Potential Modulators

Previously proposed mediators of HPV such as the autonomic nervous system, histamine, bradykinin, serotonin, arachidonic acid metabolites, and nitric oxide (NO), have now been shown to have significant roles as modulators. As a case in point, it is now well documented that HPV can be accentuated by inhibiting cyclooxygenase. This is particularly evident in the isolated dog lung, which has no significant response to hypoxia unless aspirin, which inhibits the synthesis ofdilator prostaglandins, is administered to the dog before study. After aspirin treatment, the dog lung shows a vigorous HPV (2).

One of the earliest proposed modulators of HPV was pH when it was shown that acidosis augmented and alkalosis attenuated preexisting HPV. The finding that extracellular alkalosis attenuated HPV (26) was verified in numerous preparations and became a common treatment for neonatal and pediatric pulmonary hypertension. A study in isolated rat lungs (45), however, showed that intracellular alkalization with weak bases actually potentiated HPV and amiloride and acetate which decreased intracellular pH (pHj), decreased HPV. Later, Gordon et al. (14) showed differing effects of acute and prolonged alkalosis on HPV in isolated lamb lungs. Acute hypocarbia decreased the hypoxia-induced elevation of the total pressure gradient and subsequent normoxia with alkalosis decreased it still further. However, re-exposure to hypoxia after 1 hr ofnormoxic alkalosis significantly increased the total pressure gradient to a level similar to that seen during normocarbic hypoxia. The increased hypoxic reactivity during prolonged alkalosis was due to an enhanced HPV of the small arteries. It appeared that increasing or decreasing pH during hypoxic constriction modulated the response by release of other factors that resulted in dilation of an artery constricted by hypoxia.

It should be noted that identifying and studying the exact contribution of a single purported modulator is difficult since there appears to be a great deal of redundancy among all the modulators. Also, some modulators are inhibitory, e.g., prostacyclin and NO, while others, e.g., endothelin (ET), appear to be permissive. Thus, interpreting the data from studies in which modulators are individually inhibited can be difficult.

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