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1 Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, Madrid, Spain
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(Received 9 February 2006;
accepted after revision 12 June 2006; first published online 15 June 2006)
Corresponding author G. Diéguez: Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, Arzobispo Morcillo 2, 28029 Madrid, Spain. Email: gdieguez{at}uam.es
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Introduction |
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The mechanisms by which coronary RH are mediated are unclear, and it has been suggested that vascular myogenic factors, myocardial metabolic factors, ATP-sensitive K+ (KATP) channels in vascular smooth muscle, nitric oxide and hydrogen peroxide are involved in RH (Dole et al. 1981; Feigl, 1983; Kirkeboen et al. 1994; Komaru et al. 2000; Kingsbury et al. 2001; Koller & Bagi, 2004; Zatta & Headrick, 2005). Because arterial pressure is a main determinant of coronary blood flow and represents the afterload for the left ventricle, changes in arterial pressure may affect coronary flow by altering the driving pressure, myocardial metabolic and mechanical factors (extravascular compressive forces on intramural vessels), and vascular mechanosensitive mechanisms, and each of these factors might also affect coronary RH. Studies of the relationship between coronary RH and arterial pressure have been performed using various experimental approaches (Dole et al. 1981; Kelley & Gould, 1981; Hickey et al. 1983; Koller & Bagi, 2004). One of these studies was performed using dogs in which one coronary artery was cannulated and perfused while ventricular pressure, cardiac contractility and the heart rate were maintained (Dole et al. 1981). Hickey et al. (1983) induced local stenosis with hypotension distal to stenosis within the left descending coronary artery in dogs, and Koller & Bagi (2004) changed the intravascular pressure or altered both pressure and flow in coronary arteries isolated from rats. Unfortunately, the approaches used in the aforementioned studies fail to reproduce the natural responses because these conditions exclude the possible contribution of changes in myocardial metabolic and mechanical factors that may normally accompany changes in arterial pressure. Knowledge of coronary RH (vasodilatory reserve) during acute, transient changes in arterial pressure in intact experimental preparations is of interest because transient changes in arterial pressure occur in humans. For example, transient increases in arterial pressure in humans occur throughout the day and during exercise, and transient decreases in arterial pressure may occur as a consequence of postural changes, heart diseases and adverse reactions to drugs.
The present experiments were performed to analyse the coronary hyperaemic response during acute changes in arterial pressure in anaesthetized goats. Blood flow through the left circumflex coronary artery was measured electromagnetically, and hyperaemic responses of this artery to 5, 10 and 20 s of occlusion were recorded under control conditions, during acute arterial hypertension and during acute arterial hypotension. Arterial hypertension was induced by constriction of the thoracic aorta or by intravenous infusion of noradrenaline; hypotension was induced by constriction of the caudal vena cava within the thorax or by intravenous infusion of the ß-adrenergic receptor agonist isoprenaline.
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Methods |
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The procedure used to measure coronary RH has been described elsewhere (García et al. 1992). Briefly, after opening the thorax and pericardium and exposing the proximal segment of the left circumflex coronary artery, an electromagnetic flow transducer (Biotronex, Silver Spring, MD, USA) was placed on this artery to measure blood flow. A snare-type occluder was placed immediately distal to the flow probe on the same artery to obtain a zero-flow baseline and produce transient periods of ischaemia. Systemic arterial pressure was measured through a polyethylene catheter (PE-90) that was inserted into one of the temporal arteries and connected to a Statham P23 ID transducer (Gould Statham Instruments, Oxnard, CA, USA). Blood flow through the left circumflex coronary artery (coronary flow), systemic arterial pressure and heart rate were recorded simultaneously for each animal on a Dynograph Recorder (model R611, Sensor Medics, Bilthoven, The Netherlands).
Coronary hyperaemic responses were recorded after arterial occlusions for 5, 10 and 20 s at intervals of 
5 min. Arterial occlusion was repeated twice in a random sequence under each experimental condition. To determine RH, we calculated: (a) the ratio of peak in hyperaemic flow to control blood flow; and (b) the ratio of repayment to theoretical blood flow debt. Arterial hypertension was induced by mechanical constriction of the thoracic aorta performed with an adjustable occluder placed around this artery (n
= 7) or by intravenous infusion of noradrenaline (L-arterenol hydrochloride, Sigma, 1–2 µg kg–1 min–1; n
= 6). Arterial hypotension was induced by mechanical constriction of the caudal vena cava performed with an adjustable occluder placed around this vein within the thorax (n
= 6) or by intravenous infusion of the ß-adrenergic receptor agonist isoprenaline ((+/–)-isopropylarterenol hydrochloride, Sigma, 0.5–1 µg kg–1 min–1) (n
= 6). After recording hyperaemic responses during isoprenaline-induced hypotension, four of the six isoprenaline-treated animals were subjected to aortic constriction to normalize arterial pressure. Thereafter, hyperaemic responses were recorded under these conditions.
Blood samples were withdrawn from the temporal artery during normotension, hypertension and hypotension to measure the partial pressures of CO2 and O2 and the blood pH using standard methods (Radiometer ABL 300, Copenhagen, Denmark). Resistance to blood flow through the left circumflex coronary artery (mmHg ml–1 min–1) was calculated for each experimental condition by dividing the mean systemic arterial pressure by coronary blood flow. After termination of the experiments, the goats were killed with an overdose of thiopentone sodium and potassium chloride injected intravenously.
The animals were obtained legally from licenced stockbreeders. The experimental procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85-23, revised 1996), and were approved by the institutional Animal Research Committee.
The effects of aortic constriction, administration of noradrenaline, caudal vena cava constriction, administration of isoprenaline, or isoprenaline administration combined with aortic constriction on each of the parameters measured (coronary blood flow, coronary vascular resistance, systemic arterial pressure, blood gases and blood pH) were analysed using Student's paired t tests in which each animal served as its own control. A repeated measures ANOVA followed by Dunnett‘s test was applied to the hyperaemic responses obtained under normotension and during each condition of hypertension or hypotension; the same method was used to compare hyperaemic responses during hypertension induced by aortic constriction to hyperaemic responses during hypertension induced by noradrenaline, or to compare the hyperaemic responses during hypotension induced by constriction of the caudal vena cava to those obtained during hypotension induced by isoprenaline and to those obtained during isoprenaline administration combined with aortic constriction. Data are expressed as mean values ± S.E.M. P < 0.05 was assumed to indicate statistical significance.
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Results |
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Coronary occlusions for 20 s, but not those for 5 and 10 s, caused the mean systemic artery pressure to decrease by 7 ± 2 mmHg, without affecting the heart rate. This hypotension coincided with coronary occlusion, and arterial pressure recovered within 30 s of release of occlusion.
Table 1 summarizes the mean values of the haemodynamic parameters, blood gases and blood pH under control conditions (normotension), during hypertension and during hypotension.
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During aortic constriction (n = 7), mean arterial pressure increased from 86 ± 4 mmHg under control conditions to 141 ± 6 mmHg (P < 0.01), while coronary blood flow increased by 44 ± 5% (P < 0.05). Coronary vascular resistance, heart rate, blood gases and blood pH did not change significantly with respect to control conditions during constriction of the aorta. Reactive hyperaemia during aortic constriction was not significantly different from that under control conditions irrespective of the duration of ischaemia (Fig. 1).
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25% lower, respectively (P < 0.05 for both) than during normotension (Fig. 1). Hypotension
During constriction of the caudal vena cava (n
= 6), mean arterial pressure decreased from 85 ± 4 mmHg in the control situation to 40 ± 4 mmHg (P < 0.01), coronary blood flow decreased by 45 ± 5% (P < 0.01), coronary vascular resistance decreased by 22 ± 4% (P < 0.05) and the heart rate increased significantly. During constriction of the caudal vena cava, blood gases and blood pH were unaffected. During hypotension induced by constriction of the caudal vena cava, hyperaemic responses were samaller than those under control conditions for each of the three durations of ischaemia. The ratio of the peak in hyperaemic flow to control flow and the ratio of repayment to debt was 25% and 65% lower, respectively (P < 0.05 and 0.01, respectively) than under control conditions (Fig. 2).
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55 and 100% lower, repectively (P < 0.01 for both) than under control conditions (Fig. 2). In the four animals that received isoprenaline at the same time as undergoing aortic constriction, mean systemic arterial pressure (86 ± 6 mmHg) in this situation was not significantly different from that during normotension.
During isoprenaline infusion and aortic constriction, coronary flow was 49 ± 5% higher (P < 0.01) than during normotension and 24 ± 3% higher (P < 0.05) than during isoprenaline-induced hypotension, while coronary vascular resistance was 30 ± 4% lower (P < 0.05) than during normotension and 64 ± 7% higher (P < 0.01) than during isoprenaline-induced hypotension. The heart rate remained increased to the same degree as that observed during isoprenaline-induced hypotension. Blood gases and blood pH were not significantly different from those under control conditions. During isoprenaline administration and aortic constriction, hyperaemic responses were smaller than those under control conditions; specifically the ratio of the peak in hyperaemic flow to control flow and the ratio of the repayment to debt was 30 and 45% lower, respectively (P < 0.05 and P < 0.01, respectively). By contrast, during isoprenaline administration and aortic constriction, hyperaemic responses were greater than those during isoprenaline-induced hypotension; specifically, the ratio of the peak in hyperaemic flow to control flow and the ratio of repayment to debt was 40 and 75% higher, respectively (P < 0.05 and P < 0.01, respectively; Fig. 2).
During the peak in hyperaemic flow, coronary vascular resistance decreased significantly compared to that found during the resting condition (basal or control condition). The magnitude of this decrease during hypertension induced by aortic constriction was similar to that during normotension (Fig. 1), but was smaller during noradrenaline-induced hypertension (Fig. 1), during hypotension induced by constriction of the caudal vena cava (Fig. 2) and especially during isoprenaline-induced hypotension (Fig. 2; (P < 0.05 for each condition). During isoprenaline administration and aortic constriction, the decrease in coronary vascular resistance during the peak in hyperaemic flow was smaller than that during normotension, but was higher than that during isoprenaline-induced hypotension (Fig. 2). The absolute value of coronary vascular resistance reached during the peak in hyperaemic flow that followed each duration of ischaemia was similar during normotension, hypertension, hypotension and isoprenaline administration combined with aortic constriction.
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Discussion |
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The aim of the present study was to examine the effects of acute changes in systemic arterial pressure on coronary RH. Kelley & Gould (1981) reported that canine coronary RH following brief total occlusions was different from RH that followed deoxygenated perfusion of an equal duration. These authors suggested that this difference resulted from the mechanical effects of sudden changes in coronary flow and perfusion pressure that accompany release of occlusion, which they thought was independent of the myocardial oxygen supply. Dole et al. (1981) observed that an increase in coronary pressure from 60 to 160 mmHg in dogs was associated with a linear increase in the peak and duration of hyperaemic flow after 10 s of arterial occlusion. These authors suggested that the apparent pressure dependency of coronary RH might result in part from a passive flow response, which could be explained by a transient depression of the normal reactivity to postocclusion pressure. In the preparation used by Dole et al. (1981), coronary RH during changes in arterial pressure might differ from that occurring during the natural condition because in their preparation the myocardial metabolic and mechanical factors that normally accompany the changes in arterial pressure were not present. Using coronary arteries isolated from rats, Koller & Bagi (2005) found that when only pressure was changed, the peak in hyperaemic dilatation increased as a function of the duration of occlusion, and when both pressure and flow were changed both the peak and duration of reactive diltatation increased as a function of the duration of occlusion. These authors suggested that mechanosensitive mechanisms that respond to deformation, pressure, stretching and shear stress induce the release of nitric oxide and hydrogen peroxide, thereby effecting reactive coronary vasodilatation (Koller & Bagi, 2005).
In the present experiments, we found that coronary hyperaemic responses were not altered during arterial hypertension induced by aortic constriction, were slightly smaller during noradrenaline-induced hypertension, and were substantially smaller during hypotension induced by constriction of the caudal vena cava or induced by isoprenaline. These observations suggest that coronary RH responses depend, at least in part, on systemic arterial pressure, while the degree of RH depends on the origin of hypertension or hypotension. Changes in coronary RH paralleled changes in coronary vascular resistance, which suggests that the observed dependency of coronary RH on systemic arterial pressure might be related to the level of coronary vascular resistance reached after a change in arterial pressure. Collectively, our observations suggest that the level of coronary vascular resistance during hypertension and hypotension may be determined partly by the action on the coronary vasculature of myocardial vasodilatory metabolic and mechanical factors, as well as drugs.
The decrease in coronary vascular resistance at the peak in hyperaemia during hypertension induced by aortic constricton was similar to that during normotension, but was smaller during noradrenaline-induced hypertension, during hypotension induced by constriction of the caudal vena cava, during isoprenaline-induced hypotension and during the combination of isoprenaline with aortic constriction. The absolute levels of coronary vascular resistance during the peak in hyperaemic flow were similar under each of the experimental conditions tested (Figs 3 and 4). If, as expected, a myogenic response were present in coronary vessels during the early stage (the peak in hyperaemic flow) of the RH response, then the decrease in coronary vascular resistance at the peak of hyperaemia during normotension, hypertension and hypotension should be similar, and the absolute levels of coronary vascular resistance reached during the peak in hyperaemia should be higher during hypertension and lower during hypotension than during normotension. However, this was not the case in the present study, which implies that a vascular myogenic response did not occur immediately after the release of occlusion. Therefore, the pre-existing level of vascular resistance in each case may determine the degree of coronary vasodilatation that occurs during arterial occlusion as a consequence of an autoregulatory process in coronary vessels. The possible contribution of the overswing of perfusion pressure into the coronary vasculature after the release of occlusion might not be important, because RH did not change during hypertension induced by aortic constriction while RH decreased during a similar degree of hypertension induced by noradrenaline. Also, during isoprenaline-induced hypotension, RH was smaller than that during a similar level of hypotension induced by vena cava constriction. The experimental preparation used in the study of Dole et al. (1981) circumvented the involvement of myocardial metabolic and mechanical factors, and therefore examination of the effects of vascular myogenic factors and the overswing of intravascular pressure into coronary vessels is possible without interference from the effects of myocardial factors. Our preparation does not allow us to discriminate between the role played by coronary vascular response and the effects of myocardial factors on coronary vessels. In addition, because we did not measure myocardial oxygen consumption we do not know whether this factor influenced the degree of RH. In a previous study of anaesthetized goats (García et al. 1995), we found that cerebral RH increased during acute increases in arterial pressure induced by aortic constriction or noradrenaline. Furthermore, cerebral RH decreased markedly during acute hypotension induced by constriction of the caudal vena cava or isoprenaline (García et al. 1995). These observations suggest that cerebral RH is related to the change in vascular resistance that follows variations in arterial pressure, but that the relative importance of the mechanisms that modulate cerebral and myocardial RH may differ. During hypertension induced by aortic constriction or noradrenaline, cerebrovascular resistance and RH increased (García et al. 1995). This difference between RH in the brain and the myocardium is probably due to an increase in the metabolic activity and mechanical forces of the myocardium, whereas in the brain these factors do not change during either type of hypertension.
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-adrenergic stimulation, thus limiting vasodilatation after the release of occlusion. Farsang et al. (1977) reported that noradrenaline reduced coronary RH in isolated canine hearts. The difference between coronary RH (present study) and cerebral RH (García et al. 1995) found during hypertension induced by noradrenaline may be partly attributable to vascular bed-specific effects of this drug. Nevertheles, we cannot exclude the possibility that ß-adrenergic receptor activation in coronary vessels contributes to hyperaemic vasodilatation during isoprenaline-induced hypotension, as well as during isoprenaline administration combined with aortic constriction. Other factors might be involved in coronary RH during acute changes in arterial pressure. For example, nitric oxide may regulate coronary vascular tone during basal conditions and during changes in intravascular pressure and blood flow (García et al. 1992; Bassenge, 1995). In addition, nitric oxide and KATP channels might mediate ß-adrenergic coronary vasodilatation (Parent et al. 1993; Ming et al. 1997; Fernández et al. 2000) and might modulate adrenergic coronary vasoconstriction (Woodman & Pannangpetch, 1994; Tanaka et al. 1997). We reported previously that inhibition of nitric oxide release leads to an increase in coronary RH in response to a brief period of ischaemia (García et al. 1992); we attributed this to supersensitivity to factors released from the myocardium and/or endothelium. Because nitric oxide and KATP chnannels may mediate coronary RH (Kingsbury et al. 2001; Koller & Bagi, 2004; Zatta & Headrick, 2005), these two intermediaries may be involved in coronary hyperaemic responses during acute changes in arterial pressure.
In conclusion, the results of the present study suggest that arterial pressure is an important determinant of coronary RH after a brief period of ischaemia, and that the relationship between arterial pressure and coronary RH may depend on the change in coronary vascular resistance after variations in arterial pressure. This change in coronary vascular resistance may be related to the effects on coronary vessels of myocardial factors and of vascular myogenic mechanisms.
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and open bars) and hypertension (• and filled bars) 
and hatched bars). Top panels illustrate coronary reactive hyperaemia; bottom panels show coronary vascular resistance during control conditions (top of bars) and during the corresponding peak in hyperaemic flow (bottom of bars). *P < 0.05 and **P < 0.01 between normotension and hypotension or isoprenaline plus aortic constriction.
