HANDBOOK OF PHYSIOLOGY ^ CIRCULATION II 



substances have been categorized as pulmonary vaso- 

 constrictors. These include serotonin (5-hydroxy- 

 tryptamine) (34, 302, 356) adenosine triphosphate 

 (4), small quantities of hypertonic saline (28), bacte- 

 rial endotoxins (245) and alloxan (4). 



Serotonin, which has captured physiological and 

 clinical imaginations on many different accounts, is 

 also generally held to be a uniquely effective pulmo- 

 nary arterial and venous vasoconstrictor (43, 227). 

 The evidence rests largely on animal experiments 

 (4, 366) and on the behavior of isolated lungs (158) 

 since "safe" doses in intact man are without discerni- 

 ble pulmonary vascular effect (193). At first en- 

 counter, the disprepancies between the effects of 

 serotonin in animals and man might be attributed to a 

 "species" difference; however, even this refuge is un- 

 certain because of the diffuse and bizarre effects of 

 serotonin: a) its tendency to produce "temporary em- 

 boli,'' so that an increase in pulmonary arterial pres- 

 sure and an increase in pulmonary vascular resistance 

 may arise from transient occlusion of small pulmo- 

 nary vessels as well as from vasoconstriction (235), b) 

 its bronchoconstricting effects (366), c) its respiratory 

 and Bezold-like circulatory effects in the intact animal 

 (193), and d) the discrepancies between the doses of 

 serotonin used in the different experiments. Finally, 

 the ineffectiveness of tolerable closes of serotonin as a 

 pulmonary vasoconstrictor in man is consistent with 

 the lack of pulmonary hypertension in patients with 

 serotonin-secreting tumors (399). 



Aside from their apparent proclivity for the venous 

 side of the pulmonary circulation, these pharmaco- 

 logical pulmonary "vasoconstrictors" have little in 

 common. For example, in contrast to serotonin and 

 alloxan, endotoxin requires contact with blood to be- 

 come effective (4). Moreover, hypertonic saline (333, 

 376), as well as serotonin, has been shown to conglu- 

 tinate red cells (235). It is clear that much remains 

 unknown about these pulmonary vasoconstrictors. 



Pulmonary Vasodilatm 1 



Interest in pulmonary vasodilators has been stimu- 

 lated both by the clinical need for therapeutic agents 

 to relieve pulmonary hypertension and the physio- 

 logic concern with pulmonary vasomotor tone. Aviado 

 (4) has sorted the substances which have been tested 

 into five groups: /) musculotropics (aminophylline); 

 2) parasympathomimetics (acetylcholine); 3) sym- 

 pathomimetics (isoproterenol); -/.) adrenergic blockers 

 (tolazoline); and 5) ganglionic blockers (hexa- 

 methonium). A good number of these have been 



used to treat systemic hypertension, indicating the 

 complex hemodynamic changes which may be ex- 

 pected to complicate the interpretation of their 

 effects on the pulmonary circulation. It is also note- 

 worthy that none have yet found a place in the treat- 

 ment of pulmonary hypertension, and that, except 

 for acetylcholine, none have provided any fresh 

 insights into the regulation of the pulmonary circula- 

 tion. 



Acetylcholine has achieved clinical pre-eminence 

 as a pulmonary vasodilator. This reputation arises 

 largely from recent experiences with pulmonary 

 hypertensive patients since previous studies on intact 

 animals, artificial preparations and normal man have 

 been contradictory (132). As mentioned previously, 

 the experiments which have adduced evidence for a 

 pulmonary vasodilating effect of acetylcholine have 

 exploited the rapid destruction of acetylcholine by 

 the cholinesterases of the blood to restrict the action 

 of acetylcholine to the pulmonary circulation (122, 

 401). The experiments have involved either a single 

 injection of acetylcholine into the venous circulation 

 or pulmonary artery (187, 192, 441), or a continuous 

 infusion of acetylcholine into the pulmonary arterv 

 at a rate (0.5 mg/min) insufficient, at least by con- 

 ventional tests, to affect either the lungs, the respira- 

 tion, the left heart, or the systemic circulation (153). 

 The evidence that acetylcholine elicits pulmonary 

 vasodilatation includes: a) a decrease in the pressure 

 gradient across the lungs in pulmonary hypertensive 

 subjects in whom the pulmonary vessels are pre- 

 sumably hypertonic (192, 282, 441); b) a partial or 

 complete reversal of the anticipated increase in 

 calculated pulmonary vascular resistance during 

 acute hypoxia (153); c) the prevention of the increase 

 in unilateral resistance during unilateral hypoxia by 

 the infusion of acetylcholine on the hypoxic side 

 (go); and d) a decrease in the peripheral arterial 

 oxygenation of patients with supposed ventilation- 

 perfusion abnormalities (383). The last effect is 

 generally believed to reflect the diversion of mixed 

 venous blood to hypoventilated portions of the lungs 

 as local hypoxic vasoconstriction is relieved by the 

 acetylcholine; however, alternate explanations such 

 as the opening of arteriovenous shunts or atelectasis 

 have also been proposed. It has been indicated 

 elsewhere that while these experiments on man are 

 consistent with a pulmonary vasodilating effect of 

 acetylcholine, they are not entirely convincing (132). 



Other vasodilator substances and autonomic block- 

 ing agents (including spinal anesthesia) have also 

 been used in the attempt to elicit pulmonary vaso- 



