Noradrenaline In Mesenteric Arteries Research Articles

Progranulin Maintains Blood Pressure and Vascular Tone Dependent on EphrinA2 and Sortilin1 Receptors and Endothelial Nitric Oxide Synthase Activation.

Background The mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether progranulin sustains the vascular tone that helps regulate blood pressure. Methods and Results We used male and female C57BL6/J wild type (progranulin+/+) and B6(Cg)-Grntm1.1Aidi/J (progranulin-/-) to understand the impact of progranulin on vascular contractility and blood pressure. We found that progranulin-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which is restored by supplementing the mice with recombinant progranulin. In ex vivo experiments, recombinant progranulin attenuated the vascular contractility to noradrenaline in male and female progranulin+/+ arteries, which was blunted by blocking EphrinA2 or Sortilin1. To understand the mechanisms whereby progranulin evokes anticontractile effects, we inhibited endothelial factors. N(gamma)-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor) prevented the progranulin effects, whereas indomethacin (cyclooxygenase inhibitor) affected only the contractility in arteries incubated with vehicle, indicating that progranulin increases nitric oxide and decreases contractile prostanoids. Finally, recombinant progranulin induced endothelial nitric oxide synthase phosphorylation and nitric oxide production in isolated mesenteric endothelial cells. Conclusions Circulating progranulin regulates vascular tone and blood pressure via EphrinA2 and Sortilin1 receptors and endothelial nitric oxide synthase activation. Collectively, our data suggest that deficiency in progranulin is a cardiovascular risk factor and that progranulin might be a new therapeutic avenue to treat high blood pressure.

Adrenergic Response of Splanchnic Arteries from Cirrhotic Patients: Role of Nitric Oxide, Prostanoids, and Reactive Oxygen Species

Peripheral and splanchnic vasodilatation in cirrhotic patients has been related to hyporesponsiveness to vasoconstrictors, but studies to examine the vascular adrenergic response provide contradictory results. Hepatic arteries from cirrhotic patients undergoing liver transplantation and mesenteric arteries from liver donors were obtained. Segments 3 mm long from these arteries were mounted in organ baths for testing isometric adrenergic response. The concentration-dependent contraction to noradrenaline (10(-8) to 10(-4) M) was similar in hepatic and mesenteric arteries, and prazosin (alpha 1-adrenergic antagonist, 10(-6) M), but not yohimbine (alpha 2-adrenergic antagonist, 10(-6) M), produced a rightward parallel displacement of this contraction in both types of arteries. Phenylephrine (alpha 1-adrenergic agonist, 10(-8) to 10(-4) M) and clonidine (alpha 2-adrenergic agonist, 10(-8) to 10(-4) M) also produced concentration-dependent contractions that were comparable in hepatic and mesenteric arteries. The inhibitor of cyclooxygenase meclofenamate (10(-5) M), but not the inhibitor of nitric oxide synthesis N(w)-nitro-l-arginine methyl ester (l-NAME, 10(-4) M), potentiated the response to noradrenaline in hepatic arteries; neither inhibitor affected the response to noradrenaline in mesenteric arteries. Diphenyleneiodonium (DPI; 5 x 10(-6) M), but neither catalase (1000 U/ml) nor tiron (10(-4) M), decreased the maximal contraction for noradrenaline similarly in hepatic and mesenteric arteries. Therefore, it is suggested that, in splanchnic arteries from cirrhotic patients, the adrenergic response and the relative contribution of alpha 1- and alpha 2-adrenoceptors in this response is preserved, and prostanoids, but not nitric oxide, may blunt that response. Products dependent on NAD(P)H oxidase might contribute to the adrenergic response in splanchnic arteries from control and cirrhotic patients.

Pharmacological investigation of signaling mechanisms contributing to phasic and tonic components of the contractile response of rat arteries to noradrenaline.

The mechanisms contributing to the contractile responses to two different concentrations of noradrenaline (NA) in rat aorta and mesenteric artery were compared using nifedipine, which inhibits calcium influx through dihydropyridine-sensitive channels, ryanodine, which depletes intracellular calcium stores, and calphostin C, which inhibits protein kinase C (PKC). Both submaximal and maximal concentrations of NA induced a biphasic response in aorta and mesenteric artery, with an early fast phase and a later sustained tonic component. Calcium release from intracellular stores contributed to the phasic component of contraction to both concentrations of NA in aorta, although to a greater extent to the submaximal concentration. In aorta, inhibiting both intracellular calcium release and calcium influx through dihydropyridine-sensitive channels simultaneously or inhibiting PKC activity alone significantly reduced the tonic response to a maximal concentration of NA. However, the tonic response to a submaximal concentration of NA in aorta was significantly inhibited only when intracellular calcium stores were depleted with ryanodine. In mesenteric artery, the phasic response to a maximal concentration of NA was significantly depressed only when both calcium influx and intracellular calcium release were inhibited simultaneously. However, the phasic response to a submaximal concentration of NA was significantly inhibited by blocking calcium influx alone, but not by blocking intracellular calcium release alone. The tonic component of the contractile response to both concentrations of NA in mesenteric artery appeared to be mediated in part by calcium from both intracellular and extracellular sources.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged treatment with (±)propranolol induces supersensitivity to ( l)noradrenaline in mesenteric arteries in the rat

1. 1.|In the isolated perfused mesenteric arteries of the rat, neither (±)propranolol (0.1 μM) nor (±)isoproterenol (0.05 μM) modified the overflow of dl-[ 3H]noradrenaline ( dl-[ 3H]NA) induced by sympathetic nerve stimulation at either 5 or 10 Hz. 2. 2.|The blockade of α presynaptic receptors with phentolamine (4.7 μM) increased the 3H-transmitter overflow at 5 and 10 Hz. (±)Propranolol (0.1 μM) failed to modify this effect. 3. 3.|Vasoconstrictor responses to exogenous NA or sympathetic nerve stimulation were not modified by (±)propranolol (0.1 μM). 4. 4.|Prolonged treatment with (±)propranolol (7 mg/kg) for 15 days potentiates responses to both exogenous NA and sympathetic nerve stimulation; however, the fractional release per pulse of dl-[ 3H]NA was not modified at either 5 or 10 Hz. 5. 5.|These results provide no evidence to support the hypothesis that the release of NA is regulated by presynaptic β-adrenoreceptors in the mesenteric arteries of the rat. The enhancement of vascular responses after prolonged treatment with propranolol could be caused by postsynaptic supersensitivity.