Cyclooxygenase Inhibition Restores Nitric Oxide Activity in Essential Hypertension

Abstract

Abstruct To evaluate whether cyclooxygenase constructor substances can nnparr mtnc oxide-mediated vasodrlatron m essentral hypertension, in seven normotensive sublects (43 324 1 years, BP, 117-+6/81t2 mm Hg) and seven essential hypertensave patients (47 l-t5 2 years, BP, 151C8/98+4 mm Hg) we studied forearm blood flow (strain-gauge plethysmography) modrficatrons induced by mtrabrachral acetylcholme (0.15, Cl 45, 1 5, 4 5, 15 pg 100 mL-' mm-') m basal condrtrons, durmg mfuston of NC-monomethyl-L-argnnne (L-NMMA, 100 pg 100 mL-' mn-'), a mtnc oxide synthase mhrbrtor, or mdomethacm (50 /-lg 100 mL-' mm-'), a cyclooxygenase mhrbrtor, or srmultaneous mdomethacm and L-NMMA In normotensrves, vasodrlatron to acetylcholme was blunted by L-NMMA (maximum flow increase' 671+64% and 386+42%, respectrvely, P< Ol), and this effect was unchanged by mdomethacm In contrast, m hypertensrve patients, vasoddatron to acetylcholme (maxrmum llow increase 458233%) was unchanged by L-NMMA Indomethacm stgmficantly (P< 01) increased the response to acetylcholme (maximum flow increase 635t53%) and restored the mhrbrtory effect of L-NMMA (maximum flow Increase 445&36%, P< 01 versus mdomethacm alone) In an adJunctive seven normotensaves (51 4t4 2 years, BP, 114+5/79+3 mm Hg) and seven essential hypertenstves (53 247 6 years, BP, 153?9/100&3 mm Hg) we repeated the same protocol by replacmg L-NMMA with L-argmme (200 pg 100 mL-r mn-'), the substrate for NO synthase In normotensrves, vasodrlatron to acetylchohne was mcreased by L-argmme (maximum flow Increase 539~48% and 806?61%, respectrvely) and this effect was unchanged by mdomethacm In hypertensive patrents, vasodrlatron to acetylchohne (maximum flow Increase 339532%) was unchanged by L-argnnne but was srgnrficantly (P< 01) increased by mdomethacm (maxrmum flow increase 592238%)Moreover, mdomethacm restored the facrlrtatory effect of L-argmme (maxrmum flow increase 804?56%, P< 01 versus mdomethacm alone) Therefore, cyclooxygenase mhrbrtron restores mtrrc oxide-mediated vasodrlatron m essential hypertension, suggestmg that cyclooxygenase-dependent substances can rmparr mtnc oxide productron (Hypertenszon. 1997;29[part 21: 274-279.) Key Words l hypertension l endothelmm l mtrrc oxtde l endothehum-derived factors l mdomethacm E ndothelmm plays a major role m the modulation of vascular tone through the productton and release of different relaxing and constricting factors acting on the underlying smooth muscle cells r The major endothehum-derived relaxing factor is NO,* a labile substance derived from L-argmine by the activity of the enzyme NO synthase.3 Importantly, this process can be competitively mhtbited by r.-argmme analogues such as L-NMMA.4.5 Moreover, EDCF are mainly cyclooxygenase-dependent prostanoids (thromboxane A2 and prostaglandm H2)6-9 or superoxrde anions 10The crucial role of endothehal cells in vascular homeostasis is further emphasized by the evidence of tmpaired endotheltum-dependent responses m cardtovascular disease such as essential hypertension Thus, m essential hyper...

Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients

“…18 In contrast, in essential hypertensive patients, the response to bradykinin was significantly increased, suggesting that, in line with the results observed with acetylcholine, 18,27 oxidative stress may be the main mechanism leading to impaired vasodilation to bradykinin in essential hypertension. Whether cyclooxygenase activity could be the source of oxidative stress in these experimental conditions, as observed with acetylcholine, 28 is still to be established. However, the relevant finding is that during vitamin C administration, inhibition to L-NMMA was restored, whereas ouabain was no longer effective in blunting the response to bradykinin.…”

Linking erectile dysfunction and coronary artery disease

“…51,52 Changes in the cyclooxygenase pathway also appear to play a major role, as increased COX activity can lead to increased ROS, with further disruption of 'normal' endothelial activity. 50,53,54 Decreased NOS levels in essential hypertension have been reported, as well as muted vasoconstrictor response to L-NMMA, although this is not a universal finding. 55 It should be emphasized that dysfunctional endothelium-dependent vasodilation is not merely a cause of hypertension; it exists in several disease states (as outlined here), and degree of endothelial dysfunction does not correlate with blood pressure values.…”

Working under pressure: the vascular endothelium in arterial hypertension

“…96 In hypertensive patients, indomethacin, a COX inhibitor, significantly increased the response to acetylcholine, an effect that could be blocked by confusion of L-NMMA, an inhibitor of NO synthesis. 97 Therefore, COX inhibition restores NO-mediated vasodilation in essential hypertension, suggesting that COX-dependent substances can impair NO bioavailability. COX is indeed a source of the NO-scavenger O …”