Rabbit Renal Artery Research Articles

Characterization of nitric oxide- and prostaglandin-independent relaxation in response to acetylcholine in rabbit renal artery.

1. We investigated the characterization of acetylcholine (ACh)-induced NG-nitro-L-arginine methyl ester (L-NAME)- and indomethacin (IND)-resistant relaxations, which can be mediated by endothelium-derived hyperpolarizing factor (EDHF), in rabbit renal arterial rings. 2. The relaxations were inhibited by SKF 525A, a cytochrome P450 inhibitor, but were not affected by other inhibitors, namely clotrimazole, 17-octadecynoic acid and alpha-naphthoflavone. Furthermore, 11,12-epoxyeicosatrienoic acid, a cytochrome P450 metabolite, did not relax arterial rings. 3. Arterial relaxations were significantly attenuated by charybdotoxin and iberiotoxin, but not by apamin, all K+ channel blockers. 4. In a sandwich bioassay experiment, ACh-induced L-NAME- and IND-resistant relaxations were not transferred to the detector site. 5. Relaxations were also significantly attenuated by 1-heptanol and 18 alpha-glycyrrhetinic acid, gap junctional coupling inhibitors. 6. These results indicate that, in the rabbit renal artery, L-NAME- and IND-resistant relaxations are mediated by factors other than cytochrome P450-derived arachidonic acid metabolites, which may be able to diffuse into the lumen but be partly transferred via myoendothelial gap junctions to adjacent vascular smooth muscle cells and relax muscles by opening high-conductance Ca(2+)-activated K+ channels.

Prevention of contrast medium-induced renal vasospasm by phosphodiesterase inhibition.

This study investigated the involvement of cyclic adenosine monophosphate (cAMP) in contrast medium-induced renal vasomotor effects and the efficacy of selective phosphodiesterase (PDE) inhibitors influencing cAMP in preventing contrast medium-induced renal vasospasm. Isometric contractions of rabbit renal artery rings were subjected to increasing concentrations of the ionic contrast medium sodium/meglumine diatrizoate (DIA) and the nonionic contrast media iopamidol (IOP) and iodixanol (IOD) and compared with a potassium chloride control. Subsequently increasing concentrations of the nonselective phosphodiesterase inhibitors theophylline and papaverine and the following selective phosphodiesterase inhibitors were applied: vinpocetine, trequinsin, zardaverine, rolipram, and dipyridamole (subtypes I-V) before restimulation of the arterial tissue with contrast medium. Diatrizoate, iopamidol, and iodixanol induced contractions up to 30%, 15%, and 3.5% of the potassium chloride control, respectively. All phosphodiesterase inhibitors markedly inhibited the contrast medium-induced contractions in a dose-dependent manner. The selective phosphodiesterase inhibitors rolipram and trequinsin attenuated these contractions significantly more (92% and 94%) than did zardaverine, dipyridamole, and vinpocetine, with an inhibitory potency of 37%, 41%, and 62%, respectively. Nonionic contrast media induced renal vasoconstriction less potently than ionic contrast media. Significant differences in the ability to prevent contrast medium-induced vasoconstriction were observed among the various phosphodiesterase subtypes studied. selective phosphodiesterase inhibition with inhibitor subtypes II and IV showed the most promising results in specifically preventing contrast medium-induced renal vasospasm.

Purinoceptors mediate renal vasodilation by nitric oxide dependent and independent mechanisms

Adenosine triphosphate (ATP) and its metabolites including adenosine modulate renal vascular tone under physiological and pathophysiological conditions. Their effects are brought about by activation of membrane bound P1- and P2-purinoceptors located on smooth muscle and endothelial cells. In this study we analyzed the purinoceptor mediated dilation of rabbit and human renal arteries, and evaluated the possible involvement of endothelium-derived relaxing factors. Segments of rabbit and human renal arteries were incubated and perfused with medium containing indomethacin. After preconstriction, drug induced changes in the vessel diameters were measured by a photoelectric device. ATP (EC50 = 1 mumol/liter), added intraluminally, caused maximal vasodilation of 80 to 100% of the preconstriction response in both species. This effect was inhibited by the P1-purinoceptor antagonist 8-p-(sulphophenyl)theophylline (100 mumol/liter), suggesting that it was in part due to breakdown of ATP to adenosine. The nature of purinoceptor mediated renal vasodilation was studied further in rabbit renal arteries. Adenosine (EC50 = 1 mumol/liter) as well as the P2Y-receptor agonists ADP beta S (EC50 = 0.4 mumol/liter) and 2-MeSATP (EC50 = 0.2 mumol/liter) dilated the arteries by 80 to 100%. The effects of 2-MeSATP, which were to a much lesser extent that of ADP beta S but not that of adenosine, were attenuated by the P2Y-antagonist reactive blue 2 (3 mumol/liter). Removal of the endothelium almost abolished the vasodilation induced by adenosine and ATP. In contrast, these dilator response were only slightly attenuated by the nitric oxide synthase blockers NG-nitro-L-arginine methyl ester and NG-nitro-L-arginine (300 mumol/liter each), whereas acetylcholine and 2-MeSATP induced dilation was markedly reduced by NG-nitro-L-arginine methyl ester. P1-purinoceptors activated by adenosine dilate rabbit renal arteries by an endothelium-derived relaxing factor that appears to be distinct from nitric oxide. In contrast, P2Y-purinoceptor induced renal dilation is mediated by nitric oxide. ATP, the physiological activator of P2Y-purinoceptors, is rapidly broken down to adenosine in rabbit and human renal arteries. Therefore, in rabbit and human renal arteries the vasodilatory effect of exogenous ATP mainly results from P1-purinoceptor activation probably through its breakdown product, adenosine.

Functions of large conductance Ca2+‐activated (BKCa), delayed rectifier (KV) and background K+ channels in the control of membrane potential in rabbit renal arcuate artery

1. The types of K+ channel which determine the membrane potential of arcuate artery smooth muscle cells were investigated by patch-clamp recording from isolated cells and lumenal diameter measurements from intact pressurized renal arcuate arteries. 2. Single cells had a mean resting potential of -38 mV and were depolarized by 130 mM K+ but not by the Cl- channel blocker 4,4'-diisothiocyanatostilbene-2, 2'-disulphonic acid (DIDS). 3. Iberiotoxin did not affect the resting potential but inhibited spontaneous transient hyperpolarizations. Iberiotoxin or 1 mM tetraethylammonium (TEA+) constricted intact arteries. 3,4-Diaminopyridine (3,4-DAP)-sensitive delayed rectifier K+ (KV) channel current was elicited by depolarization but 3,4-DAP did not affect the resting potential or induce constriction in the intact artery. 4. A voltage-independent K+ current was inhibited by >= 0.1 mM barium (Ba2+) and unaffected by iberiotoxin, glibenclamide, apamin, 3,4-DAP and ouabain. In six out of ten cells, 1 mM Ba2+ depolarized the resting potential, while in the other cells the potential was resistant to all of the K+ channel blockers and ouabain. Ba2+ (0.1-1 mM) constricted the intact artery, but 10 microM Ba2+, 1 microM glibenclamide or 100 nM apamin had no effect. 5. The data suggest that resting potential is determined by background K+ channels, one type being Ba2+ sensitive and voltage independent, and another type being poorly defined due to its resistance to any inhibitor. Large conductance Ca2+-activated K+ (BKCa) and KV channels do not determine the resting potential but have separate functions to underlie transient Ca2+-induced hyperpolarizations and to protect against depolarization past about -30 mV.

K(+)-induced dilation of a small renal artery: no role for inward rectifier K+ channels.

To investigate the mechanism of K(+)-induced vasodilation in a small artery from the kidney, with a particular emphasis on the role of inward rectifier K+ channels. Lumen diameter and isometric tension recordings have been made from rabbit renal arcuate artery using pressurised- and wire-myography respectively. In addition, conventional whole-cell and amphotericin-perforated patch whole-cell recordings have been made from single smooth muscle cells isolated from the vessel. Arcuate arteries dilated when the extracellular K+ concentration was raised to 8-10 mM from either zero or a normal physiological level of about 6 mM. The effect was not endothelium-dependent. Application of 0.01-1 mM Ba2+ to block inward rectifier K+ channels had no significant effect on K(+)-induced vasodilation in the arcuate artery, but under the same experimental conditions K(+)-induced dilation of the rat posterior cerebral artery was abolished by Ba2+. In the presence of 60 mM extracellular K+, inward rectifier K(+)-current was detectable in some single smooth muscle cells isolated from arcuate arteries but on average the current density was low (-1.44 pA pF-1 at -60 mV). K(+)-induced vasodilation of the arcuate artery was abolished by 10 microM ouabain and the half-effective concentration of K+ which induced vasodilation was 0.9-1.5 mM. The observations suggest that an increase in the extracellular K+ concentration (up to about 10 mM) dilates the rabbit renal arcuate artery and that the primary mechanism underlying the effect may be stimulation of Na(+)-K+ ATPase in the smooth muscle cell membrane. Inward rectifier K+ channels have a low average density in smooth muscle cells isolated from arcuate arteries and play no significant role in K(+)-induced vasodilation.

Nonadhesive liquid embolic agent: Role of its components in histologic changes in embolized arteries

The authors evaluated the safety and efficacy of a nonadhesive liquid embolic material and the role of its components in histologic changes in embolized arteries. A Eudragit-E mixture (Rohm Chemische Fabrik, Darmstadt, Germany) was made of a cationic copolymer (Eudragit-E) dissolved in an equal volume of absolute ethanol and iopamidol. The Eudragit-E mixture, an ethanol-iopamidol mixture, and an iopamidol-saline mixture were injected into 12 rabbit renal arteries each. Three rabbits from each group were followed up for 1 day, 1 week, 1 month, and 3 months, at which time they were sacrificed. Kidneys were removed for histologic examination. The Eudragit-E mixture occluded all renal arteries without difficulty: the arteries did not recanalize. Histologically, acute vasculitis was caused by both the Eudragit-E and ethanol-iopamidol mixtures, but not by the iopamidol-saline mixture. Small infarctions were elicited with the ethanol-iopamidol mixture but not with the iopamidol-saline mixture. The Eudragit-E mixture is effective and easy to handle. Fifty percent ethanol may play a role in vessel occlusion with Eudragit-E mixture and in acute vasculitis.

P-58 - Nitric oxide and prostaglandin-independent relaxation in response to acetylcholine in rabbit renal artery

P-58 - Nitric oxide and prostaglandin-independent relaxation in response to acetylcholine in rabbit renal artery

Renal Damage induced by Doxorubicin-Lipiodol Emulsion infused into Rabbit Renal Artery: Comparison with CT andHistologic Findings

Renal Damage induced by Doxorubicin-Lipiodol Emulsion infused into Rabbit Renal Artery: Comparison with CT andHistologic Findings

The effect of endotoxin (ET) and methyl-prednisolone (MP) injection on cyclooxygenase levels in the rabbit aorta and renal artery

The effect of endotoxin (ET) and methyl-prednisolone (MP) injection on cyclooxygenase levels in the rabbit aorta and renal artery

P-324 - Existence of postsynaptic dopamine D2-like receptors in the isolated rabbit renal artery

P-324 - Existence of postsynaptic dopamine D2-like receptors in the isolated rabbit renal artery

Attenuation of contrast material-induced renal artery vasoconstriction by nitric oxide donors.

The authors studied the role of the endothelium and associated endothelial pathways in contrast material-induced renal vasoconstriction. Isometric contractions in human and rabbit renal artery rings with intact and denuded endothelium were stimulated with phenylephrine and increasing concentrations of the ionic contrast material diatrizoate, the nonionic contrast materials iopamidol and iomeprol, and the dimeric contrast material iodixanol in a tissue perfusion bath. Rings with intact endothelium were incubated with endothelium-stimulating compounds such as the NO synthetase inhibitor Ng nitro-L-arginine methyl ester (L-NAME) to study the endothelium-mediated vasomotor regulation and the NO-liberating substances molsidomine (SIN-1) and nitroprusside (NPR) to study the endothelial-mediated vasorelaxation before being stimulated with contrast material. Contrast material-induced, dose-dependent, reversible renal artery contractions are dependent on the type of contrast material. No differences in the contractions were found between intact and denuded rings. L-NAME had no effect on contrast material-induced contractions. Contractions were inhibited by the NO donors SIN-1 and NPR. SIN-1 was the most potent inhibitor. Contrast material-induced renal vasoconstriction is endothelium-independent. Selective pharmacologic stimulation of the endothelium by NO donors, however, may still be useful in the prophylaxis of contrast material-induced renal vasoconstriction and, thus, potentially nephrotoxicity.

NG-nitro- l-arginine- and indomethacin-resistant endothelium-dependent relaxation in the rabbit renal artery: effect of hypercholesterolemia

Studies were designed to compare the N G-nitro- l-arginine- and indomethacin-resistant, endothelium-dependent relaxation to acetylcholine in isolated renal artery rings from normal and cholesterol-fed rabbits. It was assumed that the resistant part in response to acetylcholine is mediated by the endothelial-derived hyperpolarizing factor (EDHF). Rabbits were fed normal ( n=15) or cholesterol enriched chow ( n=13, 1% cholesterol for 4 weeks, 0.5% for 12 weeks). In organ chamber experiments, renal artery rings were precontracted with 0.1–1 μM phenylephrine or 35 mM KCl, and relaxed with acetylcholine (0.001–10 μM) in the presence of 10 μM indomethacin. Studies were performed in the presence or absence of: 100 μM N G-nitro- l-arginine ( l-NOARG) to inhibit the nitric oxide pathway, 100 nM charybdotoxin (CTX) or 1 mM tetrabutylammonium (TBA) to inhibit Ca 2+-activated K + channels, and 100 μM SKF 525a to inhibit cytochrome P 450 monoxygenase pathway. In normal arteries, l-NOARG partially inhibited acetylcholine-induced relaxation. The resistant part was almost abolished when the arteries were depolarized with KCl, or when l-NOARG was combined with either CTX, TBA or SKF 525a. In arteries from hypercholesterolemic animals, the relaxation to acetylcholine was only slightly impaired as compared to normal animals. However, in comparison to arteries from normal animals, the l-NOARG-resistant part of acetylcholine-induced endothelium-dependent relaxation was enhanced. It is speculated that differences in the balance between nitric oxide (NO)- and EDHF-mediated control of vascular tone may maintain acetylcholine-induced vasodilatation of the renal artery in hypercholesterolemia.

A neuromodulatory role for neuronal nitric oxide in the rabbit renal artery.

1. The effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on vasoconstrictor responses to transmural electrical nerve stimulation and noradrenaline were examined in the rabbit isolated renal artery with and without an intact endothelium. In addition, the effect of removing the endothelium from the renal artery on vasoconstrictor responses to transmural electrical nerve stimulation and noradrenaline was also investigated. Immunohistofluorescence techniques were carried out to determine if there were any nitrergic nerves supplying the renal artery. 2. The vasoconstriction produced in response to transmural electrical nerve stimulation (2-64 Hz) was significantly enhanced in the presence of L-NAME (3 x 10(-6), 10(-5), 3 x 10(-5) and 10(-4) M). 3. L-NAME (3 x 10(-6), 10(-5), 3 x 10(-5) and 10(-4) M) did not significantly affect the maximum vasoconstriction produced in response to noradrenaline. However, the noradrenaline dose-response curve was significantly shifted to the left by the addition of L-NAME (3 x 10(-6), 10(-5), 3 x 10(-5) and 10(-4) M). 4. The increase in the amplitude of the vasoconstriction, produced in response to transmural electrical nerve stimulation (16 Hz) and noradrenaline (10(-5) M) in the presence of L-NAME (10(-5) M) was not observed when L-arginine (10(-3) M) was added in addition to L-NAME (10(-5) M). 5. Removing the endothelium did not significantly affect the response to transmural electrical nerve stimulation (1-64 Hz). The maximum vasoconstriction in response to noradrenaline was also unaffected by the removal of the endothelium. The pD2 value for noradrenaline obtained from vessels with no endothelium was significantly greater than the pD2 value obtained from vessels with an intact endothelium (5.90 +/- 0.11 and 5.16 +/- 0.03, respectively). 6. On renal artery segments with no endothelium L-NAME (3 x 10(-5) M) significantly enhanced the response to transmural electrical nerve stimulation (2-64 Hz). L-NAME did not affect the maximum response to noradrenaline. However, there was a significant shift to the right of the noradrenaline doseresponse curve in the presence of L-NAME (3 x 10(-5) M). 7. Both nitric oxide synthase-containing and NADPH-diaphorase stained nerves were located on the adventitial-medial border of the rabbit renal artery. 8. The present study has suggested a presynaptic inhibitory action for nitric oxide (probably derived from identified perivascular nitrergic nerves), on perivascular sympathetic vasoconstrictor nerve mediated responses of the rabbit renal artery. In contrast, the enhancement of the response to noradrenaline by L-NAME can be attributed to inhibition of the synthesis of endothelium-derived nitric oxide.

Structure−Activity Relationships in a Series of Orally Active γ-Hydroxy Butenolide Endothelin Antagonists

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

Comparative regulation of ?1-adrenergic receptor mediated contraction in urogenitally derived smooth muscle

Contractility of smooth muscle within mammalian urogenital organ systems has an established role in physiological/pathophysiological functioning of the component structures. Our aim was to examine the direct effect of epidermal growth factor (EGF) on smooth muscle tone as well as its indirect effects in regulating alpha1-adrenoceptor-mediated contraction of the prostate, the vas deferens and renal arteries. Tissues were mounted isometrically, under controlled conditions, and changes in tension in response to treatment with phenylephrine (PE) with or without pretreatment with EGF were recorded on a physiological recorder via force transducers. In the rabbit prostate, EGF potentiated the magnitude of contraction to PE. The potentiation appeared to be dependent on cyclo-oxygenase products. In the human prostate, EGF potentiated the contractile response to PE. EGF had no effect on the PE-induced contraction of the rabbit renal artery and vas deferens. EGF alone did not alter smooth muscle tone in any of the above-mentioned tissues. The main finding of this study is the difference in the regulation by EGF of the alpha1-adrenoceptor-mediated response in smooth muscle of the prostate, from that by the vas deferens and renal artery. The reasons for this difference in response remain to be elucidated. This study may form the basis for further investigation into receptor transregulation and its relevance to symptomatic benign prostatic hyperplasia (BPH).

Extracellular ATP in the human kidney: mode of release and vascular effects.

1. We have previously shown that ATP is a co-transmitter of noradrenaline in the rat kidney. In the present study the release of ATP and noradrenaline from human kidney cortex was investigated. Vascular effects of ATP and stable analogues were tested in human and rabbit isolated renal blood vessels. 2. Sympathetic nerve stimulation (20 Hz for 1 min) in human kidney slices released 89 +/- 16 fmol noradrenaline per mg wet weight and 99 +/- 20 fmol ATP per mg wet weight in controls (n = 12). The Na+ channel blocker tetrodotoxin (1 microM) abolished ATP and noradrenaline release. 3. In human isolated extrarenal arteries the P2X-purinoceptor agonist beta, gamma-methylene-L-ATP caused almost no constrictor responses, beta, gamma-methylene-L-ATP induced moderate constrictor responses in intrarenal arteries. In preconstricted human intrarenal arteries ATP induced vasodilation. 4. ATP and the P2Y-receptor agonist 2-methyl-thio-ATP (2-MeSATP) dilated preconstricted rabbit renal arteries. The P2Y-receptor antagonist Reactive Blue 2 (3 microM) shifted the concentration response curves of ATP and 2-MeSATP to the right. 5. In conclusion, sympathetic nerve stimulation induces the release of ATP and noradrenaline in human renal cortex. ATP activates vasoconstrictory P2X- and vasodilatory P2Y-receptors in human renal blood vessels. The net vascular response to ATP in vivo will depend on the tissue distribution of these purinoceptors.

Role of intracellular calcium stores in contrast medium-induced renal vasoconstriction.

Renovascular smooth muscle contractility, an important factor in contrast media-induced nephrotoxicity, depends on intracellular Ca2+ concentration, which is composed of extracellular Ca2+ influx and intracellular Ca2+ release. These factors were investigated in contrast media-induced renal vasoconstriction in an in vitro model. KCl-induced isometric contractions of rabbit renal artery were compared with contractions elicited by contrast media (diatrizoate, iohexol, iopamidol). Measurements were made after incubation with the Ca2+ channel blockers nifedipine, verapamil, and diltiazem to assess the role of extracellular Ca2+ influx and after ryanodine and thapsigargin to investigate the role of intracellular Ca2+ release. The Ca2+ channel blockers partially inhibited contractions induced by contrast media, while KCl-induced contractions were completely abolished. Ryanodine and thapsigargin also markedly inhibited contrast media-induced contractions. Ionic and nonionic contrast media induced quantitatively different renal vasocontractions. Ca2+ channel blockers inhibited this vasocontraction only slightly compared with intracellular Ca2+ release blockers.

Impairment of endothelium-dependent dilation in rabbit renal arteries by oxidized lipoprotein(a). Role of oxygen-derived radicals.

Hyperlipoproteinemia is associated with impairment of nitric oxide (NO)-mediated, endothelium-dependent dilation in renal arteries. In the present study, we assessed and compared the effects of human lipoprotein(a) and LDL on endothelium-dependent and -independent dilation in vitro. Dilator responses were detected in isolated, saline-perfused, preconstricted arterial segments by a photoelectric device. Acetylcholine-induced, endothelium-dependent dilator responses of rabbit renal arteries were not significantly attenuated after 150 minutes of incubation with native lipoprotein(a) (30 and 100 micrograms/mL). However, exposure to in vitro oxidized lipoprotein(a) (150 minutes, 30 and 100 micrograms/mL) suppressed acetylcholine-induced dilator responses in a dose-dependent manner. At similar concentrations, native and oxidized LDL had no effect. Endothelium-independent dilations induced by the NO-donor sodium nitroprusside were also impaired by oxidized lipoprotein(a), whereas forskolin-induced dilator responses were unaffected, indicating that smooth muscle dilator capacity was not impaired. Attenuation of dilator responses by oxidized lipoprotein(a) was potentiated in the presence of superoxide dismutase (SOD). The SOD effect was completely blunted by coincubation with catalase (100 U/mL) or deferoxamine. In the absence of SOD, catalase or deferoxamine had no effect on dilator responses. Using a chemiluminescence assay, we could detect increased O2- production by arteries pretreated with oxidized lipoprotein(a), which suggested that enhanced NO inactivation by O2- could be the underlying mechanism for impairment of endothelium-dependent dilations. These data indicate that oxidized lipoprotein(a) impairs endothelium-dependent dilation and is more potent than oxidized LDL in this effect. The mechanism of the impairment may involve formation of O2- and inactivation of NO.

Ca 2+ and Cyclic Adenosine Monophosphate Involvement in Radiographic Contrast Medium–induced Renal Vasoconstriction

To investigate the role of extracellular Ca2+ and cyclic 3'-5' adenosine monophosphate (cAMP), a known second messenger promoting smooth muscle relaxation, in preventing renal vasoconstriction induced by radiographic contrast medium (RCM). Isometric contractions of rabbit renal artery were elicited by potassium chloride and increasing concentrations of meglumine/sodium diatrizoate. To determine the contribution of extracellular Ca2+, nifedipine, a blocker of voltage-dependent L-type Ca2+ channels (VDCC), was applied. The contribution of cAMP was investigated by applying the nonspecific phosphodiesterase (PDE) inhibitors papaverine and theophylline and the specific PDE inhibitor milrinone, all of which prevent degradation of cAMP. Forskolin, an activator of cAMP by stimulating adenylyl cyclase (AC), was also investigated. RCM elicited contractions that were 24.5% of the KCl control contraction, which was reduced by nifedipine (100 mumol/L) by 34.7%. Papaverine, theophylline, and milrinone inhibited RCM-induced contractions by 69.8%, 64.3%, and 43.7%, respectively. Forskolin reduced the response by 82.2%. Ca2+ influx through VDCC partially contributes to RCM-induced renal artery vasoconstriction. Intracellular cAMP appears to be an important second messenger pathway for prevention of this response. These findings emphasize the role of second messenger systems involved in adverse RCM effects and the potential prevention of these effects.

5-HT1-like and 5-HT2A receptors mediate 5-hydroxytryptamine-induced contraction of rabbit isolated mesenteric artery.

The contractions induced by 5-hydroxytryptamine (5-HT) and the 5-HT1-like receptor agonist, sumatriptan, were investigated in the open ring preparations of rabbit mesenteric artery in order to characterize the 5-HT receptors. 5-HT induced concentration-dependent contractions. Sumatriptan did not induce any contraction of unstimulated rings, whereas it elicited concentration-dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2 alpha (PGF2 alpha). Pargyline, cocaine or normetanephrine were without significant effect on the contractions induced by 5-HT and sumatripan. The 5-HT concentration-effect curve was clearly biphasic. Methiothepin (0.01 microM) shifted the both phases of the concentration-effect curve to the right. Ketanserin (0.1 microM) shifted the second, low affinity, phase and prazosin did not alter concentration-effect curve to 5-HT. The sumatriptan concentration-effect curve was shifted by methiothepin (0.01 microM) to the right (pKB = 9.19) but not by ketanserin (1 microM). Concentration-effect curves to 5-HT and sumatriptan were not affected by the 5-HT3 receptor antagonist tropisetron (1 microM). These results suggest that 5-HT1-like type receptors are responsible for the first phase of 5-HT-induced contraction and 5-HT2A receptor for the second phase, in rabbit mesenteric artery. Sumatriptan-induced contractions appear to be mediated by 5-HT1-like type receptors in this artery. These results also suggest that this kind of amplification may be a common feature of vascular 5-HT1-like type receptor as has been shown in other vascular segments such as rabbit femoral, iliac and renal arteries, and guinea-pig iliac artery.