Biomedical subjects

P J Kadowitz

Publications and source records attributed to P J Kadowitz.

At least 19 recordsLinked to original sources

PubMed1999

Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses.

The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVbetagal, expression of the beta-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVbetagal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVbetagal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Responses to propofol in the pulmonary vascular bed of the rat.

BACKGROUND: Although a great deal is known about responses to propofol, controversy remains about its mechanism of action. The present study was undertaken to investigate the direct effects of 2,6-diisopropyl phenol, disodium edetate, and its intralipid emulsion in the rat pulmonary vascular bed and to better understand the mechanisms involved in propofol-mediated responses. METHODS: The effects of N omega-l-nitro-l-arginine benzyl ester (L-NABE), an inhibitor of nitric oxide synthase, of the cyclooxygenase blocker, meclofenamate, and the K + ATP channel antagonist, U-37883A, an ATP-sensitive potassium channel antagonist, on responses to propofol, acetylcholine, nitroglycerin, and isoproterenol were investigated in the isolated blood-perfused rat lung under low tone and high steady-state tone. RESULTS: Propofol produced a dose-dependent decrease in pulmonary arterial perfusion pressure. L-NABE significantly reduced vasodilator responses to acetylcholine, whereas the nitric oxide synthase inhibitor had no significant effect on responses to propofol. Meclofenamate significantly reduced vasodilator responses to arachidonic acid without effecting responses to propofol. Responses to propofol were not significantly changed in the presence of U-37883A, whereas U-37883A reduced vasodilator responses to levcromakalim. Additionally, 2,6-diisopropylphenol in a pure preparation as well as an intralipid preparation similar to propofol emulsion had no significant effect while disodium edetate had a dose-dependent depressor effect under high steady-state tone. CONCLUSION: Propofol has significant vasodilator activity in the pulmonary vascular bed of the rat but responses to propofol are not mediated or modulated by the release of nitric oxide, opening of K + ATP channels, or the release of vasodilator cyclooxygenase products.

Acetylcholine↗

PubMed1999

Adrenomedullin and calcitonin gene-related peptide (CGRP) interact with a common receptor of the CGRP1 subtype in the human adrenal zona glomerulosa.

Frozen sections of normal adrenal glands, obtained from patients undergoing unilateral nephrectomy for kidney cancer, were labeled in vitro with human [125I]ADM(1-52). Autoradiography showed the presence of abundant ADM binding sites in the zona glomerulosa (ZG) and the outermost portion of the zona fasciculata, which were completely displaced by the addition of an excess of cold ADM(1-52). Calcitonin gene-related peptide (CGRP) and the non-selective ligand of the CGRP-receptor subtypes 1 and 2 CGRP(8-37) eliminated [125I]ADM(1-52) binding in the ZG, while the selective ligand of CGRP receptor subtype 2 [Cys(acm)2,7]-CGRP and CGRP(1-8) were ineffective. These findings confirm the presence of ADM binding sites in the human ZG, and provide the first morphological evidence that ADM and CGRP interact with a common receptor of the CGRP1 subtype.

Adrenomedullin↗

PubMed1999

Vasodepressor responses to [D-Ala2]-endomorphin 2 (TAPP) are mediated by an L-NAME-sensitive mechanism in the rat.

Endomorphin 1 and 2 are newly discovered endogenous ligands for the mu-opioid receptor. We recently showed that endomorphin 1 and 2 have vasodepressor activity, and in this study, responses to a novel endomorphin analog [D-Ala2]-endomorphin 2 (TAPP) were investigated in the systemic vascular bed of the rat. Intravenous injections of TAPP, endomorphin 1, and endomorphin 2 decreased systemic arterial pressure in a dose-related manner. Decreases in systemic arterial pressure in response to TAPP were similar to vasodepressor responses to endomorphin 1 and 2 and were not altered by passage of time. Decreases in systemic arterial pressure in response to TAPP, endomorphin 1, and endomorphin 2 were attenuated by the opioid receptor antagonist naloxone (2 mg/kg, i.v.) when the vasodepressor response to the ORL1-receptor agonist nociceptin (orphanin FQ) was not altered. Decreases in systemic arterial pressure in response to TAPP, endomorphin 1 and 2, and acetylcholine were attenuated by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg, i.v.) when decreases in systemic arterial pressure in response to nociceptin and calcitonin gene-related peptide (CGRP) were not altered. These results indicate that TAPP, endomorphin 1, and endomorphin 2 decrease systemic arterial pressure by a naloxone-sensitive mechanism and suggest that the vasodepressor response to TAPP, endomorphin 1 and 2, but not nociceptin, is mediated by the release of nitric oxide.

Amidines↗

PubMed1999

Endothelial cell regrowth and morphology after balloon catheter injury of alloxan-induced diabetic rabbits.

Neointimal thickening after catheter injury has been reported to be influenced by the integrity of the vascular endothelium. We have previously shown that neointimal thickening is significantly reduced in alloxan-induced diabetic New Zealand White rabbits after catheter injury compared with euglycemic rabbits. In the present study, it was hypothesized that endothelial cell regrowth, morphology, and endothelium-dependent vasoreactivity after catheter injury are improved in the diabetic rabbit (glucose >/=400 mg/dl) compared with the euglycemic rabbit. Two weeks after catheter injury, the percent endothelial regrowth was significantly increased in diabetic animals compared with euglycemic animals (32.1 +/- 2 and 15.6 +/- 1, respectively; P < 0.05). The endothelial cell morphology analyzed by scanning electron microscopy was also restored 2 wk after catheter injury in thoracic aortas from the diabetic animals compared with vessels from euglycemic animals. Endothelium-dependent relaxation to ACh in vessels from diabetic and euglycemic rabbits was attenuated 2 wk after injury, and, although improved by 4 and 8 wk, relaxation remained significantly depressed. These results suggest that endothelial cell regrowth and morphology in diabetic animals was improved compared with euglycemic animals; however, endothelium-dependent vasoreactivity remained impaired. Thus the attenuated neointimal thickening seen in the diabetic rabbit may be a function of the rate and degree of regrowth rather than the normalization of ACh-induced relaxation.

Animals↗

PubMed1999

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.

Adrenal Glands↗

PubMed1999

Induction of penile erection by intracavernosal and transurethral administration of novel nitric oxide donors in the cat.

PURPOSE: The effects of novel nitric oxide (NO) donors administered intracavernosally and transurethrally on erectile function in the anesthetized cat were evaluated. MATERIALS AND METHODS: In pentobarbital-anesthetized cats, increases in intracavernosal pressure, penile length, and duration of erectile response were determined after intracavernosal and transurethral injections of novel NO donors (MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO). All parameters were measured after administration of NO donors intracavernosally via a 30-gauge needle and urethrally via a Jelco i.v. catheter in a volume of 200 microliters. Systemic arterial pressure was also assessed in these experiments. All NO donors were compared with a triple-drug control combination comprised of papaverine (1.65 mg.), prostaglandin E1 (0.5 microgram.), and phentolamine (25 micrograms.). RESULTS: MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO induced dose dependent increases in intracavernosal pressure and penile length (p < 0.05) when administered intracavernosally. The increases in cavernosal pressure and penile length were comparable to those observed with the triple-drug control combination. The maximum increase in cavernosal pressure in response to PROLI/NO and PAPA/NO was associated with no significant change in systemic arterial pressure. Transurethral administration of PROLI/NO and PIPERAZI/NO induced dose-dependent increases in cavernosal pressure and penile length (p < 0.05). The response was similar to that of the triple-drug control combination, except that transurethral PROLI/NO and PIPERAZI/NO had no significant effect on systemic blood pressure. CONCLUSIONS: NO donors caused dose-dependent increases in cavernosal pressure when administered intracavernosally and transurethrally. These data suggest further exploration of the use of NO donors for the treatment of erectile dysfunction.

Animals↗

PubMed1999

The influence of candesartan and PD123319 on responses to angiotensin II in the hindquarters vascular bed of the rat.

The effects of the AT1 and AT2 receptor blockers candesartan and PD123319 on hemodynamic responses to angiotensin II (AngII) were investigated in the anesthetized rat. Injections of AngII caused dose-related increases in systemic arterial and in hindquarters perfusion pressure that were reduced by candesartan. The inhibitory effects of candesartan were insurmountable, and a vasodepressor or vasodilator response to AngII was not unmasked. The AT2 receptor antagonist PD 123319 had no effect on increases in systemic arterial and hindquarters perfusion pressure in response to AngII. The present results suggest that pressor responses to AngII are mediated by the activation of AT1 receptors, and that AT2 receptors do not appear to modulate hemodynamic responses to AngII in the anesthetized rat.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Effects of candesartan and PD123319 on responses to angiotensin II in the anesthetized mouse.

The effects of candesartan (30 microg/kg i.v.) and PD123319 (10 mg/kg i.v.) on changes in systemic arterial pressure in response to angiotensin II (AngII) were investigated in the anesthetized mouse. Intravenous injections of AngII caused dose-related increases in systemic arterial pressure. Pressor responses to AngII were attenuated by candesartan but were not altered by PD123319. Neither candesartan nor PD123319 had a significant effect on baseline systemic arterial pressure or on the increase in arterial pressure in response to norepinephrine. The present results suggest that increases in systemic arterial pressure in response to AngII in the anesthetized mouse are mediated by AT1 receptors and that AT2 receptors do not modulate the pressor response to AngII.

Angiotensin II↗

PubMed1999

Analysis of the effects of candesartan on responses to angiotensin II in the hindquarters vascular bed of the cat.

The effects of the nonpeptide angiotensin II (AngII) AT1 receptor blocker candesartan on responses to AngII were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of AngII into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 microg/kg intravenously (i.v.) decreased vasoconstrictor responses to AngII in a surmountable manner. At doses of 30 and 300 microg/kg i.v., candesartan shifted the dose-response curve to AngII to the right in an insurmountable manner, indicating an insurmountable blockade of AT1 receptors. The inhibitory effects of the larger doses of candesartan on responses to AngII were long in duration, and the AT1 receptor blocker had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2alpha, vasopressin, BAY K8644; biphasic responses to endothelin-1; or on vasodilator responses to acetylcholine, albuterol, or levcromakalim. These results indicate that candesartan is a potent and selective angiotensin AT1 receptor blocker that can induce both surmountable and insurmountable AT1 receptor blockade and provide support for the hypothesis that there are "spare" AT1 receptors in the hindquarters vascular bed of the cat.

Angiotensin II↗

PubMed1998

Nociceptin, a novel endogenous ligand for the ORL1 receptor, dilates isolated resistance arteries from the rat.

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein coupled receptor, ORL1. In the present study, responses to nociceptin were investigated in isolated pressurized resistance arteries from the rat mesenteric vascular bed. Nociceptin in bath concentrations of 10(-9)-10(-6) M induced concentration-dependent increases in arterial diameter when the artery was precontracted with U46619; and administration of the structurally related opioid agonists, dynorphin A and met-enkephalin, had no effect on arterial diameter. Vasodilator responses to nociceptin were not altered by the opioid receptor antagonist naloxone or by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine. Responses to nociceptin were not altered by the muscarinic receptor blocking agent atropine or phentolamine, or the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37). These data suggest that nociceptin has direct vasodilator activity that is not dependent upon the activation of a traditional opioid receptor, muscarinic or CGRP receptors, an inhibitory effect on the adrenergic nervous system, or the release of nitric oxide in isolated resistance arteries from the rat mesentery.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1998

R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat.

Responses to the histamine H3 receptor agonist R-(-)-alpha-methyl-histamine were investigated in the mesenteric vascular bed of the cat under constant-flow conditions. Injections of R-(-)-alpha-methyl-histamine and histamine caused dose-related decreases in mesenteric perfusion pressure with R-(-)-alpha-methyl-histamine being 1000-fold less potent than histamine when doses were compared on a nmol basis to take molecular weight into account. Responses to R-(-)-alpha-methyl-histamine were not altered by histamine H1 or H2 receptor antagonists at a time when responses to histamine were significantly reduced. The histamine H3 receptor antagonist thioperamide reduced responses to R-(-)-alpha-methyl-histamine but was without effect on responses to histamine [6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoro-methylphenyl)heptaneca rdoxamide dimaleate] (HTMT), or dimaprit. These data suggest the presence of histamine H1, H2 and H3 receptors mediating vasodilation in the mesenteric vascular bed. Responses to R-(-)-alpha-methyl-histamine and histamine were reduced by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) but were not altered by the cyclooxygenase inhibitor meclofenamate, the alpha-adrenoceptor blocker phentolamine, or adrenergic nerve terminal depleting agent reserpine. The present data suggest that histamine H3 receptors mediating vasodilation are present in the mesenteric vascular bed and that responses are mediated by the release of nitric oxide but not vasodilator prostaglandins or an effect on the adrenergic nervous system. These results indicate that vasodilator responses to histamine involve the activation of histamine H1 and H2 receptors and the release of nitric oxide in the mesenteric vascular bed of the cat.

Animals↗

PubMed1998

Endomorphin 1 and 2, endogenous mu-opioid agonists, decrease systemic arterial pressure in the rat.

The endogenous opioid peptides, endomorphin 1 and 2, are newly isolated, potent, and selective mu-opioid receptor agonists. In the present study, responses to endomorphin 1 and 2 were investigated in the systemic vascular bed of the rat. Endomorphin 1 and 2 induced dose-related decreases in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, endomorphin 1 and 2 were approximately equipotent with each other and with the ORL1 ligand, nociceptin (orphanin FQ), and were about 10-fold more potent than met-enkephalin in decreasing systemic arterial pressure. Vasodepressor responses to endomorphin 1 and 2 and met-enkephalin, but not to nociceptin, were inhibited by the opioid receptor antagonist, naloxone. These results demonstrate that endomorphin 1 and 2 produce significant naloxone-sensitive decreases in systemic arterial pressure.

Analgesics, Opioid↗

PubMed1998

Endomorphin 1 and 2, the endogenous mu-opioid agonists, produce biphasic changes in systemic arterial pressure in the cat.

The endogenous peptides endomorphin 1 and 2 are newly isolated, potent, selective mu-opioid receptor agonists. In the present study, responses to the endomorphin peptides were investigated in the systemic vascular bed of the cat. Endomorphin 1 and 2 induced dose-related biphasic changes in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. The biphasic responses to endomorphin 1 and 2 were characterized by an initial increase followed by a decrease in systemic arterial pressure. In terms of relative vasodepressor activity, endomorphin 1 and 2 were similar in potency and approximately 10-fold less potent than the ORL1 ligand nociceptin (orphanin FQ) in decreasing systemic arterial pressure. The biphasic arterial pressure changes in response to endomorphin 1 and 2 were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. These results demonstrate that endomorphin 1 and 2 produce significant, naloxone-sensitive changes in systemic arterial pressure that are characterized by an initial increase followed by a secondary decrease in arterial pressure in the cat.

Analgesics, Opioid↗

PubMed1998

Inhibitory effect of adrenomedullin (ADM) on the aldosterone response of human adrenocortical cells to angiotensin-II: role of ADM(22-52)-sensitive receptors.

Human adrenomedullin (ADM) is a 52-amino acid hypotensive peptide, which possesses a disulfide bridge-formed six-membered ring in 16-21 position. The ring structure, and both the N- and C-terminal amino-acid sequences seem to play a key role in the vascular effects of ADM(1-52), and we have investigated whether the same is true for the inhibitory effect of this peptide on the aldosterone response of zona glomerulosa (ZG) cells to angiotensin-II (ANG-II). Autoradiography showed the presence of abundant [125I]ADM(1-52) binding sites in the ZG of human adrenals, which were displaced not only by cold ADM(1-52), but also by both ADM(13-52) and ADM(22-52); ADM fragments 1-12, 15-22 and 16-31 were ineffective. ADM(1-52) and ADM(13-52), but not other fragments, concentration-dependently inhibited ANG-II-stimulated aldosterone secretion of dispersed human adrenocortical cells. The aldosterone antisecretagogue actions of ADM(1-52) and ADM(13-52) were counteracted by ADM(22-52) in a concentration-dependent manner, while other ADM fragments were ineffective. In light of these findings the following conclusions could be drawn: (i) human ZG cells are provided with ADM(22-52)-sensitive receptors; (ii) the six-membered ring structure and the C-terminal, but not N-terminal, amino-acid sequence are both essential for ADM(1-52) to exert its antimineralocorticoid action; and probably (iii) the C-terminal sequence is needed for ADM(1-52) to bind its ZG receptors, while the ring structure is required for the receptor activation.

Adrenal Cortex↗

PubMed1998

Pharmacologic management of peripheral vascular disease.

Although our understanding of the pathophysiology of atherosclerosis and peripheral vascular disease continues to grow, we have yet to discover a medication that can safely and efficaciously be given to most claudicants that will alleviate their symptoms to prevent disease progression. Many patients with intermittent claudication improve or remain stable without therapy if they attempt to alter their risk factors (e.g., control of diabetes, smoking cessation, lowering of cholesterol levels). However, many require concomitant drug therapy to alleviate symptoms of PVD, and some require surgical intervention. Even with the recent advances in therapeutic development and the promise of agents currently in clinical trials, the questions of who to treat, when treatment should begin, and which agent to use remain uncertain.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Endomorphin 1 and 2 have vasodepressor activity in the anesthetized mouse.

The endogenous peptides endomorphin 1 and 2 are newly discovered, potent, selective mu-opioid receptor agonists. In the present study, we investigated responses to the endomorphin peptides in the systemic vascular bed of the anesthetized mouse. Endomorphin 1 and 2 induced dose-related decreases in mean arterial pressure when injected in doses of 3-100 nmol/kg i.v. Mean arterial pressure decreased 14 +/- 4, 23 +/- 4, and 42 +/- 5 mm Hg at the 10, 30, and 100 nmol/kg doses, respectively, of endomorphin 1 (n = 5-7; p < 0.05), and similar changes were observed in response to endomorphin 2. In terms of relative vasodepressor activity, endomorphin 1 and 2 were about equipotent and about threefold more potent than the mu-opioid selective agonist PL017 in decreasing mean arterial pressure; all three peptides decreased heart rate. The time-course of the vasodepressor responses to endomorphin 1 and 2 were similar in rate of onset and decay. Vasodepressor responses to endomorphin 1 and 2 and PL017 but not to nociceptin were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. When compared in the mouse and rat, the relative decreases in systemic arterial pressure in response to i.v. injections of endomorphin 1 and 2 did not differ greatly. However, the duration of the vasodepressor response was significantly longer in the rat. These results demonstrate that endomorphin 1 and 2 have significant, naloxone-sensitive, vasodepressor activity in the mouse.

Analysis of Variance↗

PubMed1998

Nitric oxide release mediates vasodilator responses to endomorphin 1 but not nociceptin/OFQ in the hindquarters vascular bed of the rat.

We have recently shown that endomorphin 1, an endogenous ligand for the mu-opioid receptor, and nociceptin (Orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have substantial vasodilator activity in the hindquarters vascular bed of the rat. In the present study, the role of nitric oxide, vasodilator prostaglandins, and the opening of K+ ATP channels in mediating vasodilator responses to endomorphin 1, PL017, and DAMGO was investigated in the regional vascular bed in the rat. Under constant-flow conditions, injections of the mu-selective agonists endomorphin 1, 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, and the endothelium-dependent vasodilators acetylcholine and adrenomedullin were attenuated by the nitric oxide synthase inhibitor L-NAME (50 mg/kg IV) at a time when vasodilator responses to nociceptin/OFQ were not altered. Vasodilator responses to isoproterenol and prostaglandin E1, agents known to increase cAMP levels, and the nitric oxide donor DEA/NO were not altered by the nitric oxide synthase inhibitor. Responses to endomorphin 1, PL017, DAMGO, and nociceptin/OFQ were not altered by sodium meclofenamate at a time when vasodilator responses to arachidonic acid were reduced significantly or after administration of U-37883A at a time when vasodilator responses to levcromakalim were reduced significantly. The results of these studies indicate that responses to endomorphin 1, 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 the opening of K+ATP channels the hindquarters vascular bed.

Adamantane↗