Shepherd, John T.

Abstract The sections in this article are: Basal Vascular Resistance and Autoregulation Role of Myogenic Mechanism in Reactive Hyperemia Role of Myogenic Mechanism in Exercise Hyperemia Types of Skeletal Muscle Fibers Muscle Blood Flow During Exercise Oxygen Lack Lactic Acid, pH, and CO 2 Potassium Inorganic Phosphate Osmolarity Prostaglandins Adenosine and Adenine Nucleotides Intrinsic Neurons and Exercise Dilatation General Conclusions Mechanical Hindrance to Blood Flow in Skeletal Muscle Reactive Hyperemia Are Exercise and Reactive Hyperemia Due to the Same Mechanism(s)? Propagated Vasodilatation Sympathetic Vasomotor Outflow Noradrenergic Innervation of Resistance Vessels in Muscles Neuroeffector Junction α‐Adrenergic Activation Factors that Modulate Transmitter Output From Sympathetic Nerve Endings Metabolic Action Neurohumoral Action Reflex Regulation of Skeletal Muscle Resistance Vessels by Sympathetic Noradrenergic Nerves Carotid and Aortic Baroreflex Carotid and Aortic Chemoreflex Reflexes From the Heart and Lungs Diving Reflex Reflex From Receptors in Skeletal Muscles Rhythmic Exercise Isometric Exercise Influence of Sympathetic Noradrenergic Fibers on the Blood Flow to Active Muscles β 2 ‐Adrenergic Activation Cholinergic Vasodilator Nerves Role of Cholinergic Nerves in the Carotid Baroreflex Cholinergic Vasodilatation in Humans Histaminergic Vasodilatation Role of Histamine in the Vasodilatation Resulting From Reflex Inhibition of Sympathetic Outflow Conclusions

During exercise the normal pulmonary vessels can accommodate a three to fourfold increase in flow with about a 50 per cent increase in perfusion pressure. There is about a 10 per cent increase in the total volume of blood in the lungs, which may be accounted for mainly by an increase in capillary blood volume. The diffusion capacity is increased, the concentration of red blood cells is increased, and a relatively uniform ventilation-perfusion ratio is achieved throughout the lung.

In studies on six experienced subjects lying supine, cardiac output and oxygen content of femoral venous blood were measured with the subject at rest, during the increase in muscle blood flow caused by intravenous infusion of epinephrine, during mild leg exercise, and during identical exercise combined with an infusion. The oxygen content of the blood from the exercising limb was much higher (average, 50%) during an infusion than when no infusion was given (average, 32%). The mean increase in cardiac output during the combined maneuver (8.2 liters/min) almost equaled the sum of the increases during the separate infusion (3.7 liters) and during exercise (4.7 liters). All individual studies showed approximately this same result. Thus, the additional blood supplied to the leg muscles by the infusion did not appear to be used for metabolic purposes during exercise. cardiac output; muscle blood flow Submitted on March 22, 1963

Normal subjects have been studied to assess the response of the capacitance vessels in the forearm during supine leg exercise. Measurements were made of changes in forearm volume (strain-gauge and water-filled plethysmographs) at a given pressure in the large forearm veins, of changes in pressure in the forearm veins with the circulation to the forearm arrested and in “isolated” vein segments. The results were consistent and demonstrated that exercise with a work load of 270–810 kg/min caused constriction of forearm capacitance vessels via the sympathetic nerves proportional to the severity of the exercise. Venoconstriction also occurred in the hand, and in the calf during arm exercise. Local exercise of the forearm muscles during supine leg exercise, which increased forearm blood flow by dilating the resistance vessels, did not prevent the increase in venous tone in the forearm. Thus a reflex increase in tone in the limb veins, both in the exercising and in the nonexercising parts, contributes to the cardiovascular adaptation to exercise. venoconstriction in exercising and nonexercising limbs; reflex venoconstriction with exercise graded to severity of work; reflex venoconstriction with exercise mediated through sympathetic nerves Submitted on June 15, 1964

Changes in cardiac output, stroke volume, and systemic blood pressure have been correlated with changes in muscle blood flow during the periods of initial transient and subsequent sustamed vasodilatation during intravenous infusion of epinephrine. In the initial phase blood pressure decreased slightly; forearm blood flow increased by 308%, cardiac output by 50%, and stroke volume by 10%. During the sustained phase the systolic blood pressure increased; corresponding increases for the other measurements were 87, 47, and 25%, respectively. The lack of correlation between these changes in cardiac output and forearm blood flow suggests that in the transient phase vasodilatation does not occur simultaneously in all muscle groups. Stroke volume makes a greater contribution to the increased output during the sustained phase. Submitted on May 29, 1961

Cardiac output was measured simultaneously with blood flow in hand and forearm in eight healthy subjects before and during body heating. The heating was carried out by immersing the feet and legs in water at 44 C. and wrapping the body with blankets. After 50 min of heating the oral temperature had risen to between 99.5 and 100.8 F. The cardiac output had increased by 1.9—4.5 (mean 3.3) liters/min, mainly because of an increase in heart rate. The blood flow through the fingers increased rapidly to reach maximal values soon after heating started, whereas the forearm blood flow, like the cardiac output, increased gradually throughout the heating period. Since the increase in limb blood flow is confined to the skin vessels and since there is no evidence that flow to the internal organs is increased, the total increase in skin flow amounts on the average to 1.8 liters/m2/min. Submitted on June 2, 1961

Dilution curves were obtained by sampling from the aortic root or a carotid artery after injection of indicator dye into the pulmonary artery in five dogs at rest and during exercise. On four occasions a common sampling system was used; curves were recorded simultaneously and in parallel from a cuvette oximeter assembly with a slow dynamic response and from a phototube densitometer with a fast response. In the fifth study, separate slow and fast sampling systems were used interchangeably with the two detecting instruments. Values for cardiac output were similar with the two instruments; maximal divergence for any single observation was 9% from the line of identity. The aortic root is a favorable sampling site for such a comparison, since extrapolation of the dilution curves is usually unnecessary. Under these conditions measurement of cardiac output was not influenced by the dynamic response characteristics of the sampling-detecting-recording system. When mean transit times of the respective curves were corrected for instrumental delay, there was also satisfactory agreement in values for “central” blood volume. However, since the time correction for the densitometer is relatively small, it is the preferable instrument for this measurement. Submitted on October 24, 1960

With the use of a strain-gauge plethysmograph, the effect of a brief (0.3 sec) contraction of the forearm muscles on forearm blood flow has been studied in eight healthy adults. An increase in flow due to dilatation of the muscle vessels could be detected within a second after the completion of the contraction. This increase was proportional to the strength of the contraction. The blood flow was maximal immediately and decreased rapidly. A second contraction of the same magnitude made during the period of increased flow caused an additional increase in flow. The maximal increase in flow caused by a strong brief contraction was only about 25% of that recorded after strong repeated rhythmic contractions or a sustained contraction. Cervical sympathectomy did not change these findings, indicating the local nature of the response. Since breathing oxygen failed to reduce the dilatation for a given strength of contraction, it is unlikely that oxygen lack was the stimulus for vasodilatation. The oxygen saturation of blood that drained the muscles could not be determined accurately immediately after contraction because at this time, muscle venous blood was contaminated by venous blood from the skin. exercise-induced vasodilatation; local mechanism of vasodilatation; venous O2 saturation during muscle contraction; brachial arterial pressure during vasodilatation; speed of muscle vasodilatation Submitted on May 8, 1963

Ten consecutive time trials were run at 2-day intervals by six racing greyhounds over a 5/16-mile track. Cardiac denervation was then performed on four dogs, and a sham operation that included removal of the pericardium was performed on two dogs. After cardiac denervation, one dog died and another was rejected from the study because of a massive intrathoracic hemorrhage. The time trials were repeated with the addition of telemetry of the heart rate in the four survivors. There was no significant difference between mean preoperative and postoperative race times in the control group. The mean postoperative running speeds of 33.6 and 33.3 mph in the denervated group, although representing a significant slowing of 1.1 and of 2.1 mph, respectively, from preoperative values, indicate the adequate manner in which the denervated heart meets the circulatory demands of maximal running effort. cardiac output; heart rate and exercise Submitted on March 11, 1964

Normal subjects were studied to determine whether exercise of the muscles of one forearm causes changes in venous tone in that forearm by some local mechanism. Forearm venous pressure-volume relationships and the pressure in “isolated” vein segments were unchanged after exercise of forearm muscles. Following venous occlusion, the forearm volume increases and reaches a plateau later than forearm venous pressure. This delayed volume change increased with increasing venous filling rate regardless of whether this was accomplished by exercise or by other means. Thus, the local mechanism which dilates resistance vessels in active muscles does not seem to change the contractile state of the muscle in the capacity vessels. The viscous properties of the venous wall, however, act to damp the volume oscillations in intervals between muscular contractions when arterial inflow and venous filling rate are high. The ratio between initial rate of rise in forearm venous pressure and volume following venous occlusion could not be used as an index of active changes in tension of the smooth muscle of the capacitance vessels. strain-gauge plethysmography; isolated vein segments; venous response to varying filling rates; venous response to local exercise; veins and exercise Submitted on November 16, 1964