Species dependent relaxation of intrapulmonary arteries (IPA) of rabbits, dogs and humans by prostacyclin

Helically cut strips of successive IPA segments of rabbits, dogs and human patients were set up for isometric recording in vitro. High tone was produced by norepinephrine (NE, 3 microM). This tone was markedly reduced by prostacyclin (PGI2) in the secondary, tertiary and quaternary branches of human and canine pulmonary trunk. The IC50 values for PGI2 ranged from 22 to 503 nM, the human vessels being more sensitive to prostacyclin than canine IPA. Under these conditions, the primary and secondary branches of the rabbit pulmonary trunk were not relaxed by PGI2. The contractile potency of NE was determined in each pulmonary vessel studied. The secondary segments of rabbit IPA were about ten times as sensitive to NE (EC50 for NE: 38 +/- 7 nM) as compared to the secondary IPA from dogs and humans (EC50 values: 370 +/- 84 and 440 +/- 50, respectively). When high tone was induced by equieffective contractile concentrations of NE (3 microM for canine and human IPA and 0.3 microM for rabbit vessels), PGI2 was still less effective (P less than 0.01) in relaxing secondary IPA of rabbits (IC25: 220 +/- 55) than the corresponding segments of dogs and humans (IC25: 51 +/- 12 and 17 +/- 4, respectively). The difference between canine and human vessels was also significant (P less than 0.02). These results indicate that there is an interspecies difference in the sensitivity of IPA to NE and PGI2.     

Role of intracellular Ca2+ in endothelium-dependent contraction and relaxation of rabbit intrapulmonary arteries

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR). In the noncontracted preparations, ionomycin-induced EDC was significantly attenuated by quinacrine (10(-5) M), manoalide (10(-6) M), both phospholipase A(2) inhibitors, indomethacin (10(-5) M) and aspirin (10(-4) M), both COX inhibitors, and ozagrel (10(-5) M), a TXA(2) synthetase inhibitor. In the precontracted arteries, EDR was markedly reduced by L-NAME (10(-4) M), a NOS inhibitor, and methylene blue (10(-6) M), a guanylate cyclase inhibitor, and was enhanced by indomethacin, aspirin and ozagrel, probably due to inhibition of EDC. ZM230487, a 5-lipoxygenase inhibitor, had no effect on EDR. EIR was not affected by L-NAME, indomethacin or ZM230487. Arachidonic acid (10(-6) M) evoked EDC sensitive to indomethacin and ozagrel. L-Arginine (10(-3) M) caused EDR sensitive to L-NAME in the ionomycin-stimulated preparations. In conclusion, Ca(2+) mobilizers cause EDC and EDR via production of TXA(2) and NO, respectively.     

Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol)

The effect of a single dose of 500 mg acetaminophen (paracetamol) on the in vivo synthesis of prostacyclin was studied in healthy volunteers by measurements of the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha. Acetaminophen caused a marked reduction of prostacyclin synthesis for 6-8 hours without any obvious effect on the thromboxane synthesis. Thus, acetaminophen may at least theoretically be disadvantageous for patients suffering from diseases where prostacyclin mediated vascular defence mechanisms are activated, like myocardial infarction, deep vein thrombosis and following surgery.     

The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits

Experimental atherosclerosis in rabbits was associated with a suppression of prostacyclin generation from exogenous arachidonic acid by the coronary vascular bed. The spontaneous formation of prostacyclin by incubated rings of mesenteric artery was also diminished. These results suggest that in atherosclerosis an impaired activity of the endothelial prostacyclin synthesizing system contributes to the intra-arterial formation of thrombi.     

The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits.

Experimental atherosclerosis in rabbits was associated with a suppression of prostacyclin generation from exogenous arachidonic acid by the coronary vascular bed. The spontaneous formation of prostacyclin by incubated rings of mesenteric artery was also diminished. These results suggest that in atherosclerosis an impaired activity of the endothelial prostacyclin synthexizing system contributes to the intra-arterial formation of thrombi.     

Species variations in the relaxation of tail arteries to electrical stimulation

Relaxation in response to electrical stimulation has been studied in isolated tail arteries from rats, cats and pigs. Electrical stimulation elicited contractile responses in unstimulated strips, but caused frequency-dependent relaxations in tail arteries from all species studied, following contractile responses by various agents. The order of susceptibility to the relaxant effect of electrical stimulation in arteries from all three species was pig greater than cat greater than rat. Relaxations to electrical stimulation were unaffected by prior treatment of arteries with atropine, propranolol, tetrodotoxin, indomethacin, ouabain, pyrilamine and chemical denervation with 6-hydroxy-dopamine, but were prevented, dose-dependently, by cimetidine and aminophylline (antagonists of histamine H2-receptor and adenosine P1-receptor, respectively). The results suggest that relaxation of tail arteries from the rat, cat and pig in response to electrical stimulation is modulated by histamine and adenosine.     

Architectonics of the arteries of the latissimus dorsi muscle in humans and dogs

Vascularisation of musculus latissimus dorsi in man and dog was studied in 50 preparations. Methods of x-ray angiography, preparation and macro-microscopy of cleared preparations were used. The nutrition of the muscle was stated to carry out at the expense of the thoracodorsal artery and of the musculocutaneous branches of the intercostal arteries. Vascular-neuronal "gate" of the muscle is projected on the upper third of its lateral portions. A rich network of intrasystemic and intersystemic anastomoses makes it possible to switch off one or several sources of additional nutrition for the muscle. The most favourable conditions of blood supply exist for the muscle lateral portions which are reasonable to use for plastic purposes.     

Species packing and temperature dependent competition among burying beetles (Silphidae, Nicrophorus)

Abstract. 1. Burying beetles are carrion feeders that specialize on small carcasses. We investigated interactions among congeners at two sites in Michigan, U.S.A., that differ in both number and relative proportion of species.
2. Intra- and interspecific competition for carcasses is intense. The majority of carcasses are found within 24 h of their placement.
3. Competition between N.arbicollis and N.defodiens is temperature dependent. N.orbicollis can displace N.defodiens on single carcasses, but requires warm temperatures to find the carcasses. Cool weather therefore serves as a refuge for N.defadiens .
4. The southern edge of N.defodien's geographical range is probably determined by competition with N.orbicollis .
5. N.sayi and N.tomenrosus are spring and autumn breeders respectively, and rarely interact with each other or the other two species. Nevertheless, interspecific competition is the most likely evolutionary force leading to seasonal segregation.     

Comparison in anesthetized dogs of the anti-aggregatory and hemodynamic effects of prostacyclin and a chemically stable prostacyclin analog, 6a-carba-PGI2 (carbacyclin)

The intravascular anti-aggregatory and systemic and hemodynamic effects of prostacyclin and carbacyclin were compared by intravenous infusion in pentabarbital anesthetized dogs. Ten times as much carbacyclin was needed to produce comparable inhibition of platelet aggregation in the lumen of partially obstructed circumflex coronary arteries. These doses of carbacyclin caused similar decreases in total peripheral resistance as equi-effective anti-aggregatory doses of prostacyclin. There was a trend for the decrease in blood pressure with carbacyclin to be less than that produced by equi-effective anti-aggregatory doses of prostacyclin because carbacyclin caused somewhat greater increases in cardiac output. Changes in heart rate were similar with both substances. During carbacyclin and prostacyclin infusion resistance in normal (unobstructed) coronary arteries decreased. Both substances had comparable effects on pulmonary vascular resistance, right atrial pressure and left ventricular dp/dt at equivalent anti-aggregatory doses both before and after atropine (1 mg/kg) and hexamethonium (5 mg/kg). During 5 to 6 hour infusions of carbacyclin there was no evidence of desensitization of dog platelets to the anti-aggregatory activity. These results show that carbacyclin has a similar spectrum of activity as prostacyclin and is about one-tenth as potent.     

Effect of respiratory gases on compliance of intrapulmonary arteries and veins

A method was developed that permitted changes in the pressure-volume characteristics of large intrapulmonary vessels occurring with changes in the composition of alveolar gas to be studied in excised lungs. The capillary bed was emptied by keeping intravascular pressure well below alveolar pressure, and the relationship between changes in the volume of the pulmonary arteries or veins with changes in transpulmonary pressure was measured. The volume of the arteries and veins always decreased with a decrease in transpulmonary pressure, but when the alveoli contained carbon dioxide, the decrease in vascular volume was less, for the same decrease in transpulmonary pressure, than when the alveoli contained oxygen or nitrogen without carbon dioxide. This change with carbon dioxide was probably due to a decrease in the compliance of the larger intrapulmonary arteries and veins. Since there was no pathway for carbon dioxide to enter these vessels except by diffusion from the alveoli, it is concluded that carbon dioxide can act directly on the intrapulmonary arteries and veins to reduce their compliance, but it is not known whether this effect has physiological significance. No effect on the large pulmonary vessels was found with variations in alveolar concentrations of oxygen. blood vesselsblood volumecarbon dioxidediffusionlungspulmonary circulation     

Prostacyclin (PGX) is the endogeneous metabolite responsible for relaxation of coronary arteries induced by arachidonic acid

The actions of prostacyclin (PGX) and several other derivatives of arachidonic acid were examined on spiral strips of bovine coronary artery. The strips were contracted by PGE₂ and thromboxane A₂. Although PGH₂ usually caused a transient contraction followed by a relaxation, a few strips were only contracted whilst others were only relaxed. Prostacyclin invariably relaxed coronary artery strips. Sodium arachidonate usually relaxed the strips but occasionally had no effect.Indomethacin increased the resting tone and abolished or substantially reduced the relaxation induced by sodium arachidonate. 15-Hydroperoxy arachidonic acid (15-HPAA), a specific inhibitor of prostacyclin synthetase, also increased the resting tone, abolished the effects of sodium arachidonate and the relaxation component of the PGH₂ response, but did not greatly modify the relaxation induced by exogenous prostacyclin. These results strongly suggest that prostacyclin mediates the relaxation induced by arachidonic acid in bovine coronary artery strips. As PGH₂ is avidly converted into prostacyclin by the vascular tissue of several species including man, prostacyclin is probably involved in the local regulation of the coronary vascular bed.     

Pelvic visceral arteries of rabbits (Oryctolagus cuniculus)]

40 pelvic preparations of rabbits (oryctolagus cuniculus) were bilaterally studied by dissection under the stereomicroscope and angiography. The arterial pattern of the pelvis, i.e. origin and branching of the umbilical, urogenital and internal pudendal arteries (visceral branches), is described. The main characteristics observed are as follows: (1) The umbilical artery is permeable in adults and gives origin to the cranial vesical artery and a caudal branch that irrigates the pelvic urogenital organs and, eventually, the rectum, with six patterns of branching in both sexes. (2) Usually, the urogenital artery is the continuation of the visceral branch of the internal iliac artery. In 1 animal, unilaterally, it arises from the median sacral artery. In 12 animals (6 bilaterally and 6 unilaterally) the urogenital artery is absent. When present, it forms two branches, a cranial and a caudal one, that irrigate of the urogenital organs in both sexes. (3) The internal pudendal artery is the direct continuation of the internal iliac artery and gives to rise to some visceral branches that irrigate the penis, bulbourethral gland and rectum (with six patterns of branching) in males, and the vagina, clitoris and rectum (with three patterns of branching) in females.     

Inhibition of carbonic anhydrase by plasma of dogs and rabbits

Carbonic anhydrase (CA) activity was measured by the Bowes-Davis technique in diluted hemolysates of dog erythrocytes, rabbit erythrocytes, and dog lung tissue homogenates. Plasma (from the same animal) inhibited the CA activity in each case. For 1:16,700 dilution of dog erythrocytes, the CA catalyzed the CO2 hydration reaction by 5.3 +/- 0.4-fold above the uncatalyzed rate, and half that activity was inhibited by plasma concentrations of 0.44 +/- 0.05%. Similar rabbit CA concentrations were inhibited by plasma concentrations of 1.02 +/- 0.24%. CA from dog lung tissue homogenate is only partially inhibited by plasma even at high plasma concentrations, suggesting different isozymes, at least one of which is not inhibited by plasma. The results suggest that extrapolating from artificially perfused lungs or histological observations to in vivo conditions may not be valid, and the possibility of inhibition by plasma in at least some species should be considered.     

Promotion of sleep by targeting the orexin system in rats, dogs and humans

Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.     

Phosphorylation of phospholamban correlates with relaxation of coronary artery induced by nitric oxide,adenosine, and prostacyclin in the pig

The intracellular mechanisms underlying the action of the endogenous vasodilators such as NO/EDRF, adenosine, and prostacyclin acting through cGMP and cAMP, respectively, are not well understood. One important action of cyclic nucleotides in smooth muscle relaxation is to lower the cytosolic Ca²⁺ concentration by enhanced sequestration into the sarcoplasmic reticulum. The present study was undertaken to elucidate the potential role of phosphorylation of phospholamban, the regulator of sarcoplasmic reticulum Ca²⁺ pump, for the control of coronary vascular tone by NO/EDRF, adenosine, and prostacyclin. Phospholamban was identified in pig coronary artery preparations by immunofluorescence microscopy, Western blotting and in vitro phosphorylation. Segments of pig coronary artery, with either intact or denuded endothelium, were precontracted with prostaglandin F_2α (PGF_2α). In endothelium-denuded preparations 3-morpholinosydnonimine (SIN-1), 5′-N-ethylcarboxiamidoadenosine (NECA), and iloprost (ILO) caused both relaxation and phospholamban phosphorylation with the potency: SIN-1 > NECA > ILO. The regulatory myosin light chain was significantly dephosphorylated only by SIN-1. In endothelium-intact pig coronary artery, L-NAME caused additional vasoconstriction and a decrease in phospholamban phosphorylation, while phosphorylation of myosin light chain remained unchanged. An inverse relationship between phospholamban phosphorylation and vessel tone was obtained. Our findings demonstrate significant phospholamban phosphorylation during coronary artery relaxation evoked by NO, prostacyclin, and adenosine receptor activation. Because of the close correlation between phosphorylation of phospholamban and vessel relaxation, we propose that phospholamban phosphorylation is an important mechanism by which endogenous vasodilators, especially endothelial NO/EDRF, control coronary vascular smooth muscle tone. J. Cell. Biochem. 70:49–59, 1998. © 1998 Wiley-Liss, Inc.     

Modulation of human platelet adenylate cyclase by prostacyclin (PGX)

Prostacyclin (PGX) ($\text{5Z}\text{)-9-}\text{deoxy}\text{-6,9α-}\text{epoxy}\text{-Δ}{}^5\text{-}\text{PGF}{}_{\mathrm{1\alpha }}$ has been found to be a potent stimulator of cAMP accumulation in human platelet rich plasma (PRP), and a direct stimulator of platelet microsome adenylate cyclase. Prostacyclin is, on a molar basis, at least 10 times more potent a stimulator of cAMP accumulation in platelets than PGE₁. The prostacyclin stimulation of platelet cAMP accumulation can be antagonized by the prostaglandin endoperoxide PGH₂, and a PGH₂-induced platelet aggregation is antagonized by prostacyclin. A model of platelet homeostasis is proposed that suggests platelet aggregation is controlled by a balance between the adenylate cyclase stimulating activity of prostacyclin, and the cAMP lowering activity of PGH₂.