Vasoconstrictors: a tale of two circulations

A cell can not survive without oxygen (O2) or nutrients. A single-celled organism can get both O2 and nutrients by simple diffusion. Since our body is built up of ~100 trillion (1014) cells, most of which never come into contact with outside air, we need to transport both O2 and nutrients actively in order to get them to all of our cells. The substance that mammals, like ourselves, use to accomplish this is blood. Blood is transported through the body using blood vessels, the complex of which is called the circulation. The movement of blood through the circulation is not a passive process, but is driven by one of the most amazing achievements of evolution: the heart (Fig. 1). The heart is a pump that, on average, contracts 60 times each minute at rest, a number which can increase to 200 contractions during maximum exercise. By contracting, the heart builds up the pressure, in the arterial side of the circulation, which is required for blood to flow

Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement

We previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of P1 receptors

Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitroso-redox balance

Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening

Aims More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction

Both β1- and β2-adrenoceptors contribute to feedforward coronary resistance vessel dilation during exercise

During exercise, β-feedforward coronary vasodilation has been shown to contribute to the matching of myocardial oxygen supply with the demand of the myocardium. Since both β1- and β2-adrenoceptors are present in the coronary microvasculature, we investigated the relative contribution of these subtypes to β-feedforward coronary vasodilation during exercise as well as to infusion of the β1-agonist norepinephrine and the β1- and β2-agonist isoproterenol. Chronically instrumented swine were studied at rest and during graded treadmill exercise (1-5 km/h) under control conditions and after β1-blockade with metoprolol (0.5 mg/kg iv) and β1/β2-blockade with propranolol (0.5 mg/kg iv). The selectivity and degree of β-blockade of metoprolol and propranolol were confirmed using isoproterenol infusion (0.05-0.4 μg· kg-1·min-1) under resting conditions. Isoproterenol-induced coronary vasodilation was mediated through the β2-adrenoceptor, whereas norepinephrine-induced coronary vasodilation was principally mediated through the β1- adrenoceptor. Exercise resulted in a significant increase in left ventricular norepinephrine release and epinephrine uptake. β1-Adrenoceptor blockade with metoprolol had very little effect under resting conditions. However, during exercise, metoprolol attenuated the increase in myocardial oxygen supply in excess of the reduction in myocardial oxygen demand, as evidenced by a progressive decrease in coronary venous PO2. Consequently, metoprolol caused a clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous PO2. Additional β2-adrenoceptor blockade with propranolol further inhibited myocardial oxygen supply during exercise, resulting in a further clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous PO2. In conclusion, both β1- and β2-adrenoceptors contribute to the β-feedforward coronary resistance vessel dilation during exercise. Copyrigh

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability. J Appl Physiol 115: 17671776, 2013. First published October 24, 2013; doi:10.1152/japplphysiol.00619.2013. Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exerciseinduced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-L-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 μg·min-1·kg-1 iv) each produced coronary vasodilation at rest

Cytochrome P-450 2C9 exerts a vasoconstrictor influence on coronary resistance vessels in swine at rest and during exercise

A significant endotheliumdependent vasodilation persists after inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) in the coronary vasculature, which has been linked to the activation of cytochrome P-450 (CYP) epoxygenases expressed in endothelial cells and subsequent generation of vasodilator epoxyeicosatrienoic acids. Here, we investigated the contribution of CYP 2C9 metabolites to regulation of porcine coronary vasomotor tone in vivo and in vitro. Twenty-six swine were chronically instrumented. Inhibition of CYP 2C9 with sulfaphenazole (5 mg/kg iv) alone had no effect on bradykinininduced endothelium-dependent coronary vasodilation in vivo but slightly attenuated bradykinin-induced vasodilation in the presence of combined NOS/COX blockade with N ω-nitro-L-arginine (20 mg/kg iv) and indomethacin (10 mg/kg iv). Sulfaphenazole had minimal effects on coronary resistance vessel tone at rest or during exercise. Surprisingly, in the presence of combined NOS/COX blockade, a significant coronary vasodilator response to sulfaphenzole became apparent, both at rest and during exercise. Subsequently, we investigated in isolated porcine coronary small arteries (~250 μm) the possible involvement of reactive oxygen species (ROS) in the paradoxical vasoconstrictor influence of CYP 2C9 activity. The vasodilation by bradykinin in vitro in the presence of NOS/COX blockade was markedly potentiated by sulfaphenazole under control conditions but not in the presence of the ROS scavenger N-(2-mercaptoproprionyl)-glycine. In conclusion, CYP 2C9 can produce both vasoconstrictor and vasodilator metabolites. Production of these metabolites is enhanced by combined NOS/COX blockade and is critically dependent on the experimental conditions. Thus production of vasoconstrictors slightly outweighed the production of vasodilators at rest and during exercise. Pharmacological stimulation with bradykinin resulted in vasodilator CYP 2C9 metabolite production when administered in vivo, whereas vasoconstrictor CYP 2C9 metabolites, most likely ROS, were dominant when administered in vitro

Pulmonary vasoconstrictor influence of endothelin in exercising swine depends critically on phosphodiesterase 5 activity

Both phosphodiesterase 5 (PDE5) inhibition and endothelin (ET) receptor blockade have been shown to induce pulmonary vasodilation. However, little is known about the effect of combined blockade of these two vasoconstrictor pathways. Since nitric oxide (NO) exerts its pulmonary vasodilator influence via production of cyclic guanosine monophosphate (cGMP) as well as through inhibition of ET, we hypothesised that interaction between the respective signalling pathways precludes an additive vasodilator effect. We tested this hypothesis in chronically instrumented swine exercising on a treadmill by comparing the vasodilator effect of the PDE5-inhibitor EMD360527, the ETA/ETB-antagonist tezosentan, and combined EMD360527 and tezosentan. In the systemic circulation, vasodilation by tezosentan and EMD360527 was additive, both at rest and during exercise, resulting in 17 ± 2% drop in blood pressure. In the pulmonary circulation, both EMD360527 and tezosentan produced vasodilation. However, tezosentan produced no additional pulmonary vasodilation in the presence of EMD360527, either at rest or during exercise. Moreover, in isolated preconstricted po

Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction

The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT1 receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1-4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of AT1 receptors (irbesartan,