Effects of organophosphate esters on blood vessels: a physiological, pharmacological, and histological assessment of involvement in organophosphorus-induced delayed neuropathy (OPIDN)

The contribution of the cardiovascular system. to organophosphate-induced delayed neuropathy (OPIDN) was examined using in situ and in vitro models for demonstration of response to vasoactive agents (e.g., the cholinergic agonist, acetylcholine; the α1 agonist, phenylephrine; and the β2 agonist, salbutamol). These responses were compared before and 1, 3, 7, and 21 days after hens were administered cyclic phenyl saligenin phosphate (PSP, 2.5 mg/kg i.m.), an OP that induces OPIDN but does not significantly inhibit acetylcholinesterase activity, and paraoxon (PXN, 0.1 mg/kg i.m.), an OP that inhibits acetylcholinesterase activity but does not induce OPIDN. The capability of verapamil, a calcium channel blocker, to attenuate these responses was examined, as this agent ameliorates OPIDN. For the in situ study, the ischiadic artery was cannulated and alterations in pressure measured at a constant flow used to indicate changes in vascular resistance. Changes in vascular resistance in response to acetylcholine, phenylephrine, and salbutamol that were different from those in control and PXN-treated hens were noted 1 and 3 days after administration of PSP. These changes were attenuated in hens given PSP and verapamil. Vascular segments from the ischiadic artery were used to provide an in vitro model to determine if OPs caused direct vascular damage that was responsible for effects seen in the in situ model. In the in vitro model, however, responses of PSP and PXN were similar and not modified in vascular segments from hens given verapamil as well as the OPs. This indicated that the contribution of the cardiovascular system to OPIDN was due to more than a direct effect on relatively large caliber vessels. The contribution of the cardiovascular system to OPIDN also did not appear to relate to morphological changes induced by administration of OPs, as no changes in vascular morphology were noted. An OP-induced effect that could contribute to vascular effects noted are levels of plasma catecholamines. These levels were altered in hens given PSP or PXN, with increases seen after administration of PSP and decreases seen after administration of PXN. These alterations in plasma catecholamine levels were attenuated in hens given both verapamil and OP.