Smooth muscle dilatation in the human uterine artery induced by substance P, vasoactive intestinal polypeptide, calcitonin gene-related peptide and atrial natriuretic peptide: relation to endothelium-derived relaxing substances.

The relaxatory influences of substance P (SP), vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and atrial natriuretic peptide (ANP) were investigated in human uterine arteries precontracted by noradrenaline in vitro. SP, VIP, CGRP and ANP all relaxed isolated uterine arteries with intact endothelium. When tested on vessels devoid of their endothelium VIP and SP had no effect on smooth muscular tone, while ANP and CGRP still induced unchanged vasodilatation. These results suggest an involvement of an endothelium-derived relaxing substance in the mechanisms by which VIP and SP induce relaxation of the isolated human uterine artery. On the other hand, ANP and CGRP seem to act on the same vessel preparation in vitro independently of the vascular endothelium. Both addition of noradrenaline and exchange of sodium against potassium in the organ chambers resulted in smooth muscle contraction irrespective of the integrity of the endothelium.     

Blockade of nitric oxide decreases the renal vasodilatory effect of neuropeptide Y in the insulin-treated diabetic rat

 The effect of 50 days of streptozotocine-induced diabetes mellitus (blood glucose 20 mmol/l) on contraction and relaxation of isolated renal and intrarenal arteries in rats were examined. Strong and similar contractions were induced by potassium (60 mM), 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) in renal and intrarenal arteries in diabetic and control rats. The vasodilatory reactivity, after precontraction with 5-HT, of neuropeptide Y (NPY) was similar to that of acetylcholine (ACh), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and was similar in diabetic and control rats. The relaxing effect of NPY was decreased (40%) only in the diabetic group by blockade of nitric oxide synthase with N ^G-nitro-L-arginine methyl ester (10^–4 M) and by blockade (50%) of NPY with α-trinositol (10^–6 M). In conclusion, the present study showed that diabetes mellitus in the rat is associated with normal vasoconstrictive and vasodilatory capacities. However, the vasodilatory response to NPY was largely eliminated by blockade of nitric oxide synthesis only in the diabetic animals. This indicates that the vasodilatory effect of NPY in diabetes mellitus may be dependent on nitric oxide synthesis. Received: 12 November 1996 / Received after revision: 10 March 1997 / Accepted: 7 April 1997     

Transmural field stimulation-induced relaxation in the rat common hepatic artery.

Hepatic arteries are reportedly innervated by vasoconstrictor and vasodilator nerves. Experiments were carried out to investigate the possible involvement of calcitonin gene related peptide (CGRP) and nitric oxide as neurotransmitters during the relaxation of the rat common hepatic artery produced by transmural electrical field stimulation (ES). Common hepatic arteries were excised under ether-anesthesia from 6 weeks-old female rats, and isometric tensions recorded from endothelium-damaged ring preparations. In the presence of atropine and guanethidine, ES relaxed arteries which had been previously contracted with vasopressin. The relaxation response to ES was attenuated by either tetrodotoxin or capsaicin-pretreatment. CGRP induced a concentration-dependent relaxation, which was inhibited by the CGRP antagonist CGRP(8-37). The ES-induced relaxation was attenuated either slightly by the nitric oxide synthesis inhibitor L-nitroarginine (L-NNA) or markedly by CGRP(8-37). The relaxation response was nearly abolished in the presence of both CGRP(8-37) and L-NNA. These results may indicate that the nerve stimulation-induced vasodilatation of the rat common hepatic artery is mediated mainly by CGRP and partly by nitric oxide.     

Hypertension and impairment of endothelium-dependent relaxation of arteries from spontaneously hypertensive and L-NAME-treated Wistar rats.

Effects of chronic treatment of normotensive Wistar rats with N(omega)-nitro-L-arginine methyl ester (L-NAME) on blood pressure and on endothelium-dependent relaxation of the aorta, carotid and iliac arteries were studied. The endothelium-dependent relaxation was compared in arteries from normotensive Wistar Kyoto rats (WKY) and genetically hypertensive rats (stroke-prone spontaneously hypertensive rats, SHRSP). Chronic treatment of normotensive Wistar rats with L-NAME caused an elevation of blood pressure. The elevated blood pressure at 15 weeks of age was significantly higher in these animals than that of untreated Wistar rats, but lower than that of SHRSP. Endothelium-dependent relaxation of the arteries induced by acetylcholine (ACh) was almost abolished by chronic treatment with L-NAME. The remaining small relaxation in arteries from L-NAME-treated rats was completely inhibited by application of L-NAME (10(-4) M). In such preparations, higher concentrations of ACh induced a contraction, which was abolished by removal of the endothelium or by an application of indomethacin (10(-5) M). Endothelium-independent relaxation induced by sodium nitroprusside was similar between preparations from untreated and L-NAME-treated Wistar rats. Endothelium-dependent relaxation was significantly impaired in preparations from SHRSP, when compared with that in those from WKY. However, the impairment was less prominent in preparations from SHRSP than in those from L-NAME-treated rats. These results suggest that the impairment of endothelium-dependent relaxation in the arteries from L-NAME-treated rats is not due to the elevated blood pressure resulting from the chronic treatment, and that impairment of NO synthesis by the endothelium does not play a major role in the initiation of hypertension in SHRSP.     

Functional contribution of voltage-dependent and Ca2+ activated K+ (BK(Ca)) channels to the relaxation of guinea-pig aorta in response to natriuretic peptides.

We examined the relaxant effects of natriuretic peptide family on the isolated guinea-pig aorta to determine the receptor subtype which primarily mediates this vascular relaxation, with particular attention to the apparent contribution of voltage-dependent and Ca2+-activated KS (BK(Ca)) channels to the response. Three endogenous natriuretic peptide ligands (natriuretic peptide, ANP; brain natriuretic peptide, BNP; C-type natriuretic peptide, CNP) produced a concentration-dependent relaxation in de-endothelialized guinea-pig aorta pre-contracted by noradrenaline (NA), with a potency order of ANP > or = BNP > CNP. Although the relaxations elicited by these three natriuretic peptide ligands were significantly diminished by iberiotoxin (IbTx, 10(-7) M), a selective BK(Ca) channel blocker, the inhibitory effect of IbTx was most pronounced for the CNP-induced relaxation; when estimated at 10(-7) M of each peptide, the apparent extent of BK(Ca) channel contribution to the total relaxant response was approximately 60% for CNP > approximately 20% for either ANP or BNP. Supporting the substantial role of BK(Ca) channels in the vascular responses, high-KCl (80 mM) potently suppressed the relaxations induced by these natriuretic peptide ligands. The relaxant response to 8-Bromo-cyclic GMP, a membrane permeable cyclic GMP analogue, was also diminished by IbTx (10(-7) M) and high-KCl (80 mM), which indicates the key role of cyclic GMP in the BK(Ca) channel-mediated, natriuretic peptide-elicited vascular relaxation. These results indicate that the A-type receptor (NPR-A, which is more selective for ANP and BNP) rather than the B-type receptor (NPR-B, which is more selective for CNP) predominates in the guinea-pig aorta as the natriuretic peptide receptor which mediates this vascular smooth muscle relaxation. Although activation of BK(Ca) channels substantially contributes to both NPR-A- and NPR-B-activated relaxations, particularly in the NPR-B-activated relaxation, this K channel may function as a primary relaxant mediator in this conduit artery.     

Effect of chronic treatment with perindopril on endothelium-dependent relaxation of aorta and carotid artery in SHRSP.

Endothelium-dependent relaxation of aorta and carotid artery from stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of chronic treatment of SHRSP with perindopril, an angiotensin converting enzyme inhibitor, on endothelium-dependent relaxation were studied. Endothelium-dependent relaxation was induced by acetylcholine (ACh) in preparations of SHRSP and normotensive Wistar Kyoto rats (WKY) precontracted with noradrenaline. The ACh-induced relaxation in both preparations was abolished by L-nitroarginine. The ACh-induced relaxation was impaired in preparations from SHRSP and contraction was observed at high concentrations of ACh. In the presence of indomethacin, impairment of endothelium-dependent relaxation in SHRSP was minimized and the contraction was inhibited. The relaxation with sodium nitroprusside did not differ between the preparations from WKY and SHRSP. Treatment of SHRSP with perindopril (2 mg/kg/day) for 6 weeks decreased systolic blood pressure and improved the ACh-induced relaxation of aorta and carotid artery. The treatment inhibited the contraction by higher concentrations of ACh in the presence of L-nitroarginine. These results indicate that the impairment of endothelium-dependent relaxation in aorta and carotid artery of SHRSP may be caused by the reduced availability of nitric oxide. The perindopril-treatment may prevent these changes in SHRSP.     

Effects of neuropeptides and capsaicin on tracheobronchial blood flow of the pig

Blood flow changes upon systemic i.v. injections in the pig of various neuropeptides, capsaicin, bradykinin and histamine were directly monitored by a Transonic blood flowmeter in the superior laryngeal, bronchial and femoral arteries and indirectly in the larynx and skin using laser Doppler flowmetry. To minimize influence of compensatory reflexes and indirect effects, the pigs were pre-treated with atropine, guanethidine, chlorisondamine and capsaicin. Substance P (SP), vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), calcitonin gene-related peptide (CGRP), capsaicin, bradykinin and histamine all decreased vascular resistance, suggesting vasodilation in the superior laryngeal and bronchial arteries. All peptides and histamine when given i.v. exerted vasodilatory effects independent of autonomic motor nerves and capsaicin-sensitive afferents. SP was the most potent vasodilator agent tested in both tracheal and bronchial circulation, being about 1000-fold more active than histamine. VIP was about 10-fold more potent than PHI in decreasing vascular resistance and had a preferential action on the SLA compared to CGRP. In the femoral artery capsaicin and also SP in the highest dose increased vascular resistance. Capsaicin increased the laser Doppler signal in both laryngeal mucosa and skin, while i.v. peptides caused variable effects. In conclusion, SP and CGRP mimicked capsaicin-induced vasodilation in the tracheobronchial circulation while VIP had a preferential effect on the tracheal circulation.     

Cirrhosis decreases vasoconstrictor response to electrical field stimulation in rat mesenteric artery: role of calcitonin gene-related peptide

Our study determines alterations in the vasoconstrictor response elicited by electric field stimulation (EFS) in mesenteric arteries from cirrhotic rats treated with CCl(4), and how calcitonin gene-related peptide (CGRP) participates in this response. Vasoconstriction induced by EFS was analysed in the absence and presence of the CGRP receptor antagonist CGRP(8-37) in arterial segments from control and cirrhotic rats. The vasodilator response to exogenous CGRP was tested in both groups of rats, and the interference of the guanylate cyclase inhibitor ODQ or the K(ATP) channel blocker glibenclamide was analysed only in segments from cirrhotic rats. The vasodilator response to the K(ATP) channel opener pinacidil and to 8-bromo-cyclic GMP was tested. The K(ATP) currents were recorded using the patch-clamp technique. Expression of receptor activity-modifying protein 1 (RAMP1), calcitonin receptor-like receptor, Kir 6.1 and sulfonylurea receptor 2B (SUR2B) was also analysed. Release of CGRP and cGMP was measured. The EFS-elicited vasoconstriction was less in segments from cirrhotic rats. The presence of CGRP(8-37) increased the EFS-induced response only in segments from cirrhotic rats. The CGRP-induced vasodilatation was greater in segments from cirrhotic rats, and was inhibited by ODQ or glibenclamide. Both pinacidil and 8-bromo-cyclic GMP induced a stronger vasodilator response in segments from cirrhotic rats. Pinacidil induced greater K(ATP) currents in cirrhotic myocytes. Expression of RAMP1, calcitonin receptor-like receptor, Kir 6.1 and SUR2B was not modified by liver cirrhosis. Liver cirrhosis increased CGRP release, but did not modify cGMP formation. The decreased vasoconstrictor response to EFS in cirrhosis is mediated by increased vasodilator response to CGRP, as well as increased K(ATP) channel gating. This effect of CGRP may play a role in the splanchnic vasodilatation present in liver cirrhosis.     

Pathophysiologic role of natriuretic peptides

To evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) in hypertension, hemodynamic effects of human ANP and antiserum against rat ANP were investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous administration of human ANP caused greater hypotension associated with a decrease of cardiac output in SHR than in WKY, which suggests that SHR have enhanced responsiveness to exogenous ANP. The antiserum increased blood pressure and cardiac output, with the latter being significantly greater in SHR than in WKY. These results suggest that endogenous ANP counteract, in part, the maintenance of hypertension. In addition, hemodynamic and renal excretory effects of brain natriuretic peptide (BNP), a novel natriuretic peptide identified from porcine, were studied in SHR and WKY. BNP caused marked natriuresis and hypotension in a dose-dependent fashion, as observed with ANP. Not only ANP but also BNP may have a role in the regulation of blood pressure and water-electrolyte balance.     

Regional differences in endothelium-dependent relaxation in the rat: contribution of nitric oxide and nitric oxide-independent mechanisms

Relaxant effects of acetylcholine (ACh), histamine, calcitonin gene-related peptide (CGRP) and the calcium ionophore A23187 were examined in rat femoral (Ø ? 0.2 mm), mesenteric (0.2 mm), intrarenal (0.2 mm) and hepatic (0.3 mm) arteries, and aorta (2 mm). Acetylcholine elicited an endothelium-dependent relaxation in all arteries. Histamine induced an endothelium-dependent relaxation in aorta, and mesenteric and intrarenal arteries, whereas a partly endothelium-dependent and mainly endothelium-independent relaxation was observed in hepatic and femoral arteries, respectively. In hepatic, mesenteric and intrarenal arteries, CGRP induced an endothelium-independent relaxation, whereas either small or no relaxation was obtained in aorta and femoral arteries respectively. A23187 induced an endothelium-dependent relaxation in the aorta and hepatic artery, whereas A23187 had no relaxant effect in femoral, mesenteric and intrarenal arteries. Nω-nitro-l -arginine (l -NOARG, 0.3 mM) reduced the maximum ACh-induced relaxation (in the presence of 10 μM indomethacin) by 66% in the aorta, and abolished the relaxation in femoral and intrarenal arteries. A marked l -NOARG/indomethacin-resistant relaxation was obtained in mesenteric and hepatic arteries. Levcromakalim induced a concentration-dependent and almost complete relaxation in all arteries. When contracted by a 60 mM K⁺ solution, all arteries responded to ACh with a relaxation that was abolished by l -NOARG. These results demonstrate marked regional differences with regard to the vascular effects of ACh, histamine, CGRP and A23187. Whereas nitric oxide appears to mediate endothelium- dependent relaxation regardless of the vascular region, an l -NOARG/indomethacin-resistant relaxation, presumably mediated by an endothelium-derived hyperpolarizing factor, was observed only in mesenteric and hepatic arteries, and aorta.     

自发性高血压鼠脑底动脉血管活性肠多肽能神经纤维的分布

目的 探讨肽能神经对高血压鼠脑血管的神经源性调节的形态学基础。方法 应用免疫组织化学ＡＢＣ法和图介分析技术，观察了１０只自发性高血压鼠（ＳＨＲ）和１０只正常血压鼠脑底动脉血管活性肠多肽能神经纤维的分布。结果 在自发性高血压鼠脑的大脑前动脉、中动脉、后动脉和基底动脉及其分支均可见棕褐色的免疫反应性纤维，纤维似细曲线状，多呈网状分布，与正常血压鼠同一部位脑底动脉血管壁上的免疫反应性纤维密度比较，自发性高血压鼠大脑前动脉、中动脉和后动脉的免疫反应性纤维明显减少。结论 高血压鼠脑底动脉血管活性肠多肽能神经纤维密度的减少，提示在ＳＨＲ脑血流的自动调节作用中，由于非交感性血客扩张神经减少，导致神经源性血管扩张作用减弱，交感神经活性相对增加，表明血管活性肠多肽神经在高血压鼠脑血管的神经源性调节中起着重要的作用。     

Electrical and mechanical properties of spontaneous contraction in hypertensive rat portal vein

Contractile and electrical activities of longitudinal smooth muscle of portal vein from normotensive Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were compared. Amplitude and duration of spontaneous contraction of SHRSP portal vein were greater than those of WKY portal vein. No significant differences were observed in the resting membrane potentials between these preparations. Spontaneous spike activity appeared as a form of bursts. Duration of the burst and the number of spikes in each burst was greater in the portal vein of SHRSP than that of WKY. The amplitude of phasic and tonic components of K-contracture was also greater in SHRSP portal vein. Adrenergic and cholinergic nerves were not involved in the differences in contractions of the portal vein of these animal strains. Cross-sectional area of the longitudinal muscle layer was greater in SHRSP portal vein. These results suggest that the differences in spontaneous electrical activity are the cause of the differences in force and duration of the spontaneous contraction of portal vein from WKY and SHRSP, although the difference in excitation-contraction coupling of smooth muscle may be involved in much less extent.     

Do natriuretic peptides modify arterial baroreflexes in sheep?

While atrial and B-type natriuretic peptides (ANP and BNP) have been shown to enhance reflex responses attributed to cardiac vagal afferents, their effects on arterial baroreceptor reflex function remain controversial. The actions of C-type natriuretic peptide (CNP) in this regard are unknown. To clarify their actions on arterial baroreflexes, we tested whether i.v. infusions of ANP, BNP or CNP at 10 pmol kg(-1) min(-1) modified the steady-state mean arterial blood pressure-heart rate (MAP-HR) relationship in conscious sheep. At this dose, all three natriuretic peptides are known to enhance the cardiac chemoreflex response to phenylbiguanide (Bezold-Jarisch reflex). Sigmoid MAP-HR relationships were constructed from the steady-state responses to alternating injections of vasopressor (phenylephrine, 1-15 microg kg(-1)) and vasodepressor agents (nitroprusside, 1-15 microg kg(-1)) in the absence and presence of infused ANP, BNP or CNP (tested in random order at least 1 week apart). No parameter of the steady-state baroreflex relationship was significantly altered by infusion of any of the three natriuretic peptides. We conclude that in conscious sheep, normal arterial baroreceptor-HR reflex function prevails in the presence of moderate doses of ANP, BNP or CNP.     

Effects of nitric oxide donors and inhibitors of nitric oxide signalling on endothelin- and serotonin-induced contractions in human placental arteries

In order to explore the role of nitric oxide (NO) in the control of fetoplacental vascular tone in normal pregnancy we have examined the effects of NO donors on uteroplacental arteries pre-contracted with the vasoconstrictor endothelin-1 (ET-1) or serotonin (5-HT). We have furthermore examined the effects of guanylate cyclase inhibitors on the NO-induced relaxation. Segments of placental arteries (n=102) obtained from 39 placentas immediately after delivery were mounted in organ baths and superfused with Krebs-Ringer solution at 37 degrees C. The vessel segments were exposed to drugs for various intervals and the tension was recorded isometrically and registered on a polygraph. Cyclic guanosine monophosphate (cGMP) analysis was performed after extraction of vessel segments using a specific radioimmunoassay. The placental artery segments responded to ET-1 and 5-HT with a dose-dependent vasoconstriction. After pre-contraction with ET-1 (10(-7) M) or 5-HT (10(-6) M), the vessels relaxed in response to the NO donors glyceryltrinitrate (GTN) (10(-6) M) and S-nitroso-N-acetyl-penicillamine (SNAP) (10(-5) M). In the presence of the non-specific guanylate cyclase inhibitor LY 83583 (10(-6) M), the vessels responded with a small contraction. In the presence of the soluble guanylate cyclase (sGC) inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) the non-treated vessels responded with a relaxation. 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one gave no obvious relaxation in pre-contracted vessels. Addition of 8-Br-cGMP, the cell-permeant analogue of cGMP, with or without pre-contraction had no effect on the vessels. Cyclic guanosine monophosphate analysis showed that GTN treatment caused an increase in cGMP after 12 min. Our results indicate that NO acts as a vasodilator in placental vessels. The cGMP-dependent mechanisms may be involved in NO-induced relaxation but cGMP-independent mechanisms appear also to be involved.     

Expression patterns of natriuretic peptides in pre-hibernating and hibernating anatolian ground squirrel (Spermophilus xanthoprymnus) lung

Anatolian ground squirrel (Spermophilus xanthoprymnus) is a true hibernator. This animal transiently reduces pulmonary function during hibernation. Continuance of pulmonary function is very important to survive ground squirrels during the hibernation. Natriuretic peptides may be key players in the modulation of pulmonary hemostasis. However, NPs’ role in pulmonary function during hibernation remains unclear. We aimed to investigate the localization and distribution of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) in squirrel lungs during pre-hibernation and hibernation periods using immunohistochemistry. Our immunohistochemical data indicate that ANP, BNP, and CNP were produced by the mucosal epithelium of terminal and respiratory bronchioles, smooth muscle cells in the lamina propria of terminal bronchioles and vascular smooth muscle cells, alveolar type II cells, and macrophages. ANP immunoreactivity was weaker than BNP and CNP immunoreactivities in these cells. The results also demonstrate that the number of ANP, BNP and CNP positive alveolar type II cells tended to increase, although statistically non-significant, during the hibernation period, but the expression of NPs in other pulmonary cells is unaffected by hibernation. This study firstly investigates ANP, BNP and CNP distribution in the Anatolian ground squirrel lung. However, further studies are required to dissect their functional roles during the hibernation.     

COPD患者血清ANP、BNP和CNP测定及其临床意义

目的：探讨慢性阻塞性肺疾病（COPD）患者血清心钠素（ANP）、脑钠肽（BNP）、C型钠尿肽（CNP）水平的变化及其临床意义。方法：采用放射免疫分析79例COPD患者和36例健康对照组血清ANP、BNP和CNP水平,并进行统计分析。结果：COPD组血清ANP、BNP和CNP水平显著地高于健康对照组（t=3.6841,P〈0.01;t=11.70,P〈0.01;t=2.177,P〈0.05）,但Ⅰ、Ⅱ、Ⅲ和Ⅳ级组间血清ANP、BNP和CNP水平方差检验无显著性意义（F=2.123、F=1.515、F=0.165,P均〉0.05）。相互间相关性分析揭示：ANP、BNP和CNP三者间均呈显著正相关（r=0.369,P〈0.01;r=0.354,P〈0.01;r=0.426,P〈0.01）。住院期间死亡的患者血清ANP、BNP和CNP水平显著地高于好转出院的患者（t=5.149,P〈0.01;t=4.875,P〈0.01;t=2.830,P〈0.01）。结论：COPD患者血清ANP、BNP和CNP显著升高,且与病人的稳定情况、肺动脉压力及预后相关。     

Endothelin-induced contractions in placental arteries is mediated by both ETA- and ETB-receptors

We have examined the contractile response to the vasoconstrictor endothelin-1 (ET-1) in uteroplacental arteries from normal pregnant women in the presence and absence of specific ET-receptor antagonists and agonists, and the vasodilator nitric oxide. Segments of placental arteries (n = 97) obtained from 37 placentas immediately after delivery were mounted in organ baths superfused with Krebs-Ringer solution at 37 °C. The tension was recorded isometrically and registered on a polygraph. We found that the placental artery segments responded to ET with a dose-dependent vasoconstriction. Half-maximal response was obtained at 2.6 × 10^?8 M . At 10^?7 M , the contractile response was 52% of the maximum KCl-response. The ET-1 induced contraction at 10^?7 M was inhibited by 74% after addition of the ET_A -antagonist BQ-123 (10^?6 M ), and by 58% by the ET_B -antagonist BQ-788 (10^?6 M ). Both BQ-123 and BQ-788 almost completely abolished the response to ET (10^?7 M ). The selective ET_B -agonist IRL-1620 also elicited vasoconstriction in the placental artery with a half maximal response at 8 × 10^?7 M . On a molar basis at 10^?7 M , the contraction by IRL-1620 as compared to ET was 30-fold lower. The contractile response of IRL-1620 (10^?6 M ) was inhibited by 99% by BQ-788 (10^?6 M ). After pre-contraction of the placental arteries with ET-1 (10^?7 M ), the vessels relaxed in response to the nitric oxide donor, nitroglycerin (10^?6 M ). The present results show that ET-1 contracts placental arteries through both ET_A- and ET_B-receptor activation. Nitric oxide (10^?6 M ) was able to relax more than half of the initial ET-1 contraction, indicating that nitric oxide may be an important vasodilator in the placenta.     

Oscillatory contractions in vertebral arteries from hypertensive subjects.

In response to several agonists, tail arteries from spontaneously hypertensive stroke prone rats (SHRSP) contract in an oscillatory manner not observed in tail arteries from normotensive rats. This study evaluated whether oscillations in force development characterize the contractile pattern of vertebral arteries from hypertensive humans. Vertebral arteries were isolated and studied within 18-24 h post mortem. Helical strips of the arteries were mounted in a muscle bath for isometric force recording. Contractile responses to serotonin (10(-7)M) and endothelin (10(-8)M) in arteries from hypertensive subjects were characterized by fluctuations in force development whereas those in arteries from normotensive subjects usually remained constant with time. The frequency of the response was approximately 1-2 contraction/relaxation cycles per min. This pattern of oscillatory contractile activity was observed in all but one of the hypertensive arteries (n = 15), and in approximately 40% of the normotensive arteries (n = 12). Oscillatory activity was converted to maintained contraction by nifedipine (10(-7)M) which also caused relaxation of the contractile response. Relaxation to acetylcholine (10(-6)M) and nitroglycerin (10(-6)M) did not alter the oscillatory contractions. Endothelium removal did not influence the oscillatory pattern of contraction. These observations suggest that oscillatory contractile activity in vertebral arteries from hypertensive subjects is related to abnormal calcium entry into the smooth muscle cells. This altered membrane property may contribute to changes in vascular reactivity in hypertension.     

Impaired flow-mediated vasodilation in vivo and reduced shear-induced platelet reactivity in vitro in response to nitric oxide in prothrombotic,stroke-prone spontaneously hypertensive rats

Previous investigations using an He-Ne laser-induced thrombosis method have shown that stroke-prone spontaneously hypertensive rats (SHRSP) have an enhanced thrombotic tendency in vivo compared to normotensive, Wistar Kyoto rats (WKY). In addition, studies in the presence of acetylcholine have suggested the presence of endothelial dysfunction in SHRSP. In contrast, shear-induced platelet reactivity in vitro appeared to be depressed in SHRSP. The aim of the present study was to investigate endothelial function in SHRSP using a new physiological in vivo model, and to determine the response of platelets to nitric oxide (NO) in non-anticoagulated blood using a shear-induced platelet function in vitro method (haemostatometry). Endothelial function was estimated by measuring flow-mediated vasodilation (FMV) of the femoral artery. Vessels were exposed and blood flow was arrested using a silicone-coated arterial clamp. Vasodilation was measured by computer-assisted image analysis 3 min after release of stasis. Arterial vasodilation was observed in the femoral artery of WKY, but not in SHRSP. Vasodilation was seen in both WKY and SHRSP; however, in response to the NO donor, 1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC 5). In contrast, 100 microM NOC 5 did not affect platelet reactivity in SHRSP. The NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, sodium salt (carboxy-PTIO) and the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester, hydrochloride (L-NAME), did not affect shear-induced platelet reactivity. NOC 5 at 10 microM (final concentration) inhibited shear-induced platelet reactivity in WKY. These results confirm the presence of endothelial dysfunction in SHRSP and indicate that platelets are non-responsive to NO in this hypertensive model. The data suggest that defective endothelial reactions or disturbed thrombogenic mechanisms outweigh the platelet hyporeactivity and contribute to the prothrombotic status in SHRSP.     

Capsaicin-induced vasodilatation of human coronary arteries in vitro is mediated by calcitonin gene-related peptide rather than substance P or neurokinin A

In the present study the possible influence of capsaicin on human arterial coronary tone in vitro was studied in relation to the vasodilatory properties of calcitonin gene-related peptide (CGRP), substance P (SP) or neurokinin A (NKA). In addition, the influence of vasoactive intestinal polypeptide (VIP) and somatostatin (SOM) on the arteries was investigated. CGRP application to potassium-pre-contracted human epicardial coronary arteries (0.4-0.6 mm in inner diameter) induced a concentration-dependent, long-lasting relaxation. SP also relaxed these pre-contracted arteries, but the relaxation was transient and tachyphylaxis developed rapidly upon repeated administration. SP tachyphylaxis did not influence the relaxatory effects of CGRP. Furthermore, pre-incubation with gossypol, an inhibitor of the formation and release of endothelium-derived relaxing factors (EDRF), completely abolished the effects of SP without influencing the dilatory action of CGRP. NKA only induced a very minor relaxation of the pre-contracted arteries. Both VIP and SOM concentration-dependently relaxed the pre-contracted arteries. Capsaicin evoked a relaxation of the potassium-pre-contracted arteries. This effect was not influenced by SP tachyphylaxis or gossypol incubation. Thus, CGRP but not SP mimics the vasodilatory effects of capsaicin on human coronary arteries. This suggests that CGRP rather than SP is likely to mediate the relaxatory effects seen upon activation of cardiac sensory nerves.