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CARDIOVASCULAR

Contributions of Nitric Oxide and Prostanoids and Their Signaling Pathways to the Renal Medullary Vasodilator Effect of U46619 (9-11-Dideoxy-11,9a-Epoxymethano-Prostaglandin F_2a) in the Rat

Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas

Received June 20, 2002; accepted September 20, 2002.

	Abstract

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We recently demonstrated that U46619 (9-11-dideoxy-11,9a-epoxymethano-prostaglandin F_2a) evoked a medullary vasodilation and a reduction in blood pressure despite a potent cortical vasoconstriction in the anesthetized rat. The present study tested the hypothesis that nitric oxide (NO) and prostanoids contribute to U46619-induced increase in medullary blood flow (MBF). U46619 at 1, 3, and 5 µg/kg increased MBF (above basal values) by 16 ± 3, 45 ± 10, and 58 ± 8 perfusion units, respectively, and increased NO current in the medulla by 17 ± 4, 34 ± 7, and 60 ± 12 pA, respectively. N-L-Nitro-arginine methyl ester (5 mg/kg), the inhibitor of NO production, attenuated the increase in MBF (75 ± 8%, p < 0.05) as did indomethacin (10 mg/kg), the inhibitor of cyclooxygenase (38 ± 5%, p < 0.05), suggesting the involvement of NO and dilator prostanoids. H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH, a synthetic peptide and selective inhibitor of cGMP-dependent protein kinase, attenuated U46619-induced medullary perfusion (52 ± 6%, p < 0.05), but H-89 ((N-[2-((p-bromocinnamyl)aminoethyl)]-5-isoquinolinesulfonamide hydrochloride), a cell-permeable, selective, and potent inhibitor of cAMP-dependent protein kinase A, was without effect. Glybenclamide, a K_ATP channel blocker, also blunted the increase by U46619 in MBF (58 ± 7%, p < 0.05). These data suggest that NO and prostanoids contribute to U46619-induced medullary perfusion and that the effects of these mediators are coupled to activation of protein kinase G and K_ATP channels but not protein kinase A.

Nitric oxide (NO) and PGs play major roles in the regulation of the renal circulation. NO in particular exerts a selectively strong effect in the kidney, promoting a vasodilation that may or may not be mediated through activation of guanylate cyclase and generation of cGMP. On the other hand, PGs produce vascular effects that differ according to the family they belong to and according to the region of the kidney, cortex versus the medulla. The renal medulla is increasingly being recognized as an important region for overall regulation of hemodynamics. Thus, although prostanoids are important regulators of renal blood flow in the kidney, their major site is the medulla, where, besides the endothelium of vasa recta, interstitial cells, and collecting ducts, a large quantity of dilator PGs are produced (Mattson and Roman, 1991; Mene and Dunn, 1992; Murray and Brater, 1993). PGs are known to relax vascular smooth muscle in many tissues including the rat preglomerular vessel by increasing intracellular concentration of cAMP (Armstead, 1995). However, recent studies suggest that alternative second messengers may also contribute to prostanoid-induced vasodilation. This suggestion is supported by the finding that PGE₂-induced relaxation in human hand veins was partially endothelium-dependent (Arner et al., 1994). In addition, a role for NO in prostanoid-induced vasodilation was suggested based on the demonstration that inhibition of NO production attenuated PGI₂-induced increase in coronary flow in the dog (Zhao et al., 1994).

The present study extends our previous observation on the renal hemodynamic effect of U46619 (Hercule et al., 2001) and was designed to further characterize the renal hemodynamic effect of U46619 and evaluate the mechanisms involved. We tested the hypothesis that NO and prostanoids are the mediators of the medullary vasodilator effect of U46619 in the rat kidney.

	Materials and Methods

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U46619 was obtained from Cayman Chemical (Ann Arbor, MI) and initially dissolved in absolute ethanol, 1 mg/ml, diluted in normal saline to 50 µg/ml, and stored frozen in aliquots at –70°C. Indomethacin was prepared fresh dissolved in 0.1 M NaHCO₃ and pH was adjusted to 7.6. 8-Bromo-adenosine 3',5'-cyclic monophosphate sodium salt (8-Br-cAMP), 8-bromo-guanosine 3',5'-cyclic monophosphate sodium salt (8-Br-cGMP), and N-L-nitro-arginine methyl ester (L-NAME) were obtained from Sigma-Aldrich (St Louis, MO) and dissolved in 0.9% NaCl. (N-[2-((p-Bromocinnamyl)aminoethyl]-5-isoquinolinesulfonamide hydrochloride (H-89) and H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH supplied as the trifluoroacetate salt (protein kinase G inhibitor, PKGI) were obtained from Calbiochem-Novabiochem Corp. (San Diego, CA) and dissolved in 0.9% NaCl. Diazoxide and glybenclamide were obtained from Sigma-Aldrich), were initially dissolved in 0.1 N NaOH and dimethyl sulfoxide, respectively, in a stock solution of 10 mg/ml, and diluted in normal saline to 30 µg/ml aliquots and stored frozen (–70°C). These agents were kept on ice during the experiments.

The experiments were performed on male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA; body weight 340–375 g). The animals were maintained on standard rat food (Purina chow) and were allowed ad libitum access to water and food until the beginning of the experiments.

Hemodynamic measurements for medullary blood flow (MBF) and mean arterial blood pressure (MABP) were made in inactin-anesthetized (100 mg/kg i.p.) rats as described previously (Hercule and Oyekan, 2000; Hercule et al., 2001). In some experiments (n = 4), online generation of NO in the medulla was measured as NO current via probes (30 µm) placed in the medulla and connected to the Isolated Nitric Oxide Meter (Iso-NO Mark II; World Precision Instruments, New Haven, CT).

Experimental Protocol. After surgery and placing of probes for recording MBF, a 30- to 45-min equilibration period was allowed after which a dose-response relationship was established to U46619 (1, 3, and 5 µg/kg). These doses were given randomly by bolus intravenous injection. The rat was allowed to recover fully from the effect of one dose before another dose was given. After testing the responses to the last dose of U46619, an inhibitor/antagonist or its vehicle was administered and responses to U46619 or the other agonists were reestablished after 5 min. In time controls (n = 4), responses to U46619 were obtained 1 h after the equilibration period and again 45 min later. To ascertain the selectivity of the inhibitors and to demonstrate that U46619 produced a qualitatively different effect in the medulla from another agent, responses to phenylephrine (PE, 10 µg/kg) were also evaluated.

The effect of U46619 on MBF was studied in the presence of indomethacin, an inhibitor of COX (10 mg/kg i.v., n = 8), [SCAP]L-NAME, an inhibitor of NO synthase (5 mg/kg i.v., n = 5); H-89 (100 µg/kg bolus + 2 µg/kg/min; n = 5), a cell-permeable, selective and potent inhibitor of cAMP-dependent protein kinase A (Findik et al., 1995), PKGI (250 µg/kg bolus + 3.5 µg/kg/min; n = 7), a synthetic peptide and specific inhibitor of cGMP-dependent protein kinase (Glass, 1983), glybenclamide (40 µmol/kg bolus + 0.4 µmol/kg/min, n = 6), a K_ATP-sensitive blocker, or their respective vehicles: 0.1 M NaHCO₃ for indomethacin, 0.25% dimethyl sulfoxide for glybenclamide, or normal saline for the other agents. In all cases, changes in MBF were continuously monitored. The doses of indomethacin and L-NAME used were those that we used in our previous studies to effectively diminish prostanoid- or NO-induced renal hemodynamic responses (Hercule and Oyekan, 2000). 8-Br-cGMP (250 and 500 µg/kg i.v.) and 8-Br-cAMP salts (1, 2.5, and 5 mg/kg i.v.) were used to evaluate the efficacy of the PKG inhibitor and H-89, respectively. The doses of H-89 and PKGI employed in this study were those found in preliminary experiments to selectively attenuate the effects of 8-Br-cAMP and 8-Br-cGMP by 50–85%, respectively, without affecting responses to PE. The dose of glybenclamide was based on literature (Findik et al., 1995) and on its inhibition of the hemodynamic effects of diazoxide (10 and 30 µg/kg), a K_ATP-channel agonist. The effects of the inhibitors/antagonists on the changes in MABP and MBF were evaluated by comparing the effects of U46619, 8-Br-cAMP, 8-Br-cGMP, or PE before and after the administration of the inhibitors/antagonists.

Data Analysis. All responses were recorded as changes () relative to pre injection values or during vehicle treatment and data expressed as mean ± S.E. Analysis of variance was used to compare dose response curves between controls (vehicle-treated) and treated groups followed by Bonferroni test. In all cases, p 0.05 was considered significant.

	Results

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Basal MBF and MABP in the rats used for this study were 117 ± 14 perfusion units (PU) and 105 ± 5 mm Hg, respectively. Basal MBF and MABP were not different in rats that received the vehicles for the different inhibitors; thus, these values were pooled to represent control data. In time controls, increases in MBF and reductions in MABP in response to U46619 were not significantly different when evaluated at the beginning of the study and 90 to 120 min later.

Role of NO in U46619-Induced Hemodynamics. U46619 produced pressor responses at 1 µg/kg and depressor responses at 5 µg/kg dose levels. Irrespective of the changes in MABP, U46619 elicited dose-dependent increases in MBF at all doses. On its own, L-NAME (5 mg/kg) reduced MBF (=–22 ± 5 PU; data not shown) and increased MABP to 135 ± 4 mm Hg (Table 1). L-NAME also blunted U46619-induced increases in MBF (75 ± 8%, p < 0.05) (Fig. 1a) and the reductions in MABP (Table 1). U46619 increased the NO current in the medulla in a dose-dependent manner (Fig. 1B) from a basal value of 784 ± 27 pA. However, under the same experimental condition, phenylephrine, 10 µg/kg, was without effect (Fig. 1B).

View larger version (20K): [in this window] [in a new window]   Fig. 1. Dose-dependent effect of U46619 (1, 3, and 5 µg/kg) on medullary blood flow before (Control) or after the administration of 5 mg/kg L-NAME (L-NAME) (A). , p < 0.05 compared with Control (n = 5). The effect of U46619 or phenylephrine (PE) on NO current in the medulla is presented in B. , p < 0.05 versus preinjection (basal) value.

Effect of Indomethacin. Indomethacin (5 mg/kg) decreased basal MBF (=–17 ± 3 PU; data not shown) and elicited a modest increase in MABP (= 8 ± 2 mm Hg, p < 0.05). Indomethacin blunted the increases in MBF by U46619 (38 ± 5%; p < 0.05) (Fig. 2) and attenuated U46619-induced reduction in MABP (Table 1), uncovering modest pressor effect at lower doses.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Effect of graded concentrations of U46619 (1, 3, and 5 µg/kg) on medullary blood flow before (Control) or after the administration of 10 mg/kg indomethacin (Indo). , p < 0.05 compared with Control (n = 8).

Role of PKG/Effects of 8-Br-cGMP. 8-Br-cGMP at 250 and 500 µg/kg elicited dose-related increases in MBF and reductions in MABP (Table 2). PKGI, the inhibitor of cGMP-dependent protein kinase G, blunted the effects of 8-Br-cGMP on MABP and MBF by 54 ± 3 and 66 ± 9% (p < 0.05), respectively (Table 2). PKGI also markedly attenuated a U46619-induced increase in MBF (47 ± 4%, p < 0.05) (Fig. 3) and the reduction in MABP (p < 0.05) (Table 2). However, PKGI did not alter the changes in MBF and MABP produced by 8-Br-cAMP or phenylephrine (10 µg/kg; Table 2).

View larger version (23K): [in this window] [in a new window]   Fig. 3. Effect of U46619 (1, 3, and 5 µg/kg) on medullary blood flow before (Control) or after the administration of protein kinase G inhibitor, 250 µg/kg bolus + 3.5 µg/kg/min (PKGI). , p < 0.05 compared with Control (n = 7).

Role of PKA/Effects of 8-Br-cAMP. H-89 reduced basal MBF (=–14 ± 6 PU) without affecting MABP (=–6 ± 4 mm Hg) and attenuated dose-related reduction in MABP and the increases in MBF by 8-Br-cAMP, by 59 + 5 and 84 ± 12% (p < 0.05), respectively (Table 2). However, H-89 was without effect on U46619-induced increases in MBF (Fig. 4) and the reduction in MABP (Table 1). Moreover, under the same experimental condition, responses to 8-Br-cGMP were not affected, nor were responses to phenylephrine (Table 2).

View larger version (32K): [in this window] [in a new window]   Fig. 4. Dose-dependent effect of U46619 (1, 3, and 5 µg/kg) on medullary blood flow before (Control) or after the administration of H-89, 100 µg/kg bolus + 2 µg/kg/min (H-89).

Role of K_ATP-Sensitive Channels. Diazoxide, a K_ATP-sensitive channel agonist, at 10 and 30 µg/kg doses increased MBF by 40 ± 8 and 79 ± 20 PU, respectively (Fig. 5) and reduced MABP by 39 ± 4 and 77 ± 8 mm Hg, respectively (data not shown). Glybenclamide, a K_ATP-sensitive channel blocker, blunted the increases in MBF by diazoxide (61 ± 5%; p < 0.05) (Fig. 5), as well as the reduction in MABP, attenuating the values to 8 ± 10 (10 µg/kg) and 24 ± 12 mm Hg (30 µg/kg) (data not shown). Glybenclamide also blunted U46619-induced increase in MBF (58 ± 7%, p < 0.05) (Fig. 5), and the reduction in MABP. However, glybenclamide was without effect on phenylephrine-induced reduction in MBF (Fig. 5), or the increase in MABP (= 33 ± 4 mm Hg, Control; versus 36 ± 3 mm Hg, Glybenclamide).

View larger version (19K): [in this window] [in a new window]   Fig. 5. Effect of U46619 (1, 3, and 5 µg/kg), diazoxide (10 and 30 µg/kg), and phenylephrine (PE) on medullary blood flow before (Control) or after the administration of glybenclamide, 40 µmol/kg bolus + 0.4 µmol/kg/min (Glybenclamide). , p < 0.05 compared with Control (n = 6).

	Discussion

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The results of the present study demonstrate that inhibition of NO production with L-NAME attenuated the increase by U46619 in medullary perfusion, as did inhibition of COX with indomethacin or antagonism of K_ATP channel with glybenclamide. In addition, inhibition of protein kinase G but not protein kinase A diminished medullary vasodilation produced by U46619.

The renal vasculature is extremely sensitive to NO, and stimulation of endogenous NO increased the diameter of large preglomerular vessels (Gulbins et al., 1993), the afferent and efferent arterioles (Deng and Baylis, 1993), and vasa recta (Pflueger et al., 1999), leading to decreases in renal vascular resistance. Moreover, NO as an important modulator of vascular tone in the kidney provides counter-regulating renoprotective mechanisms in response to pressor hormones including angiotensin II and norepinephrine (Parekh et al., 1996; Navar et al., 2000), and ET-1 (Gurbanov et al., 1996; Hercule and Oyekan, 2000) and, possibly, TxA₂. However, NO production and/or activity are subject to regional variation, and this may determine the degree of effect produced by vasoactive hormones in the medulla versus the cortex. Thus, there is a significantly greater Ca²⁺-dependent NOS activity but lower Ca²⁺-independent NOS activity in the cortex but not the medulla of angiotensin II-infused rats (Navar et al., 2000). Moreover, NO production is greater in the medulla compared with the cortex (Zou and Cowley, 1997). In our previous study, we provided evidence that this regional difference may contribute to the cytochrome P450-dependent, ET-1-induced regional renal hemodynamic effect in the rat (Oyekan and Hercule, 2000). Taken together, these observations suggest that the mediator role of NO for various agents will depend on the region of the kidney and/or the type of NOS activity in that region. In these experiments, L-NAME inhibited U46619-induced medullary vasodilation (Fig. 1A), suggesting a role for NO in the hemodynamic effect of U46619 in the medulla. Direct evidence for a role for NO was provided by the increase in NO current in the medulla following the administration of U46619 (Fig. 1B). It has generally been assumed that the renal actions of NO are solely mediated by activation of guanylyl cyclase, which increases the levels of cGMP. However, this scheme for NO-induced vasodilation recently has been questioned because, in a variety of vascular beds including the renal circulation, NO has been demonstrated to act via cGMP-dependent and cGMP-independent mechanisms involving activation of potassium channels (Bolotina et al., 1994; Trottier et al., 1998). In the present study, the diminution of the hemodynamic effects of U46619 following inhibition of protein kinase G provides evidence that a cGMP-dependent mechanism is involved, at least in part, in U46619-induced release of NO.

PGs are released not only in response to shear stress but also following administration of many vasoactive agents including U46619 (Mehta et al., 1984; Hercule et al., 2001). PGE₂ and/or PGI₂, either released by hormones or when administered exogenously, produce vasodilation in most vascular beds. However, in the rat, PGE₂ and PGA₂ produced vasoconstriction in the isolated perfused kidney (Malik and McGiff, 1975). PGs generally produce vasodilation and thus antagonize the effects of vasoconstrictor hormones in an agonist-specific manner. For example, PGs antagonize the effects of angiotensin II and norepinephrine in the medulla but not that due to vasopressin or NO inhibition (Parekh and Zou, 1996). Given this evidence, we speculate that U46619-induced hypotension and medullary vasodilation may be due to 1) release of dilator PGs in the systemic circulation or in the medullary vascular bed, and 2) PG-induced stimulation of adenylate cyclase and subsequent increase in cAMP in vascular smooth muscle cells (Parfenova et al., 1995). The attenuation by indomethacin of U46619-induced medullary perfusion and hypotension in these experiments provides evidence for the contribution of dilator prostanoids to this effect. This finding is consistent with the demonstration that U46619 produced PGI₂ when incubated with cultured endothelial cells (Nicholson et al., 1984), a finding that corroborates the observation that infusion of U46619 elicited release of prostanoids in the dog (Mehta et al., 1984). Consistent with the second-messenger role of cAMP for prostanoids and its relaxing action on vascular smooth muscle cells (Pfitzer et al., 1984), cAMP salt increased medullary blood flow and produced hypotension (Table 2). H-89, an inhibitor of cAMP-dependent protein kinase, attenuated the increase as expected. However, H-89 was without effect on U46619-induced increase in MBF (Fig. 4), suggesting that although a prostanoid/prostanoid-like compound may contribute to U46619-induced medullary perfusion, cAMP may not be the second messenger. This notion finds support in observations in other studies that reported that cAMP makes a minimal contribution to PGI₂-induced medullary vasodilation in the rat (Parekh and Zou, 1996). In line with this observation, it was demonstrated that prostanoids (PGE₂ and PGI₂) involved in basal medullary circulation exert their effects via the opening of K⁺ channels (Bouchard et al., 1994) and may contribute greatly but not exclusively to PGI₂-induced medullary perfusion (Parekh and Zou, 1996). It is therefore possible that U46619 evoked the release of prostanoids that may or not be coupled to activation of K_ATP channels. We first verified a role for K_ATP channels in systemic and renal hemodynamics by demonstrating that glybenclamide, a K_ATP-sensitive blocker, blunted hemodynamic effects induced by diazoxide. The observation that glybenclamide inhibited U46619-induced medullary perfusion indeed suggests that activation of K_ATP channels contributes to the hemodynamic effects of U46619 in the rat.

In conclusion, we have provided evidence that NO and prostanoids contribute to the hemodynamic effects of U46619 in the rat and that these primary mechanisms are coupled to downstream signaling events involving cGMP/protein kinase G and activation of K_ATP channels.

	Acknowledgements

 
I acknowledge the technical support provided by Dr. Gbadebo Ogungbade.

	Footnotes

 
This work was supported by National Institutes of Health Grants HL59884 and HL03674. A.O.O. is an Established Investigator of the American Heart Association (Award # 0040119N). The facilities of the Research Center for Minority Investigators were used for these studies. The findings in this study were presented at the 55th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research, September 22–25, 2001.

DOI: 10.1124/jpet.102.040170.

ABBREVIATIONS: PG, prostaglandin; COX, cyclooxygenase; U46619, 9-11-dideoxy-11,9a-epoxymethano-prostaglandin F_2a; TxA₂, thromboxane A₂; ET, endothelin; NO, nitric oxide; L-NAME, N-L-nitro-arginine methyl ester; H-89, (N-[2-((p-bromocinnamyl)aminoethyl)]-5-isoquinolinesulfonamide hydrochloride; PKGI, protein kinase G inhibitor (H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH); MBF, medullary blood flow; MABP, mean arterial blood pressure; PE, phenylephrine; PU, perfusion unit(s).

Address correspondence to: Adebayo O. Oyekan, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004. E-mail: Oyekan_AO{at}TSU.EDU

	References

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