Emergence of acetylcholine resistance and loss of rhythmic activity associated with the development of hypertension,obesity, and type 2 diabetes

The aim of this work was to study the influence of aging, obesity, metabolic syndrome (MS), hypertension (HT), and type 2 diabetes (T2D) on the endogenous rhythmic activity and the development acetylcholine resistance in aorta rings of male rats. T2D was produced by a free access to fat (lard). It was shown that phenylephrine (PE) or 5-hydroxytryptamine (5-HT) induces two types of rhythmic contractions: with periods T ₁ = 3–10 s and T ₂ = 50–70 s and amplitudes A ₁ = 1–5% and A ₂ = 20–40% of the maximal contraction force (F _max), respectively. Such periodic modes can be caused by the operation of two known positive feedback loops (PFL) based on the Ca²⁺-induced activation of IP3 receptor (IP3R) or phospholipase C PFL1 and PFL2, respectively, and are not eliminated by L-NAME. Slow rhythmic activity induced by acetylcholine (Ach) with period T ₃ = 7–20 min and amplitude A ₃ = 20–30% of F _max was observed only in young animals (under 6 months) and can be determined by the operation of PFL3, involving Ca²⁺, NO, kinase G, cADP-ribose, and the ryanodine receptor (RyR). Fast mode of contractions (T ₁, A ₁) is maintained regardless of age and the presence of MS and HT (140 mm Hg and higher) and disappears only at later stages of the T2D development. Probability of intermediate mode of contractions (T ₂, A ₂) decreases to 0.20–0.25 at the age of 14–16 months or during the development of HT and MS. In these circumstances, Ach could cause relaxation of preconstricted rings only to 40 and 60% of F _max, respectively. At the stages of the T2D development characterized by high values of arterial pressure (above 150 mm Hg) and of the glucose (10–12 mM), ammonium (120–180 μM), and blood lipid levels, as well as by liver dysfunction (fibrosis/cirrhosis), the rhythmic activity of any type is lost and dysfunction of the initial part of the signaling cascade with the participation of PFL3 is manifested by the absence of responses to Ach or L-NAME. Coenzyme NAD (agonist of the P2Y receptors, К⁺ channel activator and a precursor of cADP-ribose) can exert a partial relaxation of aorta rings from healthy animals and animals with MS. Nicotinamide (product and an inhibitor of ADP-ribosyl cyclase) and SNP (donor of NO) produce an effective relaxation of aorta rings from healthy animals and animals with T2D. Relaxing effect of nicotinamide may suggest a tandem operation of IP3R and RyR in the control of intracellular Ca²⁺ stores in vascular cells.     

The inhibitors of the 5HT-transporter fluoxetine and clomipramine attenuate serotonin-induced constriction of the aorta and the calcium signal in smooth muscle cells of the rat

We found that the inhibitors of the serotonin (5HT) transporter fluoxetine and clomipramine significantly inhibit 5HT-induced constriction of isolated rings of the aorta. The most prominent inhibitory effect was observed for clomipramine, which at a concentration of 2 μM, prevented aorta constriction in response to low and moderate doses of 5HT and multiply attenuated it in response to high doses (10 μM). The inhibitors of the 5HT-transporter attenuated the strength of norepinephrine-induced aorta constriction by 40–60% and eliminated long-term tonic constriction. Application of clomipramine or fluoxetine on the vessels preliminarily constricted by norepinephrine resulted in 100% relaxation, which was maintained in the presence of the NO-synthase inhibitor L-NAME. The inhibitors of the 5HT-transporter decreased but did not prevent 5HT-induced [Ca²⁺]_cyt increase in smooth muscle cells (SMCs) of the aorta even at high concentrations. Clomipramine and fluoxetine did not affect the vasopressin-induced [Ca²⁺]_cyt increase in SMCs and the strength of constriction of isolated aorta rings. We found that the sensitivity of the rat aorta to the vasoconstrictor effect of 5HT and the role of the 5HT-transporter in regulation of the vascular tone increased with aging.     

Mediation of H2O2-induced vascular relaxation by endothelium-derived relaxing factor

We investigated the effects of H₂O₂ generated by glucose (G) and glucose oxidase (GO) on the isolated rabbit aorta suspended in Krebs-Ringer solution. H₂O₂ produced contraction in small concentration and relaxation followed by contraction in large concentration. Contraction produced by large concentration was smaller than that produced by small concentration of H₂O₂. Relaxation was prevented by deendothelialization or N^G-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis. These results suggest that H₂O₂ in large concentrations produces relaxation followed by contraction, and that the relaxation is endothelium-dependent and is mediated by nitric oxide, an endothelium-derived relaxing factor.     

Peptidoleukotrienes induce an endothelium-dependent relaxation of guiena pig main pulmonary artery and thoratic aorta

The purpose of our investigation was to assess the role of the endothelium in the vasomotor effects of leukotrienes. Norepinephrine-preconstricted rings isolated from guinea pig main pulmonary artery and thoraic aorta responded to LTC₄ and LTD₄ with a concentration-dependent relaxation. In endothelium-denuded rings, both LTC₄ and LTD₄ caused a concentration-dependent contraction. The LTD₄ receptor antagonist ICI 198, 615 inhibited both LTC₄- and LTD₄-induced relaxation and contraction. Inhibition of γ-glutamyl transpeptidase with AT-125 prevented the effects of LTC₄, but not those of LTD₄. The relaxant effect of LTD₄ was not modified by indomethacin, but was abolished by methylene blue. We conclude that: 1)LTD₄ induces a receptor-mediated endothelium-dependent relaxation of cavian pulmonary artery and aorta; 2) the vasorelaxant effect of LTC₄ requires its conversion to LTD₄; 3) the vasorelaxant effect of LTD₄ is unrelated to PGI₂ release, and is probably due to the release of an “EDRF”; 4) the removal of the endothelium reveals a direct receptor-mediated vasoconstricting effect of leukotrienes.     

Adult development of the hippocampal-serotonin system of C57BL/6N mice; analysis of high-affinity uptake of 3H-5HT in slices and synaptosomes

The saturable and specific high-affinity uptake of [³H]serotonin ([³H]5HT) (5 × 10^?8 M) was studied in slices from the hippocampus, parietal cortex, septum-preoptic area, and hypothalamus of male 2, 6, 12 and 24–32 month old C57BL/6N mice. Hippocampal [³H]5-HT uptake showed a significant biphasic relationship to age, with lower values in the 2 and 24–32 month old mice compared to 6 month old mice. No significant age effects were seen in the other regions, or in [³H]norepinephrine high-affinity uptake in the hippocampus.Studies of the high-affinity uptake mechanism in synaptosomal preparations were made in a subgroup of 12 and 24 month old mice. A micro-assay using a tissue-harvester measured high-affinity uptake on 8–30 μl of the P₂ suspension (crude-synaptosomal preparation). The high-affinity uptake was linear for 4 min at 37°C and inhibited in both the adult and aged tissue by 10^?5 M cold 5-HT (83 and 78% respectively), 10^?5 M fluoxetine (85 and 82% respectively) and 10^?3 M NaCN (57 and 57% respectively). Kinetic analysis of the [³H]5HT high-affinity uptake in the hippocampus (3 min, 37°C) revealed the same apparent K_m for serotonin at both ages (6.7 x 10^?8 M), but a 44% decrease in V_max in the aged hippocampal synaptosomal high-affinity uptake compared to adults (120 vs 215 pmol of 5-HT/g-tissue/3 min).These results are discussed in relationship to the reported age effects on the intrinsic neurons of the hippocampus.     

Involvement of calmodulin in realization of vasoconstrictive effects of serotonin and norepinephrine

The involvement of calmodulin in adrenergic and serotoninergic regulation of vascular contractility has been studied. Calmodulin inhibitors trifluoperazine and W-13 suppress vasoconstriction of the rat aorta in response to norepinephrine, serotonin, and serotonin 5HT1A and 5HT2A receptor agonists (8-OH-DPAT and DOI, respectively) and do not affect the vasodilatory effect of 5HT1B, 5HT2B, and 5HT4 receptors. The force of aorta contraction in response to 8-OH-DPAT increases after the activation of calcium entry through voltage-gated Ca²⁺ channels. This effect is not related to nonspecific activation of ??1-adrenoceptors, since it is realized in the presence of prazosin. The inhibitor of calmodulin-dependent myosin light chain kinase KN93 decreases the vasoconstrictive response to norepinephrine and serotonin by only 20%. Calmodulin inhibitors slightly decrease aortic constriction in response to endothelin-1, vasopressin, angiotensin II, and KCl. Trifluoperazine does not suppress vasoconstriction induced by the G protein activator AlF ₄ ^? . It is assumed that the target of trifluoperazine and W-13 is calmodulin interacting directly with ??₁-adrenoceptors and serotonin (5HT1A and 5HT2A) receptors.     

UDP-induced relaxation is enhanced in aorta from female obese Otsuka Long–Evans Tokushima Fatty rats

Uridine 5′-diphosphate (UDP) plays an important role in controlling vascular tone; however, UDP-mediated response in metabolic syndromes, including obesity and type 2 diabetes in females, remains unclear. In this study, we investigated UDP-mediated response in the aorta of female obese Otsuka Long–Evans Tokushima Fatty (OLETF) rats and control Long–Evans Tokushima Otsuka (LETO) rats. In OLETF rat aortas precontracted by phenylephrine (PE) (vs. LETO), (1) UDP-induced relaxation was increased, whereas acetylcholine (ACh)-induced relaxation was decreased; (2) no UDP- or ACh-induced relaxations were observed in endothelial denudation, whereas UDP-induced small contraction was observed; and (3) N^G-nitro-L-arginine [L-NNA, a nitric oxide (NO) synthase inhibitor] eliminated UDP-induced relaxation and small contraction, whereas caused contrasting responses by ACh, including slight relaxations (LETO) and contractions (OLETF). Indomethacin, a cyclooxygenase inhibitor, eliminated the difference in UDP- and ACh-induced relaxations between the groups by increased UDP-induced relaxation in the LETO group and increased ACh-induced relaxation in the OLETF group. MRS2578, a P2Y₆ receptor antagonist, eliminated the difference in UDP-induced relaxations between the groups by decreasing UDP-induced relaxation in the OLETF group. MRS2578 had no effect on UDP-induced contraction in endothelium-denuded aortas. Therefore, these findings demonstrate opposite trends of relaxations by UDP and ACh in OLETF and LETO rat aortas. These differences may be attributed to the imbalance between NO and vasoconstrictor prostanoids upon stimulations. Increased UDP-induced relaxation in OLETF rat aorta may be caused by the activation of endothelial MRS2578-sensitive P2Y₆ receptor.     

The relaxing effect of SCH 23390 in the molluscan smooth muscle

1. SCH 23390 (SCH, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) produced the relaxation of ACh-induced contraction in the anterior byssus retractor muscle of Mytilus edulis (ABRM) in a dose-dependent manner between 10⁻⁹-10⁻⁶M.2. The dose-response curve of SCH was shifted in parallel to the right by ketanserin (KET) with pA₂ value of 5.14 ± 0.08 and by 1-(1-naphthyl)piperazine (NAP) with that of 5.06 ± 0.01, but not by cyproheptadine (CYP), mianserin (MIA), butaclamol (BUTA), ICS 205–930 (ICS) and MDL 72222 (MDL) at 3 × 10⁻⁵ M.3. α-Methyl-serotonin (α-Me-5-HT), a selective 5-HT₂ receptor agonist dose-dependently relaxed the ACh-induced contraction of ABRM. The dose-response curve of α-Me-5-HT was shifted in parallel to the right by KET with pA₂ value of 5.01 ± 0.02, but not by BUTA, CYP, MIA, ICS and MDL at 3 × 10⁻⁵ M.4. These findings suggest that 5-HT₂-like receptors exist in the ABRM, and that the relaxation induced by SCH is mediated through these receptors.     

The effect of ionizing irradiation on vasomotor reactivity in the rat thoracic aorta in vitro

Purpose: Ionizing irradiation inhibits restenosis in animal models and human. Vasomotor tone preservation during and after radiation therapy is of clinical importance. We therefore investigated vascular reactivity following radiation therapy.Methods and Materials: Wistar Sabra rats were treated with a single dose of 1000 cGy external X-ray irradiation. Vascular reactivity of 192 segments of rat thoracic aorta was studied in vitro in four groups (12 rats in each group, four segments from each aorta). Immediately after in vivo irradiation, immediately after ex vivo irradiation, 1 month after irradiation, and no irradiation (control).Results: Vasoconstriction to phenylephrine (PE) 10⁻⁹–10⁻⁵ M or KCl 118.0 mM in all the irradiated groups was similar to controls. Endothelium-dependent vasorelaxation to acetylcholine (ACh) 10⁻⁹–10⁻⁵ M in segments studied immediately after in vivo irradiation was increased compared to controls at all concentrations (109.7±35. and 90.0±40.0%, respectively, at 10⁻⁵ M, P=.006). Endothelium-independent relaxation to nitroglycerin 10⁻⁹–10⁻⁵ M in all irradiated groups was similar to controls.Conclusions: External-ionizing irradiation with 1000 cGy in the rat aortic model induces acute and transient increase in endothelium-dependent relaxation to ACh, and does not alter vasoconstriction and endothelium-independent relaxation.     

Effects of prostaglandins and arachidonic acid on baboon cerebral and mesenteric arteries

Effects of prostaglandins (PGs) E₁, E₂, F_2α and I₂ in a wide range of concentration were examined in mesenteric and cerebral arteries isolated from mature baboons. PGs E₁, E₂ and F_2α at low concentrations (10⁻¹⁰ to 10⁻⁷ M) elicited relaxation in helically cut strips of cerebral arteries precontracted with phenylephrine. In contrast, the PGs did not cause relaxation in the mesentric artery. PGI₂ (10⁻⁹ to 10⁻⁶ M) produced marked relaxation in both arteries. The EC₂₅ for PGI₂ in the mesenteric artery was significantly lower than that in the cerebral artery. During baseline conditions, cerebral arteries contracted in response to high concentrations (greater than 10⁻⁷ M) of PGs E₁, E₂ and F_2α. In mesentric arteries, a large contraction was induced by PGs F_2α and E₂ but not by PGE₁. Arachidonic acid (10⁻⁶ M) produced an aspirin-inhibitable relaxation in both arteries to a similar extent, so that the vasodilator PG(s) formed in the two different arterial walls appear to exert a similar relaxant action. Thus, the baboon mesenteric artery was more sensitive to PGI₂ for the relaxant effect than was the cerebral artery, while PGs F_2α, E₁ and E₂ caused only a contraction in the mesenteric artery but both relaxation and contraction in the cerebral artery.     

慢性缺氧对自发性高血压大鼠血液动力学和血管反应性的影响

本研究观察了鼠龄10周的自发性高血压大鼠(SHR)在慢性缺氧条件下(模拟海拔5000m,15d)体动脉压(SBP)、平均肺动脉压(MPAP)、左、右心室收缩指数(LVIC、RVIC)和舒张指数(LVIR、RVIR)以及血管反应性的变化。结果表明,慢性缺氧明显阻抑SHR大鼠SBP升高(P<0.05),但使SHR大鼠MPAP升高(P<0.001)。慢性缺氧还可增大SHR大鼠LVIC和LVIR,增强SHR大鼠胸主动脉对乙酰胆碱(ACh)的舒张反应,减弱其对5-羟色胺(5-HT)的收缩反应。SHR大鼠肺动脉对ACh和5-HT的反应则与主动脉相反。实验结果提示,慢性缺氧阻抑SHR大鼠血压升高与血管反应性的改变有关。     

Agonist of serotonin 5HT1A-receptors 8-OH-DPAT increases the force of contraction of rat aorta and mesenteric artery in the presence of endothelin-1 or vasopressin and causes relaxation of the vessels preconstricted with noradrenaline

Agonist 5HT1A serotonin receptors 8-OH-DPAT at 70–80% in rats relax the isolated aorta and mesenteric artery, precollapsed with noradrenaline. An inhibitor of NO-synthase L-NAME two or more times suppresses vasodilatatornyh reaction in response to the effect of 8-OH-DPAT. The addition of 8-OH-DPAT to the aorta in a state of rest or precollapsed with endothelin-1 or vasopressin causes an increase in apower reduction. A blocker of α₁-adrenoceptors prazosin almost completely suppresses the aorta collapse reaction to the effect of 8-OH-DPAT in the absence of vasoconstrictives, but does not affect the contraction force in response to 8-OH-DPAT of the aorta in the presence of endothelin-1 or vasopressin and does not shift the curve of the dependence of force collapse on the concentration of 8-OH-DPAT. Our data show the existence in the rat aorta of vasodilator and vasoconstrictive 5HT1A-receptors.     

Developmental responses to oxygen,arachidonic acid,and indomethacin in the fetal lamb ductus arteriosus in vitro

It has been suggested that ineffective constriction in response to an increase in P0₂ is the primary cause for delayed closure of the ductus arteriosus in preterm infants. The isometric contractile effects of increased P0₂ and prostaglandin synthetase inhibitors (indomethacin and tranylcypromine) were studied on isolated rings of lamb ductus arteriosus from animals of two gestational ages (87–110 days and 135–150 days, term is 150 days). Rings from animals less than 110 days have a significantly smaller oxygen-induced contraction (2.5 ± .3 g/mm², n=16) when compared with rings from animals near term (4.6 ± .7 g/mm², n=9).Oxygen-contracted rings from both gestational age groups contract further upon addition of either prostaglandin synthetase inhibitor. Rings from animals less than 110 days have a significantly larger indomethacin-induced contraction (1.10 ± 1.7 g/mm², n=16) than vessels near term (0.52 ± .12 g/mmm², n=9). In addition, arachidonic acid produces a greater relaxation in the immature oxygen contracted ring (42 ± 9%, n=10) than in the vessel near term (6 ± 2%, n=4). This is consistent with the hypothesis that, early during gestation, endogenous prostaglandins inhibit the vessel's ability to contract in response to oxygen. These observations are also consistent with the ability of indomethacin to constrict the patent ductus arteriosus in preterm infants.     

The effect of prostacyclin on the human umbilical artery

Prostacyclin was tested on human umbilical artery obtained after spontaneous delivery or by Cesarean section. Isometric and isotonic responses were measured on spiral preparations in Krebs-bicarbonate buffer at 37°C equilibrated with 95% O₂ and 5% CO₂. Spiral artery strips, whether superfused or mounted in organ baths isometrically or isotonically, responded in a dose-dependent manner to both prostacyclin and serotonin; the PGI₂ response was biphasic in that low doses (2.5 × 10^-8 M - 1.0 × 10^-6 M) elicited a dose-dependent relaxation which changed with higher concentrations (1.0 × 10^-6 M - 2.53 × 10⁵ M) to a contractile response. The maximum tension exerte was 50% less than that elicited by serotonin. The data indicate that the human umbilical artery is responsive to prostacyclin and may be involved in the regulation of fetal placenta blood flow.     

Phytoextraction of Cadmium and Zinc By Sedum plumbizincicola Using Different Nitrogen Fertilizers,a Nitrification Inhibitor and a Urease Inhibitor

Cadmium (Cd) and zinc (Zn) phytoavailability and their phytoextraction by Sedum plumbizincicola using different nitrogen fertilizers, nitrification inhibitor (dicyandiamide, DCD) and urease inhibitor (N-(n-Butyl) thiophosphoric triamide, NBPT) were investigated in pot experiments where the soil was contaminated with 0.99 mg kg^?1 of Cd and 241 mg kg^?1 Zn. The soil solution pH varied between 7.30 and 8.25 during plant growth which was little affected by the type of N fertilizer. The (NH₄)₂SO₄+DCD treatment produced higher NH₄⁺?N concentrations in soil solution than the (NH₄)₂SO₄ and NaNO₃ treatment which indicated that DCD addition inhibited the nitrification process. Shoot Cd and Zn concentrations across all treatments showed ranges of 52.9–88.3 and 2691–4276 mg kg^?1, respectively. The (NH₄)₂SO₄+DCD treatment produced slightly higher but not significant Cd and Zn concentrations in the xylem sap than the NaNO₃ treatment. Plant shoots grown with NaNO₃ had higher Cd concentrations than (NH₄)₂SO₄+DCD treatment at 24.0 and 15.4 mg kg^?1, respectively. N fertilizer application had no significant effect on shoot dry biomass. Total Cd uptake in the urea+DCD treatment was higher than in the control, urea+NBPT, urea+NBPT+DCD, or urea treatments, by about 17.5, 23.3, 10.7, and 25.1%, respectively.     

A novel response to propranolol: Contractile response in the isolated rabbit ear artery

Propranolol caused a contractile response in the isolated rabbit ear artery (EA). The concentration of propranolol causing a threshold contraction was 1.76 × 10^?6M while that causing a maximal contraction of 2.2 ± 0.18 g was 3 × 10^?5M. Higher concentrations caused tissue relaxation. Phentolamine, 10^?7 and 10^?6M reduced the propranolol-induced contractions by 50% and 90%, respectively while prazosin, 10^?8, 10^?7 and 10^?6M caused reductions of 54, 74 and 88%, respectively. Reserpinization of the rabbit with 5 mg/kg 24 hours before use eliminated the EA contractile response to tyramine but had no effect on that to propranolol. Desmethylimipramine plus deoxycorticosterone acetate enhanced the submaximal contraction of the EA to propranolol. $\text{In vitro}$ denervation with 6-hydroxydopamine (6-OHDA) decreased the response of the EA to tyramine and propranolol by 96% and 85% respectively but increased that to norepinephrine (NE) by 11%. Rabbit thoracic aorta (TA) did not respond to propranolol. In EA contracted with vasopressin o or 30 mM potassium, propranolol 10^?4 and 3 × 10^?4M caused a 20% and 100% relaxation, respectively. It is concluded that propranolol elicits a contractile response in the EA, at least in part, by direct activation of postsynaptic alpha adrenoceptors.     

Thrombin receptor activating peptides induce Ca2+ mobilization,barrier dysfunction,prostaglandin synthesis,and platelet-derived growth factor mRNA expression in cultured endothelium

Endothelial cell activation by thrombin is a key event in wound healing, Inflammation, and hemostasis. To better define thrombin-endothelial cell interactions we synthesized several peptides of varying length corresponding to the initial 14 amino acid sequence of the cloned human platelet thrombin receptor after cleavage at an arginine⁴¹ site (R/SFLLRNPNDKYEPF). Thrombin receptor activating peptides (TRAPs) as short as 5 amino acids induced significant levels of PGl₂ synthesis and expression of PDGF mRNA in human endothelium and produced dose-dependent cellular contraction and permeability of confluent human umbilical vein and bovine pulmonary artery endothelial monolayers. To explore whether TRAPs utilized similar signal transducing pathways as α-thrombin to accomplish endothelial cell activation, phospholipase C production of the Ca²⁺ secretagogue IP₃ was measured and detected 10 seconds after either TRAP 7 or α-thrombin. Furthermore, TRAPs ranging from 5-14 residues induced significant dose-dependent incsreases in Fura-2 fluorescence indicative of Ca²⁺ ₁ mobilization. These results indicate that thrombin-mediated proteolytic cleavage of the human and bovine thrombin receptor initiates stimulus/coupling respones such phospholipase C activation, Ca²⁺ mobilization, and protein kinase C activation. The functional consequence of this cellular activation via the cleaved receptor is enhanced cellular contraction, barrier dysfunction, PGI₂ synthesis, and expression of PDGF mRNA. © 1993 Wiley-Liss, Inc.     

Contractile activities of leukotrienes C4 and D4 on vascular strips from rabbits

Leukotrienes C₄ (LTC₄) and D₄ (LTD₄), major components of slow-reacting substances of anaphylaxis (SRS-A), caused dose-dependent contractions of rabbit coronary arteries in concentrations of 10^?9 to 10^?7 M and 10^?10 to 10^?7 M, respectively. The potency of LTC₄ and LTD₄, when compared with the concentration that elicits half of the contraction induced by 25 mM KCl, was 17 and 76 times, respectively, greater than that of histamine. In contrast, other blood vessels from rabbits were either unresponsive (renal artery and vein, mesenteric artery and thoracic aorta) or only weakly responsive (pulmonary artery and vein and portal vein) to both leukotrienes even at 10^?7 M. The LTD₄-induced coronary contraction was inhibited by FPL 55712 (10^?7 and 10^?6 M), a selective SRS-A inhibitor, in a dose-dependent manner, but not by diphenhydramine (10^?7 M), a histamine H₁-receptor blocker or by indomethacin (10^?5 M), a prostaglandin synthetase inhibitor, suggesting that LTD₄ has a direct effect on the coronary arteries. These results indicate that the leukotrienes may act as potent, selective coronary vasoconstrictors and that SRS-A responsive receptors exist in the rabbit coronary artery.     

Plasma membrane depolarization and activation of receptors for endogenous vasoconstrictors as possible mechanisms of potentiation of vasoconstrictive response to serotonin in traumatic shock in rats

The goal of this work was to study possible mechanisms underlying the potentiation of vasopressor response to serotonin observed in traumatic shock. Experiments with isolated aorta and mesenteric artery of the rat showed that vasoconstriction is caused by the activation of 5HT2A receptors. Agonists of 5HT1B, 5HT1D, 5HT2B, and 5HT4 receptors induced vasodilation. Agonists of 5HT1A receptors had a dual effect determined by interaction with α₁-adrenergic receptors and 5HT1A receptors. Plasma membrane depolarization with 15 mM KCl increased the vasoconstrictive force in response to serotonin. This effect was determined by the ability of KCl to activate voltage-gated calcium channels, as a result of which the intracellular calcium stores are replenished. Inhibition of the response to serotonin by ketanserin, a 5HT2A receptor blocker, did not depend on the presence of 15 mM KCl. Constriction in response to serotonin was potentiated after its addition to vessels preconstricted with noradrenaline or endothelin-1. The constriction response partially retained in the presence of 2 × 10^?7 M ketanserin, which completely suppressed the serotonin-induced constriction of dilated vessels both at normal membrane potential and after plasma membrane depolarization. It can be assumed that noradrenalin and endothelin-1 alter the characteristics of 5HT2A receptors and possibly 5HT1A receptors as a result of their heterodimerization with the receptors for these vasoconstrictive hormones or receptor-receptor interaction at the level of signaling systems. Along with the potentiating effect of KCl, this mechanism may underlie the enhancement of vasopressor response to serotonin in shock.     

Prostacyclin (PGI2) mediates hypoxic relaxation of bovine coronary arterial strips

Bovine coronary arterial strips (BCA) exhibiting spontaneous tone, relax in response to a decrease in the PO₂ of the batching medium. Experiments were performed to determine if prostaglandins (PGs) mediate the oxygen-induced changes in tension. BCA were equilibrated in Krebs-bicarbonate solution at 37 °C gassed with 95% O₂, 5% CO₂ and tension was measured isometrically. When the PO₂ of the bathing medium was decreased, BCA exhibited reversible reductions in tension. Switching from 95% O₂, 5% CO₂ to 95% N₂, 5% CO₂ (anoxia) elicited an initial relaxation followed by a contraction. In contrast, a change to 5% O₂, 5% CO₂, 90% N₂ (hypoxia) was followed by a sustained relaxation. Re-introduction of O₂ to anoxic strips produced a biphasic response: relaxation followed by contraction. Indomethacin or eicosatetraynoic acid (EYA) increased tone and inhibited the relaxation produced by anoxia or hypoxia. Indomethacin or EYA did not inhibit the relaxation of anoxic strips during re-introduction of O₂, but did inhibit the contraction partially. Relaxation of arterial strips to arachidonic acid (AA) was similar to relaxation to prostacyclin (PGI₂). Anoxia limited the relaxation to AA but not to PGI₂. We conclude that PG synthesis contributes to the basal tone and the hypoxia-induced relaxation of CBA. In addition, hypoxia, unless severe, does not prevent the conversion of AA to PGI₁.