Don D. Sheriff

Muscle chemoreflex-induced increases in right atrial pressure

When oxygen delivery to active muscle is too low for the ongoing rate of metabolism, metabolites accumulate and stimulate sensory nerves within the muscle leading to sympathetic activation (muscle chemoreflex). To date, studies on this reflex have focused primarily on its ability to increase arterial pressure or on the activity of the nerves that mediate this response. Clearly, a rise in cardiac output (CO) constitutes an important adjustment, because it increases the total blood flow available to be distributed among organs competing for flow. However, increments in heart rate and contractility provide limited means of raising CO because of the inverse relationship that exists between CO and right atrial pressure (RAP) in the intact circulation. Our goal was to test whether muscle chemoreflex activation, achieved via graded reductions in hindlimb blood flow by partial vascular occlusion, elicits peripheral vascular adjustments that raise RAP. In four conscious dogs exercising on a treadmill at 3.2 km/h 0% grade, RAP was well maintained during reflex activation despite increases in CO and arterial pressure that are expected to reduce RAP. Thus peripheral vascular adjustments elicited by the reflex successfully defend RAP in a setting where it would otherwise fall. To isolate the effects of the reflex on RAP, CO was maintained constant by ventricular pacing in conjunction with beta1-adrenergic blockade with atenolol. When the reflex was activated by reducing hindlimb blood flow from 0.6 to 0.3 l/min, RAP rose from 5.1 +/- 0.8 to 7.4 +/- 0.4 mmHg (P < 0.05) despite continued large (40 mmHg) increases in arterial pressure. During heavier exercise (6.4 km/h 10% grade) in five dogs with normal ventricular function, the reflex raised RAP from 5.7 +/- 0.9 to 6.6 +/- 0.8 mmHg (P < 0.05) despite increases in CO and arterial pressure. We conclude that the muscle chemoreflex is capable of eliciting substantial increases in RAP.When oxygen delivery to active muscle is too low for the ongoing rate of metabolism, metabolites accumulate and stimulate sensory nerves within the muscle leading to sympathetic activation (muscle chemoreflex). To date, studies on this reflex have focused primarily on its ability to increase arterial pressure or on the activity of the nerves that mediate this response. Clearly, a rise in cardiac output (CO) constitutes an important adjustment, because it increases the total blood flow available to be distributed among organs competing for flow. However, increments in heart rate and contractility provide limited means of raising CO because of the inverse relationship that exists between CO and right atrial pressure (RAP) in the intact circulation. Our goal was to test whether muscle chemoreflex activation, achieved via graded reductions in hindlimb blood flow by partial vascular occlusion, elicits peripheral vascular adjustments that raise RAP. In four conscious dogs exercising on a treadmill at 3.2 km/h 0% grade, RAP was well maintained during reflex activation despite increases in CO and arterial pressure that are expected to reduce RAP. Thus peripheral vascular adjustments elicited by the reflex successfully defend RAP in a setting where it would otherwise fall. To isolate the effects of the reflex on RAP, CO was maintained constant by ventricular pacing in conjunction with β1-adrenergic blockade with atenolol. When the reflex was activated by reducing hindlimb blood flow from 0.6 to 0.3 l/min, RAP rose from 5.1 ± 0.8 to 7.4 ± 0.4 mmHg ( P < 0.05) despite continued large (40 mmHg) increases in arterial pressure. During heavier exercise (6.4 km/h 10% grade) in five dogs with normal ventricular function, the reflex raised RAP from 5.7 ± 0.9 to 6.6 ± 0.8 mmHg ( P < 0.05) despite increases in CO and arterial pressure. We conclude that the muscle chemoreflex is capable of eliciting substantial increases in RAP.

Role of mechanical factors in governing muscle blood flow

This study evaluates how mechanical factors impact cardiac output at the systemic level, and how mechanical factors influence muscle blood flow at the local level. Importantly, the two are intertwined; events that work locally in the periphery to augment muscle blood flow can also act centrally to contribute to the development of a high cardiac output.

Very low frequency blood pressure variability is modulated by myogenic vascular function and is reduced in stroke-prone rats

Background Cerebrovascular myogenic function, which protects the brain from hemorrhagic stroke, is impaired in stroke-prone spontaneously hypertensive rats. Furthermore, myogenic function contributes to very low frequency blood pressure variability and dynamic autoregulation of cerebral blood flow is most effective at very low frequency in rats. Therefore, we hypothesized that very low frequency blood pressure variability is reduced in stroke-prone spontaneously hypertensive rats compared with stroke-resistant spontaneously hypertensive rats. In addition, we investigated if myogenic function also contributes to very low frequency blood pressure variability in conscious dogs. Methods In 8-week-old normotensive Wistar–Kyoto rats, 8-week-old and 15-week-old stroke-prone spontaneously hypertensive rats and stroke-resistant spontaneously hypertensive rats, and dogs, blood pressure variability was studied during control conditions, inhibition of myogenic function (nifedipine) and hypotension induced by sodium nitroprusside. In dogs, transfer function analysis between blood pressure and total peripheral resistance was performed to study the contribution of myogenic function to blood pressure variability. Results Inhibition of myogenic function, but not hypotension induced by sodium nitroprusside, significantly reduced very low frequency variability of systolic blood pressure (rats: 0.02–0.2 Hz; dogs: 0.02–0.075 Hz) in conscious rats and dogs. In dogs, the gain of the transfer function was high (0.28 ± 0.04 min/l) in the very low frequency band and was decreased to 0.11 ± 0.01 min/l (P < 0.05) by nifedipine but not by sodium nitroprusside (0.26 ± 0.02 min/l). Very low frequency blood pressure variability was significantly smaller in stroke-prone spontaneously hypertensive rats than in stroke-resistant spontaneously hypertensive rats (8 weeks of age: 7.8 ± 1.1 vs. 13.1 ± 2.2 mmHg2; P < 0.05; 15 weeks of age: 7.1 ± 1.2 vs. 16.5 ± 3.6 mmHg2; P < 0.05). Conclusion Myogenic function affects very low frequency blood pressure variability in conscious rats and dogs. The smaller very low frequency blood pressure variability in stroke-prone spontaneously hypertensive rats compared with stroke-resistant spontaneously hypertensive rats suggests that impaired cerebrovascular myogenic function is reflected in reduced very low frequency blood pressure variability.

Frequency response characteristics of whole body autoregulation of blood flow in rats

Previously, we demonstrated that very low-frequency (VLF) blood pressure variability (BPV) depends on voltage-gated L-type Ca(2+)-channels, suggesting that autoregulation of blood flow and/or myogenic vascular function significantly contributes to VLF BPV. To further substantiate this possibility, we tested the hypothesis that the frequency response characteristic of whole body autoregulation of blood flow is consistent with the frequency range of VLF BPV (0.02-0.2 Hz) in rats. In anesthetized rats (n = 11), BPV (0.016-0.5 Hz) was induced by computer-regulated cardiac pacing while blood pressure, heart rate, and cardiac output (CO) were recorded during control conditions (NaCl, 1 ml/h iv) and during alpha(1)-adrenergic receptor stimulation (phenylephrine, 1 mg.ml(-1).h(-1) iv) that has been reported to facilitate myogenic vascular function. Baroreceptor-heart rate reflex responses were elicited to confirm a functional baroreflex despite anesthesia. During control conditions, transfer function analyses between mean arterial pressure (MAP) and CO, and between MAP and total vascular conductance (CO/MAP) indicated autoregulation of blood flow at 0.016 Hz, passive vascular responses between 0.033 and 0.2 Hz, and vascular responses compatible with baroreflex-mediated mechanisms at 0.333 and 0.5 Hz. Stimulation of alpha(1)-adrenergic receptors extended the frequency range of autoregulation of blood flow to frequencies up to 0.033 Hz. In conclusion, depending on sympathetic vascular tone, whole body autoregulation of blood flow operates most effectively at frequencies below 0.05 Hz. This frequency range overlaps with the lower end of the frequency band of VLF BPV in rats. Baroreceptor reflex-like mechanisms contribute to LF (0.2-0.6 Hz) but not VLF BPV-induced vascular responses.

Does limb angular motion raise limb arterial pressure

Aim:  Mechanical factors such as the muscle pump have been proposed to augment flow by several mechanisms. The potential for limb angular motion to augment local perfusion pressure (pressure = ½ρr2ω2, where ρ is the fluid density, r the radius and ω the angular velocity) has been overlooked. We sought to test the hypothesis that limb angular motion augments limb arterial pressure.

Retrograde arterial leg blood flow during tilt-back from a head-up posture: importance of capacitive flows when arterial pressure changes.

The windkessel function of the arterial system converts the intermittent action of the heart into more continuous microcirculatory blood flow during diastole via the return of elastic energy stored in the walls of the arteries during systole. Might the same phenomenon occur regionally within the arterial system during tilting owing to regional differences in local arterial pressure imposed by gravity? We sought to test the hypothesis that during tilt-back from a head-up posture, the return of stored elastic energy in leg arteries would work to slow, or perhaps transiently reverse, the flow of blood in the femoral artery. Femoral artery blood flow and arterial pressure were recorded during tilt back from a 30 degrees head-up posture to supine (approximately 0.5 G) in young, healthy subjects (n = 7 males and 3 females) before and during clonidine infusion. During control (no drug) conditions femoral artery blood flow ceased for an entire heart beat during tilt-back. During clonidine infusion femoral artery blood flow reversed for at least one entire heart beat during tilt-back, i.e., blood flow in the retrograde direction in the femoral artery from the leg into the abdomen. Thus substantial capacitive effects of tilting on leg blood flow occur in humans during mild changes in posture.

Does venous insufficiency impair the exercise-induced rise in arterial leg blood flow?

Objectives It has been shown that the leg muscle pump increases the immediate rise in arterial leg blood flow during upright exercise in healthy subjects. The present study is the first to investigate the muscle pump effect in exercise hyperaemia in patients with venous insufficiency, who should be lacking an optimally functioning muscle pump. Methods Any muscle pump effect is more pronounced in an upright position because of gravitation. The exercise-induced rise in femoral artery flow (FF) (ultrasound Doppler) was thus compared in the supine and 30° head-up tilted position in 10 patients. Results Neither the transient nor the steady-state rise in FF showed any difference between positions. This is in contrast to the previous findings in healthy subjects, where the transient rise in FF was larger in the tilted position. Conclusion The muscle pump effect in exercise hyperaemia seems to be reduced or lacking in these patients.

Does the great saphenous vein stripping improve arterial leg blood flow during exercise

OBJECTIVES It has been shown that the leg muscle pump increases arterial leg blood flow during upright exercise in healthy subjects, and that this effect is reduced in patients with incompetence of the great saphenous vein (GSV). In this study, patients with GSV reflux causing varicose veins were investigated after GSV stripping, to see whether the muscle pump effect on arterial leg blood flow is improved. DESIGN Prospective case study. METHODS Nine patients with GSV incompetence resulting in symptomatic varicose veins, but without peripheral artery disease were included in this study. Patients exercised in the supine and 30° head up tilted positions by rhythmically pressing down a pedal with one foot. Blood flow was measured in the femoral artery using Doppler ultrasound. The Exercise-induced rise in femoral artery blood flow was compared in the supine and 30° head up tilted positions. Patients were investigated both before and after undergoing saphenofemoral ligation and GSV stripping as a treatment for their varicose veins. The arterial blood flow response to exercise was compared between the pre and postoperative observations. RESULTS Prior to GSV stripping the immediate rise in femoral flow was 0.25 l min(-1) above rest in both supine and tilted positions. After GSV stripping however, the rise in flow was 30% larger in the tilted position than in the supine position (0.26 vs. 0.20 l min(-1), P < 0.05). CONCLUSIONS GSV stripping modestly improves arterial leg blood flow at the onset of exercise in patients with GSV insufficiency, because of an improved effect of the leg muscle pump.

Role of splanchnic constriction in governing the hemodynamic responses to gravitational stress in conscious dogs

Octreotide is a somatostatin analog that constricts the splanchnic circulation, thereby improving orthostatic tolerance. We tested the hypotheses that octreotide improves orthostatic tolerance by 1)increasing cardiac filling (right atrial) pressure via reductions in vascular capacity; 2) by causing an upward (i.e., cranial) shift of the hydrostatic indifferent point; and 3) by increasing arterial pressure via a reduction in total vascular conductance. Studies were carried out in acepromazine-sedated, hexamethonium-treated atrioventricular-blocked conscious dogs lightly restrained in lateral recumbency. Beat-by-beat cardiac output was held constant via computer-controlled ventricular pacing at rest and during 30 s of 30° head-up tilt. Octreotide (1.5 μg/kg iv) raised right atrial pressure by 0.5 mmHg and raised mean arterial pressure by 11 mmHg by reducing total vascular conductance (all P < 0.05). Right atrial pressure fell by a similar amount in response to tilting before and after octreotide, thus there was no difference in location of the hydrostatic indifferent point. These data indicate that octreotide improves orthostatic tolerance by decreasing total vascular conductance and by increasing cardiac filling pressure via a reduction in unstressed vascular volume and not by eliciting a cranial shift of the location of the hydrostatic indifferent point.