Mark I. M. Noble

Oxygen and coronary vascular resistance during autoregulation and metabolic vasodilation in the dog

The hypothesis that tissue oxygen tension controls coronary vascular resistance during changes in perfusion pressure and oxygen consumption was expressed in a simplified mathematical form capable of making quantitative predictions. The predictive value of this formulation of the hypothesis was tested in experiments on anaesthetized mongrel dogs subjected to constant‐pressure perfusion of the left main coronary artery, with measurements of coronary blood flow and arterio‐venous oxygen content differences. Coronary venous oxygen content was used as an index of tissue oxygenation. The responses of coronary blood flow and arterio‐venous oxygen content difference, made over a range of perfusion pressures (which caused autoregulation) and heart rates (which caused metabolic regulation) were predicted qualitatively by the model. Coronary vascular conductance was positively related to metabolic rate only during metabolic regulation (heart rate changes); during autoregulation the relationship between these two variables was inverse. Coronary vascular conductance and resistance values taken from both interventions (both perfusion pressure and heart rate variations) were closely related to coronary venous oxygen content and calculated PO2. These findings suggest that further examination of oxygen tension, as the controller of the coronary vascular bed under physiological conditions should be considered.

Differential inhibition by hyperglycaemia of shear stress- but not acetylcholine-mediated dilatation in the iliac artery of the anaesthetized pig

Clinical hyperglycaemia affects vascular endothelial function, but the effect on shear stress‐induced arterial dilatation has not yet been established. We hypothesized that hyperglycaemia would inhibit this response via impaired glycocalyx mechanotransduction. Experiments were carried out in the anaesthetized pig in which pressure, blood flow and diameter of the left iliac artery were measured at two sites: proximal (d1) and distal (d2). Infusion of glucose, sufficient to raise blood glucose to 16–30 mm along the whole length of the artery, attenuated the shear stress‐dependent dilatation in both sections of the artery with preservation of the responses to acetylcholine. The distal site was then isolated using snares and the lumen exposed to blood containing 25–35 mm glucose for 20 min. In the control situation, after exposure of both sections to normoglycaemia (5.7 mm glucose), both sections of artery showed increases in diameter in response to shear stress and acetylcholine. Hyperglycaemia attenuated the shear stress‐dependent dilatation in the distal section only (P < 0.25), but not the response to acetylcholine. It is concluded from these results that the hyperglycaemia‐impaired dilatation is consistent with loss of mechanotransducing properties of the endothelial glycocalyx by hyperglycaemia. These findings offer a possible explanation for the increased incidence of vascular disease in diabetic patients.

Basal and hyperaemic myocardial blood flow in regionally denervated canine hearts: an in vivo study with positron emission tomography

PurposePositron emission tomography (PET) studies in patients with diabetic autonomic neuropathy (DAN) have demonstrated the impact of this disease on cardiac sympathetic innervation and myocardial blood flow (MBF). To investigate the effects of selective partial sympathetic denervation of the left ventricle (LV) on baseline and hyperaemic MBF, we measured myocardial presynaptic catecholamine re-uptake (uptake-1), β-adrenoceptor (β-AR) density and MBF non-invasively by means of PET in a canine model of regional sympathetic denervation.MethodsIn 11 anaesthetised dogs, the sympathetic nerves of the free wall and septum of the LV were removed by means of dissection and phenol painting. Three weeks later, the animals were studied with PET. MBF was measured at baseline and following i.v. adenosine (140xa0μgxa0kg−1xa0min−1) and dobutamine (20xa0μgxa0kg−1xa0min−1) using15O-labelled water. Sympathetic denervation was confirmed by an 80±12% decrease in the volume of distribution (Vd) of [11C]hydroxyephedrine (HED) compared with innervated regions. Myocardial β-AR density was measured using [11C]CGP12177.ResultsInnervated and denervated regions showed no differences in MBF at baseline and during adenosine or dobutamine. [11C]HED Vdwas inversely correlated with MBF in both regions at baseline, and the correlation was lost during hyperaemia in denervated regions. However, for any given value of MBF, [11C]HED Vdwas significantly lower in the denervated regions. β-AR density was comparable in denervated and innervated regions (17.9±4.2 vs 18.4±3.3xa0pmolxa0g−1;p=NS).ConclusionIn this experimental model, selective, regional sympathetic denervation of the LV, which results in a profound reduction in [11C]HED Vd, did not affect baseline or hyperaemic MBF. In addition, we demonstrated that, under baseline conditions, there was a significant inverse correlation between [11C]HED Vdand MBF in both denervated and innervated regions.

What is the mechanism of flow-mediated arterial dilatation

The present review attempts to explain the controversies concerning the mechanism of shear stress‐mediated arterial dilatation, commonly called flow‐mediated arterial dilatation (FMD). Flow‐mediated dilatation occurs in an artery when the blood flow to the organ supplied by the artery is increased. There are two hypotheses regarding the stimulus for FMD: (i) a wave of endothelial and smooth muscle hyperpolarization, conducted in a retrograde fashion from the vasodilated peripheral vascular bed towards the relevant conduit artery; and (ii) an increase in shear stress sensed by the endothelial cells. The latter hypothesis is associated with two further postulates concerning the method of mechanotransduction of the shear stress stimulus: (i) direct transmission from endothelial cell cytoskeleton to the vascular smooth muscle to induce dilatation; and (ii) indirect transmission to the endothelial cell cytoskeleton via the glycocalyx. The virtues and inconsistencies of these hypotheses are discussed. The first hypothesis is excluded because a vasodilated peripheral vascular bed does not cause dilation of the upstream conduit artery if an increase in flow within the conduit artery is prevented and because FMD is completely blocked by inhibition of nitric oxide synthase (NOS). It is probable that the stimulus is an increase in shear stress between the blood and the adjacent layer of the arterial wall, the glycocalyx. Ultimately, a change in the endothelial cell cytoskeleton is the likely event that leads to activation of NOS and this activation does not occur without a functioning glycocalyx.

Chronic catecholamine depletion switches myocardium from carbohydrate to lipid utilisation.

AbstractPurpose: Chronic cardiac transplantation denervation (i.e., global sympathetic denervation with myocardial catecholamine depletion, plus parasympathetic denervation) is known to inhibit myocardial oxidation of glucose. It is not known whether this is due to increased utilization of lactate, lipid or ketone bodies. The purpose of the present study was to test the hypothesis that the extraction and contribution of blood-borne fatty acids (FA) to overall oxidative energy conversion is increased.nMethods: In anaesthetised dogs (control n = 6, cardiac denervated n = 6), we investigated fatty acid (FA) utilization. The studies were made at least four weeks after surgical cardiac denervation. Measurements were made of total FAs and with a radio-labelled tracer (U-14C palmitate).nResults: The contribution of FA utilisation to overall substrate oxidation rose from 31% (control) to 48% (cardiac denervated). The increase in the ratio (%) of CO2 production from palmitate oxidation to total CO2 production increased from 4.0 ± 1.8 (control) to 10.6 ± 5.8 (denervated, p = 0.04). The time from uptake of FA to release of CO2 product was unaltered.nConclusion: We conclude that the contribution of FA oxidation to overall energy conversion is increased in chronically denervated hearts, which is postulated to result from a decline in the active form of pyruvate dehydrogenase. This would appear to be a result of chronic catecholamine depletion.

Responses of iliac conduit artery and hindlimb resistance vessels to luminal hyperfructosemia in the anaesthetized pig

High fructose levels are found in diabetes mellitus, associated with high corn syrup diets, and have been claimed to cause hypertension. As the direct effects on conduit and resistance arteries have not been previously reported, we measured these in vivo in the anaesthetized pig with instrumented iliac arteries.

Metformin causes nitric oxide-mediated dilatation in a shorter time than insulin in the iliac artery of the anesthetized pig.

Abstract We tested the hypothesis that metformin produces arterial dilatation indirectly, by directly exposing the endothelial surface, of an occluded test segment of the pig iliac artery in vivo, to test blood containing metformin or excess insulin, with and without the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride. Such exposure to metformin 1 &mgr;g/mL caused the artery to dilate at constant pressure, and this was abolished when NG-nitro-L-arginine methyl ester hydrochloride was coadministered with metformin. The onset of dilatation occurred approximately 4 minutes after the commencement of endothelial exposure to metformin; this contrasts with the approximate 10 minutes required for a similar response to luminal hyperinsulinemia. After the release of flow occlusion, the subsequent flow-mediated dilatation was slightly but significantly enhanced compared with control for metformin; the effect of insulin on flow-mediated dilatation was not statistically significant. The hypothesis was disproved, as we have shown that insulin and metformin, like insulin, directly stimulate NO production by endothelium of a conduit artery; this function may be of value in delaying the atherothrombotic process. The time taken for the commencement of NO production is shorter for metformin than for insulin; the clinical relevance of this finding is unclear.

Review: Hyperglycaemia and the vascular glycocalyx: the key to microalbuminuria and cardiovascular disease in diabetes mellitus?

The vascular glycocalyx is a gel layer between endothelium and the blood, 0.5 µm thick. Evidence is presented from published studies to indicate that hyperglycaemia causes damage to the vascular glycocalyx. This damage results in microalbuminuria, excess fluid transfer to the interstitium, reduction in nitric oxide (NO) production by arterial endothelium, and leukocyte and platelet adhesion to endothelium leading to atherothrombosis. The lack of NO production proceeds from the fact that glycocalyx is the mechanotransducer transmitting the signal for increased shear stress between blood and arterial wall, and this function is inhibited by hyperglycaemia. When hyperinsulinaemia is also present, the problem is compounded by general arterial dilatation leading to low shear rates throughout the arterial tree. These findings explain the predisposition to atherothrombosis in the prediabetic condition of insulin resistance/metabolic syndrome/obesity and diabetes mellitus. It is proposed that greater efforts than ever are required to detect occult insulin resistance, to treat such patients and diabetics with ever more strict blood glucose control while minimising insulin levels, and to carry out further research into how glycocalyx structure and function can be preserved. Br J Diabetes Vasc Dis 2010;10:66-70

Dilatation in the femoral vascular bed does not cause retrograde relaxation of the iliac artery in the anaesthetized pig

Aim:u2002 We tested the hypothesis that dilatation of a feeding artery may be elicited by transmission of a signal through the tissue of the arterial wall from a vasodilated peripheral vascular bed.

Law of Poiseuille

With laminar and steady flow through a uniform tube of radius r i , the velocity profile over the cross-section is a parabola. The formula that describes the velocity (v) as a function of the radius, r is: n n