Endothelial dysfunction is present only in the microvasculature and microcirculation of early diffuse systemic sclerosis patients.

OBJECTIVES: To evaluate endothelial function and vascular stiffness in large, medium, small and microcirculatory blood vessels in very early diffuse systemic sclerosis (SSc). METHODS: We studied consecutive early diffuse SSc patients, defined as <2 years from first SSc symptom who did not have a prior cardiovascular event. Age, gender and race-matched controls were recruited. All underwent assessment of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) brachial flow-mediated dilation (FMD), digital peripheral artery tonometer (EndoPAT) assessment and laser speckle contrast imaging (LSCI). RESULTS: Fifteen early diffuse SSc and controls were evaluated. The average age was 49 years, 63% were female and 93% were Caucasian. There were no differences in body mass index, hypertension, diabetes or hyperlipidaemia between controls and SSc patients. Mean SSc disease duration was 1.3 years. In the large central vessels, there was no difference in aortic PWV (p=0.71) or carotid IMT (p=0.92) between SSc patients and controls. Similarly, there was no difference in endothelial dysfunction with brachial artery FMD after ischaemia (p=0.55) and nitroglycerin administration (p=0.74). There were significantly lower values for digital EndoPAT measures (p=0.0001) in SSc patients. LSCI revealed a distinct pattern of microcirculatory abnormalities in response to ischaemia in SSc patients compared to controls. Imaging demonstrated a blunted microcirculatory hyperaemia of the hand with greater subsequent response to nitroglycerin. CONCLUSIONS: These findings suggest that the earliest endothelial changes occur in smaller arterioles and microvascular beds, but not in medium or macrovascular beds, in early diffuse SSc.

NADPH oxidase-derived ROS and the regulation of pulmonary vessel tone.

Pulmonary vessel constriction results from an imbalance between vasodilator and vasoconstrictor factors released by the endothelium including nitric oxide, endothelin, prostanoids, and reactive oxygen species (ROS). ROS, generated by a variety of enzymatic sources (such as mitochondria and NADPH oxidases, a.k.a. Nox), appear to play a pivotal role in vascular homeostasis, whereas elevated levels effect vascular disease. The pulmonary circulation is very sensitive to changes in the partial pressure of oxygen and differs from the systemic circulation in its response to this change. In fact, the pulmonary vessels contract in response to low oxygen tension, whereas systemic vessels dilate. Growing evidence suggests that ROS production and ROS-related pathways may be key factors that underlie this differential response to oxygen tension. A major emphasis of our laboratory is the role of Nox isozymes in cardiovascular disease. In this review, we will focus our attention on the role of Nox-derived ROS in the control of pulmonary vascular tone.

Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of neurohormonal activation that is useful in the diagnosis and prognosis of various forms of pulmonary arterial hypertension (PAH). We sought to characterise and compare NT-proBNP in a cohort of PAH related to systemic sclerosis (PAH-SSc) and idiopathic PAH (IPAH) patients. NT-proBNP levels, collected from PAH-SSc and IPAH patients followed prospectively, were compared and correlated with haemodynamic variables. Cox proportional hazard models were created to assess the predictive value of NT-proBNP. 98 patients (55 PAH-SSc, 43 IPAH) were included. Haemodynamics were similar, except for lower mean pulmonary arterial pressure in PAH-SSc. NT-proBNP levels were significantly higher in PAH-SSc (3,419+/-3,784 versus 1,393+/-1,633 pg x mL(-1); p<0.01) and were more closely related to haemodynamics in PAH-SSc than IPAH. 28 patients died. NT-proBNP predicted survival (hazard ratio (HR) 3.18; p<0.01) in the overall cohort; however, when stratified by group, predicted survival only in PAH-SSc (HR 3.07, p<0.01 versus 2.02, p = 0.29 in IPAH). This is the first description showing NT-proBNP levels are 1) significantly higher in PAH-SSc than IPAH despite less severe haemodynamic perturbations, and 2) stronger predictors of survival in PAH-SSc, suggesting that neurohormonal regulation may differ between PAH-SSc and IPAH. Future studies to define pertinent mechanisms are warranted.

Assessment of pulmonary vasculature and right heart by invasive haemodynamics and echocardiography.

Understanding the haemodynamical profile of the right ventricle and pulmonary circulation is critical to not only the initial evaluation of, but also the continued management of pulmonary hypertension. Despite advances in non-invasive imaging techniques, right heart catheterisation (RHC) remains the gold standard for diagnosis of pulmonary hypertension and its various causes. Even so, integration of invasive haemodynamical data with the echo-Doppler exam provides the most comprehensive assessment of the pathophysiology of pulmonary hypertension in the individual patient. Here, we review technical aspects of basic RHC as well as specialised procedures including exercise and fluid challenge in the evaluation of pulmonary hypertension. Interpretation of data in the context of pulmonary vascular disease is discussed. Echocardiographical assessment of the right ventricular structure and function in pulmonary vascular disease are discussed along with the integration of haemodynamical and echocardiographical data in the clinical context.

Right heart function and haemodynamics in pulmonary hypertension.

The primary challenge in the care of the patient with advanced pulmonary arterial hypertension (PAH) is right ventricular dysfunction with concomitant right heart failure. Right heart function is closely tied to survival in this disease, and there is a growing interest in the study of this unique structure. While echocardiography and cardiac magnetic resonance (CMR) have augmented our ability to image the right ventricle (RV), the primary means of assessing right heart function remains right heart catheterisation. Several of the currently available treatments for PAH have been shown to have effects on the RV, not just the pulmonary vasculature, and, in future, therapies aimed at optimizing right ventricular function may allow better outcomes in this challenging disease. New directions in right ventricular assessment including measurement of pulmonary vascular impedance and more widespread availability of CMR may allow greater knowledge about this little studied, yet highly important, right side of the heart.

In vivo gene transfer of prepro-calcitonin gene-related peptide to the lung attenuates chronic hypoxia-induced pulmonary hypertension in the mouse.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and in modulating pulmonary vascular responses to chronic hypoxia; however, the effects of adenovirally mediated gene transfer of CGRP on the response to hypoxia are unknown. METHODS AND RESULTS: In the present study, an adenoviral vector encoding prepro-CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP on increases in PVR, right ventricular mass (RVM), and pulmonary vascular remodeling that occur in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP, followed by 16 days of chronic hypoxia (FIO(2) 0.10), increased lung CGRP and cAMP levels. The increase in pulmonary arterial pressure (PAP), PVR, RVM, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP, whereas systemic pressure was not altered while in chronically hypoxic mice, angiotensin II and endothelin-1-induced increases in PAP were reduced, whereas decreases in PAP in response to CGRP and adrenomedullin were not changed and decreases in PAP in response to a cAMP phosphodiesterase inhibitor were enhanced by AdRSVCGRP. CONCLUSIONS: In vivo CGRP lung gene transfer attenuates the increase in PVR and RVM, pulmonary vascular remodeling, and pressor responses in chronically hypoxic mice, suggesting that CGRP gene transfer alone and with a cAMP phosphodiesterase inhibitor may be useful for the treatment of pulmonary hypertensive disorders.

Pharmacotherapy for erectile dysfunction.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. An estimated 20-30 million men suffer from some degree of sexual dysfunction. The past 20 years of research on erectile physiology have increased our understanding of the biochemical factors and intracellular mechanisms responsible for corpus cavernosal smooth muscle contraction and relaxation, and revealed that ED is predominantly a disease of vascular origin. Since the advent of sildenafil (Viagra), there has been a resurgence of interest in ED, and an increase in patients presenting with this disease. A thorough knowledge of the physiology of erection is essential for future pharmacological innovations in the field of male ED.

Adrenomedullin enhances cell proliferation and deoxyribonucleic acid synthesis in rat adrenal zona glomerulosa: receptor subtype involved and signaling mechanism.

The effect of adrenomedullin (ADM) on the proliferative activity of the rat adrenal cortex has been investigated in vivo, using an in situ perfusion technique of the intact left gland. ADM and other chemicals were dissolved in the perfusion medium, and the perfusion was continued for 180 min. ADM infusion concentration dependently increased the mitotic index and [3H]thymidine incorporation into DNA in the zona glomerulosa (ZG; the maximal effective concentration was 10(-8) M), but not in inner adrenocortical layers, where basal proliferative activity was negligible. The effect of 10(-8) M ADM was equipotently counteracted by both the calcitonin gene-related peptide (CGRP) type 1 receptor antagonist CGRP-(8-37) and ADM-(22-52). The adenylate cyclase inhibitor SQ-22536 (10(-4) M), the cAMP blocker Rp-cAMP-S (10(-3) M), and the protein kinase A inhibitor H-89 (10(-5) M), although counteracting the ZG proliferogenic action of 10(-9) M ACTH, did not affect the 10(-8) M ADM-elicited increase in ZG DNA synthesis. Similar results were obtained using the phospholipase C inhibitor U-73122 (10(-5) M), the inositol-1,4,5-trisphosphate antagonist D,L-myo-inositol-1,4,5-trisphosphothiate (10(-4) M), and the protein kinase C inhibitor calphostin C (10(-5) M), which, however, significantly inhibited the ZG proliferogenic effect of 10(-9) M angiotensin II. The growth-promoting action of 10(-8) M ADM was not affected by the phospholipase A2 inhibitor AACOCF3 (10(-5) M), the cyclooxygenase (COX) inhibitor indomethacin (10(-5) M), or the mixed COX/lipoxygenase inhibitor phenidone (10(-5) M). In contrast, the ZG proliferogenic effect of 10(-8) M ADM was abolished by either the tyrosine kinase (TK) inhibitor tyrphostin-23 (10(-5) M) or the mitogen-activated protein kinase (MAPK) antagonists PD-98059 and U0216 (10(-4) M). ADM (10(-8) M) stimulated TK and p42/p44 MAPK activity in dispersed ZG, but not ZF, cells, and the effect was reversed by either 10(-6) M CGRP-(8-37) and ADM-(22-52) or preincubation with 10(-5) M tyrphostin-23. Collectively, our findings indicate that 1) ADM stimulates cell proliferation in the rat ZG, through CGRP-(8-37)- and ADM-(22-52)-sensitive receptors, probably of the CGRP1 subtype; and 2) the mitogenic effect of ADM is mediated by activation of the TK-MAPK cascade, without any involvement of the adenylate cyclase/protein kinase A-, phospholipase C/protein kinase C-, and COX- or lipoxygenase-dependent signaling pathways.

Analysis of the effects of candesartan in the mesenteric vascular bed of the cat.

The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 microg/kg i.v.. After administration of the AT1 receptor antagonist in a dose of 3 microg/kg i.v., the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT1 receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, alpha,beta-methylene ATP, adenosine, acetylcholine, and bradykinin. Treatment with the AT2 receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan on responses to angiotensin II. Candesartan also decreased pressor responses to angiotensin III and IV with a parallel shift at the low dose and a nonparallel shift to the right of the dose-response curve at the high dose. These results indicate that candesartan is a potent, selective, long-acting AT1 receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.

Catecholamine release mediates pressor effects of adrenomedullin-(15-22) in the rat.

Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene-related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg i.v. increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene-related peptide and human amylin, human calcitonin gene-related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of alpha-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.

Proadrenomedullin N-terminal 20 peptide (PAMP), acting through PAMP(12-20)-sensitive receptors, inhibits Ca2+-dependent, agonist-stimulated secretion of human adrenal glands.

Proadrenomedullin N-terminal 20 peptide (PAMP) is a 20-amino acid hypotensive peptide expressed in the adrenal medulla. We investigated the localization and function of PAMP receptors in the human adrenal gland. Autoradiography showed the presence of [125I]PAMP-binding sites in both zona glomerulosa and adrenal medulla that were displaced by cold PAMP and PAMP(12-20) but not by other preproadrenomedullin-derived peptides. PAMP, but not PAMP(12-20), counteracted, in a concentration dependent manner, both aldosterone response of zona glomerulosa cells and catecholamine response of adrenal medulla cells to BAYK-8644, the selective agonist of voltage-activated Ca2+ channels, as well as to K+ and angiotensin II. PAMP(12-20) partially reversed this antisecretagogue effect of PAMP. Collectively, these findings suggest (1) that PAMP inhibits Ca2+-dependent, agonist-stimulated aldosterone and catecholamine secretion, acting via specific receptors and through a mechanism involving the impairment of Ca2+ influx; and (2) that PAMP(12-20) acts as a weak antagonist of PAMP receptors, thereby suggesting that both C- and N-terminal sequences of the PAMP molecule are required for this peptide to exert its antisecretagogue action on the human adrenal gland.

Endothelin-1[1-31], acting as an ETA-receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells.

Endothelin-1 (ET-1)[1-31] is a novel hypertensive peptide that mimics many of the vascular effects of the classic 21 amino acid peptide ET-1[1-21]. However, at variance with ET-1[1-21] that enhances aldosterone secretion from cultured rat zona glomerulosa (ZG) cells by acting via ETB receptors, ET-1[1-31] did not elicit such effect. Both ET-1[1-21] and ET-1[1-31] raised the proliferation rate of cultured ZG cells, the maximal effective concentration being 10(-8) M. This effect was blocked by the ETA-receptor antagonist BQ-123 and unaffected by the ETB-receptor antagonist BQ-788. Quantitative autoradiography showed that ET-1[1-21] displaced both [(125)I]PD-151242 binding to ETA receptors and [(125)I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1-31] displaced only [(125)I]BQ-3020 binding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of ET-1[1-31], while the protein kinase-C (PKC) inhibitor calphostin-C significantly reduced it. ET-1[1-31] (10(-8) M) stimulated TK and MAPK activity of dispersed ZG cells, an effect that was blocked by BQ-123. The stimulatory action of ET-1[1-31] on TK activity was annulled by tyrphostin-23, while that on MAPK activity was reduced by calphostin-C and abolished by either tyrphostin-23 and PD-98059. These data suggest that ET-1[1-31] is a selective agonist of the ETA-receptor subtype, and enhances proliferation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade.

Safety of over-the-counter inhalers for asthma: report of the council on scientific affairs.

The occasional use of over-the-counter (OTC) epinephrine inhalers appears to be safe and effective when used according to labeled instruction by individuals with mild, intermittent asthma. However, gross misuse of these products can cause severe adverse reactions, including death. Limited survey data suggest that approximately 20% of individuals using OTC epinephrine inhalers have mild-to-moderate persistent asthma. According to recent consensus guidelines, these individuals should be under a physician's care and receiving corticosteroid therapy. If these products continue to be marketed, labeling should be strengthened to better educate users about appropriate and inappropriate use of OTC epinephrine inhalers intended for patients with mild, intermittent asthma.

Vasodilator responses to the endomorphin peptides, but not nociceptin/OFQ, are mediated by nitric oxide release.

The endomorphin peptides, endogenous ligands for the mu-opioid receptor, and nociceptin (orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have substantial vasodilator activity in the rat. The roles of nitric oxide, vasodilator prostaglandins, and the opening of K+ATP channels in mediating vasodilator responses to these novel agonists were investigated in the hindquarters vascular bed of the rat. Under constant-flow conditions, injections of the mu-selective agonists, endomorphin 1 and 2, PL017 ([N-MePhe3, D-Pro4]-morphiceptin), and DAMGO, and the ORL1 receptor agonist, nociceptin/OFQ, produced dose-dependent decreases in hindquarters perfusion pressure. Vasodilator responses to endomorphin 1, PL017, and DAMGO were attenuated by the nitric oxide synthase inhibitor L-NAME at a time when vasodilator responses to nociceptin/OFQ were not altered. Responses to endomorphin 1 and 2, PL017, DAMGO, and nociceptin/OFQ were not altered by the cyclooxygenase inhibitor sodium meclofenamate or the K+ATP channel blocker U-37883A. The results of these studies indicate that responses to endomorphin 1 and 2, PL017, and DAMGO are mediated in large part by the release of nitric oxide, while responses to nociceptin/OFQ are mediated by an L-NAME-insensitive mechanism. Moreover, these results demonstrate that responses to these peptides are not mediated by the release of vasodilator prostaglandins or K+ATP channel opening in the hindquarters vascular bed.

Analysis of cardiovascular responses to PACAP-27, PACAP-38, and vasoactive intestinal polypeptide.

Responses to pituitary adenylate cyclase polypeptide (PACAP)-27, PACAP-38, and vasoactive intestinal peptide (VIP) were compared in the peripheral and pulmonary vascular beds of the cat and in the isolated perfused neonatal pig heart. Intravenous injections of PACAP-27 and PACAP-38 produced biphasic changes in systemic arterial pressure whereas iv injections of VIP caused only decreases in arterial pressure. When blood flow to the hind limb and mesenteric vascular beds was maintained constant, PACAP-27 and PACAP-38 caused dose-related biphasic changes in perfusion pressure, whereas VIP only decreased perfusion pressure. PACAP-27 was approximately threefold more potent than PACAP-38, and the pressor component of the biphasic response was blocked by alpha-adrenergic antagonists and adrenalectomy. PACAP-27, PACAP-38, and VIP produced decreases in pulmonary vascular resistance, and all three peptides had significant vasodilator activity in the isolated perfused neonatal pig heart. Although all three peptides decreased coronary vascular resistance, only PACAP-27 and PACAP-38 increased left ventricular contractility, with PACAP-27 approaching isoproterenol in potency. The results of these experiments show that PACAP-27, PACAP-38, and VIP have significant effects on vasomotor tone that depend on the vascular bed studied and the contribution of adrenal catecholamines.

Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

Nociceptin, an endogenous ligand for the ORL1 receptor, decreases cardiac output and total peripheral resistance in the rat.

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein coupled receptor, ORL1. In the present study, responses to intravenous injections of nociceptin were investigated in the systemic vascular bed of the rat. Nociceptin induced dose-related decreases in systemic arterial pressure and total peripheral resistance when injected in doses of 1-30 nmol/kg i.v.. Nociceptin decreased heart rate and in doses of 10 and 30 nmol/kg i.v., significantly decreased cardiac output. In terms of relative vasodilator activity, nociceptin was approximately 10-fold less potent than the beta-adrenergic receptor agonist isoproterenol. These data show that nociceptin has novel vasodilator activity in the systemic vascular bed of the rat.

Nociceptin, an endogenous ligand for the ORL1 receptor, has vasodilator activity in the hindquarters vascular bed of the rat.

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the G-protein coupled, opioid-like receptor ORL1. In the present study, responses to intra-arterial injections of nociceptin were investigated in the hindquarters vascular bed of the rat. Under constant-flow conditions nociceptin induced dose-dependent decreases in hindquarters perfusion pressure when injected in doses of 1-30 nmol into the hindquarters perfusion circuit. The decreases in hindquarters perfusion pressure were rapid in onset and pressure returned to control values over a 3-6 min period. In terms of relative vasodilator activity, nociceptin was approximately equipotent to the nitric oxide donor, DEA/NO, and 30-fold less potent than adrenomedullin. These data demonstrate that nociceptin has significant vasodilator activity in the hindquarters vascular bed of the rat.

Decreases in systemic arterial and hindquarters perfusion pressure in response to nociceptin are not inhibited by naloxone in the rat.

Nociceptin, the endogenous ligand for the ORL1 receptor, has been shown to decrease systemic arterial and hindquarters perfusion pressures in the rat. The present study was undertaken to determine if decreases in systemic arterial and hindquarters perfusion pressures, in response to nociceptin, are mediated by a naloxone-sensitive mechanism. Injections of nociceptin decreased systemic arterial and hindquarters perfusion pressures in a dose-related manner. The decreases in systemic arterial and hindquarters perfusion pressure in response to nociceptin were not altered by the administration of naloxone in a dose of 2 mg/kg i.v. Met-enkephalin decreased systemic arterial and hindquarters perfusion pressures and responses to the opioid receptor agonist were significantly reduced by naloxone, whereas decreases in systemic arterial pressure in response to the nitric oxide donor, DEA/NO, were not altered. The results of the present study show that decreases in systemic arterial and hindquarters perfusion pressure in response to nociceptin are not mediated by a naloxone-sensitive mechanism in the rat.