Role of Histamine in Hypoxic Pulmonary Hypertension in the Rat

Abstract

The present investigation was undertaken to see if any of the naturally occurring vasoactive substances was likely to act as a mediator for the pulmonary vasoconstrictor response to acute alveolar hypoxia. Rats were treated with agents that deplete local stores of vasoactive amines or inhibit their synthesis. Lungs from these animals were isolated, ventilated, and perfused with homologous blood at constant volume inflow. Their pressor responses to 2-to 3-minute periods of ventilation hypoxia (2% O 2 ) were observed.The histamine-releasing agent 48/80 or the histidine decarboxylase inhibitor NSD 1055, or both, depleted 73% of the histamine in the lung but had no consistent effect on the pressor responses to hypoxia. When 48/80 (0.2 to 1 mg) was given in vitro, histamine in the lung was reduced to 10% of normal, or less, and the pressor response to alveolar hypoxia was completely abolished.Reserpine, guanethidine, or alpha-methyl-tyrosine reduced catecholamine stores in heart tissue (as an index of general tissue changes) by a maximum of 90% and reserpine decreased serotonin in the lung by 93% without inhibiting the hypoxic pressor responses. The findings strengthen the concept that histamine mediates the pressor response to acute alveolar hypoxia in the rat.ADDITIONAL KEY WORDS reserpine guanethidine alpha-methyl-tyrosine blood platelets 48/80 NSD 1055 rat lungs• Histamine long has been known as a potent constrictor of pulmonary vessels (1). An investigation of the role of vasoactive substances as mediators of the pulmonary vasoconstrictor response to acute hypoxia suggested that endogenous histamine was important for this response (2). The approach was mainly to use a series of pharmacologic agents that blocked the action of a variety of naturally occurring pressor substances. In the present work we have tried to approach this problem by another route. The vasoactive amines in the lung were reduced by agents that depleted their stores and inhibited their synthesis, and the effect of these procedures on the pressor response to alveolar hypoxia was observed. The importance of blood platelets and serotonin in platelets was also evaluated. The results support the concept that endogenous histamine plays an important role in the hypoxic pulmonary pressor response in the rat. Materials and MethodsPreparation.-Isolated rat lungs were perfused with heparinized homologous blood at 37 to 38 °C under conditions of constant-volume, pulsatile inflow, and ventilated with a positive-pressure pump. The pulmonary arterial pressure (PPA), the ventilation overflow volume and the oxygen tension in the effluent blood were recorded continuously. The left atrial pressure was kept at 2 to 4 cm of water in each experiment.

Regional Vascular Response to Hypoxia in the Lungs of Anaesthetised Sheep

“…Haas and Bergofsky (1972) have implicated mast cells in the hypoxic response of the lung by demonstrating that these are degranulated and that histamine release is increased in the hypoxic rat and guinea-pig. This work supported the earlier work of Hauge (1968), who used pharmacological agents to block or potentiate the effects of histamine during hypoxia to demonstrate a role for this agent, and suggested that histamine was involved in the hypoxic vasoconstrictor response. Adrenaline, however, antagonises the action of histamine (Colebatch, 1970), and it is possible that our differential reactivity is due to an increased delivery of adrenaline to the upper and lower lung zones that minimises the e£Fect of histamine.…”

H1 AND H2 HISTAMINE ACTIONS ON LUNG VESSELS; THEIR RELEVANCE TO HYPOXIC VASOCONSTRICTION

“…A constrictor response can be demonstrated only with very large doses in this species [Hauge, 1968]. We attempted to inhibit the dilator action with metiamide but found that this drug diminished hypoxic vasoconstriction making it impossible to demonstrate further dilator effects.…”

Plasma Histamine Levels Under Hypoxic Stress

“…Evidence in favour of histamine as a me diator of the pulmonary vascular response to hypoxia was provided by Hauge [1968]. Histamine was also implicated to play some role in the production of pulmonary oedema of high altitude because of its well-regulated property of alteration of blood vessel permeability [Luisada, 1950].…”

“…Antihistamines have been shown to prevent the development of hypoxic pulmonary hy pertension in experimental animals Susmanno and Carleton, 1973]. Histamine depletor substance 48/80 has also been shown to possess a similar effect [Hauge, 1968], Failure to observe a difference in the de gree of rise in the histamine level on admin istration of hypoxia between the 3 groups, makes it difficult to postulate that the de gree of rise in the histamine level, is the fac tor responsible for the susceptibility of cer tain subjects to develop POHA. However, it can be concluded with certainty that there is a very significant and consistent rise in the plasma histamine level within a short period of exposure to hypoxia and the available data thus suggest that histamine subserves an important function in mediating pulmon ary vascular response to hypoxia.…”