [11, 12]. In the present study, inhibition of the L-arginine/NO/cGMP pathway in normal hearts resulted in decreased peak reactive flow, decreased duration of the hyperemic response and decreased total reactive hyperemic blood flow, which demonstrates the contribution of NO to myocardial reactive hyperemia. Although endotoxin-treated hearts showed a pattern of reactive hyperemia (Fig. 5), flow repayment was only one third of that of control hearts. Vasoconstriction through inhibition of the L-arginine/NO/cGMP pathway with NNLA or MB could improve flow repayment in endotoxin-treated hearts and resulted in similar reactive hyperemic flow patterns to those in control hearts with NNLA or MB. However, also vasopressin, a direct smooth muscle vasoconstrictor, could improve flow repayment and resulted in a ‘normal’ reactive hyperemia pattern. These results suggest that an excessive coronary flow secondary to endogenous NO production minimized flow reserve and blunted the reactive hyperemic response in endotoxin-treated hearts.
In conclusion, the massive coronary vasodilatation due to increased myocardial production of NO during sepsis and endotoxemia may result in dysfunction of coronary autoregulation. Increasing vascular tone by inhibition of the L-arginine/NO/cGMP pathway with NNLA or MB can restore these changes, unlike direct smooth muscle constriction with vasopressin. These findings may help us understand some of the pathophysiological processes that lead to cardiovascular dysfunction during sepsis and endotoxemia. Improvement of vascular autoregulation may be one of the mechanisms by which inhibitors of the L-arginine/NO/cGMP pathway contribute to correction of the cardiovascular derangements during human septic shock [35].
Time for primary review 34 days.
|
Acknowledgements |
|---|
This investigation was supported in part by the Netherlands Heart Foundation (grant 90298). The authors are thankful for support by Friends of the Rotterdam Blood Bank.
|
References |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Dole W.P. Autoregulation of the coronary circulation. Prog Cardiovasc Dis (1987) 29:293–323.[CrossRef][Web of Science][Medline]
- Feigl E.O. Coronary physiology. Physiol Rev (1983) 63:1–205.
[Abstract/Free Full Text] - Johnson PC. The myogenic response. In: Bohr DF, Somlyo AP, Sparks HV Jr, editors. Handbook of physiology, sect 2: The cardiovascular system, vol II. Vascular smooth muscle, ch 15. Bethesda, MD: The American Physiological Society, 1981;409–442.
- Aukland K, Nicolaysen G. Interstitial fluid volume: Local regulatory mechanisms. Physiol Rev (1981) 61:556–643.
[Free Full Text] - Davis M.J. Microvascular control of capillary pressure during increases in local arterial and venous pressure. Am J Physiol (1988) 254:H772–H784.[Web of Science][Medline]
- Moncada S, Palmer R.M, Higgs E.A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev (1991) 43:109–142.[Web of Science][Medline]
- Amezcua J.L, Palmer R.M, de Souza B.M, Moncada S. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol (1989) 97:1119–1124.[Web of Science][Medline]
- Chu A, Chambers D.E, Lin C.C, et al. Effects of inhibition of nitric oxide formation on basal vasomotion and endothelium-dependent responses of the coronary arteries in awake dogs. J Clin Invest (1991) 87:1143–1149.
- Pohl U, Lamontagne D, Bassenge E, Busse R. Attenuation of coronary autoregulation in the isolated rabbit heart by endothelium derived nitric oxide. Cardiovasc Res (1994) 28:414–419.
[Abstract/Free Full Text] - Ueeda M, Silvia S.K, Olsson R.A. Nitric oxide modulates coronary autoregulation in the guinea pig. Circ Res (1992) 70:1296–1303.
[Abstract/Free Full Text] - Kostic M.M, Schrader J. Role of nitric oxide in reactive hyperemia of the guinea pig heart. Circ Res (1992) 70:208–212.
[Abstract/Free Full Text] - Yamabe H, Okumura K, Ishizaka H, Tsuchiya T, Yasue H. Role of endothelium derived nitric oxide in myocardial reactive hyperemia. Am J Physiol (1992) 263:H8–H14.[Web of Science][Medline]
- Cunnion R.E, Schaer G.L, Parker M.M, Natanson C, Parillo J.E. The coronary circulation in human septic shock. Circulation (1986) 73:637–644.
[Abstract/Free Full Text] - Dhainaut J.F, Huygebaert M.F, Monsallier J.F, et al. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation (1987) 75:533–541.
[Abstract/Free Full Text] - Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol (1992) 105:575–580.[Web of Science][Medline]
- Smith R.E, Palmer R.M, Moncada S. Coronary vasodilatation induced by endotoxin in the rabbit isolated perfused heart is nitric oxide-dependent and inhibited by dexamethasone. Br J Pharmacol (1991) 104:5–6.[Web of Science][Medline]
- Avontuur J.A, Bruining H.A, Ince C. Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats. Circ Res (1995) 76:418–425.
[Abstract/Free Full Text] - Moore P.K, al-Swayeh O.A, Chong N.W, Evans R.A, Gibson A. L-NG-Nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilation in vitro. Br J Pharmacol (1990) 99:408–412.[Web of Science][Medline]
- Martin W, Villani G.M, Jothianandan D, Furchgott R.F. Selective blockade of endothelium dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther (1985) 232:708–716.
[Abstract/Free Full Text] - Ruffolo R.R, Hieble J.P, Brooks D.P, Feuerstein G.Z, Nichols A. Drug receptors and control of the cardiovascular system: recent advances. Prog. Drug. Res. (1991) 36:117–360.[Medline]
- Norris C.P, Barnes G.E, Smith E.E, Granger H.J. Autoregulation of superior mesenteric flow in fasted and fed dogs. Am J Physiol (1979) 237:H174–H177.[Web of Science][Medline]
- Baydoun A.R, Peers S.H, Cirino G, Woodward B. Vasodilator action of endothelin-1 in the perfused rat heart. J Cardiovasc Pharmacol (1990) 15:759–763.[Web of Science][Medline]
- Coffman J.D, Gregg D.E. Reactive hyperemia characteristics of the myocardium. Am J Physiol (1960) 199:1143–1149.
[Abstract/Free Full Text] - Olsson R.A. Myocardial reactive hyperemia. Circ Res (1975) 37:263–270.
[Free Full Text] - Chilian W.M, Eastham C.L, Marcus M.L. Microvascular distribution of coronary vascular resistance in beating left ventricle. Am J Physiol (1986) 251:H779–H788.[Web of Science][Medline]
- Frame M.D, Sarelius I.H. Regulation of capillary perfusion by small arterioles is spatially organized. Circ Res (1993) 73:155–163.[Abstract]
- Brady J.B, Poole-Wilson P.A, Harding S.E, Warren J.B. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol (1992) 263:H1963–H1966.[Web of Science][Medline]
- Gregg D.E. Effect of coronary perfusion pressure or coronary flow on oxygen usage of the myocardium. Circ Res (1963) 13:497–500.
[Free Full Text] - Weisfeldt M.L, Shock N.W. Effect of perfusion pressure on coronary flow and oxygen usage of nonworking heart. Am J Physiol (1970) 218:95–101.
[Free Full Text] - Brayden J.E, Nelson M.T. Regulation of arterial tone by activation of calcium-dependent potassium-channels. Science (1992) 256:532–535.
[Abstract/Free Full Text] - Davis M.J, Donovitz J.A, Hood J.D. Stretch-activated single channel and whole cell currents in vascular smooth muscle cells. Am J Physiol (1992) 262:C1083–C1088.[Web of Science][Medline]
- Griffith T.M, Edwards D.H. Myogenic autoregulation of flow may be inversely related to endothelium-derived relaxing factor activity. Am J Physiol (1990) 258:H1171–H1180.[Web of Science][Medline]
- Solzbach U, Eigler NL, Zeiher AM. Enhanced coronary autoregulation during nitric oxide suppression in the intact canine circulation (Abstract). Circulation 1992;86(suppl 1):I510.
- Broten T.P, Feigl E.O. Role of myocardial oxygen and carbon dioxide in coronary autoregulation. Am J Physiol (1992) 262:H1231–H1237.[Web of Science][Medline]
- Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res (1994) 28:34–39.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. C. Doerschug, A. S. Delsing, G. A. Schmidt, and W. G. Haynes Impairments in microvascular reactivity are related to organ failure in human sepsis Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1065 - H1071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Bateman, C. Tokunaga, T. Kareco, D. R. Dorscheid, and K. R. Walley Myocardial hypoxia-inducible HIF-1{alpha}, VEGF, and GLUT1 gene expression is associated with microvascular and ICAM-1 heterogeneity during endotoxemia Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H448 - H456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Wildhirt, S. Weismueller, C. Schulze, N. Conrad, A. Kornberg, and B. Reichart Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury Cardiovasc Res, August 15, 1999; 43(3): 698 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. M. Avontuur, F. Boomsma, A. H. van den Meiracker, F. H. de Jong, and H. A. Bruining Endothelin-1 and Blood Pressure After Inhibition of Nitric Oxide Synthesis in Human Septic Shock Circulation, January 19, 1999; 99(2): 271 - 275. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||