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The effects of [Arg(0),Trp(5),Leu(8)]-BK (cod [Arg(0)]BK) on vascular preparations from branches of the cod celiac artery and on longitudinal smooth muscle preparations from the cod intestine were investigated. Cod [Arg(0)]BK (3 x 10(-8) M) caused a relaxation of the celiac artery precontracted with adrenaline. The relaxation was abolished by the cyclooxygenase inhibitor indomethacin, suggesting that the effect is mediated through the release of prostaglandins, but there was no evidence for the involvement of leukotrienes or nitric oxide in the response. In the intestinal preparations, cod [Arg(0)]BK produced concentration-dependent contractions (pD(2) = 8.28 +/- 0.16). Experiments with N-terminally and C-terminally truncated analogs and with alanine-substituted analogs of cod [Arg(0)]BK demonstrate that the central amino acid Gly(4) and the C-terminal amino acids Leu(8) and Arg(9) are the most important in determining the conformation of the peptide that interacts with the receptor. The results indicate that the ligand binding properties of the cod BK receptor are considerably different from the receptor present in trout tissues and may resemble those of the mammalian B(2) receptor more closely.

We have investigated the modifications of cytosolic [Ca2+] and the activity of Ca2+ channels in freshly dispersed arterial myocytes to test whether lowering O2 tension (PO2) directly influences Ca2+ homeostasis in these cells. Unclamped cells loaded with fura-2 AM exhibit oscillations of cytosolic Ca2+ whose frequency depends on extracellular Ca2+ influx. Switching from a PO2 of 150 to 20 mmHg leads to a reversible attenuation of the Ca2+ oscillations. In voltage-clamped cells, hypoxia reversibly reduces the influx of Ca2+ through voltage-dependent channels, which can account for the inhibition of the Ca2+ oscillations. Low PO2 selectively inhibits L-type Ca2+ channel activity, whereas the current mediated by T-type channels is unaltered by hypoxia. The effect of low PO2 on the L-type channels is markedly voltage dependent, being more apparent with moderate depolarizations. These findings demonstrate the existence of O2-sensitive, voltage-dependent, Ca2+ channels in vascular smooth muscle that may critically contribute to the local regulation of circulation.

1. The importance of adenylate cyclase-mediated vascular relaxation in the macro and microcirculation was assessed in rabbit aortic and coeliac artery bioassay rings in vitro and skin microvessels in vivo. 2. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP38), the beta-agonist, isoprenaline, and the prostaglandins, PGE1 and PGE2, were compared with the activity of nitroprusside, which acts by stimulating guanylate cyclase. 3. In aortic tissue the relative relaxant potencies were (-log M EC50, 100% = response to nitroprusside 10(-6) M): nitroprusside 7.0, PACAP38 6.8, isoprenaline 6.3; PGE1 and PGE2 were weak constrictors. In coeliac artery rings relative potencies were (-log M EC50, 100% = response to nitroprusside 10(-5) M): PACAP38 6.6, PGE1 6.6, nitroprusside 6.5, PGE2 4.9, and isoprenaline 4.3. 4. Comparative potencies when injected into anaesthetized rabbit skin in vivo were (-log mol/site required to increase blood red cell flux by 75%): PACAP38 13.0, PGE2 10.7, isoprenaline 9.7, PGE1 9.1, nitroprusside < 7. 5. Nitroprusside, the most effective relaxant tested in the aorta, was 10(7) fold less potent than PACAP in its effect on skin blood flow. PGE1 and PGE2 were constrictors of the aorta, of intermediate effect in the coeliac artery, but potent vasodilators of the microcirculation. 6. In this model, the importance of adenylate cyclase-mediated vascular relaxation increases with decreasing vessel size.

The abdominal site or sites for the satiety action of exogenous, peripherally administered bombesin (BN) were investigated. By use of a chronic arterial catheterization technique, the effects of 1, 2, and 4 micrograms/kg BN on liquid food intake of nondeprived male rats were assessed. Comparisons were made between the effects of these doses infused into the celiac or superior mesenteric arteries or injected intraperitoneally. The satiating potency of exogenous BN was significantly enhanced by direct administration into the celiac artery, which directly perfuses the stomach, pancreas, liver, spleen, and proximal duodenum. By this route, 4 micrograms/kg BN produced greater than 60% suppression of 15-min food intake. By contrast, BN infused into the superior mesenteric artery was no more effective than intraperitoneal injection. Celiac infusion of 1 micrograms/kg BN produced a suppression (30%) of intake that was equivalent to, or exceeded, that obtained after intraperitoneal injection or superior mesenteric infusion of 4 micrograms/kg. These results strongly support an upper abdominal, and possibly gastric, site for the satiety action of peripherally administered BN.

The role of the endothelium and vascular tone was studied on histamine-induced relaxation and contraction of the rabbit coeliac artery. Histamine contracted the tissue via the release of noradrenaline (NA), an action blocked by prazosin and mepyramine but not influenced by endothelial removal. Tachyphylaxis readily developed to histamine-induced contractions. After a moderate tone (40-55%) was induced with NA, histamine relaxed the tissues concentration-dependently. This relaxation was absent when the endothelium was removed indicating that the receptors involved are located on the endothelium. When the tone was increased to 80-85% with NA, relaxation could only be demonstrated after blocking H1-receptors. Removal of the endothelium did not influence this response. The relaxant effect of histamine in both preparations, however, was blocked by metiamide indicating that it is H2-receptor mediated. In the rabbit coeliac artery, endothelial H2-receptors are readily activated at moderate tone while muscular H2-receptors are stimulated at high tone after blocking H1-receptors. The predominance of H2-receptors in this artery may serve the physiological function of vasodilation in the blood vessels of the stomach.

1. The aim of the study was to assess and quantify any synergism occurring between the stable analogues of prostacyclin (iloprost) and nitric oxide (sodium nitroprusside) with respect to both relaxation of vascular smooth muscle and inhibition of platelet aggregation in the rabbit. 2. Iloprost (0.3-3 ng ml-1) and sodium nitroprusside (0.3-3 ng ml-1) caused dose-dependent relaxation of the rabbit mesenteric and coeliac arteries. 3. Iloprost (0.3-30 ng ml-1) and sodium nitroprusside (0.03-30 micrograms ml-1) caused dose-dependent inhibition of rabbit platelet aggregation induced by adenosine diphosphate or collagen. 4. In combination, iloprost and sodium nitroprusside caused an inhibition of platelet aggregation that was 2-3 fold greater than would be expected by summation, while no such potentiation was observed on vascular smooth muscle. 5. Thus, our results indicate that under physiological conditions the mediators prostacyclin and endothelium-derived relaxing factor (NO) can exert a synergistic action on platelets, but have only an additive effect on vascular smooth muscle.

The effects of prostaglandin synthetase inhibitors PGF2 alpha and PGI2 on the tone of isolated basilar and coeliac arteries were studied in healthy and alloxan-diabetic dogs. PGF2 alpha (1 mumol 1-1) produced a significantly higher tone in diabetic basilar arteries (1.15 +/- 0.16 mN) than in normal cerebral vessels (0.7 +/- 0.10 mN). By contrast, the contractile responses of normal and diabetic coeliac arteries to PGF2 alpha did not differ. The cyclooxygenase inhibitors indomethacin (3 mumol 1-1) and suprofen (0.58 mumol 1-1) potentiated the PGF2 alpha-evoked contractions in all of the vessels studied. The percent potentiation was greater (50-60%) in the basilar arteries from alloxan-treated dogs than in normal basilar vessels (22-30%). There was not such a difference between diabetic and normal coeliac arteries. Prostacyclin produced a concentration-related relaxation in the presence of indomethacin or indomethacin + PGF2 alpha. The relaxant potencies of PGI2 were similar in the vessels from metabolically healthy and diabetic dogs. The IC50 values for PGI2 were 11.6 +/- 1.3 and 11.8 +/- 1.8 nmol 1-1 in normal and diabetic basilar arteries, respectively; they were 25.4 +/- 3.2 and 26.2 +/- 3.9 nmol 1-1 in control and alloxan-treated coeliac vessels. These results indicate that normal and diabetic vessels may have differential reactivity to cyclooxygenase inhibitors, this difference being dependent on the vascular region.

Bioassays of prostacyclin by inhibition of velocity and maximum of both irreversible and biphasic platelet aggregation, and by relaxation of the potassium-contracted isolated superfused rabbit coeliac artery have been undertaken. The use of each parameter is possible within a range of PGI2 concentrations, which have been determined for each of the five parameters studied. The optimal concentrations of PGI2 for a bioassay have also been determined, corresponding to each range.

In the present study we have investigated the pre- and post-synaptic actions of PGE2 and indomethacin on the adrenergic transmission in isolated coeliac arteries of rabbits. The artery segment was preloaded with (3H)NA and suspended in an organ bath (37 degrees C, 5% CO2 - 95% O2, isometric recording). The preparation was superfused with Krebs-solution containing the uptake blockers cocaine and corticosterone. To release neurotransmitter, the artery was stimulated by electrical square-wave pulses (0.5 ms, 5 Hz, 60 s) using platinum wire electrodes. The perfusate was collected in 3 or 6 min samples. The outflow of labelled neurotransmitter was expressed in pmol/3 min. Inhibition of endogenous prostaglandin-biosynthesis by indomethacin (3/mumol/l) potentiated the contractile responses to nerve stimulation (57 +/- 15%, n = 4), but did not influence the release of NA (the release ratio was 1.02 +/- 0.03, n = 4). The endogenous prostaglandins may modulate vascular neuroeffector transmission postjunctionally, because cyclooxygenase inhibition did not cause any change in transmitter release. The effects of exogenous PGE2 on adrenergic transmission and contraction were also studied. In this case, indomethacin was present to minimize the potential complicating actions of endogenous prostanoids. At low concentrations (1, 3 and 10 nmol/l) PGE2 dose-dependently inhibited vasoconstrictor responses to nerve stimulation (IC50 = 4.7 +/- 1.5 nmol/l, n = 4), but was ineffective in influencing transmitter release (the stimulation evoked release ratios were 0.95 +/- 0.05, 1.00 +/- 0.00 and 0.93 +/- 0.11, n = 4, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of iloprost (ZK 36 374), a stable analogue of prostacyclin, and prostaglandin E2 (PGE2) were studied on isolated spirally cut strips of rabbit aorta, celiac, mesenteric and renal arteries continuously superfused in cascade. Iloprost and PGE2 elicited a concentration-dependent relaxation of phenylephrine-contracted celiac and mesenteric strips having equal affinities as verified by identical pD2 values. Iloprost also produced a concentration-dependent relaxation in precontracted renal artery strips at relatively higher concentrations but had little relaxing action on precontracted aortic strips. Contrary, PGE2 induced a concentration-dependent relaxing effect on precontracted aortic strips without producing an appreciable action on renal artery strips. Acetylsalicylic acid (ASA) when added to the superfusion medium elicited an increase in basal tonicity of celiac and mesenteric strips without altering the basal tonicity of renal artery and aortic strips. Iloprost at very low concentrations (10(-10)-10(-9) mol/l) produced a complete recovery in increased tonicity of both strips while at the same concentrations PGE2 had little effect. These results indicate that endogenous PGI2 may have an important role in the regulation of vascular tonicity in celiac and mesenteric arteries.