Decreased response of rat knee joint blood vessels to phenylephrine in chronic inflammation: involvement of nitric oxide

The effect of chronic inflammation induced by Freund's Complete Adjuvant (FCA) on rat articular blood vessels and knee joint diameter was investigated. Blood now changes in response to phenylephrine (an alpha(1)-adrenoceptor agonist) in FCA-treated and contralateral knee joints were studied over a 40 day period, using the laser Doppler flowmetery (LDF) technique. Unilateral injection of BCA (0.2 ml) increased the injected knee diameter on all days examined post-injection (P < 0.001) and its maximum increase (53 +/- 2%) was reached on day 3. after this, the diameter decreased gradually but did not return to its initial value. In control animals, topical application of 10-(13)-10(-7) mol phenylephrine onto the exposed joint capsule decreased blood now dose dependently (11.1 +/- 4.4 to 58.2 +/- 4.5%, respectively, P < 0.001). Unilateral injection with FCA attenuated the phenylephrine response in both ipsilateral and contralateral knees compared with the response of control animals (5.2 +/- 1.6 to 48.3 +/- 6.1% and 1.9 +/- 2.2 to 45.3 +/- 5.6%, respectively, P < 0.05). The reduction persisted for 3 weeks after FCA injection (ipsilateral for 21 days; contralateral for 30 days, P < 0.001). Subsequently the response returned towards normal. To avoid the influence of alpha(2)-adrenoceptors, yohimbine (an alpha(2)-adrenoceptor antagonist) was injected (0.5 mg kg(-1), I.P.) 30 min before phenylephrine application. Yohimbine blocked the vasoconstrictor effect of 10(-10)-10(-7) md clonidine (an alpha(2)-adrenoceptor agonist, topical application) by 44-67.7% inhibition, respectively (P < 0.001). Prazosin (an alpha(1)-adrenoceptor antagonist, 0.1 mg kg(-1), I.P.) blocked the vasoconstrictor effect of phenylephrine (10(-10)-10(-7) mol, topical application) effectively (42 to 69.8% inhibition, respectively, P < 0.001). To assess the role of nitric oxide (NO) on the observed responses, NC-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) was applied topically (0.2 mu mol) 5 min before phenylephrine application. L-NAME application at 7 and 14 days after FCA injection potentiated the vasoconstrictor response in the FCA-treated knee (P < 0.001) but had no significant effect on the contralateral knee. Blood pressure monitoring during phenylephrine, clonidine and L-NAME administration indicated that topical application of the drugs had no significant effect on the systemic blood pressure. These findings indicate that the vasoconstrictor response to phenylephrine was decreased in chronic inflammation and increased NO production could be involved.