Serotonin reuptake inhibitor, fluoxetine, dilates isolated skeletal muscle arterioles. Possible role of altered Ca2+ sensitivity.
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1. Inhibitors of serotonin reuptake in the central nervous system, such as fluoxetine, may also affect the function of vascular tissues. Thus, we investigated the effect of fluoxetine on the vasomotor responses of isolated, pressurized arterioles of rat gracilis muscle (98 +/- 4 microns in diameter at 80 mmHg perfusion pressure). 2. We have found that increasing concentrations of fluoxetine dilated arterioles up to 155 +/- 5 microns with an EC50 of 2.5 +/- 0.5 x 10(-6) M. 3. Removal of the endothelium, application of 4-aminopyridine (4-AP, an inhibitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an inhibitor of ATP-sensitive K+ channels) did not affect the vasodilator response to fluoxetine. 4. In the presence of 10(-6), 2 x 10(-6) or 10(-5) M fluoxetine noradrenaline (NA, 10(-9)-10(-5) M) and 5-hydroxytryptamine (5-HT, 10(-9)-10(-5)M)-induced constrictions were significantly attenuated resulting in concentration-dependent parallel rightward shifts of their dose-response curves (pA2 = 6.1 +/- 0.1 and 6.9 +/- 0.1, respectively). 5. Increasing concentrations of Ca2+ (10(-4) 3 x 10(-2) M) elicited arteriolar constrictions (up to approximately 30%), which were markedly reduced by 2 x 10(-6)M fluoxetine, whereas 10(-5)M fluoxetine practically abolished these responses. 6. In conclusion, fluoxetine, elicits substantial dilations of isolated skeletal muscle arterioles, a response which is not mediated by 4-AP- and ATP-sensitive K+ channels or endothelium-derived dilator factors. The findings that fluoxetine had a greater inhibitory effect on Ca2+ elicited constrictions than on responses to NA and 5-HT suggest that fluoxetine may inhibit Ca2+ channel(s) or interfere with the signal transduction by Ca2+ in the vascular smooth muscle cells. (+info)
Attenuated in vitro coronary arteriolar vasorelaxation to insulin-like growth factor I in experimental hypercholesterolemia.
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Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10(-12) to 10(-7) mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10(-4) mol/L N(G)-monomethyl-L-arginine (L-NMMA) or the potassium channel blocker 10(-2) mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5+/-1.0 versus 1.9+/-0.08 mmol/L; P<0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin (P=0.80) or IGF-1 (P=0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79+/-6% versus 42+/-8%; P=0.01) but not insulin (43+/-6% versus 53+/-7%; P=0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA (P<0.001) and TEA (P=0.01), whereas only L-NMMA attenuated insulin (P<0.001). Staining for IGF-1 and IGF binding protein 2 was increased (P<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia. (+info)
Alteration of microtubule polymerization modulates arteriolar vasomotor tone.
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Microtubules are important cytoskeletal elements that have been shown to play a major role in many cellular processes because of their mechanical properties and/or their participation in various cell signaling pathways. We tested the hypothesis that depolymerization of microtubules would alter vascular smooth muscle (VSM) tone and hence contractile function. In our studies, isolated cremaster arterioles exhibited significant vasoconstriction that developed over a 20- to 40-min period when they were treated with microtubule depolymerizing drugs colchicine (10 microM), nocodazole (10 microM), or demecolcine (10 microM). Immunofluorescent labeling of microtubules in cultured rat VSM revealed that both colchicine and nocodazole caused microtubule depolymerization over a similar time course. The vasoconstriction was maintained over a wide range of intraluminal pressures (30-170 cmH(2)O). The increased tone was not affected by endothelial denudation, suggesting that it was due to an effect on VSM. Microtubule depolymerization with demecolcine or colchicine had no effect on VSM intracellular Ca(2+) concentration ([Ca(2+)](i)). These data indicate that microtubules significantly interact with processes leading to the expression of vasomotor tone. The mechanism responsible for the effect of microtubules on vasomotor tone appears to be independent of both the endothelium and an increase in VSM [Ca(2+)](i). (+info)
Myogenic reactivity of rat epineurial arterioles: potential role in local vasoregulatory events.
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Local control of neural blood flow is considered to reside in innervation of epineurial and endoneurial arterioles rather than in intrinsic autoregulatory mechanisms. With the use of an isolated vessel preparation and an in vivo approach, the present studies examined intrinsic vasomotor responsiveness of epineurial arterioles. Segments of epineurial arterioles, cannulated on glass micropipettes (40 micrometers) and pressurized in the absence of intraluminal flow, showed sustained pressure-dependent (30-90 mmHg) vasoconstriction and acute myogenic reactivity. Myogenic tone was unaffected by phentolamine (10(-6) M). Removal of extracellular Ca(2+) resulted in loss of spontaneous tone and passive behavior. Concentration-response curves for norepinephrine (10(-9)-3 x 10(-6) M) and relaxation to both acetylcholine (10(-8)-10(-5) M) and adenosine (10(-8)-10(-4) M) were obtained. Acetylcholine dilator responses were inhibited by N(G)-nitro-L-arginine methyl ester. Epineurial blood flow was measured in vivo using a laser-Doppler flow probe. Blood flow declined over a 2-h period after surgery, and during this time preparations developed responsiveness to the dilator acetylcholine. Phentolamine blocked vasoconstrictor responses to exogenous norepinephrine but only partially reversed the in vivo baseline tone. The time-dependent decline in epineurial blood flow was observed despite the presence of tetrodotoxin (1 microM), further confirming that tone was predominantly caused by myogenic rather than neurogenic mechanisms. It is concluded that because epineurial arterioles exhibit intrinsic myogenic reactivity, they have the potential to participate in local regulation of neural hemodynamics independently of their own innervation. (+info)
NO and prostanoids: age dependence of hypercapniaand histamine-induced dilations of pig pial arterioles.
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Responses to hypercapnia and acetylcholine by newborn piglet pial arterioles are prostanoid dependent but appear to require both prostanoids and nitric oxide in juvenile pigs. We hypothesized that cerebrovascular dilatory responses become less prostanoid dependent and more NO dependent with development. Pial arteriolar responses to hypercapnia and histamine were recorded from alpha-chloralose-anesthetized newborn and juvenile pigs with closed cranial windows. Responses were recorded during control, after indomethacin or N(omega)-nitro-L-arginine (L-NNA), and after inhibitor plus iloprost or sodium nitroprusside. Indomethacin blocked newborn hypercapnic responses and markedly attenuated histamine dilations, but only reduced the dilations to about half in juveniles. Iloprost at subdilator concentrations restored newborn responses to hypercapnia and histamine but did not alter either response in indomethacin-treated juveniles. L-NNA attenuated juvenile, but not newborn, hypercapnia-induced dilations. Sodium nitroprusside did not restore the response. L-NNA did not alter responses to histamine in either age group. Cerebrovascular dilations to hypercapnia and histamine are prostanoid dependent and nitric oxide independent in the newborn pig, whereas nitric oxide assumes an increasing role in hypercapnic, but not histamine, responses with development. (+info)
Neuronal NOS contributes to biphasic autoregulatory response during enhanced TGF activity.
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To assess the afferent arteriolar autoregulatory response during increased activity of the tubuloglomerular feedback (TGF) mechanism and to delineate the contribution of neuronal nitric oxide synthase (nNOS) to this response, afferent arteriolar diameter responses to changes in renal perfusion pressure (RPP) were monitored in vitro using the blood-perfused rat juxtamedullary nephron preparation. At RPP of 100 mmHg, basal afferent arteriolar diameter averaged 21.1 +/- 1.4 micrometer (n = 9). The initial and sustained constrictor responses of afferent arterioles to a 60-mmHg increase in RPP averaged 14.8 +/- 1.4% and 13.3 +/- 1.3%, respectively. Acetazolamide treatment, which enhances TGF responsiveness by increasing distal nephron volume delivery, significantly decreased basal afferent arteriolar diameter by 8.2 +/- 0.5% and enhanced the initial response (25.5 +/- 2.3%) to a 60-mmHg increase in RPP but did not alter the sustained response (14.3 +/- 1.5%). In another series of experiments, nNOS inhibition with 10 microM S-methyl-L-thiocitrulline (L-SMTC) significantly decreased afferent arteriolar diameter from 20.3 +/- 1.3 to 18.3 +/- 1.1 micrometer (n = 7) and enhanced both the initial (34.4 +/- 3.5%) and sustained constrictor responses (27.6 +/- 2.9%) to a 60-mmHg increase in RPP. Treatment with acetazolamide further enhanced both initial (56.4 +/- 3.0%) and sustained responses (54.6 +/- 2.7%). Interruption of distal delivery by transection of the loops of Henle prevented the enhanced responses to increases in RPP elicited with either acetazolamide or L-SMTC. These results indicate that nNOS contributes to the counteracting resetting process of biphasic afferent arteriolar constrictor responses to increases in RPP through a TGF-dependent mechanism. (+info)
Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study.
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Narrowing and other changes in retinal arterioles may reflect damage due to hypertension, which may predict stroke and other cardiovascular diseases independently of blood pressure level. Newly developed quantitative methods of assessing retinal narrowing are used to determine whether this sign is related only to current blood pressure or whether it also independently reflects the effects of previous blood pressure. Retinal photography was performed at the third examination of Atherosclerosis Risk in Communities (ARIC) Study in 1993-1995, and results are presented for the 9,300 nondiabetic participants aged 50-71 years. Generalized narrowing of smaller arterioles was strongly and monotonically related to current blood pressure in men and women, whether they were taking antihypertensive medications or not, and, independent of current blood pressure, was consistently and monotonically related to blood pressure levels measured 3 and 6 years before the retinal assessment. Arteriovenous nicking was also independently related to both current and previous blood pressures. The patterns of association suggested that these signs reflect both transient and persisting structural effects of elevated blood pressure, in agreement with the scant pathologic literature available. The findings suggest that retinal assessment may be useful for research on the microvascular contributions to clinical cardiovascular diseases. (+info)
Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature.
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BACKGROUND: Angiotensin type 1 (AT1) receptor-deficient mice (Agtr1-/-), which selectively lack both AT1A and AT1B receptor genes, are characterized by marked intrarenal vascular thickening. In the present study, we explored the possible involvement of the kinin-kallikrein system in the development of this renal vascular hypertrophy. METHODS: Wild-type and Agtr1-/- mice were examined for the developmental regulation pattern of the kinin-kallikrein system and treated with aprotinin (a kallikrein inhibitor), AcLys [D-b Nal7, Ile8] des-Arg9-bradykinin (a bradykinin B1 receptor antagonist), or Hoe-140 (a bradykinin B2 receptor antagonist) from 3 to 14 days of age. RESULTS: The normal postnatal up-regulation of kininase II was organ-specifically suppressed in Agtr1-/- kidneys at 2 and 3 weeks of age. Immunohistochemical staining in Agtr1-/- mice revealed tissue kallikrein staining along the nephron from connecting tubules to cortical collecting tubules in proximity to the hypertrophic vasculature, whereas tissue kallikrein staining was confined to connecting tubules in wild-type mice. Aprotinin and Hoe-140 accelerated the vascular hypertrophy significantly as determined by wall thickness ratio, whereas B1 receptor antagonism had no effect. CONCLUSION: The kinin-kallikrein system in the Agtr1-/- mouse kidney is functionally activated by local suppression of kininase II and extensive redistribution of kallikrein to perivascular areas. This activation, specific to the kidney, serves to dampen a development of the marked vascular hypertrophy. These results demonstrate, to our knowledge for the first time, the antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature in vivo. (+info)