Acute Cyclooxygenase Inhibition Research Articles

Acute Cyclooxygenase Inhibition and Baroreflex Sensitivity in Lean and Obese Adults

PurposeObese adults exhibit increased levels of inflammation which may negatively affect blood pressure regulation. Based on existing literature, we hypothesized: 1) baroreflex sensitivity would be lower in obese adults when compared to lean adults and 2) acute ibuprofen (IBU, a cyclooxygenase inhibitor and nonsteroidal anti‐inflammatory agent) administration would increase baroreflex sensitivity in obese adults, with no effect in lean adults.MethodsSeven lean (4M, 3F; 25±2 yrs; 23±1 kg/m2) and six obese (5M, 1F; 30±3 yrs; 36±1 kg/m2) adults completed two visits randomized to control (CON) or IBU (800 mg oral). On each visit, blood pressure (intra‐arterial catheter), heart rate (electrocardiogram), and muscle sympathetic nerve activity (MSNA, microneurography) were measured continuously and venous blood was sampled for measures of systemic inflammation [C‐Reactive protein (CRP) and Interleukin‐6 (IL‐6)]. Sympathetic and cardiac baroreflex sensitivity were assessed using the modified Oxford technique, which consisted of a 5‐min resting period, followed by a 100 μg intravenous bolus of sodium nitroprusside. One minute later, subjects were administered a 150 μg intravenous bolus of phenylephrine HCl and data were collected for an additional 2‐min.ResultsCRP and IL‐6 were higher in obese adults when compared to lean adults, and tended to decrease with IBU (IL‐6: p<0.05; CRP: p=0.14). Cardiac baroreflex sensitivity was lower in obese adults (14±2 vs 24±2 ms/mmHg, p=0.02), whereas sympathetic baroreflex sensitivity was higher in obese adults (−3.6±0.5 vs −2.1±0.5 bursts/100 beats/mmHg, p=0.03) when compared to lean. There was no effect of IBU on cardiac or sympathetic baroreflex sensitivity in either group (p‐value range 0.20 – 0.71).ConclusionIn our present group of relatively healthy individuals with obesity, we observed lower cardiovagal baroreflex sensitivity but higher sympathetic baroreflex sensitivity in the obese group compared to lean controls. We found no effect of an acute dose of 800 mg ibuprofen on cardiac or sympathetic baroreflex sensitivity, suggesting that chronic effects of obesity‐related inflammation on baroreflex sensitivity may not be reversed by a single acute pharmacological anti‐inflammatory intervention.Support or Funding InformationNIH HL083947 (NC, MJJ), DK082424 (TBC), AG038067 (JNB), and UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). AHA 0750036Z (NC) from the American Heart Association.

Acute cyclooxygenase inhibition and baroreflex sensitivity in lean and obese adults.

Obese adults exhibit increased levels of inflammation, which may negatively affect blood pressure regulation. Based on existing literature, we hypothesized: (1) baroreflex sensitivity would be lower in obese adults when compared to lean adults; (2) acute ibuprofen (IBU, a cyclooxygenase inhibitor and nonsteroidal antiinflammatory agent) administration would increase baroreflex sensitivity in obese adults, with no effect in lean adults. Seven lean (4 male, 3 female) and six obese (5 M, 1 F) adults completed two visits randomized to control (CON) or IBU (800mg oral). On each visit, blood pressure (intra-arterial catheter), heart rate (ECG), and muscle sympathetic nerve activity (MSNA, microneurography) were measured continuously. Sympathetic and cardiac baroreflex sensitivities were assessed using the modified Oxford technique. Measures of systemic inflammation [C-reactive protein (CRP) and interleukin-6 (IL-6)] were higher in obese adults when compared to lean adults and tended to decrease with IBU (IL-6: p<0.05; CRP: p=0.14). Cardiac baroreflex sensitivity was lower in obese adults (14±2 vs. 24±2ms/mmHg, p=0.02), whereas sympathetic baroreflex sensitivity was higher in obese adults (-3.6±0.5 vs. -2.1±0.5 bursts/100 beats/mmHg, p=0.03) when compared to lean. There was no effect of IBU on cardiac or sympathetic baroreflex sensitivity in either group (p value range 0.20-0.71). Despite obese individuals exhibiting higher levels of systemic inflammation and lower cardiac baroreflex sensitivity when compared to lean adults, an acute dose of IBU has no effect on cardiac or sympathetic baroreflex sensitivity.

Acute cyclooxygenase inhibition does not alter muscle sympathetic nerve activity or forearm vasodilator responsiveness in lean and obese adults.

Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation and decreased vasodilator responsiveness. We hypothesized that obese individuals would have greater indices of inflammation compared with lean controls, and that cyclooxygenase inhibition using ibuprofen would reduce muscle sympathetic nerve activity (MSNA) and increase forearm blood flow in these subjects. We measured MSNA, inflammatory biomarkers (C‐reactive protein [CRP] and Interleukin‐6 [IL‐6]), and forearm vasodilator responses to brachial artery acetylcholine and sodium nitroprusside in 13 men and women (7 lean; 6 obese) on two separate study days: control (CON) and after 800 mg ibuprofen (IBU). CRP (1.7 ± 0.4 vs. 0.6 ± 0.3 mg/L; P < 0.05) and IL‐6 (4.1 ± 1.5 vs. 1.0 ± 0.1pg/mL; P < 0.05) were higher in the obese group during CON and tended to decrease with IBU (IL‐6: P < 0.05; CRP: P = 0.14). MSNA was not different between groups during CON (26 ± 4 bursts/100 heart beats (lean) versus 26 ± 4 bursts/100 heart beats (obese); P = 0.50) or IBU (25 ± 4 bursts/100 heart beats (lean) versus 30 ± 5 bursts/100 heart beats (obese); P = 0.25), and was not altered by IBU. Forearm vasodilator responses were unaffected by IBU in both groups. In summary, an acute dose of ibuprofen did not alter sympathetic nerve activity or forearm blood flow responses in healthy obese individuals, suggesting that the cyclooxygenase pathway is not a major contributor to these variables in this group.

Ketorolac alters blood flow during normothermia but not during hyperthermia in middle-aged human skin

In young healthy humans full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase (COX)- and nitric oxide synthase (NOS)-dependent mechanisms. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation potentially through both platelet and vascular COX-dependent mechanisms. We hypothesized the contribution of COX-dependent vasodilators to reflex cutaneous vasodilation during localized acute COX inhibition would be attenuated in healthy middle-aged humans due to a shift toward COX-dependent vasoconstrictors. Four microdialysis fibers were placed in forearm skin of 13 middle-aged (53 +/- 2 yr) normotensive healthy humans, serving as control (Ringer), COX-inhibited (10 mM ketorolac), NOS-inhibited (10 mM N(G)-nitro-l-arginine methyl ester), and combined NOS- and COX-inhibited sites. Red blood cell flux was measured over each site by laser-Doppler flowmetry as reflex vasodilation was induced by increasing oral temperature (T(or)) 1.0 degrees C using a water-perfused suit. Cutaneous vascular conductance was calculated (CVC = flux/mean arterial pressure) and normalized to maximal CVC (CVC(max); 28 mM sodium nitroprusside). CVC(max) was not affected by localized microdialysis drug treatment (P > 0.05). Localized COX inhibition increased baseline (18 +/- 3%CVC(max); P < 0.001) compared with control (9 +/- 1%CVC(max)), NOS-inhibited (7 +/- 1%CVC(max)), and combined sites (10 +/- 1%CVC(max)). %CVC(max) in the COX-inhibited site remained greater than the control site with DeltaT(or) < or = 0.3 degrees C; however, there was no difference between these sites with DeltaT(or) > or = 0.4 degrees C. NOS inhibition and combined COX and NOS inhibition attenuated reflex vasodilation compared with control (P < 0.001), but there was no difference between these sites. Localized COX inhibition with ketorolac significantly augments baseline CVC but does not alter the subsequent skin blood flow response to hyperthermia, suggesting a limited role for COX-derived vasodilator prostanoids in reflex cutaneous vasodilation and a shift toward COX-derived vasoconstrictors in middle-aged human skin.

Acetylcholine-induced vasodilation and reactive hyperemia are not affected by acute cyclo-oxygenase inhibition in human skin.

To examine whether prostaglandins are involved in endothelium-dependent vasodilatory responses of the skin microcirculation. Twenty-three young male volunteers were studied on 2 different days 1-3 weeks apart. On each experimental day the forearm skin blood flow response to iontophoretically applied acetylcholine (Ach, an endothelium-dependent vasodilator) was determined with laser Doppler imaging following the intravenous administration of either the cyclo-oxygenase inhibitor lysine acetylsalicylate (L-AS), 900 mg, or the oral intake of indomethacin, 75 mg. Acetylcholine was iontophoresed both in presence and in absence of surface anesthesia. In some subjects, the effects of L-AS on skin reactive hyperemia were also assessed. Acute cyclo-oxygenase inhibition with either drug influenced neither the skin blood flow response to 4 different doses of Ach (0.28, 1.4, 7, and 14 mC/cm2) nor reactive hyperemia. The peak vasodilatory response to Ach was significantly increased by skin anesthesia, regardless of whether the subjects received the cyclo-oxygenase inhibitor or not. For example, the mean response (+/-SD) to the largest dose of Ach (tested in 6 subjects, expressed in perfusion units) were as follows: in absence of anesthesia: L-AS 339 +/- 105, placebo 344 +/- 68; with anesthesia: L-AS 453 +/- 76, placebo 452 +/- 65 (p <.01 for effect of anesthesia). These data give no support for a contribution of prostaglandins to acetylcholine-induced vasodilation or to reactive hyperemia in the skin microcirculation. In this vascular bed, local anesthesia seems to amplify acetylcholine-induced vasodilation via a prostaglandin-independent mechanism.

Cyclooxygenase products do not contribute to the gestational renal vasodilation in the nitric oxide synthase inhibited pregnant rat.

To determine whether vasodilatory cyclooxygenase (COX) products are activated in kidney during chronic nitric oxide synthase inhibition (NOSI) in pregnant rats. Chronically catheterized pregnant and nonpregnant Sprague-Dawley female rats were treated with daily NOSI ( L-NAME; 100 mg/L drinking water) for 14 days. Renal function experiments were conducted twice at 7-9 days of chronic NOSI (equivalent to midterm in pregnant rats) and after 14 days (equivalent to late pregnancy). Measurements were made of arterial blood pressure (BP) and renal hemodynamics, specifically glomerular filtration rate (GFR), renal plasma flow (RPF), and renal vascular resistance (RVR), in control and then during acute COX inhibition with indomethacin (2 mg/kg i.v.). Chronic NOSI increased BP and RVR in both virgin and pregnant rats. The normal midterm renal vasodilation was prevented and there was no BP or renal hemodynamic response to acute COX inhibition. By late pregnancy, RPF had fallen further and again, acute COX inhibition had no impact on renal hemodynamics, although a small reduction was seen in GFR in LV. Vasodilatory COX products cannot compensate for nitric oxide as the renal vasodilatory factor of pregnancy in the rat.

Chronic nitric oxide inhibition model six years on.

The discovery in 1987 that endothelium-derived nitric oxide (NO) mediates the vasodilatory effect of certain endothelium-dependent agonists1 2 inaugurated the current huge field of NO biology. It is now recognized that NO plays essential roles in many diverse physiological processes and in some pathophysiologic events. Development of these concepts has been based largely on evidence obtained by limiting NO biosynthesis. This review is centered on the cardiovascular and particularly the renal functional and structural consequences of chronic pharmacologic NO inhibition by l-arginine analogues. We devoted special attention to the mechanisms of hypertension and organ injury that occur under these circumstances, while appreciating the inherent limitations surrounding interpretation of this data. NO is made by the enzymatic action of several widely distributed NO synthases (NOS). In the presence of the substrates l-arginine and oxygen, as well as a number of essential cofactors, NO is produced in response to appropriate stimuli. The constitutively expressed NOS play a major role in the physiological control of vascular tone and kidney function.3 4 Vascular endothelial NOS (eNOS) and brain-type NOS (bNOS) are widely distributed throughout the kidney5 as well as the cardiovascular system and in strategic locations in the peripheral and central nervous system (CNS).6 7 Both eNOS and particularly bNOS are abundant in the kidney, glomeruli, and vasculature as well as in most segments of the tubule,3 5 and NOS activity in medulla is considerably greater than in cortex.8 NO generated within the kidney controls the glomerular filtration rate (GFR), total renal and medullary blood flow, pressure natriuresis, epithelial sodium transport, and production of various vasoactive factors including renin.3 4 5 eNOS is distributed throughout most parts of the arterial and venous circulation, although there is considerable heterogeneity in the extent to which NO controls …

Renal hemodynamics and blood flow autoregulation during acute cyclooxygenase inhibition in male rats

After the acute inhibition of prostanoid synthesis, adjustments of renal hemodynamics may not be characterized immediately. Therefore, time-related effects of indomethacin on hemodynamics and renal blood flow (RBF) autoregulation were studied in anesthetized euvolemic male rats injected intravenously with vehicle, indomethacin (3, 4, or 5 mg/kg body wt), or meclofenamate (4 or 5 mg/kg body wt). Hemodynamics and RBF autoregulation were not influenced by vehicle injection, nor by time (n = 6). In contrast, mean arterial pressure (MAP) decreased significantly from 117 +/- 4 to 103 +/- 3 mmHg, and RBF progressively and significantly increased from 8.00 +/- 0.34 to 9.17 +/- 0.50 ml/min in the 3 mg/kg body wt indomethacin group (n = 8). Treatment with the higher doses of indomethacin (n = 9) or meclofenamate (n = 6) did not change RBF, while MAP decreased by 15 mmHg. A time-dependent significant enhancement of RBF autoregulatory efficiency was found in the drug-treated rats. Changes in renal function and reductions of prostanoid excretion in urine, of plasma renin activity, or serum aldosterone were similar in the nonsteroidal antiinflammatory drug groups. In conclusion, our findings demonstrate important time-related adjustments of renal hemodynamics in male rats treated with indomethacin, especially with the lower dose (3 mg/kg body wt iv). The factor(s) responsible for the hemodynamic changes remains unknown.

Cyclooxygenase-dependent mediators of renal hemodynamic function in female rats

Previous studies have revealed a sex-dependent difference in response to cyclooxygenase inhibition in anesthetized male and female rats. Female rats have shown an unexpected vasodilation in response to prostaglandin (PG) inhibition. The present studies were designed to further investigate the sex-dependent role of the PG system in the control of normal renal hemodynamics in female Munich-Wistar rats. Renal hemodynamic studies were performed on anesthetized female rats before and during acute cyclooxygenase inhibition using a variety of protocols. One group underwent subacute unilateral renal denervation. A separate group was chronically catheterized and plasma catecholamines were measured during the awake state and then after anesthesia under the euvolemic protocol. Another group was administered the angiotensin II blocker, saralasin, before and during cyclooxygenase inhibition. In a final group, flow to the distal nephron was interrupted via placement of a wax block into the late proximal tubule to determine the role of distal nephron flow and tubuloglomerular feedback in the glomerular response to cyclooxygenase inhibition. It was determined that neither the wax block nor saralasin administration attenuated the vasodilatory response observed in normal female rats due to cyclooxygenase inhibition; however, subacute unilateral renal denervation completely blocked the vasodilatory response to PG inhibition in these female Munich-Wistar rats. Plasma catecholamines were found to be similar whether awake or under anesthesia. These studies indicate the importance of the adrenergic system in modulating PG production in the acutely anesthetized intact female rat.

Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs.

The effect of acute cyclooxygenase (CYO) inhibition on the cardiopulmonary adjustments at birth was examined in chronically instrumented, unanesthetized, term lambs before, during, and after cesarean section (spontaneous respiration). One of three infusions was started 20 min before birth: saline control (C, n = 6), indomethacin (I, n = 6), or meclofenamate (M, n = 3). The stable metabolite of prostacyclin, plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, aorta), was measured by radioimmunoassay as an index of CYO activity. Indomethacin blocked the rise of 6-keto-PGF1 alpha observed in control lambs after birth and indomethacin-treated lambs exhibited an attenuation of the postnatal decrease in mean pulmonary arterial pressure. Pulmonary arterial pressure (Ppa) was 53 +/- 2 and 47 +/- 2 Torr (mean +/- SE) at 15 min and 40 +/- 3 and 34 +/- 2 Torr at 120 min in I and C groups, respectively. There were no serial or group differences in cardiac output and cardiac right to left shunt (indicator dilution) from 15 to 120 min after birth. Arterial PO2 (PaO2) was not different between groups: 37 +/- 4 Torr at 15 min and 47 +/- 5 min at 120 min after birth (control lambs). The results for I and M were similar for all measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous prostaglandins modulate autoregulation of renal blood flow in young rats.

After uninephrectomy in the young rat, renal blood flow (RBF) increases at normal renal perfusion pressure (RPP) but not at reduced RPP. To evaluate the role of endogenous prostaglandins on these effects, RBF was measured during reduction in RPP in rats that were uninephrectomized within 1 wk of age and studied at 33-41 days of age. After acute cyclooxygenase inhibition, autoregulation improved; RBF was unchanged at normal RPP but increased at lower pressures with concomitant decrease in renal venous plasma renin activity (PRA). Prostaglandin inhibition also improved autoregulatory efficiency in acutely uninephrectomized and sham-operated young rats. Infusion of a thromboxane synthesis inhibitor had no effect on the pressure-flow relationship or on PRA, whereas angiotensin converting enzyme inhibition increased RBF at all measured RPP without affecting autoregulation. We conclude that increased RBF at normal RPP in the uninephrectomized young rat is not maintained by increased prostaglandin synthesis or decreased thromboxane- or angiotensin-dependent vasoconstriction. However, by maintaining increased vasoconstriction at reduced RPP, prostaglandin-dependent renin release reduces autoregulatory efficiency in the young rat.

Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. Serial studies in chronically instrumented, conscious rats.

Renal hemodynamics increase dramatically during pregnancy, and pressor responsiveness to exogenous administration of vasoconstrictors is attenuated. We investigated whether or not vasodilatory prostaglandins mediate these phenomena. Trained, chronically instrumented, conscious pregnant rats were used. Control values of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were elevated at midgestation (P less than 0.01 and P = 0.05 from prepregnant means, respectively), and effective renal vascular resistance was decreased (P = 0.05). Indomethacin (4.5-6.5 mg/kg body weight [BW]) failed to decrease renal hemodynamics at this stage of pregnancy; in fact, it raised GFR somewhat further (P less than 0.05). Systemic pressor responsiveness to bolus administration of norepinephrine and angiotensin II (AII) was significantly attenuated by at least gestational day 20. Neither indomethacin (7 mg/kg BW) or meclofenamate (6 mg/kg BW) affected the refractory response. The renal vasculature was also relatively unresponsive to an intravenous infusion of AII (5 ng X kg-1 X min-1) during late gestation (day 19); in particular, the fall in ERPF in response to AII (16 +/- 3%) was markedly less than that observed in the prepregnant condition (34 +/- 3%; P less than 0.05). Indomethacin (6 mg/kg BW) failed to restore this blunted response, and further attenuation was evident, despite the presence of the inhibitor (gestational day 21). We conclude that vasodilatory prostaglandins do not appear to mediate the rise in renal hemodynamics, and the attenuation of the systemic and renal pressor responsiveness observed during pregnancy, insofar as these phenomena were unaffected by acute cyclooxygenase inhibition in unstressed, conscious rats.