The study was undertaken to assess the hemodynamic effects induced by a single dose of the phosphodiesterase 4 (PDE4) inhibitor, CI-1044, which is known to cause mesenteric vascular alterations in rats. In the present study, an administration of 160 mg/kg of CI-1044 caused perivascular and interstitial inflammation, with infiltrates of admixed neutrophils and macrophages but without evidence of vascular necrosis (ileum, 15/20 rats; duodenum + jejunum, 7/20 rats). Four hours after administration, blood pressure was decreased (− 13%). A fluorescent microsphere technique demonstrated that, in these conditions, cardiac output was doubled (+ 100%) and total peripheral resistance was decreased (− 54%). The largest increases in blood flow were measured in the duodenum (+ 101%), in the jejunum (+ 110%), and in the ileum (+ 192%). Therefore, the mesentery was the most sensitive organ affected by the drug and, within this area, parts with the highest incidence of vascular alteration were those which had shown the highest increase in flow. In addition, isolated precontracted mesenteric resistance arteries dissected from untreated animals were fully relaxed when incubated with increasing concentrations of CI-1044 up to 2.5 × 10−5M. At this latter concentration, contractile abilities and sensitivities to the physiological agonist noradrenaline (NA) and to the thromboxane analogue U46619 were significantly attenuated (− 28 and − 27%, respectively). This effect could lead to a decreased response to NA and possibly to other agonists in vivo consistent with the vasodilation observed with the microsphere technique. These data provide evidence that the PDE4 inhibitor CI-1044 induces changes of vascular tone that could lead to histological alterations in the mesenteric area.
1. Relaxing effect of loop diuretics, piretanide and furosemide in comparison with acetylcholine (ACh) was investigated in guinea-pig isolated mesenteric resistance arteries. 2. Concentration-response curves to ACh (0.001 - 10 microM) and diuretics (0.0001 - 1 microM) were constructed in noradrenaline (10 - 30 microM)-precontracted arteries incubated either in normal physiological salt solution (PSS) or in 30 mM KCl PSS (K-PSS). 3. In PSS, maximal relaxations (R(max)) and pD(2) to ACh were 87+/-2% and 7.1+/-0.1 (n=10). L-N(G)-nitro-arginine methyl ester (L-NAME, 100 microM) reduced R(max) by 20% (P<0.01, n=7) and pD(2) by 10% (P<0.01). In contrast, indomethacin (10 microM) increased R(max) by 19% (P<0.01, n=8) and pD(2) by 10% (P<0.05). Combination of L-NAME+indomethacin reversed the effect observed with either of these inhibitors used alone. In K-PSS, R(max) was attenuated by 40% (P<0.001, n=6) compared to PSS. L-NAME reduced R(max) by 65% (P<0.01, n=5) and increased pD(2) by 15 fold. L-NAME+indomethacin suppressed the resistant relaxation. 4. In PSS+L-NAME+indomethacin, inhibitors of small (SK(Ca); apamin, 0.1 microM) and large (BK(Ca); iberiotoxin and charybdotoxin, 0.1 microM) conductance Ca(2+)-sensitive K(-)-channels used alone had little effect on the ACh-response. Combination of apamin+iberiotoxin reduced R(max) by 40% (P<0.05, n=7) while apamin+charybdotoxin fully abolished the resistant relaxation. 5. In PSS, piretanide and furosemide induced relaxation with R(max): 89+/-3% vs 84+/-5% and pD(2): 8.5+/-0.1 vs 7.7+/-0.2 (P<0.01) for piretanide (n=11) and furosemide (n=10), respectively. Endothelial abrasion suppressed relaxation to diuretics. L-NAME and indomethacin used alone or in combination did not significantly modify the response to diuretics. 6. In K-PSS, piretanide-induced relaxation was abolished whereas that to furosemide was reduced by 70% (P<0.001, n=9) compared to PSS and was suppressed by L-NAME+indomethacin. In PSS+L-NAME+indomethacin, apamin slightly reduced relaxation to diuretics whereas charybdotoxin or iberiotoxin abolished the response. 7. These results indicate that ACh-evoked relaxation is mediated by both NO/PGl(2)-dependent and -independent mechanisms. The EDHF-dependent component relies on activation of Ca(2+)-activated K(+) channels, is sensitive to a combination of apamin+charybdotoxin and to a smaller degree to a combination of apamin+iberiotoxin. Loop diuretic-induced relaxation is endothelium-dependent, appears to be mediated by NO, PGl(2) and EDHF for furosemide and EDHF only for piretanide. For the two diuretics, opening of BK(Ca) channels may be involved in the relaxation.
1. Pressure‐induced tone and flow‐induced dilations were studied in a rat perfused epicardial coronary artery mounted in an arteriograph. Spontaneous tone was assessed in arteries submitted either to 60 or 90 mmHg intraluminal pressure either under control conditions, after incubation with N G ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME; 100 μmol/L) or after endothelial denudation. Flow‐induced dilation was quantified under these conditions in preparations either submitted to 60 mmHg and preconstricted with 10 μmol/L 5‐hydroxytryptamine (5‐HT) or exhibiting spontaneous tone at 90 mmHg. 2. Spontaneous tone was greater at 90 mmHg compared with tone obtained at 60 mmHg (21±2 vs 10±2% reduction of the fully dilated diameter after sodium nitroprusside incubation, respectively). Incubation with L ‐NAME or removal of the endothelium significantly increased spontaneous tone at both pressures compared with control. 3. In arteries submitted to 60 mmHg and preconstricted with 10 μmol/L 5‐HT, flow (0–800 μL/min) induced a continuous dilation (maximal value 63±4%). As a function of flow, shear stress first increased and then plateaued at values of approximately 76±6 dyn/cm 2 . After L ‐NAME incubation or endothelial denudation, the flow‐induced dilation was reduced to the same extent and was obtained for higher values of shear stress (172±14 and 150±14 dyn/cm 2 , respectively). 4. In arteries exhibiting spontaneous tone, starting flow led, first, to a constriction followed by a dilation up to 76±4% of the initial tone. Incubation with L ‐NAME greatly altered flow‐ induced dilation. Endothelium removal further reduced the dilation obtained for very high values of shear stress (up to 300 dyn/cm 2 ). 5. The present study shows that different patterns of vasodilation induced by flow can be observed, depending on the initial vasoconstrictor stimulus. In 5‐HT‐preconstricted arteries, flow‐induced dilation appears to be fully dependent on the synthesis and release of nitric oxide. In arteries with spontaneous tone, a vasoconstrictor substance could be released for low values of flow. Nitric oxide is mainly, but not exclusively, responsible for the vasodilation. For both experimental conditions, removal of the endothelium greatly reduced the response, but a dilation was still observed.
1 Small calibre airway reactivity to different contractile and relaxant agents was tested in vitro using small segments (about 1 mm long and 0.2 mm in internal diameter) of guinea-pig isolated intralobular bronchi. 2 EC50 values of, and maximal contractile responses to contractile agents were as follows (mean ± s.e.mean, n = 6): acetylcholine 13.6 ± 2.6 μM and 1140 ± 80 mg; histamine 5.2 ± 0.7 μM and 1094 ± 95 mg; 5-hydroxytryptamine (5-HT) 0.7 ± 0.1 μM and 595 ± 61 mg; prostaglandin F2α (PGF2α) 8.8 ± 1.2 μM and 1100 ± 88 mg; tetraethylammonium 2.9 ± 0.3 mM and 1055 ± 94 mg; KCl 14.6 ± 0.5 mM and 965 ± 81 mg. 3 EC50 values of, and maximal relaxant responses to β-adrenoceptor stimulants on preparations precontracted with acetylcholine (1.4 × 10−4M) were: isoprenaline 0.40 ± 0.5 μM and 782 ± 65 mg, n = 18; salbutamol 0.19 ± 0.02 μM and 494 ± 55 mg, n = 5; terbutaline 0.87 ± 0.18 μM and 263 ± 40 mg n = 5; fenoterol 0.06 ± 0.02 μM and 722 ± 47 mg, n = 5; adrenaline 0.71 ± 0.13 μM and 653 ± 62 mg, n = 5; noradrenaline 10.8 ± 0.9 μM and 566 ± 97 mg, n = 5. 4 Differences in the maximal relaxant effects between the β-adrenoceptor stimulants showed that the preparation utilized is a relevant model for assessment of the intrinsic activity of these drugs. 5 The high ratio (about 180) of the EC50 for noradrenaline (β1-adrenoceptor agonist) to that for fenoterol (β2-adrenoceptor agonist), and the lack of effect of prenalterol (β1-adrenoceptor agonist) suggested that β2-adrenoceptors are preferentially involved in the relaxant activity of β-adrenoceptor stimulants in this preparation.
Objective To assess the alterations of morphological and functional properties of conductance coronary and mesenteric resistance arteries in spontaneously hypertensive rats (SHR). Design The in-vitro intrinsic elastic properties of the wall material in SHR coronary arteries were determined in comparison with those of Wistar–Kyoto (WKY) rats. Mesenteric resistance arteries from rats of both strains were also studied. Methods Arterial segments were cannulated at both ends using an arteriograph system and subjected to pressure increments with simultaneous measurements of the wall thickness and internal diameter. The strain, stress and incremental elastic modulus (Einc) were calculated from diameter–pressure curves. Results Over the full range of pressures tested (10–160 mmHg), the internal diameters of SHR coronary arteries were not significantly different from those of WKY rat arteries, whereas we observed that SHR mesenteric resistance arteries had a significantly smaller diameter. The stress-strain curve for coronary arteries was shifted significantly to the left-hand side for the SHR group indicating more stress per unit strain, whereas the opposite was found for mesenteric resistance arteries. When Einc was determined under isobaric conditions, we found no difference between SHR and WKY rat coronary arteries, whereas this parameter was decreased significantly for SHR mesenteric resistance arteries. When Einc was estimated at the respective operating pressures, it was 1.7- to 2.8-fold greater for SHR than it was for WKY rat mesenteric resistance and coronary arteries. Moreover, the total collagen area: lumen area ratio was significantly greater for the SHR than it was for the WKY rat coronary artery wall, but this ratio was similar for mesenteric preparations from the two strains. Conclusion These results show that, at a given stress or operating pressure level, the material of SHR coronary artery wall is characterized by an increase in Einc, whereas there is no increase in Einc for in mesenteric resistance arteries. This functional alteration is accompanied by an increase in the relative proportion of collagen, a component with a high elastic modulus, in the wall. In contrast, we found no change in elastic modulus and in the relative proportion of collagen for the SHR mesenteric resistance arteries. Furthermore, the present results support the hypothesis that alterations in distensibility differ among the components of the SHR vasculature.
