scholarly journals Alkaline Phosphatase Activity Is a Key Determinant of Vascular Responsiveness to Norepinephrine

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1308-1318
Author(s):  
Edwin K. Jackson ◽  
Dongmei Cheng ◽  
Vladimir B. Ritov ◽  
Zaichuan Mi
Keyword(s):  
Alkaline Phosphatase ◽  
Adenosine Receptors ◽  
Vascular Reactivity ◽  
Sympathetic Nerve Stimulation ◽  
Vascular Responses ◽  
Positive Cooperativity ◽  
Rat Mesentery ◽  
Norepinephrine Concentration ◽  
Vascular Responsiveness

Here, we tested the hypothesis that TNAP (tissue nonspecific alkaline phosphatase) modulates vascular responsiveness to norepinephrine. In the isolated, Tyrode’s-perfused rat mesentery, 50 µmol/L of L-p-bromotetramisole (L-p-BT; selective TNAP inhibitor, K i =56 µmol/L) significantly reduced TNAP activity and caused a significant 9.0-fold rightward-shift in the norepinephrine concentration versus vasoconstriction relationship. At 100 µmol/L, L-p-BT further reduced mesenteric TNAP activity and caused an additional significant right-shift of the norepinephrine concentration versus vasoconstriction relationship. A higher concentration (200 µmol/L) of L-p-BT had no further effect on either mesenteric TNAP activity or norepinephrine-induced vasoconstriction. L-p-BT did not alter vascular responses to vasopressin, thus ruling-out nonspecific suppression of vascular reactivity. Since in the rat mesenteric vasculature α 1 -adrenoceptors mediate norepinephrine-induced vasoconstriction, these finding indicate that TNAP inhibition selectively interferes with α 1 -adrenoceptor signaling. Additional experiments showed that the effects of TNAP inhibition on norepinephrine-induced vasoconstriction were not mediated by accumulation of pyrophosphate or ATP (TNAP substrates) nor by reduced adenosine levels (TNAP product). TNAP inhibition significantly reduced the Hillslope of the norepinephrine concentration versus vasoconstriction relationship from 1.8±0.2 (consistent with positive cooperativity of α 1 -adrenoceptor signaling) to 1.0±0.1 (no cooperativity). Selective activation of A 1 -adenosine receptors, which are known to participate in coincident signaling with α 1 -adrenoceptors, reversed the suppressive effects of L-p-BT on norepinephrine-induced vasoconstriction. In vivo, L-p-BT administration achieved plasma levels of ≈60 µmol/L and inhibited mesenteric vascular responses to exogenous norepinephrine and sympathetic nerve stimulation. TNAP modulates vascular responses to norepinephrine likely by affecting positive cooperativity of α 1 -adrenoceptor signaling via a mechanism involving A 1 receptor signaling.

Role of adenosine in noradrenergic neurotransmission in spontaneously hypertensive rats

1987 ◽  
Vol 253 (4) ◽  
pp. H909-H918 ◽  
Author(s):  
E. K. Jackson
Keyword(s):  
Plasma Levels ◽  
Spontaneously Hypertensive Rat ◽  
Base Line ◽  
Inhibitory Effects ◽  
Spontaneously Hypertensive ◽  
Vascular Responses ◽  
Rat Mesentery ◽  
Wistar Kyoto

The purpose of this study was to compare the in vivo role of adenosine as a modulator of noradrenergic neurotransmission in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto control rat (WKY). In the in situ blood-perfused rat mesentery, vascular responses to periarterial (sympathetic) nerve stimulation (PNS) and to exogenous norepinephrine (NE) were enhanced in SHR compared with WKY. In both SHR and WKY, vascular responses to PNS were more sensitive to inhibition by adenosine than were responses to NE. At matched base-line vascular responses, compared with WKY, SHR were less sensitive to the inhibitory effects of adenosine on vascular responses to PNS, but SHR and WKY were equally sensitive with respect to adenosine-induced inhibition of responses to NE. Antagonism of adenosine receptors with 1,3-dipropyl-8-p-sulfophenylxanthine shifted the dose-response curve to exogenous adenosine sixfold to the right yet did not influence vascular responses to PNS or NE in either SHR or WKY. Furthermore, PNS did not alter either arterial or mesenteric venous plasma levels of adenosine in SHR or WKY, and plasma levels of adenosine in both strains were always lower than the calculated threshold level required to attenuate neurotransmission. It is concluded that in vivo 1) exogenous adenosine interferes with noradrenergic neurotransmission in both SHR and WKY; 2) SHR are less sensitive to the inhibitory effects of exogenous adenosine on noradrenergic neurotransmission than are WKY; 3) endogenous adenosine does not play a role in modulating neurotransmission in either strain under the conditions of this study; and 4) enhanced noradrenergic neurotransmission in the SHR is not due to defective modulation of neurotransmission by adenosine.

Cytochrome P450 metabolites of arachidonic acid may be important mediators in angiotensin II-induced vasoconstriction in the rat mesentery in vivo

2000 ◽  
Vol 98 (3) ◽  
pp. 277-282 ◽  
Author(s):  
Z. M. CHU ◽  
K. D. CROFT ◽  
D. A. KINGSBURY ◽  
J. R. FALCK ◽  
K. M. REDDY ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Selective Inhibitor ◽  
Arterial Blood ◽  
Rat Mesentery ◽  
Mesenteric Vessels ◽  
Wistar Kyoto

We have investigated the role of cytochrome P450 (CYP-450) metabolites of arachidonic acid in the modulation of vascular reactivity to angiotensin II in vivo using an in situ blood-perfused mesenteric preparation in anaesthetized spontaneously hypertensive rats (SHR). Miconazole, a non-selective inhibitor of CYP-450 that inhibits both hydroxylation and epoxidation, substantially suppressed mesenteric vasoconstrictor responses to angiotensin II in SHR, but had no effect on responses to noradrenaline or sympathetic nerve stimulation. In normotensive Wistar–Kyoto (WKY) rats, miconazole caused only a modest suppression of vasoconstrictor responses to angiotensin II. N-Methylsulphonyl-12,12-dibromododec-11-enamide (DDMS), a new selective inhibitor of CYP-450 ω-hydroxylase activity, decreased mean intra-arterial blood pressure and significantly attenuated mesenteric angiotensin II-induced vasoconstrictor responses in SHR. Isolated mesenteric vessels were able to metabolize 14C-labelled arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) in vitro, and this was substantially inhibited by DDMS. The results from the present studies combined with the existing evidence that angiotensin II stimulates the release of 20-HETE, a CYP-450 metabolite of arachidonic acid, suggest that CYP-450-derived HETEs may be important mediators in angiotensin II-induced vasoconstriction. However, the development of more sensitive assays for the detection in vivo of 20-HETE in mesenteric vessels would be required to confirm these findings.

Vascular escape from vasoconstriction and post-stimulatory hyperemia in the superior mesenteric artery of the cat

1988 ◽  
Vol 66 (9) ◽  
pp. 1174-1180 ◽  
Author(s):  
W. Wayne Lautt ◽  
Dallas J. Legare ◽  
Leslie K. Lockhart
Keyword(s):  
Superior Mesenteric Artery ◽  
Adenosine Receptors ◽  
Mesenteric Artery ◽  
Vascular Tone ◽  
Low Dose ◽  
Data Interpretation ◽  
High Dose ◽  
Partial Recovery ◽  
Sympathetic Nerve Stimulation

Vascular escape is seen as a partial recovery from initial vasoconstriction despite continued constrictor stimuli. Escape in the feline intestine (superior mesenteric artery) occurred for i.a. norepinephrine (NE) infusions (56% escape for low dose, 40% for high dose NE) and for sympathetic nerve stimulation (SNS) (65% for 1 Hz, 49% for 3 Hz, 44% for 9 Hz). Adenosine infusion or blockade of adenosine receptors (8-phenyltheophylline) did not alter the escape, showing that endogenous adenosine levels are unlikely to play any role in the mechanism of escape. Other aspects of escape were studied: equiconstrictor doses of NE given i.a. or i.v. lead to similar degrees of escape; propranolol and ouabain did not alter escape; the degree of escape was significantly greater for the low dose NE and the 1-Hz SNS than for higher intensities of stimulation, however, escape did not inversely correlate significantly with the initial degree of vasoconstriction when all data were pooled. Post-stimulatory hyperemia occurs upon cessation of vasoconstrictor stimuli, reaches a peak conductance within 1 min, and returns to baseline within about 3 min. Hyperemia was quantitated from the peak vasodilation and from the area under the flow–hyperemia curve. The hyperemias were not related to NE dose or SNS frequency nor did they correlate with initial vasoconstriction or extent of vascular escape. Contrary to the hypothesis that adenosine may mediate hyperemia, adenosine infusions reduced the response and adenosine receptor antagonism tended to elevate the response. Propranolol and ouabain did not produce significant effects on post-stimulatory hyperemia. A discussion of the merits of using vascular resistance or conductance to assess vascular tone and vascular escape concludes that in the in vivo systems in which changes in vascular tone result mainly in changes in blood flow, the use of resistance is unacceptable and may lead to serious error in data interpretation.

Effects of capsaicin desensitization on nasal mucosal secretion in guinea pigs in vivo

1993 ◽  
Vol 75 (2) ◽  
pp. 798-804 ◽  
Author(s):  
A. Z. Gawin ◽  
J. N. Baraniuk ◽  
Y. Igarashi ◽  
M. A. Kaliner
Keyword(s):  
Alkaline Phosphatase ◽  
Protein Secretion ◽  
Total Protein ◽  
Lavage Fluid ◽  
Sensory Nerves ◽  
Protein Marker ◽  
Vascular Responses ◽  
Glandular Secretion ◽  
Mucosal Secretion

Capsaicin-sensitive mechanisms may contribute to histamine's effects on guinea pig nasal mucosal secretion in vivo. Histamine nasal provocations were performed, secretions were collected, and the following variables were measured: total protein (marker of all secretory processes), alkaline phosphatase (marker of glandular secretion), and albumin (marker of vascular permeability, epithelial permeability, and glandular transport). By challenging only one nostril (ipsilateral), the contralateral responses to these challenges were examined and the nature of "nasonasal" reflexes was determined. Histamine increased albumin and alkaline phosphatase concentrations in lavage fluid on the ipsilateral and contralateral sides. The alkaline phosphatase secretion was reduced by atropine. Capsaicin induced dose-dependent albumin exudation. To determine the roles of capsaicin-sensitive sensory nerves, one nostril was desensitized by topical application of capsaicin to one nostril in increasing doses daily for 5 wk. This led to 1) ablation of all secretory responses to capsaicin, 2) ablation of histamine-induced alkaline phosphatase and total protein secretion, 3) blunted histamine-induced albumin exudation on the desensitized side, and 4) ablation of histamine-induced contralateral reflex-mediated protein secretion. These results indicate that capsaicin stimulates vascular responses, probably by stimulating nociceptive nerve axon responses. Histamine induces vascular responses and albumin exudation by both capsaicin-sensitive sensory neuron axon responses and direct effects on vessels. Histamine stimulates glandular secretion through a capsaicin-sensitive afferent/cholinergic efferent reflex.

Enhanced vascular reactivity to various vasoconstrictor agents following pinealectomy in the rat: role of melatonin

1980 ◽  
Vol 58 (3) ◽  
pp. 287-293 ◽  
Author(s):  
Stephen C. Cunnane ◽  
Mehar S. Manku ◽  
Masatsugu Oka ◽  
David F. Horrobin
Keyword(s):  
Vascular Reactivity ◽  
Calcium Release ◽  
Calcium Influx ◽  
Extracellular Fluid ◽  
Heart Weight ◽  
Vasoconstrictor Agents ◽  
Vascular Responsiveness ◽  
Male Wistar Rats

The mesenteric vascular bed preparation of control and pinealectomized (PX) male Wistar rats was used to examine vascular reactivity to two concentrations each of norepinephrine, serotonin, angiotensin, and potassium. Vasoconstrictor responses to 50- and 100-ng injections of norepinephrine and 0.5- and 1.0-μg injections of serotonin were 30–40% higher in preparations from PX rats. Responses to 100 ng but not to 50 ng of angiotensin were also significantly higher in preparations from PX rats. Responses to 1.5- and to 3.0-mg injections of potassium did not differ significantly in either case. In vivo injection of 20 μg of melatonin 3 h prior to dissection of the preparation, or in vitro perfusion of 20 ng melatonin per millilitre of buffer completely reversed the increased vascular response to all vasoconstrictor agents tested in the PX preparations, but had little effect in control preparations. Also observed in PX rats was a significant increase in blood pressure, serum sodium, and increased body and heart weight. Arterial wall sodium was also elevated in PX rats. These changes may be relevant to the increased vascular reactivity of PX rats. The increased vascular responsiveness of PX rats may be specific for agents that stimulate calcium release from intracellular stores (norepinephrine, angiotensin) rather than those that stimulate calcium influx from extracellular fluid (potassium). Melatonin lack may be the cause of the vascular changes in the PX rats as both in vivo and in vitro it lowered the vasoconstrictor effects of the agents tested, but only in PX rats; it had no significant effect in the control rats.

In vivo and in vitro effects of lead on vascular reactivity in rats

1981 ◽  
Vol 241 (2) ◽  
pp. H211-H216 ◽  
Author(s):  
R. C. Webb ◽  
R. J. Winquist ◽  
W. Victery ◽  
A. J. Vander
Keyword(s):  
Lead Acetate ◽  
Vascular Reactivity ◽  
Blood Levels ◽  
Human Populations ◽  
Calcium Entry Blocker ◽  
Adult Rats ◽  
Vascular Responsiveness ◽  
In Vitro Effects

The effects of lead on vascular responsiveness were examined in rats. Adult rats, which had received levels of lead acetate in their drinking water to produce blood levels similar to those seen in some urban human populations, consistently had higher systolic blood pressures compared to age-matched controls. Helical strips of tail arteries from the lead-treated rats displayed a greater force-generating ability in response to the cumulative addition of methoxamine to the muscle bath. There were no differences in ED50 between the two groups. Similar results were obtained when norepinephrine was used. The calcium-entry blocker, D 600, was less effective in reducing in reducing contractions induced by methoxamine in lead-treated rats than in controls. There were no differences between the two groups in responses to KCl or electrical stimulation of nerve endings. Contractile responses to norepinephrine, methoxamine, KCl, and nerve stimulation in arteries from untreated rats were unaltered by addition of lead acetate to the muscle bath. These results demonstrate that hypertension induced by moderate levels of lead intake is associated with an increased vascular responsiveness to alpha-adrenergic agonists.

Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension

2006 ◽  
Vol 291 (2) ◽  
pp. R481-R488 ◽  
Author(s):  
Jeffrey L. Segar ◽  
Robert D. Roghair ◽  
Emily M. Segar ◽  
Melissa C. Bailey ◽  
Thomas D. Scholz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Vascular Reactivity ◽  
Systemic Hypertension ◽  
Arterial Baroreflex ◽  
Vascular Responses ◽  
Early Gestation ◽  
Arterial Blood

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces alterations in postnatal cardiovascular physiology, including hypertension. To determine whether autonomic function and systemic vascular reactivity are altered by in utero programming before the development of systemic hypertension, we examined arterial baroreflex function and in vivo hemodynamic and in vitro vascular responses to vasoactive agents in 10- to 14-day-old newborn lambs exposed to early gestation glucocorticoids. Dexamethasone (Dex, 0.28 mg·kg−1·day−1) or saline was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term 145 days), and lambs were allowed to deliver ( n = 6 in each group). Resting mean arterial blood pressure (MABP; 77 ± 1 vs. 74 ± 3 mmHg) and heart rate (HR; 249 ± 9 vs. 226 ± 21 beats/min) were similar in Dex-exposed and control animals, respectively. The arterial baroreflex curve, relating changes in HR to MABP, was significantly shifted toward higher pressure in the Dex-exposed lambs although no change in the sensitivity (gain) of the response was seen. In vivo changes in blood pressure in response to bolus doses of ANG II (20, 50, and 100 ng/kg) and phenylephrine (2, 5, and 10 μg/kg) were similar in the two groups. However, Dex lambs displayed greater decreases in MABP in response to ganglionic blockade with tetraethylammonium bromide (10 mg/kg; −30 ± 3 vs. −20 ± 3 mmHg, P < 0.05) and greater increases in MABP after nitric oxide synthase blockade with NG-nitro-l-arginine (25 mg/kg; 23 ± 3 vs. 13 ± 2 mmHg, P < 0.05) compared with control lambs. By in vitro wire myography, mesenteric and femoral artery microvessel contractile responses to KCl were similar, whereas responses to endothelin (in mesenteric) and norepinephrine (in femoral) were significantly attenuated in Dex lambs compared with controls. Femoral vasodilatory responses to forskolin and sodium nitroprusside were similar in the two groups ( n = 4). These findings suggest that resetting of the baroreflex, accompanied by increased sympathetic activity and altered nitric oxide-mediated compensatory vasodilatory function, may be important contributors to programming of hypertension.

scholarly journals Involvement of A1 adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma

2010 ◽  
Vol 299 (1) ◽  
pp. H81-H87 ◽  
Author(s):  
Dovenia S. Ponnoth ◽  
Ahmed Nadeem ◽  
Stephen Tilley ◽  
S. Jamal Mustafa
Keyword(s):  
Systemic Inflammation ◽  
Adenosine Receptors ◽  
Airway Hyperresponsiveness ◽  
Lung Inflammation ◽  
Vascular Reactivity ◽  
Vascular Responses ◽  
Significant Difference ◽  
A1 Adenosine Receptors ◽  
Allergic Mouse ◽  
Western Blot Data

Poor lung function and respiratory disorders like asthma have a positive correlation with the development of adverse cardiovascular events. Increased adenosine levels are associated with lung inflammation that could lead to altered vascular responses and systemic inflammation. We hypothesized that asthmatic lung inflammation has systemic effects through A1 adenosine receptors (A1AR) and investigated the effects of aerosolized adenosine on vascular reactivity and inflammation, using A1AR knockout (A1KO) and corresponding wild-type (A1WT) mice that were divided into three experimental groups each: control (CON), allergen sensitized and challenged (SEN), and SEN + aerosolized adenosine (SEN + AD). Animals were sensitized with ragweed (200 μg ip; days 1 and 6), followed by 1% ragweed aerosol challenges ( days 11 to 13). On day 14, the SEN + AD groups received one adenosine aerosol challenge (6 mg/ml) for 2 min, and aortae were collected on day 15. 5′- N-ethylcarboxamidoadenosine (NECA; nonselective adenosine analog) induced concentration-dependent aortic relaxation in the A1WT CON group, which was impaired in the A1WT SEN and SEN + AD groups. All groups of A1KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A1WT SEN and SEN + AD groups had a significantly higher contraction to selective A1 agonist 2-chloro- N6-cyclopentyladenosine (CCPA) compared with the CON group. Western blot data showed that aortic A1AR expression was significantly increased in WT SEN and SEN + AD mice compared with CON mice. Gene expression of ICAM-1 and IL-5 was significantly increased in allergic A1WT aorta and were undetected in the A1KO groups. A1WT allergic mice had significantly higher airway hyperresponsiveness (enhanced pause) to NECA, with adenosine aerosol further enhancing it. In conclusion, allergic A1WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A1AR is proinflammatory systemically in this model of allergic asthma.

Role of adenosine in noradrenergic neurotransmission

1988 ◽  
Vol 255 (2) ◽  
pp. H386-H393 ◽  
Author(s):  
C. J. Kuan ◽  
E. K. Jackson
Keyword(s):  
Blood Flow ◽  
Nerve Stimulation ◽  
Sympathetic Nerve ◽  
Time Course ◽  
Tissue Blood Flow ◽  
Mesenteric Blood Flow ◽  
Sympathetic Nerve Stimulation ◽  
Endogenous Adenosine ◽  
Rat Mesentery

The purpose of this study was to evaluate the hypothesis that endogenous adenosine modulates noradrenergic neurotransmission in vivo during sustained periods of sympathetic nerve stimulation associated with a reduction in tissue blood flow. This hypothesis was tested in the rat mesentery in vivo by comparing the effects of periarterial (sympathetic) nerve stimulation (PNS) on mesenteric blood flow and norepinephrine (NE) spillover from the mesentery in control rats vs. rats treated with the adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX; 10 mg + 150 micrograms/min iv). In both control rats and rats pretreated with DPSPX, sustained PNS (7 Hz for 30 min) caused an initial large decrease in mesenteric blood flow and increase in NE spillover; however, these responses attenuated over the 30-min stimulation period. The time course of PNS-induced changes in mesenteric blood flow and NE spillover were not altered by treatment with DPSPX. However, administration of DPSPX prevented inhibition of noradrenergic neurotransmission in the rat mesentery by 2-chloroadenosine, which indicated that an effective level of DPSPX was achieved. We conclude that even during sustained sympathetic nerve stimulation associated with reductions in tissue perfusion, endogenous adenosine does not modulate noradrenergic neurotransmission in vivo in the rat mesentery.

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