Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

Iron deficiency is common in idiopathic pulmonary arterial hypertension.

The aims of this study were to assess the prevalence of iron deficiency in idiopathic pulmonary arterial hypertension (IPAH) and investigate whether oral iron supplementation has effects in iron-deficient patients. Iron parameters were measure for all IPAH patients attending our centre (VU University Medical Center, Amsterdam, the Netherlands) between May 2009 and February 2010. Iron data were related to clinical parameters, including 6-min walking distance (6MWD), and haemodynamic parameters measured during right heart catheterisation. In a subset of iron-deficient patients, the uptake of iron from the bowel was studied after administering oral iron for 4 weeks. Iron deficiency was found in 30 (43%) out of 70 patients. 6MWD was reduced in iron-deficient patients compared with iron-sufficient patients (mean±sd 390±138 versus 460±143 m; p<0.05) irrespective of the existence of anaemia. In a subset of 18 patients that received oral iron, ferritin levels were significantly increased, although eight patients only slightly increased their iron storage. This study shows that iron deficiency is frequently present in IPAH and is associated with a lower exercise capacity. The small response to oral iron in 44% of the treated patients suggests impaired iron absorption in these patients.

Opposite effects of training in rats with stable and progressive pulmonary hypertension.

BACKGROUND: Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment. However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training. METHODS AND RESULTS: Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25+/-3.9 to 62+/-3.9 minutes; P<0.001). Moreover, capillary density increased significantly (from 1.21+/-0.12 to 1.51+/-0.07 capillaries per cardiomyocyte; P<0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135+/-14 to 276+/-18 leukocytes per 1 mm(2); P<0.001). CONCLUSIONS: In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings.

RC time constant of single lung equals that of both lungs together: a study in chronic thromboembolic pulmonary hypertension.

The product of resistance, R, and compliance, C (RC time), of the entire pulmonary circulation is constant. It is unknown if this constancy holds for individual lungs. We determined R and C in individual lungs in chronic thromboembolic pulmonary hypertension (CTEPH) patients where resistances differ between both lungs. Also, the contribution of the proximal pulmonary arteries (PA) to total lung compliance was assessed. Patients (n=23) were referred for the evaluation of CTEPH. Pressure was measured by right heart catheterization and flows in the main, left, and right PA by magnetic resonance imaging. Total, left, and right lung resistances were calculated as mean pressure divided by mean flow. Total, left, and right lung compliances were assessed by the pulse pressure method. Proximal compliances were derived from cross-sectional area change DeltaA and systolic-diastolic pressure difference DeltaP (DeltaA/DeltaP) in main, left, and right PA, multiplied by vessel length. The lung with the lowest blood flow was defined "low flow" (LF), the contralateral lung "high flow" (HF). Total resistance was 0.57+/-0.28 mmHg.s(-1).ml(-1), and resistances of LF and HF lungs were 1.57+/-0.2 vs. 1.00+/-0.1 mmHg.s(-1).ml(-1), respectively, P<0.0001. Total compliance was 1.22+/-1.1 ml/mmHg, and compliances of LF and HF lung were 0.47+/-0.11 and 0.62+/-0.12 ml/mmHg, respectively, P=0.01. Total RC time was 0.49+/-0.2 s, and RC times for the LF and HF lung were 0.45+/-0.2 and 0.45+/-0.1 s, respectively, not different. Proximal arterial compliance, given by the sum of main, right, and left PA compliances, was only 19% of total lung compliance. The RC time of a single lung equals that of both lungs together, and pulmonary arterial compliance comes largely from the distal vasculature.

Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.

We determined the physiological effects of exercise training on exercise capacity and quadriceps muscle function in patients with idiopathic pulmonary arterial hypertension (iPAH). In total, 19 clinically stable iPAH patients (New York Heart Association II-III) underwent a supervised exercise training programme for the duration of 12 weeks. Maximal capacity, endurance capacity and quadriceps function were assessed at baseline and after 12 weeks. In 12 patients, serial quadriceps muscle biopsies were obtained. 6-min walk distance and peak exercise capacity did not change after training. However, endurance capacity improved significantly after training, demonstrated by a shift of the anaerobic threshold to a higher workload (from 32+/-5 to 46+/-6 W; p = 0.003) together with an increase in exercise endurance time (p<0.001). Moreover, exercise training increased quadriceps strength by 13% (p = 0.005) and quadriceps endurance by 34% (p = 0.001). Training enhanced aerobic capacity of the quadriceps, by increasing capillarisation (1.36+/-0.10 to 1.78+/-0.13 capillaries per muscle fibre; p<0.001) and oxidative enzyme activity, especially of the type-I (slow) muscle fibres. No changes were found in cross-sectional area and fibre type distribution. Exercise training in iPAH improves exercise endurance and quadriceps muscle function, which is also reflected by structural changes of the quadriceps.

Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension.

Since systemic sclerosis (SSc) also involves the heart, the aim of the present study was to evaluate possible differences in right ventricular (RV) pump function between SSc-associated pulmonary arterial hypertension (PAH; SScPAH) and idiopathic PAH (IPAH). In 13 limited cutaneous SScPAH and 17 IPAH patients, RV pump function was described using the pump function graph, which relates mean RV pressure ((RV)) and stroke volume index (SVI). Differences in pump function result in shift or rotation of the pump function graph. (RV) and SVI were measured using standard catheterisation. The hypothetical isovolumic (RV) ((RV,iso)) was estimated using a single-beat method. The pump function graph was approximated by a parabola: (RV) = (RV,iso)[1-(SVI/SVI(max))(2)], where SVI(max )is the hypothetical maximal SVI at zero (RV), enabling calculation of SVI(max). There were no differences in SVI and SVI(max). Both (RV) and (RV,iso) were significantly lower in SScPAH than in IPAH ((RV) 30.7+/-8.5 versus 41.2+/-9.4 mmHg; (RV,iso) 43.1+/-12.4 versus 53.5+/-10.0 mmHg). Since higher pressures were found at similar SVI, the difference in the pump function graph results from lower contractility in SScPAH than in IPAH. Right ventricular contractility is lower in systemic sclerosis-associated pulmonary arterial hypertension than in idiopathic pulmonary arterial hypertension.

Sildenafil treatment in COPD does not affect stroke volume or exercise capacity.

In chronic obstructive pulmonary disease (COPD) patients, stroke volume response to exercise is impaired. The aim of the present study was to investigate whether 3 months of sildenafil treatment improves stroke volume and, if so, whether this improvement is related to the pulmonary artery pressure and translated into an improved exercise capacity. A total of 15 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) underwent right heart catheterisation at rest and during exercise. Stroke volume was assessed by magnetic resonance imaging (MRI) at rest and during submaximal exercise in the supine position and compared with eight age-matched controls. Additionally, a cardiopulmonary exercise test and a 6-min walking distance test were performed. Exercise tests and MRI were repeated after 12 weeks of oral therapy with 50 mg sildenafil three times daily. Stroke volume in COPD patients was significantly lower than in healthy controls (62+/-12 versus 81+/-22 mL at rest and 70+/-15 versus 101+/-28 mL during exercise). Pulmonary hypertension (PH) was diagnosed in nine patients and was absent in six. Treatment with sildenafil had no effect on stroke volume or exercise capacity. Although the stroke volume was lower in COPD patients with associated PH in comparison with non-PH patients, there was no difference in treatment response between both groups. In the present group of 15 chronic obstructive pulmonary disease patients, a reduced stroke volume was found at rest and during exercise. Neither stroke volume nor exercise capacity were improved by 3 months of sildenafil therapy.

Three- and four-element Windkessel models: assessment of their fitting performance in a large cohort of healthy middle-aged individuals.

Lumped-parameter models are used to estimate the global arterial properties by fitting the model to measured (aortic) pressure and flow. Different model configurations coexist, and it is still an open question as to which model optimally reflects the arterial tree and leads to correct estimates of arterial properties. An assessment was made of the performance of (a) the three-element Windkessel model (WK3) consisting of vascular resistance R, total arterial compliance C, and characteristic impedance Zc; (b) a four-element model with an inertance element L placed in parallel with Zc (WK4-p); and (c) a four-element model with L placed in series with Zc (WK4-s). Models were fitted to data measured non-invasively in 2404 healthy subjects, aged between 35 and 55 years. It was found that model performance segregated into two groups. In a group containing 20 per cent of the dataset (characterized by low blood pressure and wave reflection) the WK4-p model outperformed the other models, with model behaviour as envisioned by its promoters. In these cases, the WK3 and WK4-s models led to increased overestimation of total arterial compliance and underestimation of characteristic impedance. However, in about 80 per cent of the cases, the WK4-p model showed a behaviour that was very similar to that of the WK3 and WK4-s models. Here, the WK4-s model yielded the best quality of fit, although model parameters reached physically impossible values for L in about 12 per cent of all cases. The debate about which lumped-parameter model is the better approximation of the arterial tree is therefore still not fully resolved.

Characteristics of the flow velocity-pressure gradient relation in the assessment of stenoses: an in vitro study.

OBJECTIVES: The flow velocity-pressure gradient (v-dp) relation is clinically used to assess coronary stenoses. This in vitro study aimed to investigate the ability to determine the impact of each individual stenosis in the setting of two consecutive stenoses, the effect of variable stenosis reference diameters and the impact of one or two wires in a stenosis, on the v-dp relation. METHODS: The model consisted of a reservoir and different sized tubes and stenoses. Pressure gradient and flow velocity were assessed with a pressure and a Doppler wire. By plotting flow velocity and pressure gradient on an X-Y plot, the v-dp relation was determined. RESULTS: The v-dp relation of a proximal stenosis was not influenced by a distal stenosis. The diameter of the segment where flow velocity was measured influenced the v-dp relation. This could be corrected by substituting flow velocity with volume flow. The presence of one or two wires in a stenosis made the v-dp relation substantially steeper. CONCLUSIONS: The v-dp relation can be used to determine the significance of each individual stenosis in arteries with consecutive stenoses, provided that the distance between the stenoses is large enough. The diameter of the segment where flow velocity is measured and the presence of one or two wires substantially affect the v-dp relation. (Neth Heart J 2008;16:156-62.).

Nitric oxide and cardiac function.

Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with production of small amounts of cGMP, inhibit phosphodiesterase III, thus preventing the hydrolysis of cAMP. The subsequent activation of a protein-kinase A causes the opening of sarcolemmal voltage-operated and sarcoplasmic ryanodin receptor Ca(2+) channels, thus increasing myocardial contractility. High concentrations of NO induce the production of larger amounts of cGMP which are responsible for a cardiodepression in response to an activation of protein kinase G (PKG) with blockade of sarcolemmal Ca(2+) channels. NO is also involved in reduced contractile response to adrenergic stimulation in heart failure. A reduction of heart rate is an evident effect of NO-synthase (NOS) inhibition. It is noteworthy that the direct effect of NOS inhibition can be altered if baroreceptors are stimulated by increases in blood pressure. Finally, NO can limit the deleterious effects of cardiac remodeling after myocardial infarction possibly via the cGMP pathway. The protective effect of NO is mainly mediated by the guanylyl cyclase-cGMP pathway resulting in activation of PKG with opening of mitochondrial ATP-sensitive potassium channels and inhibition of the mitochondrial permeability transition pores. NO acting on heart is produced by vascular and endocardial endothelial NOS, as well as neuronal and inducible synthases. In particular, while in the basal control of contractility, endothelial synthase has a predominant role, the inducible isoform is mainly responsible for the cardiodepression in septic shock.

Pump function of the feline left heart: changes with heart rate and its bearing on the energy balance.

Pump function of the feline left heart was determined by measuring the relationship between mean left ventricular pressure and mean left ventricular output, obtained by changing the arterial load on a beat-to-beat basis. The effect of a change in heart rate from 120 to 160 beats . min-1 was studied and a parallel shift of the pump function graph was found. Care was taken to keep left ventricular end-diastolic pressure constant with the change in frequency. If the mean pressure and output values obtained at 160 beats . min-1 were multiplied by the ratio between the two frequencies (0.75), almost complete superposition of the two graphs was obtained. Changes in arterial load also caused changes in oxygen consumption, mean external power and external efficiency of the heart. We plotted these variables, altered them as a function of mean left ventricular output for easy comparison with the pump function graph. It was found that oxygen consumption decreases with increasing output. Mean external power and efficiency attain maxima for different values of mean output. If the left heart in the intact animal is controlled to function at its maximum power output, this can therefore not be achieved at the optimum efficiency level. The results of the present study and those obtained earlier were compared with the behaviour of a time varying compliance model.

Steady state and instantaneous pressure-flow relationships: characterisation of the canine abdominal periphery.

This study was performed to characterise a vascular bed in terms of pressure-flow relationships. Steady state and instantaneous relationships were obtained in the flow perfused isolated femoral beds of six mongrel dogs. The steady state pressure-flow relations were obtained by applying a series of stepwise changes of flow in random order. The relations were found to be straight and to have a zero-flow pressure intercept (P0). The slope of this relation is the differential resistance (Rd). On each steady state flow level a ramp-flow was superimposed. The pressure response was measured between 1.5 and 5 s after the start of the ramp-flow, to exclude compliance effects and (auto) regulatory effects, respectively. In this way instantaneous pressure-flow relations were obtained, the slope of this relation is the instantaneous resistance (Ri). The instantaneous resistance expresses the true physical resistance value at a working point of the steady state pressure-flow relation before the bed has performed its (auto)regulatory adaptation after a change in flow. Instantaneous resistance therefore characterises the vascular state that exists at that particular working point. After this particular vascular state has been modified by (auto)-regulation the steady state pressure-flow relation is reached again. Instantaneous resistance increases with increasing flow thereby approximating the value of the differential resistance. At the same flow a vasodilator decreases and a vasoconstrictor increases instantaneous resistance. The gain (G) of the system, that characterises the (auto)regulatory capability, was calculated as G = 1--Ri/Rd and was found to decrease with increasing flow. The (partial) reflection of travelling waves depends on both the characteristic impedance (Zc) and the instantaneous resistance rather than on differential or peripheral resistance. Furthermore it is the product of the instantaneous resistance (Ri) and vascular compliance (C) that determines the time constant of a vascular bed.

The arterial system characterised in the time domain.

When an impulse of flow is applied to the arterial system then the resulting pressure, the impulse response, is a characterisation of the arterial tree. The impulse is generated by means of an occluder around the ascending aorta. The impulse response shows an initial sharp peak followed by an exponential decay with two peaks superimposed on it. The exponential decay is due to diffuse reflection and is linked to the windkessel properties of the arterial tree. The superimposed peaks arise from two distinct reflection sites in the arterial tree. By means of the pulse wave velocity the location of these reflection sites may be calculated; one is found in the bed distal to the brachiocephalic and subclavian arteries and the other in the bed distal to the descending aorta. The distinct reflections are linked to the reflection sites in the asymmetric T-model of the arterial tree. Vasodilatation (nitroprusside) and vasoconstriction (angiotensin) mainly influence the diffuse reflections, while the locations of the distinct reflection sites appear to be unchanged. Inflation of a balloon in the descending aorta shows up as a sharp peak in the impulse response function. The results obtained are compared with the impulse response function computed from pressure and flow waves in the steady-state.

Instantaneous and steady-state pressure-flow relations of the coronary system in the canine beating heart.

Steady-state and instantaneous pressure-flow relations were both obtained from the pump-perfused left coronary bed of the beating heart in seven mongrel dogs. The steady-state pressure-flow relation was obtained by changing flow, and measuring pressure after it reached a steady level; it showed a sigmoid shape, with flow-regulation around 70 ml . min-1 . 100 g-1, and it had an average zero-flow pressure intercept of 1.9 kPa (14 mmHg). This curve was represented by an equation, using four parameters. The quality of regulation of the coronary bed could be quantified with this equation by determining the pressure range, when flow was changed from 25% below to 25% above control level. We found this pressure range to be 8.7 +/- 2.4 kPa (65 +/- 18 mmHg) on the average. The tangent at each point of steady-state pressure-flow relation was called differential resistance. Instantaneous pressure-flow relations were obtained by superimposing stepwise changes of flow of different amplitude, at several steady-state levels of flow. Pressure followed these steps with a time-constant of 0.3 +/- 0.1 s, due to capacitive effects, then remained constant during 3 to 4 s, and thereafter changed due to regulation. Pressure was measured during the plateau, assuming it to be a regulation-free period. The instantaneous pressure-flow relations were found to be linear, and the slope was called instantaneous resistance. In the physiological range of flows, instantaneous resistance increased with flow. The ratio between instantaneous and differential resistance, the regulatory index, is suggested to quantify regulation at each point of the steady-state curve. This index was between one and zero up to the upper limit of the regulatory range; at higher flows it was negative. In the maximally vasodilated bed the instantaneous pressure-flow relations fell along the steady-state relation, and the regulatory index was thus equal to zero at all flow-levels.

How to quantify an arterial stenosis: a study on the femoral arteries of dog and man.

The blood supply to the femoral bed was studied in anaesthetised dogs before and after producing arterial stenoses. The blood supply system consisted of the vessels proximal to the site of measurement in the femoral artery and was characterised by a supply graph, which related mean perfusion pressure to mean flow. The different pressures and flows were obtained using an artificial periphery, the impedance of which was changed from beat to beat. The supply graph was approximated by a parabola with two parameters: the intercepts with the pressure and flow axes, the latter indicating the maximum mean flow. For constant aortic pressure the maximum mean flow appeared to be linearly related to the cross sectional area of the stenosed section (r = 0.98). Maximum mean flow was already considerably reduced before the stenosis became critical--that is, before physiological flow was measurably diminished. The change in maximum mean flow was therefore used to quantify the haemodynamic effects of stenoses that were less than critical. Blood supply graphs of the superficial femoral arteries were determined also in seven patients undergoing a femoropopliteal bypass operation. The maximum mean flow correlated well with the degree of obstruction determined from the preoperative angiograms (r = 0.90).

Systemic compliance: does it play a role in the genesis of essential hypertension?

Arterial compliance is part of the load faced by the heart. Decreased compliance increases this load. We have studied the cardiovascular consequences of decreased systemic compliance in six closed chest anaesthetised dogs where ascending aortic flow transducers and left ventricular crystals had previously been implanted. A stiff tube was put into the abdominal aorta from the left flank and moved to the ascending aorta. Inflation of a cuff on the proximal end of the tube forced the heart to eject into a non-compliant outflow conduit. The distal end of the tube was connected to the distal aorta and, via a pump, to a carotid artery where mean pressure was kept above 80 mmHg. We measured systemic pressures (catheter-tip manometer), cardiac output (electromagnetic flowmeter) and either left ventricular end-diastolic pressure (fluid filled catheter, Statham P23Db) or left ventricular diameter (ultrasound transit time method). From these variables we calculated systemic compliance and input impedance. A 35% decrease in compliance caused a 12% increase in systolic, and a 12% decrease in diastolic pressure while mean pressure and cardiac output did not change significantly. With a decrease in compliance of 63% systolic pressure increased by 18%, while diastolic pressure decreased by 24%. Mean pressure did not change significantly but cardiac output fell by 21%. In both groups of altered compliance peripheral resistance rose slightly but this was not significant. Decreased compliance mainly caused changes in the low frequency range of the input impedance: moduli increased and phase angles became more negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflection in the systemic arterial system: effects of aortic and carotid occlusion.

Experiments were performed in seven closed-chest anaesthetized male dogs to determine the role of pulse wave reflection in the pattern of flow and pressure in the ascending aorta. Ten days after implantation of an electromagnetic flow transducer around the ascending aorta a balloon catheter was placed in the descending aorta via the femoral arteries. At the same time a tip manometer was introduced into the ascending aorta. Aortic occlusions at three different sites caused pressure pulses with secondary systolic rises and flow pulses with biphasic deceleration. Secondary rises occurred 45 +/- 9.0 ms after the initial pressure rise for high aortic occlusion; this time was 75 +/- 8.5 ms for occlusion at the level of the diaphragm and 114 +/- 16.5 ms for occlusion near the level of the renal arteries. These times approximate the times in which the pulse travels from the tip manometer to the inflated balloons and back. Forward and reflected pressure and flow waves were calculated from reflection coefficients. Aortic occlusion caused larger reflected waves and the recorded wave forms were caused by the summation of forward and backward waves, the latter contributing the secondary pressure rise and the increased flow deceleration. Occlusion of both carotid arteries showed no specific reflection site but reflected waves were larger. This increased reflection can probably be explained as the result of greater total reflection from distributed sites under increased peripheral resistance.

Measurement of left ventricular wall stress.

Forces in the myocardial wall can be measured in several ways or calculated using certain simplifying assumptions. In this study we investigated the reliability of two measurement methods, one of which was introduced by Feigl et al (1967), whereas the other method was developed in our laboratory. Both methods were tested in actively contracting skeletal muscle and beating hearts of open-chest dogs by comparing the force transferred from the muscle to the transducer under various circumstances. It appeared that changes in muscle length, be it through initial length changes or through shortening during contractions, had a great influence on the transfer of force to the transducer, for both methods, in both preparations. In the heart a decrease in internal left ventricular diameter of 15% resulted in a 50% reduction of force transferred to the transducer, independent of whether the length took place as a change in filling or as a change in ejection volume. In skeletal muscle the length-dependent effects during shortening were larger and those resulting from initial length changes were more variable than in beating hearts. That the effects of muscle length changes are of such magnitude means that, if no other errors exist, they alone would invalidate that until principally different methods of measuring wall stress in the myocardium are discovered, attempts at accurate calculation of myocardial wall stress are a better approach than wall stress measurements.

Ischaemic preconditioning changes the pattern of coronary reactive hyperaemia in the goat: role of adenosine and nitric oxide.

OBJECTIVES: After ischaemic preconditioning (IP), obtained by short episodes of ischaemia, cardiac protection occurs due to a reduction in myocardial metabolism through the activation of A1 adenosine receptors. The antiarrhythmic effect of IP is attributed to an increase in the release of nitric oxide (NO) by the endothelium. On the basis of the above consideration the present investigation studies the changes induced by preconditioning in coronary reactive hyperaemia (RH) and how blockade of A1 receptors and inhibition of NO synthesis can modify these changes. METHODS: In anaesthetised goats, an electromagnetic flow-probe was placed around the left circumflex coronary artery. Preconditioning was obtained with two episodes of 2.5 min of coronary occlusion, separated by 5 min of reperfusion. RH was obtained with a 15 s occlusion. In a control group (n = 7) RH was studied before and after IP. In a second group (n = 7), 0.2 mg kg-1 of 8-cyclopentyl-dipropylxanthine, an A1 receptor blocker, and in a third group (n = 7) 10 mg kg-1 of NG-nitro-L-arginine (LNNA), an NO inhibitor, were given before IP. Reactive hyperaemia was again obtained before and after IP. RESULTS: In the control group, after IP, the time to peak hyperaemic flow and total hyperaemic flow decreased by about 50% and 25%, respectively. The A1 receptor blockade alone did not change RH. During A1 blockade, IP reduced the time to peak of RH similar as in control (45%), but did not alter total hyperaemic flow. LNNA alone reduced resting flow and total hyperaemic flow. After NO inhibition, IP only reduced total hyperaemic flow by about 15%, but the time to peak flow was not affected. CONCLUSIONS: IP alters RH by decreasing total hyperaemic flow and reducing the time to peak hyperaemic flow. While the former effect is attributed to a reduction in myocardial metabolism through the activation of the A1 receptors, the latter is likely to be due to an increased endothelial release of NO, suggesting that in addition to a protective effect on the myocardium, IP also exerts a direct effect on the responsiveness of the coronary vasculature (vascular preconditioning).