Biomedical subjects

J J McDougall

Publications and source records attributed to J J McDougall.

At least 19 recordsLinked to original sources

PubMed2006

Electrophysiological evidence that the vasoactive intestinal peptide receptor antagonist VIP6-28 reduces nociception in an animal model of osteoarthritis.

OBJECTIVE: The present study examined whether local administration of the neuropeptide vasoactive intestinal polypeptide (VIP) could modulate joint nociception in normal rat knee joints and if the VIP antagonist VIP(6-28) could ameliorate joint mechanosensitivity in an animal model of osteoarthritis (OA). METHODS: OA was induced in male Wistar rats by intra-articular injection of 3mg sodium monoiodo-acetate with a recovery period of 14 days. Electrophysiological recordings were made from knee joint primary afferents in response to normal rotation and noxious hyper-rotation of the joint both before and following close intra-arterial injection of different doses of VIP and VIP(6-28). RESULTS: Local application of VIP to normal knees caused afferent firing rate to be significantly enhanced during normal rotation (up to 180% P<0.01; n=17) and during hyper-rotation (up to 37% P<0.01; n=17) of the knee. VIP-induced sensitization was blocked by pre-administration of the VIP receptor antagonist VIP(6-28). In the OA group, application of VIP(6-28) caused afferent firing rate to be significantly reduced during normal rotation (up to 45% P<0.05; n=17) and during hyper-rotation (up to 34% P<0.01; n=15) of the knee joint. CONCLUSION: These findings indicate that VIP is involved in peripheral sensitization of knee joint afferents especially in response to normal joint movements. OA-induced sensitization of knee joint afferents was inhibited by local administration of VIP(6-28), indicating that VIP is released into OA knee joints, potentially contributing to joint pain. As such, VIP(6-28) may prove to be a beneficial agent for the treatment of arthritis pain.

Animals↗

PubMed2003

Endomorphin-1 causes synovial hypoaemia in rat knee joints via a capsaicin-sensitive neural pathway.

In joints, synthetic mu-opioids reduce inflammatory changes such as protein extravasation and associated oedema formation. However, the effect of endogenous opioid peptides on other inflammatory processes such as altered tissue blood flow has not been investigated. The present study examined the peripheral effects of the endogenous mu-opioid ligand endomorphin-1 (EM-1) on rat knee joint blood flow using laser Doppler perfusion imaging. Topical application of EM-1 (10(-16)-10(-9) mol) to exposed rat knee joints resulted in a dose-dependent increase in synovial vascular resistance with a maximum rise of 56% occurring with the 10(-9) mol dose. Destruction of unmyelinated articular afferents by capsaicin treatment completely abolished the hypoaemic effects of EM-1. These findings suggest that EM-1 acts peripherally in knee joints to decrease synovial blood flow, and this hypoaemic response is dependent on the presence of capsaicin-sensitive nerves.

Analgesics, Opioid↗

PubMed2001

Participation of NK1 receptors in nociceptin-induced modulation of rat knee joint mechanosensitivity.

Nociceptin is known to act peripherally in the rat knee joint to modulate articular mechanosensitivity and it has been postulated that neurokinin-1 (NK1) receptors may be involved in this process. To test this hypothesis, single unit extracellular recordings were made from knee joint primary afferents in response to normal and extreme rotation of the joint. Afferent firing rate was assessed following close intraarterial injection of the NK1 antagonist RP67580 followed by administration of 20 nmol nociceptin. With both normal and hyper-rotation of the knee, nociceptin was unable to elicit its usual mechanomodulatory effect such that afferent activity was not significantly different from control (P = 0.7572 and P = 0.9182 for normal and hyper-rotation of the joint, respectively). These data indicate that nociceptin-induced mechanosensitivity changes in the rat knee depend upon NK1 receptor activation possibly through secondary release of substance P.

Action Potentials↗

PubMed2001

Abrogation of alpha-adrenergic vasoactivity in chronically inflamed rat knee joints.

It has previously been shown that chronic inflammation causes a reduction in sympathetic nerve-mediated vasoconstriction in rat knees. To determine whether this phenomenon is due to an alteration in smooth muscle adrenoceptor function, the present study compared the alpha-adrenoceptor profile of blood vessels supplying the anteromedial capsule of normal and chronically inflamed rat knee joints. While the rats were under urethan anesthesia, the alpha(1)-adrenoceptor agonists methoxamine and phenylephrine and the alpha(2)-adrenoceptor agonist clonidine (0.1-ml bolus; dose range 10(-12)-10(-7) mol) were applied to exposed normal rat knees, resulting in a dose-dependent fall in capsular perfusion. Comparison of drug potencies indicated that alpha(2)-adrenergic effects > alpha(1)-vasoactivity. One week after intra-articular injection of Freund's complete adjuvant to induce chronic joint inflammation, the vasoconstrictor effects of methoxamine, phenylephrine, and clonidine were all significantly attenuated compared with normal controls. These findings show that the preponderance of sympathetic adrenergic vasoconstriction in the anteromedial capsule of the rat is carried out by postjunctional alpha(2)-adrenoceptors. Chronic joint inflammation compromises alpha(1)- and alpha(2)-adrenoceptor function, and this change in alpha-adrenergic responsiveness may help explain the perfusion changes commonly associated with inflammatory arthritis.

Administration, Topical↗

PubMed2000

Peripheral modulation of rat knee joint afferent mechanosensitivity by nociceptin/orphanin FQ.

The peripheral effects of nociceptin were examined in normal and acutely inflamed rat knee joints by analyzing single unit recordings from articular primary afferents in response to normal and extreme rotation of the knee. Bolus close intraarterial injection of nociceptin (0.01, 1 and 100 microM) caused a sensitization of normal and inflamed knee joint afferents in response to movements in the normal working range of the joint. When the joint was hyper-rotated, nociceptin had no significant effect on afferent discharge rate in normal knees, however, in inflamed joints the top dose of the neuropeptide caused a decrease in articular mechanosensitivity. These findings suggest that nociceptin seems to be involved in the control of peripheral nociceptive mechanisms, although the behaviour of the peptide is dependent upon the inflammatory status of the tissue.

Animals↗

PubMed2000

Adaptation of post-traumatic angiogenesis in the rabbit knee by apposition of torn ligament ends.

Apposition of torn ligament ends has been shown to have a beneficial effect on healing of the medial collateral ligament; however, the mechanism underlying this improved recovery is unclear. Excessive post-traumatic angiogenesis, an inherent component of soft-tissue regeneration, may be functionally detrimental in relatively hypovascular tissues such as ligaments. The present study therefore examined the relationship between contact of transected ligament ends and vascular remodeling. Female New Zealand White rabbits were subjected to a gap injury, Z-plasty apposition, or sham operation to the midsubstance of the medial collateral ligament. Six weeks after treatment, the volume of vessels supplying the healing zone of the medial collateral ligament, as well as the ipsilateral lateral collateral ligament, posterior cruciate ligament. menisci, and medial capsule, was quantified by carmine red vascular casting. The volume of vessels supplying the neoligamentous scar formed by gap injury to the medial collateral ligament was found to be twice that of ligaments that had undergone the sham operation, and lateral collateral ligament and meniscal vascularity was also augmented in the injured joint. The medial collateral ligaments that underwent Z-plasty apposition exhibited a level of vascularity comparable with that of the control ligaments that had undergone the sham procedure, whereas meniscal and lateral collateral ligament vascularities remained elevated in this group. Capsular and posterior cruciate ligament vascularities were unaffected by gap injury or Z-plasty to the ipsilateral medial collateral ligament. These findings indicate that injury to the medial collateral ligament not only stimulates angiogenesis in the healing ligament, but other ipsilateral soft tissues also undergo vascular remodeling. Furthermore, apposition of an injured medial collateral ligament modifies these pro-angiogenic events, and this may partly explain why contact of torn ligament ends is beneficial for post-traumatic recovery of an injured joint.

Adaptation, Physiological↗

PubMed2000

Late gestational changes in sympathomimetic sensitivity in primagravid rabbit ligaments.

The adrenoceptor profile of blood vessels supplying the medial collateral ligament (MCL) of virgin and primagravid (day 29 of pregnancy) rabbit knees was examined. Topical bolus administration of the alpha1-adrenoceptor agonists methoxamine and phenylephrine, and the alpha2-adrenoceptor agonist clonidine, to exposed knee joints resulted in a dose-dependent vasoconstriction of ligamentous vessels. The rank order of potency for the alpha-agonists was found to be phenylephrine > methoxamine > clonidine. Dobutamine, which acts on beta1-adrenoceptors, and ritodrine, which is a beta2-agonist, imparted a mild vasodilatatory effect on MCL blood vessels with the efficacy of ritodrine being greater than that of dobutamine. In primagravid rabbits, the constrictor effects of methoxamine and phenylephrine were significantly attenuated compared with virgin control animals (P < 0.0001), whereas clonidine-mediated vasoconstriction was unaltered in the gravid animal (P = 0.3957). With respect to beta-adrenoceptor activity, the dilatational effect of dobutamine was the same as in controls (P = 0.5294), while ritodrine vasoactivity was completely abolished in primagravid knees (P < 0.005). These findings suggest that the adrenergic control of rabbit MCL blood flow is predominantly mediated by postjunctional alpha1 and beta2-adrenoceptors. Pregnancy leads to either downregulation and (or) desensitisation of alpha1 and beta2-adrenoceptors in the ligament which could disrupt normal joint homeostasis.

Animals↗

PubMed2000

A role for calcitonin gene-related peptide in rabbit knee joint ligament healing.

Knee joint ligament healing has been shown to be improved when the torn ligament ends remain in contact, however, the rationale for these effects is unknown. The sensory neuropeptide calcitonin gene related peptide (CGRP) has potent trophic and vasodilatatory properties and as such is thought to be advantageous in wound repair. In ascertaining a role for CGRP in rabbit medial collateral ligament healing, the present study examined changes in CGRP-like immunoreactivity (CGRP-LI) and CGRP-mediated vasomotor responses in gap injured (non-contact), Z-plasty apposed (contact), and sham operated control medial collateral ligaments. At 6 weeks post-trauma, CGRP-LI decreased in the healing zone of gap injured and Z-plasty apposed medial collateral ligaments compared with controls, and non-contact ligament nerve fibres exhibited an abnormal morphology. Topical administration of CGRP (10(-13) to 10(-9) mol) caused a dose-dependent increase in ligament perfusion in each experimental group of knees. The CGRP-mediated vasodilatation associated with gap injured ligaments was not significantly different from controls (P = 0.06), whereas apposed medial collateral ligaments showed an augmented response to the peptide (P < 0.0005). These findings indicate that the beneficial effects of ligament interposition post-trauma may be related to an enhanced responsiveness to CGRP in conjunction with a more typical re-innervation profile. Conversely, the aberrant characteristics of CGRP-LI nerves occurring in gap injured tissue is suggestive of impaired CGRP release which may explain the poor functional recovery associated with these ligaments.

Animals↗

PubMed1999

Dynamic measurement of bone blood perfusion with modified laser Doppler imaging.

Although the mechanisms are not clearly defined, blood flow may play an important role in moderating skeletal adaptation. Most techniques currently available to measure blood flow in bone are time-consuming and require destruction of the tissue, but laser Doppler technology offers a less invasive method. The present study assessed whether laser Doppler perfusion imaging could detect changes in perfusion in cortical bone. By use of modified laser Doppler perfusion imaging with an adjustable, incorporated, near infrared-laser gain photodetection system, perfusion of blood in the mid-diaphyseal tibial cortex of New Zealand White rabbits (n = 5) was measured before, during, and after occlusion of the femoral artery. During occlusion, perfusion decreased 69% compared with control levels; removal of the arterial clip caused flux values to return to near normal. Laser Doppler perfusion imaging provides a two-dimensional image related to blood flow, and the results of this pilot study suggest that it may be an effective technique for imaging in vivo dynamic changes in perfusion in cortical bone.

Animals↗

PubMed1999

Neurogenic origin of articular hyperemia in early degenerative joint disease.

It has been speculated that joint instability resulting from anterior cruciate ligament (ACL) rupture could be exacerbated by changes in vasomotor activity in the remaining supporting structures. In this study, the effect of ACL transection on medial collateral ligament (MCL) basal perfusion and its responsiveness to calcitonin gene-related peptide (CGRP) and sympathetic adrenergic influences was examined. Using urethan-anesthetized rabbits, we tested the effects of CGRP and its antagonist CGRP-(8-37) by topical application of these agents to the exposed knee while sympathetic influences were tested by electrically stimulating the saphenous nerve. It was found that MCL basal perfusion was elevated in ACL-sectioned joints; however, this effect was abrogated by prior resection of the articular nerve supply. At the doses tested, the normal vasodilator response to CGRP was abolished in ACL-sectioned joints, whereas the response to CGRP-(8-37) was attenuated. Even under the influence of increased constrictor tone, MCL and capsule blood vessels still showed substantially reduced responses to exogenous CGRP administration. By contrast, nerve-mediated constrictor responses were mostly unaffected by joint instability. This study suggests that posttraumatic knee joint hyperemia is neurogenically mediated, possibly by increased secretion of CGRP.

Animals↗

PubMed1998

Cholinergic vasoregulation in normal and adjuvant monoarthritic rat knee joints.

The role of cholinergic nerves in joint vasomotor control was investigated in normal and chronically inflamed rat knees. Joint inflammation was induced by unilateral intraarticular injection of Freund's complete adjuvant and experiments were performed on both the ipsilateral and contralateral joints one and three weeks after treatment. Blood flow measurements of the exposed joints were obtained using a laser Doppler perfusion imager which provides relative changes in tissue perfusion. One week after adjuvant induction, basal perfusion in both ipsilateral and contralateral joints was significantly reduced compared to normal. At three weeks, ipsilateral knee perfusion had returned to normal, however, contralateral blood flow showed no such sign of recovery. Topical application of the muscarinic receptor antagonist atropine caused a fall in knee joint basal perfusion suggesting that cholinergic nerves are inherently involved in the physiological control of rat knee blood vessels. Acetylcholine chloride (10(-13)-10(-8) mol) in normal rats produced a dose-dependent vasodilatation of the articular microvasculature with the highest dose causing blood flow to increase by about 85%. This dilator response was attenuated in the ipsilateral monoarthritic joint at both one and three weeks post-injection while contralateral joints showed a normal response to acetylcholine at both of the time points tested. This study implicates cholinergic nerves in rat knee joint vasoregulation, however, the impairment of this mechanism by chronic inflammation could exacerbate the disease process by starving the joint of much needed vascular nourishment. Furthermore, the preservation of cholinergic responses in the contralateral knee despite a fall in basal perfusion suggests that alternative non-cholinergic mechanisms may be responsible for the hypoaemia in this joint.

Acetylcholine↗

PubMed1998

Vascular volume determination of articular tissues in normal and anterior cruciate ligament-deficient rabbit knees.

The vasculature of diarthroidal joints has been well documented; however, the volume of vessels supplying different articular tissues is unknown. Angiogenesis, the formation of new vessels from preexisting ones, is difficult to quantify in joints due to the unavailability of a suitable technique. Although angiogenesis is known to occur in rheumatoid arthritis, the development of new vessels following joint injury has not been ascertained. A vascular casting technique was developed using carmine red dye to measure the vascular volume of the medial collateral ligament (MCL), lateral collateral ligament (LCL), menisci, medial capsule, and infrapatellar fat pad of the rabbit knee joint. Vascular volume determinations were repeated at 4 weeks in a group of anterior cruciate ligament (ACL)-transected animals and in a sham-operated control group. The volume of vessels supplying the MCL was estimated to be 0.22 +/- 0.07 microliter (mean +/- S.E.M.), the LCL volume was 0.25 +/- 0.05 microliter, the medial meniscus volume was 0.19 +/- 0.03 microliter, the lateral meniscus volume was 0.40 +/- 0.08 microliter, the medial capsule volume was 0.14 +/- 0.05 microliter, and the infrapatellar fat pad volume was 1.90 +/- 0.62 microliters. Following ACL transection, angiogenesis was found to occur in the MCL only. All other tissue vascularities were not significantly different from sham-operated controls. A quantifiable method for measuring vascular volume of knee joint tissues has been described. Joint instability stimulates angiogenesis in the ipsilateral MCL; however, the absence of angiogenic activity in other articular tissues might help explain the lack of posttraumatic healing associated with these joints.

Animals↗

PubMed1998

Repetitive activity alters perfusion of proximal interphalangeal joints of the human hand.

OBJECTIVE: To examine whether competitive volleyball players show any difference in perfusion of their proximal interphalangeal (PIP) joints compared with a healthy group of subjects. Also to assess the viability of a dual wavelength laser Doppler imager (LDI) in making these measurements. SETTING: Physiology laboratory. PARTICIPANTS: Ten active volleyball players who had experienced repetitive finger joint injury and 12 age- and sex-matched normal control subjects. MAIN OUTCOME MEASURES: Using a modified LDI incorporating a near- infrared (850 nm) laser as well as a standard red (633 nm) laser, scans were performed over the dorsum of the hands of the volleyball players and the control group. RESULTS: Higher perfusion values were obtained with the 850-nm laser than with the red 633-nm laser. When referenced to adjacent skin blood flow, perfusion over PIP joints of volleyball players was found to be significantly higher than that in control subjects (p=0.00012; n=10-12). CONCLUSIONS: The higher perfusion values obtained using the 850-nm laser suggest that the longer wavelength laser is measuring perfusion in a greater volume of tissue, which could include subcutaneous structures. Volleyball players have significantly higher perfusion over the PIP joints, which is unlikely to be due to differences in skin perfusion over the two regions but is more likely to be related to hyperemia of the underlying PIP joints. The reason for increased PIP perfusion is not clear; it may represent ongoing tissue inflammation due to repeated injury, or it could be an adaptive response to the stresses placed on these joints by this type of repetitive activity. CLINICAL RELEVANCE: Near-infrared laser Doppler imaging has the potential to provide a noninvasive clinical assessment of finger joint injuries.

Adult↗

PubMed1998

Pregnancy-induced changes in rabbit medial collateral ligament vasoregulation.

The ligaments of weight-bearing joints are known to become mechanically inferior during pregnancy, and it has been postulated that this may be due to changes in tissue perfusion. Calcitonin gene-related peptide (CGRP) and epinephrine exert a tonic influence on the vasculature of the medial collateral ligament (MCL), and the present study examined whether these vasoactive influences were altered by pregnancy. Ligament perfusion experiments were performed on primigravid New Zealand White rabbits with the use of laser Doppler perfusion imaging. In pregnant animals (day 29), MCL basal perfusion fell significantly compared with control; however, values returned to normal 5 days postpartum. In normal joints, topical application of CGRP resulted in a dose-dependent increase in MCL perfusion, whereas epinephrine administration caused a dose-dependent fall in blood flow. During pregnancy, the vasodilator effect of CGRP was completely abolished, whereas adrenergic vasoconstriction was greater than normal. Both responses returned postpartum. Pregnancy in the rabbit produces hypoemia in the MCL, and this phenomenon may be effected by a tempering of CGRP dilator responses and an augmentation of alpha-adrenoceptor-mediated vasoconstriction.

Animals↗

PubMed1997

Spatial variation in sympathetic influences on the vasculature of the synovium and medial collateral ligament of the rabbit knee joint.

1. Laser Doppler perfusion imaging was used to assess the role of the sympathetic nervous system in the control of blood flow to the medial collateral ligament and capsule (synovium and overlying fibrous tissues) of the rabbit knee joint. 2. Electrical stimulation of the saphenous nerve (width 1 ms; amplitude 20V; 1-30 Hz) produced a frequency-dependent vasoconstriction of knee joint vasculature. The response was maximal at 30 Hz and gave the greatest fall in perfusion at the femoral insertion of the ligament (by 33.8 +/- 7.4%, mean +/- S.E.M.; n = 5-6) and the smallest decrease at the tibial insertion of the ligament (by 10.6 +/- 2.9%). 3. Topical application of phentolamine (10(-6) mol) had no significant effect on basal knee joint blood flow. However, it abolished the nerve-mediated constrictor responses in all regions of the medial collateral ligament and synovium at all frequencies. 4. Topical administration of adrenaline (10(-14) to 10(-7) mol) caused a dose-dependent decrease in knee joint blood flow with the highest dose producing > 75% reduction in perfusion at all areas. 5. There was no evidence of a reactive hyperaemia in the 5 min following a 5 min period of femoral artery occlusion. Artificial manipulation of arterial blood pressure by intravenous infusion or withdrawal of blood caused a proportional change in ligament and synovial blood flow. These observations may indicate a lack of autoregulation in the joint and its exclusion from baroreflex modulation. 6. These results suggest a potential role for the sympathetic nervous system in the control of knee joint blood flow. Neuromodulation of ligament perfusion appears to predominate at the femoral insertion and this could prove to have functional significance.

Adrenergic alpha-Agonists↗

PubMed1997

Morphological and immunohistochemical examination of nerves in normal and injured collateral ligaments of rat, rabbit, and human knee joints.

BACKGROUND: Knee joints possess an abundant nerve supply that relays sensory and motor information on such aspects as proprioception, nociception, and vasoregulation. Although synovial innervation has been well documented, little is known of the nerves that supply the collateral ligaments. METHODS: The morphology of rabbit and human collateral ligament nerves was examined by silver impregnation. Immunohistochemistry was performed on rabbit and rat collateral ligaments to determine the presence of peptidergic nerves in these tissues. A 6-week gap injury was performed on three rabbit medial collateral ligaments, and the localisation of peptidergic nerves in these tissues was determined. RESULTS: Irrespective of species or type of ligament examined, the greatest density of nerve fibres was found in the epiligament. Nerve fibres commonly accompanied blood vessels along the long axis of the ligament and then entered the substance of the tissue before ramifying in the deeper layers. Substance P and calcitonin gene-related peptide-immunoreactive nerve fibres were found in the collateral ligaments of the rat and rabbit. Injured ligaments showed a higher than normal level of immunoreactivity in and around the healing zone; however, the nerve fibres appeared tangled and truncated. CONCLUSIONS: Like other structures in knee joints, collateral ligaments possess a complex nerve supply. The presence of peptidergic nerves suggests that ligaments may be susceptible to neurogenic inflammation and may be centres of articular nociception.

Aged↗

PubMed1997

Spatial heterogeneity of the effects of calcitonin gene-related peptide (CGRP) on the microvasculature of ligaments in the rabbit knee joint.

1. Experiments were performed in anaesthetized rabbits to examine the effects of calcitonin gene-related peptide (CGRP) and the CGRP antagonist CGRP8-37 on blood flow to the medial collateral ligament of the knee joint. 2. Topical application of CGRP (10(-13) to 10(-9) mol) to the exposed external surface of eight knee joints resulted in dose-dependent dilatation of vessels in both the ligament and the joint capsule. The magnitude of this response varied significantly in different regions of the medial collateral ligament, with the 10(-9) mol dose of CGRP giving the maximum response (101.5 +/- 25.3% increase) at the femoral insertion site of the medial collateral ligament and lowest (23.1 +/- 8.8%) at the tibial insertion site. 3. Topical application of CGRP8-37 (0.1, 1 and 10 nmol) produced dose-dependent constriction of vessels in the ligament and the joint capsule in five knees, with a trend towards the greatest effect occurring at the femoral insertion site (45.8 +/- 8.1% reduction in blood flow). With the 10 nmol dose, the vasoconstrictor response at the femoral insertion site differed significantly (P<0.05) from the responses obtained at the tibial insertion and joint capsule sites. 4. Topical application of CGRP8-37 (0.1, 1 and 10 nmol) to four chronically denervated knees produced substantially smaller vasoconstrictor responses at all sites. At the femoral insertion site, where 10 nmol CGRP8-37 normally produces a 45.8 +/- 8.1% reduction in blood flow (n=8), ten days following denervation this response was reduced to 6.5 +/- 6.1%, this difference being significant (P=0.01). 5. Adrenaline was applied topically to augment blood vessel tone, in order to establish how effectively co-administration of CGRP would offset this increase in tone. Adrenaline (10(-10) mol) produced vasoconstriction at all sites (n=6). In the capsule this vasoconstriction was virtually abolished when CGRP (10(-9) mol) was co-administered with adrenaline but in the ligament vasodilatation occurred at all sites. This vasodilatation was significantly greater at the femoral insertion site compared to the tibial insertion and mid ligament sites (P<0.05 for both) and the capsule (P<0.01). 6. Topical application of substance P (10(-10) or 10(-9) mol) failed to elicit dilatation of ligament blood vessels. 7. These results suggest that endogenous CGRP may play an important role in regulating blood flow to different structures in and around the knee joint.

Animals↗

PubMed1996

Inhibition of nitric oxide production during electrical stimulation of the nerves supplying the rat knee joint.

A rôle for nitric oxide in the regulation of knee joint blood flow in the male anaesthetised rat was investigated using laser Doppler perfusion imaging. Intravenous infusion of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) at a rate of 0.1 and 1 mg/kg per h caused an initial, but transient, rise in vascular resistance by about 15%. Mean arterial blood pressure was by and large unaffected by both dose of inhibitor during these first 5 min of infusion. The effect of an alternative nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) was also investigated. When 10 mg/kg per h of this drug was infused intravenously, there was a negligible effect on joint vascular resistance for the first 40 min but it then fell by about 15% over the next 20 min of infusion; mean arterial pressure gradually rose throughout administration. Electrical stimulation of the saphenous nerve in control animals elicited a frequency-dependent constriction of articular blood vessels over the range 5-30 Hz. Nerve stimulation at lower frequencies had little effect on joint capsular perfusion. When the nerve was stimulated over the same range of frequencies but in the presence of L-NAME it was found that the frequency response profile was unaffected. However, intravenous infusion of the less potent inhibitor L-NMMA caused a greater vasoconstrictor response to nerve stimulation over all but the lowest frequency tested. The results of these experiments indicate that endogenous nitric oxide may be produced in only very small amounts by the vascular bed of the rat knee joint. This differs markedly from the findings of a previous study in the rabbit knee joint where L-NAME administration resulted in a large and sustained increase in vascular resistance, suggesting substantial and continuous NO release. A unique isoform of the enzyme may possibly occur in the terminals of the nerves supplying the joint whose enzymatic activity is only inhibited by L-NMMA and not L-NAME.

Animals↗