Inhibition of cgmp mediated relaxation in small rat coronary arteries by block of Ca++ activated K+ channels

doi:10.1016/S0024-3205(97)00660-7

Life Sciences

Volume 61, Issue 12, 15 August 1997, Pages 1185-1192

https://doi.org/10.1016/S0024-3205(97)00660-7 Get rights and content

Abstract

The functional importance of Ca⁺⁺ activated K⁺ (K_ca channels in cGMP mediated relaxation of pressurized septal arteries (internal basal diameter 213 ± 4μm) was investigated. Vascular tone was increased by the thromboxane A₂ analogue, U-46619 and internal pressure was maintained at 60 mmHg. Vessels were tested with an endothelium independent agonist (nitroprusside) and endothelium dependent agonist (acetylcholine) of nitric oxide which activates soluble guanylate cyclase. Receptor activation of paniculate guanylate cyclase was tested by atrial natriuretic peptide. Direct changes in intracellular cGMP concentration were done with the cell permeable analog, 8-Bromo-cGMP. Tetraethylammonium ion (TEA⁺), 1 mM, significantly inhibited relaxation to nitroprusside from 10⁻⁷ to 10⁻³M with a maximal inhibition of 53 ± 8% at 10⁻³M. Relaxation to acetylcholine from 10⁻⁹M to 10⁻⁵M was significantly inhibited by TEA⁺ with a maximal inhibition of 52 ± 13% at 10⁻⁷M. TEA⁺ significantly inhibited relaxation to 8-Bromo-cGMP from 10⁻⁶M to 10⁻³M with a maximal inhibition of 59 ± 14% at 10⁻⁴M. The relaxation response to atrial natriuretic peptide from 10^∮12M to 10⁻⁷M was significantly inhibited by TEA⁺ with a maximal inhibition of 84 ± 5% at 10⁻¹¹M. The large conductance K_ca, channel blocker, iberiotoxin, eliminated the relaxation response to 8-Bromo-cGMP (10⁻³M). The results suggest that a large portion of the dilator action of cGMP is mediated by effects on K⁺ membrane channels.

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In isolated myocytes, ODQ decreased basal activity in the absence of any stimulation, suggesting that tonic activity of the enzyme is sufficient to stimulate the channel (Li, Jin, & Campbell, 1998). In various vascular reactivity models, manoeuvres that enhanced or mimicked cGMP evoked vasorelaxation which was often partially inhibited by BKCa inhibitors, such as IBTX, charybdotoxin (CBTX, 50–100 nM) or small concentrations of TEA (<1 mM) (Bracamonte et al., 1999; Carrier et al., 1997; Jiang et al., 1998; Paterno, Faraci, & Heistad, 1996; Price & Hellermann, 1997; Tanaka, Aida, Tanaka, Shigenobu, & Toro, 1998; Taniguchi, Furukawa, & Shigekawa, 1993). In a few studies, however, the effect of cGMP stimulation was also mediated by channels sensitive to 4-AP or glibenclamide rather than BKCa blockers (Table 4), suggesting that Em-dependent relaxant responses may rely on several K+ channel families.
Numerous mediators and drugs regulate blood flow or arterial pressure by acting on vascular tone, involving cyclic nucleotide intracellular pathways. These signals lead to regulation of several cellular effectors, including ion channels that tune cell membrane potential, Ca²⁺ influx and vascular tone. The characterization of these vasocontrictive or vasodilating mechanisms has grown in complexity due to i) the variety of ion channels that are expressed in both vascular endothelial and smooth muscle cells, ii) the heterogeneity of responses among the various vascular beds, and iii) the number of molecular mechanisms involved in cyclic nucleotide signalling in health and disease. This review synthesizes key data from literature that highlight ion channels as physiologically relevant effectors of cyclic nucleotide pathways in the vasculature, including the characterization of the molecular mechanisms involved. In smooth muscle cells, cation influx or chloride efflux through ion channels are associated with vasoconstriction, whereas K⁺ efflux repolarizes the cell membrane potential and mediates vasodilatation. Both categories of ion currents are under the influence of cAMP and cGMP pathways. Evidence that some ion channels are influenced by CN signalling in endothelial cells will also be presented. Emphasis will also be put on recent data touching a variety of determinants such as phosphodiesterases, EPAC and kinase anchoring, that complicate or even challenge former paradigms.
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This guanylate cyclase-coupled receptor is located both on endothelial and vascular smooth muscle cells [37]. Activation of NPR-A generates the second messenger cyclic guanosine monophosphate (cGMP) which, in turns, activates Ca2+ channels and ATP-sensitive K+-channels leading to vasorelaxation [21,29]. However, CNP binds to the NPR-B, a specific guanylate cyclase-coupled receptor, and it is located on the vascular smooth muscle cell, also leading to vasodilatation through hyperpolarization [19].
Crotalus oreganus abyssus is a rattlesnake that is usually found in the Grand Canyon, United States of America. Knowledge regarding the composition of C. o. abyssus venom is scarce. New natriuretic peptides (NPs) have been isolated and characterized from the venoms of members of the Crotalinae family. The NP family comprises three members, ANP (atrial natriuretic peptide), BNP (b-type natriuretic peptide) and CNP (c-type natriuretic peptide), and has an important role in blood pressure regulation and electrolyte homeostasis. The aim of the present study was to characterize a novel natriuretic-like peptide (Coa_NP2), isolated from C. o. abyssus venom. The Coa_NP2 presents an average molecular mass of 3419.88 Da (theoretical average molecular mass 3418.94 Da, monoisotopic molecular mass 3416.66 Da and theoretical PI 7.78) and its amino acid sequence presents the loop region that is characteristic of natriuretic peptides. The peptide has 32 amino acids and its complete sequence is SYGISSGCFGLKLDRIGTMSGLGCWRLLQDSP. Coa_NP2 is a natriuretic peptide of the ANP/BNP-like family, since the carboxyterminal region of CNP has its own NP domain. We demonstrate, herein, that Coa_NP2 produces a dose-dependent decrease in mean arterial pressure in rats, followed by significant increases in concentrations of markers of nitric oxide formation measured in the plasma and vasorelaxation in a thoracic aortic ring bath. The structural and biological aspects confirm Coa_NP2 as a new natriuretic peptide, isolated from snake venom.
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Until recently, most of the biological effects of nitric oxide (NO) have been attributed to its uncharged state (NO), yet NO can also exist in the reduced state as nitroxyl (HNO or NO⁻). Putatively generated from both NO synthase (NOS)-dependent and -independent sources, HNO is rapidly emerging as a novel entity with distinct pharmacology and therapeutic advantages over its redox sibling, NO. Thus, unlike NO, HNO can target cardiac sarcoplasmic ryanodine receptors to increase myocardial contractility, can interact directly with thiols and is resistant to both scavenging by superoxide (O₂⁻) and tolerance development. HNO donors are protective in the setting of heart failure in which NO donors have minimal impact. Here, we discuss the unique pharmacology of HNO versus NO and highlight the therapeutic potential of HNO donors in the treatment of cardiovascular disease.
Nesiritide Acutely Increases Pulmonary and Systemic Levels of Nitric Oxide in Patients With Pulmonary Hypertension
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Citation Excerpt :
These receptors are coupled to particulate guanylate cyclase, which generates the intracellular second messenger cGMP. Cyclic GMP, in turn, activates ATP-sensitive potassium channels in the vascular smooth muscle cells, resulting in vasodilation (Fig. 3).10,11 Aberrant production or activity of natriuretic peptides has been linked to a number of cardiovascular disorders.
Pulmonary hypertension (PH) is characterized by decreased pulmonary vascular expression of nitric oxide (NOx), a vasodilator that increases levels of smooth muscle cyclic guanosine monophosphate (cGMP). This study investigated mechanisms by which the vasodilator B-type natriuretic peptide (BNP) affects the systemic and pulmonary vasculature in PH patients.
Twenty PH patients with mean pulmonary artery (PA) pressure >25 mm Hg were enrolled. Ten had precapillary (pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg) and 10 had postcapillary (PCWP >15 mm Hg) PH. Right heart catheterization was performed before and 30 minutes after intravenous nesiritide infusion. NOx and cGMP levels from the PA and systemic (AO) arteries were obtained before and after nesiritide infusion. The postcapillary PH patients demonstrated significantly reduced pulmonary vascular resistance after nesiritide; there was no change in the precapillary PH cohort. NOx levels increased significantly in both AO (P < .0001) and PA (P = .0093), as did cGMP levels (P < .0001). There was a higher increase in NOx levels from the pulmonary arteries in precapillary PH patients compared to postcapillary PH patients (P = .020).
In PH patients, nesiritide infusion significantly increases NOx levels, suggesting a novel mechanism for its vasodilatory effects. These responses may differ between pre- and postcapillary PH patients.
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Many kinds of vasodilators induce relaxation of the vascular smooth muscle cells (VSMCs) through the production of cyclic AMP (cAMP) or cyclic GMP (cGMP). The relaxant effects mediated by these second messengers are thought to be mainly due to the decrease in intracellular Ca²⁺ concentration ([Ca²⁺]_i), as well as the decrease in Ca²⁺ sensitivity of the contractile apparatus of VSMCs. To explain the cAMP- or cGMP-mediated decrease in [Ca²⁺]_i, several mechanisms have been proposed, including the inhibition of Ca²⁺ influx due to a hyperpolarization, a stimulation of Ca²⁺ uptake into the intracellular store, and an increase in Ca²⁺extrusion from VSMCs by stimulation of sarcolemmal Ca²⁺-pump. VSMCs have two major systems for Ca²⁺ extrusion, namely, sarcolemmal Ca²⁺-pump and Na⁺/Ca²⁺ exchanger (NCX). However, the involvement of NCX in the vasodilator-induced relaxation of VSMCs has not been well established. In this article, the possible involvement of NCX in the vasodilator-induced relaxation of VSMCs will be reviewed.
G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current
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Citation Excerpt :
Furthermore, as discussed above, potentiation of the outward current by abn-cbd persisted in the presence of clamped intracellular calcium. cGMP has been identified in other preparations as the second messenger involved in the activation of Ca2+-activated K+ channels (17). In HUVEC, intracellular cGMP increased the voltage-induced outward current, comparable with the effect of abn-cbd.
The cannabinoid analog “abnormal cannabidiol” (abn-cbd) causes endothelium-dependent vasodilation in rat isolated mesenteric arteries through a G protein-coupled receptor distinct from CB₁ or CB₂. We examined the actions of abn-cbd on the electrophysiology of human umbilical vein endothelial cells (HUVEC), using the whole cell version of the patch clamp technique. Voltage steps produced noninactivating outward currents, which were abolished by iberiotoxin or by chelation of intracellular calcium. The presence of a BK_Ca channel in HUVEC was documented by reverse transcriptase-PCR. Abn-cbd concentration dependently potentiated the outward current produced by a single voltage step. This potentiation was abolished by the cannabidiol analog O-1918 or by pertussis toxin but was unaffected by CB₁ or CB₂ antagonists. HU-210, a CB₁/CB₂ receptor agonist, had no effect on the outward current. Clamping [Ca²⁺]_i did not prevent abn-cbd-induced increases in outward current. cGMP potentiated the outward current, and abn-cbd increased the cellular levels of cGMP. The increase in outward current produced by abn-cbd was blocked by KT-5823, an inhibitor of protein kinase G, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), an inhibitor of soluble guanylate cyclase. We conclude that a Ca²⁺-activated K⁺ current in HUVEC is potentiated by activation of a G_i/G_o-coupled receptor distinct from CB₁ or CB₂, which signals through cGMP and protein kinase G to increase channel availability or the sensitivity of the channel to voltage and/or Ca²⁺. Because iberiotoxin also inhibited abn-cbd-induced relaxation of intact, but not of endothelium-denuded, rat mesenteric artery segments, modulation of endothelial BK_Ca channels may underlie the mesenteric vasodilator action of abn-cbd.

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Abstract

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Topics on the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger: Involvement of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger in the vasodilator-induced vasorelaxation

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca<sup>2+</sup>-dependent K<sup>+</sup> Current