John T. Shepherd

Vasopressin causes endothelium-dependent relaxations of the canine basilar artery.

The effect of synthetic 8-argjnine vasopressin (vasopressin) was studied in isolated canine basilar, left circumflex coronary, and femoral arteries of the dog. Vascular rings with and without endothelium were suspended for isometric tension recording in physiological salt solution. The removal of the endothelium was confirmed by the absence of relaxations induced by either thrombin (basilar arteries) or acetylcholine (coronary and femoral arteries). In the basilar artery, vasopressin induced concentration-dependent inhibition of myogenic tone. In basilar and coronary arteries, the hormone caused concentration-dependent relaxations during contractions evoked by prostaglandin F2α. In femoral arteries, vasopressin caused contraction. After removal of the endothelium, the inhibitory responses to vasopressin were abolished in basilar arteries and significantly reduced in left circumflex coronary arteries. The contractions of femoral arteries were not affected by endothelium removal. The V1-vasopressinergic antagonist d(CH2)5Tyr (Me)AVP prevented the inhibitory response to vasopressin, but did not alter endothelium-dependent relaxations of basilar arteries caused by adenosine diphosphate. These results demonstrate that the endothelial cells mediate relaxation induced by vasopressin via specific Vi-vasopressinergic receptors.

Aggregating human platelets cause direct contraction and endothelium-dependent relaxation of isolated canine coronary arteries. Role of serotonin, thromboxane A2, and adenine nucleotides

Aggregating human platelets contract isolated rings of canine coronary artery without endothelium, but relax rings with intact endothelium. We performed experiments to identify the substances released from platelets responsible for these effects. The contraction in rings without endothelium was reduced by treating the platelets with thromboxane synthetase inhibitor, dazoxiben, or treating the vessels with the thromboxane-receptor antagonist, SQ 29548. The serotonergic antagonist, methiothepin, also reduced the platelet-induced contraction. The combination of methiothepin plus dazoxiben or SQ 29548 caused a further inhibition. The endothelium-dependent relaxation to platelets during contractions evoked by prostaglandin F2 alpha was nearly abolished by the ADP- and ATP-scavenger, apyrase. It was not inhibited by methiothepin, which antagonizes endothelium-dependent relaxations to serotonin. Thus, both serotonin and thromboxane A2 contribute to the direct activation of coronary smooth muscle by aggregating human platelets, whereas adenine nucleotides are the principal mediators of the endothelium-dependent relaxation.

Role of heart and lung receptors with nonmedullated vagal afferents in circulatory control.

Vagal afferents from the cardiopulmonary region exert a tonic inhibition on the vasomotor center. This is demonstrated by constriction of systemic resistance and splanchnic capacitance vessels and by increased output of renin when the vagi are cut or blocked. In dogs, removal or selective denervation of organs showed that receptors in the lungs, the atria, and the ventricles each are responsible for the vasomotor inhibition. That this inhibition is due to nonmedullated vagal afferents (C fibers) was demonstrated by selective cooling of the vagi, anodal block of medullated afferents, and selective electrical stimulation of medullated and nonmedullated fibers. In the open-chest cat the discharge frequency of individual C fibers is sparse and irregular (mean, 1.4 impulses/sec) but increases to 10 or more impulses/sec with moderate increases in cardiac filling pressure and exhibits cardiac rhythmicity or is continuous throughout the cardiac cycle. The inhibition of sympathetic vasomotor outflow effected through the cardiopulmonary receptors is inversely related to that exerted by the arterial baroreceptors. The former receptors have less influence on the muscle circulation than the latter, but have an equal or greater effect on the renal circulation. In summary, receptors in the heart and lungs with nonmedullated vagal afferents are an important component of the integrated neural control of the circulation.

Inhibition of adrenergic neurotransmission in canine vascular smooth muscle by histamine: mediation by H2-receptors.

Histamine depressed the contractions of dog saphenous vein strips caused by stimulation of their sympathetic nerves. This was due to a decrease in the release of norepinephrine which appears to be mediated by histamine H2-receptors. The evidence for this is as follows: (1) Contractions of the strips caused by activating the nerve endings electrically or by depolarization with potassium ions were depressed by histamine, whereas contractions caused by tvramine and norepinephrine were either unchanged or augmented. (2) Strips were incubated with norepinephrinc[7-2H] and mounted for supervision and isometric tension recording. The perfusate was collected for estimation of total radioactivity and for column chromatographic separation of norepinephrine and its metabolites. Histamine (0.9 μm) depressed the release of norepinephrine[7-2H] during contractions caused by electric stimulation, whereas the release of radioactive compounds caused by tvramine was unaffected. (3) The depression by histamine of the contractions and the efflux of radioactive compounds caused by electric stimulation were inhibited by an H2-receptor antagonist (metiamide), but were unaffected by an H1-receptor antagonist (pyrilamine). (4) Contractions caused by electric stimulation were depressed by an H2-receptor agonist (4-methylhistamine) and augmented by an H1-receptor agonist (2-metfaylhistamine). These findings suggest the possibility that bistamine, which is abundant in sympathetic nenes, might have a regulatory role in the release of the neurotransmitter.

Role of Vagal Afferents In the Control of Renal Sympathetic Nerve Activity in the Rabbit

The influence of vagal afferents on renal sympathetic nerve activity was studied in nine rabbits anesthetized with sodium pentobarbital and artificially ventilated with oxygen. Arterial Pco2 and pH were kept normal. The aortic depressor and the carotid sinus nerves were cut. The mean impulse frequency was determined from multifiber preparations of the renal nerve. Blood volume was altered either by bleeding or by infusing dextran. With vagi intact, an increase in blood volume of approximately 1OSE caused the nerve activity to decrease 41 ± 4%; it returned toward the control level after withdrawal of the same volume. A similar decrease in volume increased the nerve activity 33 ± 7%; it decreased toward the control level after reinfusion. These changes were unaffected by cutting the vagi at the diaphragm but were abolished or markedly attenuated by cooling or cutting the vagi in the neck. Interruption of vagal afferents resulted in a 21 ± 2% increase in nerve activity, indicating that the afferents exerted a continuous inhibition on the sympathetic outflow to the kidney. These experiments demonstrated a role for the low-pressure intrathoracic receptors in the control of renal sympathetic nerve activity in response to changes in blood volume.

Inhibition of Adrenergic Outflow to Peripheral Blood Vessels by Vagal Afferents from the Cardiopulmonary Region in the Dog

In closed-chest atropinized dogs anesthetized with chloralose and ventilated artificially, the aortic nerves were cut beneath the nodose ganglion, and the carotid sinuses were either denervated or vascularly isolated and maintained at a pressure of 40 mm Hg. Denervation was established by the failure of the pressoreceptor systems to respond to mechanical stimulation. Cold block or section of the cervical vagi resulted in statistically significant increases in arterial blood pressure (18%), heart rate (3%), central venous pressure (13%), hind-limb perfusion pressure (12%), pressure within the occluded spleen (18%), and efferent renal sympathetic nerve activity (28%). There was no change in saphenous vein perfusion pressure. The vascular responses were abolished by a-receptor blockade and were not affected by section of the vagi at the diaphragm. When the pressure in the vascularly isolated innervated carotid sinuses was varied from 40 to 220 mm Hg, the vascular responses to vagal block decreased steeply between 100 and 160 mm Hg and were absent at 200 mm Hg. Thus, receptors in the cardiopulmonary region with afferent vagal fibers exert a continuous restraint on the sympathetic adrenergic outflow to resistance and capacitance vessels, especially when the input from the carotid baroreceptors is decreased.

Comparison of Afferent Activity of Canine Aortic and Sinus Nerves

Pressure-dependent changes in afferent activity in the aortic and the sinus nerves were studied in 17 anesthetized dogs that were artificially ventilated with oxygen. Systemic arterial blood pressure was varied either continuously or in steps over the range of mean aortic blood pressure from 220 to 50 mm Hg with a pressurized reservoir connected to the abdominal aorta. Multifiber preparations from 20 aortic and 8 sinus nerves were used, and stimulusresponse curves were defined by measuring the mean impulse frequency at the various levels of pressure. Heart rate and pulse pressure were similar during recordings from both nerves. The two curves were S-shaped, with that for the aortic nerve being to the right of that for the sinus nerve. The change in activity was approximately linear from 200 to 120 mm Hg (mean aortic blood pressure) in the aortic nerve and from 180 to 80 mm Hg in the sinus nerve; there was no significant change in impulse frequency below mean blood pressures of 100 and 70 mm Hg, respectively. The threshold systolic blood pressure was 95 ± 3 (SE) mm Hg for the aortic receptors and 62 ± 4 mm Hg for the carotid sinus receptors. Thus, in the dog, the aortic baroreceptors are involved mainly in the control of high blood pressure, whereas at lower pressures the major control occurs through the carotid sinus baroreflex.

Continuous inhibition of renin release in dogs by vagally innervated receptors in the cardiopulmonary region.

Inhibition of the release of renin by vagal afferents from the heart and lungs was studied in 14 dogs with their aortic nerves cut and their carotid sinuses vascularly isolated. The release of renin from one kidney was calculated from the venous-arterial difference in plasma renin activity (radioimmunoassay) and the renal blood flow (electromagnetic flowmeter). Renin release was determined before and during temporary interruption of afferent vagal nerve traffic (bilateral cooling of the cervical vagi). With carotid sinus pressure maintained at 40 mm Hg, vagal cooling increased mean aortic blood pressure (24%), decreased renal blood flow (19%), and increased renin release (241%). With sinus pressure maintained at the mean aortic blood pressure existing during the control period, vagal cooling caused a lesser increase in mean aortic blood pressure (12%), little decrease in renal blood flow (7%), and a marked increase in renin release (522%). The changes in renal blood flow and renin release with vagal cooling were prevented by renal denervation. Thus, vagal afferents from the cardiopulmonary region exert a tonic restraint on the release of renin; this restraint occurs in circumstances in which these afferents cause little change in total renal blood flow.

The effect of warming on adrenergic neurotransmission in canine cutaneous vein.

The effect of warming on adrenergic neurotransmission was examined in canine cutaneous veins. Isometric tension was recorded from rings of saphenous veins of the dog in organ chambers filled with physiological salt solution. During contractions caused by potassium or prostaglandin F2, warming from 37 to 41°C caused an augmentation. During contractions caused by stimulation of the adrenergic nerves, and by exogenous norepinephrine, warming caused a relaxation. The relaxation with wanning was not altered by the β-adrenergic antagonist, propranolol, or by inhibitors of extraneuronal and neuronal uptake of norepinephrine. During contractions evoked by the α2-adrenergic agonists, a-methyl norepinephrine and B-HT 920, warming caused a relaxation, whereas during contractions due to the α1 -adrenergic agonists, cirazoline, methoxamine, ST 587, and phenylephrine, it caused an augmentation. The relaxation caused by warming during norepinephrine-induced contractions was prevented by the preferential α2-antagonists yohimbine and rauwolscine, but not by the preferential α1-antagonist, prazosin. In strips of saphenous vein incubated with [3H]norepinephrine, warming did not affect the release of labeled transmitter evoked by nerve stimulation. These experiments indicate that warming directly enhances contractility of vascular smooth muscle, while depressing the responsiveness of cutaneous vessels to sympathetic nerve activation by a selective inhibitory effect on postjunctional α2-adrenoceptors. Relaxation with warming is greater during nerve stimulation than during administration of exogenous norepinephrine, which may be due to a predominance of postjunctional “2-adrenoceptors in the neuromuscular junction.”

Clinical, physiological, and pathological considerations in patients with idiopathic pulmonary hypertension.

Cases of idiopathic pulmonary hypertension are uncommon. Paul Wood (1950) found 6 examples among 233 unselected patients suspected of having congenital heart disease, 152 of whom were catheterized. Dresdale et al. (1951) encountered four cases and mentioned that ten cases of pulmonary hypertension without demonstrable cause in which cardiac catheterization had been performed had been reported. To place patients into this group on the basis of clinical and physiological studies requires that all the conditions of which pulmonary hypertension is but one feature be excluded. There must be, for example, evidence of a normal mitral valve, of a competent left ventricle, and of absence of an abnormal communication between the lesser and greater circulations; and primary disease of the pulmonary parenchyma of the types that narrow the pulmonary vascular bed must have been eliminated. However, even after the most careful clinical and physiological studies, unsuspected malformations of which pulmonary hypertension is a functional accompaniment may at times be demonstrated at necropsy in a case that has been designated as an example of idiopathic pulmonary hypertension. This communication presents the clinical and physiological findings in ten patients with pulmonary hypertension. In these ten none of the disease states known to be associated with raised pulmonary arterial pressure was demonstrated clinically or physiologically. In four a venoarterial (right-to-left) shunt was present at the atrial level. Necropsy was done in three of them, in two of which there had been veno-arterial shunts. One of these (Case 8) in which an atrial septal defect of moderate size was present, should be excluded from this paper on the basis of the definition of the syndrome of idiopathic pulmonary hypertension, but careful consideration of the clinical and physiological data, even after the true nature of the condition was known, revealed no feature that would distinguish it from the others reported: hence for reasons of discussion the data for this case have been fully reported.