Birgit Houweling

Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation

OBJECTIVESnExercise-induced vasodilation is thought to be mediated through various vasodilator substances, but blunting the influence of vasoconstrictors such as ET may also play a role. However, the role of ET and its receptors in the regulation of systemic, pulmonary and coronary vascular resistance is incompletely understood. The aim of this study was to identify the contribution of ET-1 through the ET(A) and ET(B) receptors to the regulation of tone in the systemic, coronary and pulmonary beds at rest and during exercise.nnnMETHODSnTen chronically instrumented swine were studied while running on a treadmill before and after ET(A) blockade (EMD122946) or ET(AB) blockade (tezosentan).nnnRESULTSnAt rest, EMD122946 resulted in vasodilation in the coronary and systemic circulation, evidenced by a decrease in coronary and systemic vascular resistance and an increase in coronary and mixed venous O(2)-saturation. These effects waned during exercise. The effect of tezosentan on the systemic vasculature was similar to that of EMD122946, whereas it was smaller in the coronary circulation. EMD122946 had no effect on the pulmonary vasculature, whereas tezosentan decreased pulmonary resistance but only during exercise.nnnCONCLUSIONSnET exerts a constrictor influence on the coronary and systemic circulation through the ET(A)-receptor, which decreases during exercise thereby contributing to metabolic vasodilation. ET exerts a tonic vasodilator influence on coronary resistance vessels through the ET(B)-receptor. Finally, ET exerts an ET(B)-mediated constrictor influence in the pulmonary vasculature during exercise.

Functional and Structural Adaptations of Coronary Microvessels Distal to a Chronic Coronary Artery Stenosis

Distal to a chronic coronary artery stenosis, structural remodeling of the microvasculature occurs. The microvascular functional changes distal to the stenosis have not been studied in detail. We tested the hypothesis that microvascular structural remodeling is accompanied by altered regulation of coronary vasomotor tone with increased responsiveness to endothelin-1. Vasomotor tone was studied in coronary microvessels from healthy control swine and from swine 3 to 4 months after implantation of an occluder that causes a progressive coronary narrowing, resulting in regional left ventricular dysfunction and blunted myocardial vasodilator reserve. Arterioles (≈200-&mgr;m passive inner diameter at 60 mm Hg) were isolated from regions perfused by the stenotic left anterior descending and normal left circumflex coronary arteries and studied in vitro. Passive pressure–diameter curves demonstrated reduced distensibility of subendocardial left anterior descending compared with subendocardial left circumflex or control arterioles, suggestive of structural remodeling. Myogenic responses were blunted in subendocardial left anterior descending compared with left circumflex arterioles, reflecting altered smooth muscle function. However, vasodilator responses to nitroprusside and bradykinin were not different in the endocardium, suggesting preserved endothelium and smooth muscle responsiveness. Finally, vasoconstrictor responses to endothelin-1 were enhanced in left anterior descending arterioles compared with left circumflex or control arterioles. Regional myocardial vascular conductance responses to bradykinin and endothelin in vivo confirmed the in vitro observations. In conclusion, inward remodeling of coronary microvessels distal to a stenosis is accompanied by exaggerated vasoconstrictor responses to endothelin-1. These structural and functional alterations may aggravate flow abnormalities distal to a chronic coronary artery stenosis.

Control of pulmonary vascular tone during exercise in health and pulmonary hypertension

Despite the importance of the pulmonary circulation as a determinant of exercise capacity in health and disease, studies into the regulation of pulmonary vascular tone in the healthy lung during exercise are scarce. This review describes the current knowledge of the role of various endogenous vasoactive mechanisms in the control of pulmonary vascular tone at rest and during exercise. Recent studies demonstrate an important role for endothelial factors (NO and endothelin) and neurohumoral factors (noradrenaline, acetylcholine). Moreover, there is evidence that natriuretic peptides, reactive oxygen species and phosphodiesterase activity can influence resting pulmonary vascular tone, but their role in the control of pulmonary vascular tone during exercise remains to be determined. K-channels are purported end-effectors in control of pulmonary vascular tone. However, K(ATP) channels do not contribute to regulation of pulmonary vascular tone, while the role of K(V) and K(Ca) channels at rest and during exercise remains to be determined. Pulmonary hypertension is associated with alterations in pulmonary vascular function and structure, resulting in blunted pulmonary vasodilatation during exercise and impaired exercise capacity. Although there is a paucity of studies pertaining to the regulation of pulmonary vascular tone during exercise in idiopathic pulmonary hypertension, the few studies that have been performed in models of pulmonary hypertension secondary to left ventricular dysfunction suggest altered control of pulmonary vascular tone during exercise. Since the increased pulmonary vascular tone during exercise limits exercise capacity, future studies are needed to investigate the vasomotor mechanisms that are responsible for the blunted exercise-induced pulmonary vasodilatation in pulmonary hypertension.

Nitric oxide blunts the endothelin‐mediated pulmonary vasoconstriction in exercising swine

We have previously shown that vasodilators and vasoconstrictors that are produced by the vascular endothelium, including nitric oxide (NO), prostanoids and endothelin (ET), contribute to the regulation of systemic and pulmonary vascular tone in swine, in particular during treadmill exercise. Since NO and prostanoids can modulate the release of ET, and vice versa, we investigated the integrated endothelial control of pulmonary vascular resistance in exercising swine. Specifically, we tested the hypothesis that increased NO and prostanoid production during exercise limits the vasoconstrictor influence of ET, so that loss of these vasodilators results in exaggerated ET‐mediated vasoconstriction during exercise. Fifteen instrumented swine were exercised on a treadmill at 0–5 km h−1 before and during ETA/ETB receptor blockade (tezosentan, 3 mg kg−1i.v.) in the presence and absence of inhibition of NO synthase (Nω‐nitro‐l‐arginine, 20 mg kg−1i.v.) and/or cyclo‐oxygenase (indometacin, 10 mg kg−1i.v.). In the systemic circulation, ET receptor blockade decreased vascular resistance at rest, which waned with increasing exercise intensity. Prior inhibition of either NO or prostanoid production augmented the vasodilator effect of ET receptor blockade, and these effects were additive. In contrast, in the pulmonary bed, ET receptor blockade had no effect under resting conditions, but decreased pulmonary vascular resistance during exercise. Prior inhibition of NO synthase enhanced the pulmonary vasodilator effect of ET receptor blockade, particularly during exercise, whereas inhibition of prostanoids had no effect, even after prior NO synthase inhibition. In conclusion, endogenous endothelin limits pulmonary vasodilatation in response to treadmill exercise. This vasoconstrictor influence is blunted by NO but not by prostanoids.

Alterations in endothelial control of the pulmonary circulation in exercising swine with secondary pulmonary hypertension after myocardial infarction

Secondary pulmonary hypertension after myocardial infarction (MI) has been associated with endothelial dysfunction and activation of the endothelin (ET) system. Here, we investigated whether an increased ET‐mediated pulmonary vasoconstrictor influence contributes to pulmonary hypertension after MI, and whether this increased ET vasoconstriction is caused by impaired nitric oxide (NO) and prostanoid production. For this purpose, chronically instrumented swine with and without MI ran on a treadmill at 0–4 km h−1. Mixed ETA/ETB receptor blockade (tezosentan) was performed in the absence and presence of single or combined inhibition of endothelial NO synthase (eNOS, with Nω‐nitro‐l‐arginine) and cyclo‐oxygenase (COX, with indometacin). In normal swine, mixed ETA/ETB blockade decreased pulmonary vascular resistance, but only during exercise. In MI swine, an increased ET‐mediated vasoconstrictor influence was observed in the pulmonary circulation both at rest and during exercise. Inhibition of COX resulted in pulmonary vasoconstriction at rest in MI, but not in normal swine; this vasoconstriction in MI swine was normalized by ETA/ETB receptor blockade. Inhibition of eNOS enhanced the vasodilator response to ETA/ETB blockade, indicating that NO blunts the pulmonary vasoconstrictor influence of ET. However, this vasodilator response was enhanced to a similar degree in MI and normal swine. In summary, swine with a recent MI are characterized by an exaggerated pulmonary vasoconstrictor influence of ET. This increased ET‐mediated pulmonary vasoconstrictor influence is not caused by a loss of NO bioavailability, and is blunted by an increased prostanoid‐mediated vasodilatation. In conclusion, an increased ET‐mediated vasoconstriction, which does not appear to be the result of loss of endothelial vasodilators, contributes to pulmonary hypertension after MI.

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET‐mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ETA and ETB receptor subtypes. Chronically instrumented swine with (MI swine; n= 25) or without (normal swine; n= 19) MI were studied at rest and during treadmill exercise (up to 4 km h−1), in the absence and presence of the ETA antagonist EMD 122946 or the mixed ETA/ETB antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ETA blockade had no effect on PVR at rest or during exercise. Conversely, ETA/ETB blockade decreased PVR but only during exercise (at 4 km h−1, from 3.0 ± 0.1 to 2.3 ± 0.1 mmHg min l−1; P≤ 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (both P≤ 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r= 0.71; P≤ 0.01). Furthermore, the pulmonary vasoconstrictor response to ET‐1 infusion was enhanced after MI (P≤ 0.05). ETA/ETB blockade decreased PVR in MI swine from 3.6 ± 0.3 to 3.1 ± 0.5 mmHg min l−1 at rest and from 3.4 ± 0.3 to 2.4 ± 0.2 mmHg min l−1 during exercise at 4 km h−1 (both P≤ 0.05). This increased response to mixed ETA/ETB blockade in MI compared to normal swine appeared to be the result of an increased ETA‐mediated vasoconstriction, as ETA blockade decreased PVR in MI swine from 3.4 ± 0.4 to 2.8 ± 0.2 mmHg min l−1 at rest and from 3.1 ± 0.3 to 2.6 ± 0.2 mmHg min l−1 at 4 km h−1 (both P≤ 0.05). In conclusion, increased plasma ET levels together with increased pulmonary resistance vessel responsiveness to ET result in an exaggerated pulmonary vasoconstrictor influence of ET in swine with a recent MI. This vasoconstrictor influence is the result of an emergent tonic ETA‐mediated vasoconstriction in addition to the exercise‐induced ETB‐mediated vasoconstriction that is already present in normal swine.

Pulmonary vasodilation by phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in early pulmonary hypertension after myocardial infarction

Myocardial infarction (MI) may result in pulmonary hypertension (PH). Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be beneficial for PH secondary to MI. Nitric oxide (NO) is an important activator of cGMP synthesis and can be enhanced in early PH and decreased in severe PH. In the present study, we investigated if PDE5 inhibition ameliorates pulmonary hemodynamics in swine with PH secondary to MI and whether NO is essential. The PDE5 inhibitor EMD360527 was administered in awake, chronically instrumented swine with or without MI. At rest, PDE5 inhibition produced pulmonary vasodilation as evidenced by a decrease in pulmonary vascular resistance, which was more pronounced in MI ( n = 5) compared with normal swine ( n = 10, P ≤ 0.01) and was accompanied by an increase in stroke volume in MI swine. Both pulmonary vasodilation and increased stroke volume were maintained during exercise, suggesting that this therapy may improve exercise capacity in patients with PH secondary to MI. Interestingly, prior inhibition of NO significantly enhanced ( P ≤ 0.01) pulmonary vasodilation by PDE5 inhibition in both normal ( n = 8) and MI swine ( n = 5, P ≤ 0.05 vs. normal). This suggests that the increased vasodilator responses to PDE5 inhibition after MI were not due to an increase in NO-induced cGMP production. These observations indicate that PDE5 inhibition represents an interesting pharmacotherapeutic approach in early PH after a recent MI to prevent overt PH. NEW & NOTEWORTHY This research article is the first to describe that pulmonary vasodilation to phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in resting and exercising swine with pulmonary hypertension as a result of myocardial infarction. This suggests that phosphodiesterase 5 inhibition can normalize pulmonary hemodynamics in postcapillary pulmonary hypertension after a recent myocardial infarction and may improve exercise capacity.