scholarly journals Involvement of BKCa and KV Potassium Channels in cAMP-Induced Vasodilatation: Their Insufficient Function in Genetic Hypertension

2014 ◽  
pp. 275-285
Author(s):  
M. PINTÉROVÁ ◽  
M. BEHULIAK ◽  
J. KUNEŠ ◽  
J. ZICHA
Keyword(s):  
No Synthase ◽  
K Channel ◽  
Spontaneously Hypertensive ◽  
K Channels ◽  
Wky Rats ◽  
Genetic Hypertension ◽  
Kv Channels ◽  
Adrenoceptor Agonist ◽  
Vasodilator Action

Spontaneously hypertensive rats (SHR) are characterized by enhanced sympathetic vasoconstriction, whereas their vasodilator mechanisms are relatively attenuated compared to their high BP. The objective of our in vivo study was to evaluate whether the impaired function of BKCa and/or KV channels is responsible for abnormal cAMP-induced vasodilatation in genetic hypertension. Using conscious SHR and normotensive WKY rats we have shown that under the basal conditions cAMP overproduction elicited by the infusion of β-adrenoceptor agonist (isoprenaline) caused a more pronounced decrease of baseline blood pressure (BP) in SHR compared to WKY rats. Isoprenaline infusion prevented BP rises induced by acute NO synthase blockade in both strains and it also completely abolished the fully developed BP response to NO synthase blockade. These cAMP-induced vasodilator effects were diminished by the inhibition of either BKCa or KV channels in SHR but simultaneous blockade of both K+ channel types was necessary in WKY rats. Under basal conditions, the vasodilator action of both K+ channels was enhanced in SHR compared to WKY rats. However, the overall contribution of K+ channels to cAMP-induced vasodilator mechanisms is insufficient in genetic hypertension since a concurrent activation of both K+ channels by cAMP overproduction is necessary for the prevention of BP rise elicited by acute NO/cGMP deficiency in SHR. This might be caused by less effective activation of these K+ channels by cAMP in SHR. In conclusion, K+ channels seem to have higher activity in SHR, but their vasodilator action cannot match sufficiently the augmented vasoconstriction in this hypertensive strain.

Pharmacological coupling and functional role for CGRP receptors in the vasodilation of rat pial arterioles

1996 ◽  
Vol 270 (1) ◽  
pp. H317-H323 ◽  
Author(s):  
K. W. Hong ◽  
S. E. Yoo ◽  
S. S. Yu ◽  
J. Y. Lee ◽  
B. Y. Rhim
Keyword(s):  
Channel Blocker ◽  
K Channel ◽  
Receptor Subtype ◽  
Camp Production ◽  
K Channels ◽  
Cranial Window ◽  
Pial Arterioles ◽  
Vasodilator Action

In this study, we investigated the signal transduction underlying the vasodilator action of calcitonin gene-related peptide (CGRP) in the rat pial arterioles. In an in vivo experiment, changes in pial arterial diameters (20.2 +/- 1.9 microns) were observed under suffusion with mock cerebrospinal fluid containing CGRP (10(-9)-10(-7) M) directly through a closed cranial window. Changes in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in response to CGRP and levcromakalim were measured in the pial arterioles in an in vitro experiment. CGRP-induced vasodilation and cAMP production were significantly inhibited by specific CGRP antibody serum and CGRP-(8-37) fragment, suggesting involvement of the CGRP1 receptor subtype. Vasodilation and increase in cAMP production evoked by CGRP were inhibited not only by glibenclamide (ATP-sensitive K+ channel blocker) but also by charybdotoxin (large-conductance Ca(2+)-activated K+ channel blocker), but this was not the case for the isoproterenol-induced vasodilation and cAMP production. These findings implicate the ATP-sensitive K+ channels and the large-conductance Ca(2+)-activated K+ channels in the CGRP receptor-coupled cAMP production for vasodilation. Further study is required to identify whether the cAMP-dependent K+ channel activation is related to CGRP-induced vasorelaxation of the rat pial arterioles.

Age-related changes in endothelium-dependent hyperpolarization in the rat mesenteric artery

1993 ◽  
Vol 265 (2) ◽  
pp. H509-H516 ◽  
Author(s):  
K. Fujii ◽  
S. Ohmori ◽  
M. Tominaga ◽  
I. Abe ◽  
Y. Takata ◽  
...  
Keyword(s):  
Mesenteric Artery ◽  
K Channel ◽  
Aged Rats ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Age Related ◽  
Rat Mesenteric Artery ◽  
Wistar Kyoto ◽  
Age Related Changes

This study was designed to determine the age-related changes in the endothelium-dependent hyperpolarization to acetylcholine (ACh) and its contribution to relaxation in the isolated mesenteric artery from normotensive and hypertensive rats. Membrane potentials and contractions were recorded in arteries from male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) that were 5-6 wk old (young), 6-8 mo old (adult), and 20-26 mo old (aged). Endothelium-dependent hyperpolarizations produced by ACh, applied both at the resting state of the membrane and under conditions of depolarization with norepinephrine (10(-5) M), were markedly impaired in aged WKY rats, adult SHR, and aged SHR. Endothelium-dependent relaxations to ACh in arterial rings precontracted with 10(-5) M norepinephrine were also impaired in aged WKY rats, adult SHR, and aged SHR even in the presence of indomethacin. Furthermore, in these rats, N omega-nitro-L-arginine, an inhibitor of nitric oxide formation, showed potent inhibitory effects on the relaxations, whereas the 20 mM high K+ solution that reduces hyperpolarization had less pronounced effects. Hyperpolarizations and relaxations to cromakalim (10(-5) M), a K(+)-channel opener, were on the whole preserved in aged rats. It would thus appear that the endothelium-dependent hyperpolarization to ACh is reduced with aging as well as by hypertension, and this would, in part, account for the impaired relaxation to ACh in arteries of both aged rats and hypertensive rats.

scholarly journals Isoflurane Depresses the Response of Inspiratory Hypoglossal Motoneurons to Serotonin In Vivo 

2007 ◽  
Vol 106 (4) ◽  
pp. 736-745 ◽  
Author(s):  
Ivo F. Brandes ◽  
Edward J. Zuperku ◽  
Astrid G. Stucke ◽  
Francis A. Hopp ◽  
Danica Jakovcevic ◽  
...  
Keyword(s):  
Neuronal Response ◽  
Discharge Frequency ◽  
K Channel ◽  
Neuronal Membrane ◽  
Spontaneous Discharge ◽  
Channel Conductance ◽  
Membrane Hyperpolarization ◽  
K Channels ◽  
Hypoglossal Motoneurons

Background Endogenous serotonin (5-HT) provides important excitatory drive to inspiratory hypoglossal motoneurons (IHMNs). In vitro studies show that activation of postsynaptic 5-HT receptors decreases a leak K+ channel conductance and depolarizes hypoglossal motoneurons (HMNs). In contrast, volatile anesthetics increase this leak K+ channel conductance, which causes neuronal membrane hyperpolarization and depresses HMN excitability. Clinical studies show upper airway obstruction, indicating HMN depression, even at subanesthetic concentrations. The authors hypothesized that if anesthetic activation of leak K+ channels caused neuronal depression in vivo, this effect could be antagonized with serotonin. In this case, the neuronal response to picoejected serotonin would be greater during isoflurane than with no isoflurane. Methods Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The authors studied the effect of approximately 0.3 minimum alveolar concentration (MAC) isoflurane on the spontaneous discharge frequency patterns of single IHMNs and on the neuronal response to picoejection of 5-HT. Results Normalized data (mean +/- SD, n = 19) confirmed that 0.3 +/- 0.1 MAC isoflurane markedly reduced the spontaneous peak discharge frequency by 48 +/- 19% (P < 0.001) and depressed the slope of the spontaneous discharge patterns. The increase in neuronal frequency in response to 5-HT was reduced by 34 +/- 22% by isoflurane (P < 0.001). Conclusion Subanesthetic concentrations of isoflurane strongly depressed canine IHMNs in vivo. The neuronal response to 5-HT was also depressed by isoflurane, suggesting that anesthetic activation of leak K+ channels, which is expected to result in a larger 5-HT response, was not a dominant mechanism in this depression.

Nitric oxide regulates endothelium-dependent vasodilator responses in rabbit hindquarters vascular bed in vivo

1996 ◽  
Vol 271 (1) ◽  
pp. H133-H139 ◽  
Author(s):  
G. A. Cohen ◽  
A. J. Hobbs ◽  
R. M. Fitch ◽  
M. J. Zinner ◽  
G. Chaudhuri ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Physiological Role ◽  
No Synthase ◽  
No Donor ◽  
Aortic Endothelial Cells ◽  
Vascular Bed ◽  
Feedback Modulator ◽  
Vasodilator Action

The objective of this study was to determine whether nitric oxide (NO) could function as a negative feedback modulator of endothelium-dependent vasodilation in vivo. To this end, the influence of exogenous NO on vasodilator responses in the rabbit hindquarters vascular bed was determined. Previous in vitro studies have demonstrated that NO inhibits both neuronal NO synthase from rat cerebellum as well as NO synthase derived from bovine aortic endothelial cells. The present study was conducted in the rabbit hindquarters vascular bed under conditions of constant blood flow so that changes in pressure directly reflected changes in vascular resistance. Under these in vivo conditions, the NO donor agent S-nitroso-N-acetylpenicillamine (SNAP) reversibly attenuated responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin. In contrast, SNAP did not influence the endothelium-independent vasodilator response to SNAP itself or to 8-bromoguanosine 3',5'-cyclic monophosphate. These observations indicate clearly that NO interferes with endothelium-dependent vasodilator action and support the view that endogenous NO may actually play a physiological role in regulating vascular tone.

scholarly journals Low molecular weight poly(A)+ mRNA species encode factors that modulate gating of a non-Shaker A-type K+ channel.

1993 ◽  
Vol 102 (4) ◽  
pp. 713-728 ◽  
Author(s):  
L D Chabala ◽  
N Bakry ◽  
M Covarrubias
Keyword(s):  
Molecular Weight ◽  
Xenopus Oocytes ◽  
Membrane Potentials ◽  
K Channel ◽  
Low Molecular Weight ◽  
K Channels ◽  
Fourfold Increase ◽  
Mrna Species ◽  
Type K

Voltage-dependent K+ channels control repolarization of action potentials and help establish firing patterns in nerve cells. To determine the nature and role of molecular components that modulate K+ channel function in vivo, we coinjected Xenopus oocytes with cRNA encoding a cloned subthreshold A-type K+ channel (mShal1, also referred to as mKv4.1) and a low molecular weight (LMW) fraction (2-4 kb) of poly(A)+ mRNA (both from rodent brain). Coinjected oocytes exhibited a significant (fourfold) increase in the surface expression of mShal1 K+ channels with no change in the open-channel conductance. Coexpression also modified the gating kinetics of mShal1 current in several respects. Macroscopic inactivation of whole oocyte currents was fitted with the sum of two exponential components. Both fast and slow time constants of inactivation were accelerated at all membrane potentials in coinjected oocytes (tau f = 47.2 ms vs 56.5 ms at 0 mV and tau s = 157 ms vs 225 ms at 0 mV), and the corresponding ratios of amplitude terms were shifted toward domination by the fast component (Af/As = 2.71 vs 1.17 at 0 mV). Macroscopic activation was characterized in terms of the time-to-peak current, and it was found to be more rapid at all membrane potentials in coinjected oocytes (9.9 ms vs 13.5 ms at 0 mV). Coexpression also leads to more rapid recovery from inactivation (approximately 2.4-fold faster at -100 mV). The coexpressed K+ currents in oocytes resemble currents expressed in mouse fibroblasts (NIH3T3) transfected only with mShal1 cDNA. These results indicate that mammalian regulatory subunits or enzymes encoded by LMW mRNA species, which are apparently missing or expressed at low levels in Xenopus oocytes, may modulate gating in some native subthreshold A-type K+ channels.

scholarly journals Nitroxyl donors retain their depressor effects in hypertension

2013 ◽  
Vol 305 (6) ◽  
pp. H939-H945 ◽  
Author(s):  
Jennifer C. Irvine ◽  
Ravina M. Ravi ◽  
Barbara K. Kemp-Harper ◽  
Robert E. Widdop
Keyword(s):  
No Donor ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Angeli's Salt ◽  
Isolated Aorta ◽  
Vasodilatory Action ◽  
Wistar Kyoto ◽  
First Time

Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli's salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO˙ donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 μg/kg), IPA/NO (10, 50, and 200 μg/kg), and DEA/NO (1, 5, and 20 μg/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated ( P < 0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC ( P < 0.01), yet those to DEA/NO in SHR were significantly ( P < 0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.

scholarly journals Time-Related Alteration in Flow- (Shear Stress-) Mediated Remodeling in Resistance Arteries from Spontaneously Hypertensive Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Odile Dumont ◽  
Gilles Kauffenstein ◽  
Anne-Laure Guihot ◽  
Nathalie C. Guérineau ◽  
Pierre Abraham ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
High Flow ◽  
Low Flow ◽  
Resistance Arteries ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Cross Section Area

Hypertension is a major risk factor for cardiovascular disorders. As flow-mediated outward remodeling has a key role in postischemic revascularization, we investigated this remodeling in mesenteric resistance arteries of normotensive (WKY) and spontaneously hypertensive rats (SHRs) aged 3 to 9 months. Sequential ligation of mesenteric resistance arteries allowed modifying blood flowin vivo, thus exposing arteries to low, normal, or high flow. After 1, 3, 8, or 24 weeks, arteries were isolated forin vitrostudy. High flow (HF) induced outward hypertrophic remodeling in WKY rats after 1 week and persisted until 24 weeks without change in wall to lumen ratio. In SHRs, diameter increase was delayed, occurring only after 3 weeks. Nevertheless, it was reduced at 8 weeks and no longer significant after 24 weeks. In parallel, media cross-section area increased more with time in SHRs than in WKY rats and this was associated with increased contractility and oxidative stress with decreased NO-dependent relaxation. Low flow induced progressive inward remodeling until 24 weeks in both strains with excessive hypertrophy in SHRs. Thus, a chronic increase in flow induced transitory diameter expansion and long-lasting hypertrophy in SHRs. This could contribute to the higher susceptibility of hypertensive subjects to ischemic diseases.

Venoconstriction to endothelin-1 in humans: role of calcium and potassium channels

1993 ◽  
Vol 265 (5) ◽  
pp. H1676-H1681 ◽  
Author(s):  
W. G. Haynes ◽  
D. J. Webb
Keyword(s):  
Human Subjects ◽  
K Channel ◽  
K Channels ◽  
Endothelin 1 ◽  
Channel Opener ◽  
K Channel Opener ◽  
Ca2 Channels

Recent studies in vitro have suggested that there may be an interaction between endothelin-1 and ATP-sensitive K+ channels in vascular smooth muscle. Here we have investigated whether agents acting on membrane Ca2+ and K+ channels modulate endothelin-1-induced venoconstriction in vivo in human subjects. In a series of studies, six healthy subjects received, on separate occasions, local infusions into dorsal hand veins of endothelin-1 coinfused with 1) the ATP-sensitive K+ channel opener, cromakalim; 2) the dihydropyridine Ca2+ antagonist, nicardipine; 3) a control vasodilator, hydralazine; and 4) saline placebo. Endothelin-1 caused local venoconstriction with a maximum reduction in vein size of 66 +/- 4% at 60 min (P = 0.0001 vs. basal). Cromakalim prevented endothelin-1-induced venoconstriction (9 +/- 10% maximum constriction; P = 0.68 vs. basal). By contrast, nicardipine, in a dose sufficient to block depolarization-induced constriction caused by K+ infusion, had only a partial effect on endothelin-1-induced venoconstriction (35 +/- 8% maximum constriction; P = 0.001 vs. basal; P = 0.02 vs. endothelin-1), whereas a 10-fold higher dose of nicardipine had no additional effect and hydralazine had no effect. In further studies, cromakalim, but not nicardipine, reversed endothelin-1-induced venoconstriction. Cromakalim did not prevent constriction induced by norepinephrine. Although calcium entry through dihydropyridine-sensitive Ca2+ channels may account in part for the vasoconstrictor action of endothelin-1 in humans, the abolition of endothelin-1 responses by a K+ channel opener suggests additional mechanisms of action for endothelin-1.

Altered regulation of nerve growth factor secretion by cultured VSMCs from hypertensive rats

1995 ◽  
Vol 269 (2) ◽  
pp. H621-H628
Author(s):  
J. M. Spitsbergen ◽  
J. S. Stewart ◽  
J. B. Tuttle
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Sympathetic Innervation ◽  
Hypertensive Rats ◽  
Nerve Growth ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Wistar Kyoto ◽  
Shr And Wky Rats

Vascular tissues from spontaneously hypertensive rats (SHR) exhibit increased nerve growth factor (NGF) levels and increased density of sympathetic innervation compared with those from normotensive Wistar-Kyoto (WKY) rats. The present study asked whether basal NGF secretion or secretion elicited by agents analogous to sympathetic neurotransmitters differ in cultured vascular smooth muscle cells (VSMCs) from SHR and WKY rats. VSMCs were maintained in serum-free medium (SFM) for 72 h and then treated and sampled at 4, 6, 8, and 24 h. Conditioned medium was assayed for NGF using a two-site enzyme-linked immunoassay. NGF secretion by SHR (19.2 +/- 4.6 pg.well-1.48 h-1) and WKY VSMCs (16.7 +/- 5.4 pg.we..-1.48 h-1) was similar in cultures grown in serum-containing medium, whereas SHR VSMCs maintained in SFM secrete more NGF than WKY VSMCs (9.1 +/- 1.9 vs. 2.9 +/- 0.4 pg.well-1.24 h-1, respectively). Treatment of cultures with phenylephrine (0.1-10 microM), neuropeptide Y (1-1,000 nM), or alpha beta-methyleneadenosine 5'-triphosphate (10 and 100 microM) had no effect on NGF secretion by WKY VSMCs, while increasing NGF secretion by SHR VSMCs. Treatment with isoproterenol (0.1-10 microM) decreased NGF secretion by WKY VSMCs but not SHR VSMCs. These data indicate that the regulation of NGF secretion by sympathetic neurotransmitter receptors is different for cultured VSMCs from SHR and WKY rats. If similar differences exist in vivo, they could account for the alterations in NGF levels and sympathetic innervation that are observed.

Potassium channels are not involved in vasopressin-induced vasodilation in the rat lung

1994 ◽  
Vol 266 (2) ◽  
pp. H491-H495 ◽  
Author(s):  
M. R. Eichinger ◽  
R. D. Russ ◽  
B. R. Walker
Keyword(s):  
Physiological Saline ◽  
K Channel ◽  
Channel Blockers ◽  
Sprague Dawley ◽  
Synthesis Inhibitor ◽  
K Channels ◽  
Vasodilatory Response ◽  
Physiological Saline Solution ◽  
High Doses ◽  
Vasodilator Action

We have previously observed that arginine vasopressin (AVP)-induced pulmonary vasodilation is attenuated by nitric oxide (NO) synthesis inhibition; however, blockade of the response is incomplete even at very high doses of the inhibitor. Thus it was hypothesized that the remaining vasodilation might be due to release of an endothelium-derived hyperpolarizing factor acting to open vascular smooth muscle K+ channels. Lungs were isolated from male Sprague-Dawley rats and perfused at constant flow with physiological saline solution containing 4% albumin. After equilibration, lungs were treated with either glibenclamide (50 microM), Ba2+ (100 microM), tetraethylammonium (10 mM), or the respective vehicle and were then constricted with the thromboxane mimetic U-46619. Upon development of a stable degree of vasoconstriction, AVP (2.5 x 10(-9) M) was administered and its vasodilator action noted. AVP caused an approximately 60% reversal of U-46619 vasoconstriction in control lungs, and this response was not affected by any of the K+ channel blockers. In contrast, administration of the NO synthesis inhibitor N omega-nitro-L-arginine (L-NNA; 300 microM) significantly attenuated AVP-induced dilation to approximately 25%. The addition of K+ channel blockers did not further diminish the vasodilatory response in L-NNA-treated lungs. In conclusion, these results suggest that ATP- and Ca(2+)-sensitive K+ channels are not involved in the pulmonary vasodilatory response to AVP.

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