H. M. Snow

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.

Characteristics of arterial wall shear stress which cause endothelium-dependent vasodilatation in the anaesthetized dog

1 The effects of changes in the mean and amplitude of arterial wall shear stress on endothelium‐dependent arterial dilatation of the iliac artery of the anaesthetized dog were examined. 2 Changes in the mean and amplitude of blood flow and wall shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and the stimulation of the left ansa subclavia. Changes in the diameter of a segment of the iliac artery with the endothelium intact, relative to a segment with no endothelium, were used as an index of the release of nitric oxide. 3 The increase in mean blood flow was from 84 ± 12 to 527 ± 53 ml min−1 and in amplitude was from 365 ± 18 to 695 ± 38 ml min−1 (means ±s.e.m.). The increase in mean wall shear stress was from 1.78 ± 0.30 to 7.66 ± 1.01 N m−2 and in amplitude was from 7.37 ± 0.46 to 13.9 ± 2.00 N m−2 (means ±s.e.m.). 4 Increases in mean shear stress caused an increase in the diameter only of the section of artery with endothelium; the slope of the relationship was 0.064 ± 0.006 mm N−1 m2 (mean ±s.e.m., P < 0.001); changes in the amplitude of shear stress did not cause an increase in diameter. Changes in both the mean and amplitude of shear stress had no significant effect on the diameter of the section of artery with no endothelium. 5 These findings coupled with the known anti‐atheroma effects of nitric oxide and the effect of shear stress on cell adhesion and platelet aggregation offer a possible explanation for the disposition of atheroma in those parts of the arterial system which have low mean and high amplitude of wall shear stress.

Characteristics of the response of the iliac artery to wall shear stress in the anaesthetized pig

The functional significance of shear stress‐induced vasodilatation in large conduit arteries is unclear since changes in the diameter have little effect on the resistance to blood flow. However, changes in diameter have a relatively large effect on wall shear stress which suggests that the function of flow‐mediated dilatation is to reduce wall shear stress. The mean and pulsatile components of shear stress vary widely throughout the arterial system and areas of low mean and high amplitude of wall shear stress are prone to the development of atheroma. In this study, using an in vivo model with the ability to control flow rate and amplitude of flow independently, we investigated the characteristics of the response of the iliac artery to variations in both the mean and amplitude of wall shear stress. The results of this study confirm that increases in mean wall shear stress are an important stimulus for the release of nitric oxide by the endothelium as indicated by changes in arterial diameter and show for the first time, in vivo, that increases in the amplitude of the pulsatile component of shear stress have a small but significant inhibitory effect on this response. A negative feedback mechanism was identified whereby increases in shear stress brought about by increases in blood flow are reduced by the release of nitric oxide from the endothelium causing dilatation of the artery, thus decreasing the stimulus to cell adhesion and, through a direct action of nitric oxide, inhibiting the process of cell adhesion. The results also provide an explanation for the uneven distribution of atheroma throughout the arterial system, which is related to the ratio of pulsatile to mean shear stress and consequent variability in the production of NO.

Nitric oxide facilitates vagal control of heart rate via actions in the cardiac parasympathetic ganglia of the anaesthetised dog

The effects of neuronal inhibition of nitric oxide (NO) production on the bradycardia resulting from stimulation of preganglionic and postganglionic parasympathetic fibres were investigated in an anaesthetised dog preparation following transection of the cervical vagi and in the presence of a β‐adrenoreceptor antagonist. Injection of 1‐(2‐trifluoromethylphenyl) imidazole (TRIM), an inhibitor of neuronally released NO, into the sinus node artery reduced the bradycardia evoked by right cervical vagal stimulation. In contrast, when the response to preganglionic stimulation had been abolished by hexamethonium (10 mg kg−1), the bradycardia following stimulation of postganglionic parasympathetic fibres on the atrial epicardium was unaffected by TRIM. First, these results confirm the facilitatory actions of neuronally released NO on vagal heart responses in the dog. Second, they indicate that this modulatory and facilitatory role of NO is likely to be exerted at vagal preganglionic‐postganglionic synaptic mechanisms in the cardiac parasympathetic ganglia and not at the postganglionic‐sinoatrial node synapse.

Inhibition of Neuronal Nitric Oxide Reduces Heart Rate Variability in the Anaesthetised Dog

In the vagally intact anaesthetised dog, we have investigated the role of nitric oxide (NO) on a normal sinus arrhythmia using an inhibitor of neuronally released NO, 1‐(2‐trifluoromethylphenyl) imidazole (TRIM). The mean and S.D. of the R‐R interval was used to describe mean heart rate and heart rate variability, respectively. TRIM (0.8 mg I.C.) injected into the sinus node artery increased the mean heart rate slightly but reduced heart rate variability 3‐fold from a control of 790 ± 124 ms (mean ± S.D.; n = 5) to 666 ± 36 ms (P < 0.01 Students paired t test, n = 5). These results suggest that neuronally released NO may have a vagal facilitatory role in the maintenance of sinus arrhythmia in the normal heart.

The effect of tezosentan, a non-selective endothelin receptor antagonist, on shear stress-induced changes in arterial diameter of the anaesthetized dog.

The effects of changes in the mean (Sm) and pulsatile (Sp) components of arterial wall shear stress on arterial dilatation of the iliac artery of the anaesthetized dog were examined in the absence and presence of the endothelin receptor antagonist tezosentan (10 mg kg−1 I.V.; Ro 61‐0612; [5‐isopropyl‐pyridine‐2‐sulphonic acid 6‐(2‐hydroxy‐ethoxy)‐5‐(2‐methoxy‐phenoxy)‐2‐(2‐1H‐tetrazol‐5‐yl‐pyridin‐4‐yl)‐pyrimidin‐4‐ylamide]). Changes in shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and stimulation of the left ansa subclavia. An increase in Sm from 1.81 ± 0.3 to 7.29 ± 0.7 N m−2 (means ± S.E.M.) before tezosentan caused an endothelium‐dependent arterial dilatation which was unaffected by administration of tezosentan for a similar increase in Sm from 1.34 ± 0.6 to 5.76 ± 1.4 N m−2 (means ± S.E.M.). In contrast, increasing the Sp from 7.1 ± 0.8 to a maximum of 11.5 ± 1.1 N m−2 (means ± S.E.M.) before tezosentan reduced arterial diameter significantly. Importantly, after administration of tezosentan subsequent increases in Sp caused arterial dilatation for the same increase in Sp achieved prior to tezosentan, increasing from a baseline of 4.23 ± 0.4 to a maximum of 9.03 ± 0.9 N m−2 (means ± S.E.M.; P < 0.001). In conclusion, the results of this study provide the first in vivo evidence that pulsatile shear stress is a stimulus for the release of endothelin from the vascular endothelium.

An Evaluation of the Efficacy of Vasoactive Intestinal Polypeptide Antagonists in vivo in the Anaesthetized Dog

The effectiveness of competitive peptide vasoactive intestinal polypeptide (VIP) receptor antagonists was evaluated on heart rate in the anaesthetized dog. Two specific antagonists, VIP (6–28) and [D-p-Cl-Phe6, Leu17]-VIP, and a nonspecific antagonist, pituitary adenylate cyclase activating peptide fragment (6–27) (PACAP), were studied. VIP (6–28) and [D-p-Cl-Phe6, Leu17]-VIP (100 µg i.c.) increased the heart rate, whereas PACAP (100 µg i.c.) reduced the baseline heart rate. All three shifted the VIP dose-response curve to the right by two- to threefold for 30 min. In conclusion, PACAP, VIP (6–28), and [D-p-Cl-Phe6, Leu17]-VIP have a direct effect on the heart rate, are equally effective, and the effects last approximately 30 min in vivo.

Effects of fenoldopam on renal blood flow and its function in a canine model of rhabdomyolysis

Background and objective: Our hypothesis was that fenoldopam, a selective DA1 agonist, would protect against rhabdomyolysis-induced renal injury. Methods: We studied the effects of intravenous fenoldopam (0.1-1.0 μg kg−1 min−1) or saline on renal blood flow and function in 10 anaesthetized Labrador dogs in whom rhabdomyolysis and myoglobinuric acute renal failure had been induced by administration of glycerol 50% (10 mL kg−1) intramuscularly. Haemodynamic measurements including renal blood flow and derived parameters of renal function including creatinine clearance were recorded before and for the 30 min following glycerol injection, and during the 3 h following commencement of each infusion. Serum malondialdehyde concentrations were measured before and 15 min after glycerol intramuscularly, and 30 and 150 min after commencement of the infusion. Results: In the fenoldopam group, creatinine clearance was less than placebo at 1 and 2 h after commencing the infusion (12.7 ± 11.5 versus 31.3 ± 9.9 mL min−1, P = 0.04; 8.5 ± 5.3 versus 20.1 ± 7.4 mL min−1, P = 0.03). A 140-fold increase in serum malondialdehyde concentration occurred in one dog (fenoldopam group). Conclusion: Fenoldopam increased the severity of the renal injury in this canine model of myoglobinuric acute renal failure.

The potentiation of sinus arrhythmia by vasoactive intestinal polypeptide (VIP) in the anaesthetized dog

Vasoactive intestinal polypeptide (VIP) is a neuropeptide released from the vagus, which in contrast to acetylcholine has a long-acting positive chronotropic effect on the heart. The aim of this study, in the anaesthetized dog, was to examine the effects of VIP and a VIP antagonist when injected into the sinus node artery of a vagally intact heart in sinus arrhythmia. The response was compared to that produced by noradrenaline (NAD) infusion and stimulation of the sympathetic nerves to the heart. Mean +/- S.D. of 30 R-R intervals was used to describe mean heart rate interval and heart rate variability. VIP, a VIP antagonist, NAD and sympathetic nerve stimulation all caused increases in heart rate without significant increases in blood pressure. However, only VIP caused an increase in heart rate variability; VIP antagonism and NAD caused a decrease and sympathetic nerve stimulation had no effect. These results suggest that VIP and acetylcholine when released from the vagus act synergistically to increase sinus arrhythmia.

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

Aim:  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.