Association between trajectories of systolic blood pressure and frailty outcome in middle-aged and older adults.

OBJECTIVES: The association between blood pressure and frailty outcome in the middle-aged and older population remains controversial. This study aimed to examine the relationship between trajectories of systolic blood pressure (SBP) and new-onset frailty. DESIGN: Cohort study with a 7-year follow-up. SETTING AND PARTICIPANTS: Data were derived from 4 waves (2011, 2013, 2015 and 2018) of the China Health and Retirement Longitudinal Study and 6168 participants aged ≥45 years were included in the study. METHODS: The frailty index (FI) was constructed based on 40 scored items, with FI ≥ 0.25 defined as frailty. We identified the 5-year trajectory of SBP by latent class trajectory modeling. The association between SBP trajectories and frailty was explored based on hazard ratios (HR) by four Cox proportional hazards models. Furthermore, we also investigated the relationship between mean SBP and systolic blood pressure variability (SBPV) and frailty. RESULTS: 6168 participants were included in this study with a mean age of 59 years. We identified five trajectories based on SBP, which are maintained low-stable SBP (T0), moderate-stable SBP (T1), remitting then increasing SBP (T2), increasing then remitting SBP (T3), and remaining stable at high SBP levels (T4). During the 7-year follow-up period, frailty outcome occurred in 1415 participants. After adjusting for other confounders, the two trajectories labeled "T2" and "T4" were associated with a higher risk of frailty compared with T0. In addition, elevated SBP and increased SBPV were associated with risk of frailty. CONCLUSIONS: Higher risk of frailty occurred in two trajectories, remitting then increasing and remaining stable at high SBP levels, were associated with a relatively higher risk of frailty.

Vasoactive intestinal peptide release and L-citrulline production from isolated ganglia of the myenteric plexus: evidence for regulation of vasoactive intestinal peptide release by nitric oxide.

Vasoactive intestinal peptide release and L-[3H]citrulline production were examined in ganglia isolated from the myenteric plexus of guinea-pig intestine. The nicotinic agonist, 1,1-dimethyl-4-phenylpiperizinium stimulated vasoactive intestinal peptide release and L-[3H]citrulline production; the latter was considered an index of nitric oxide production. Both vasoactive intestinal peptide release and L-[3H]citrulline production were abolished by tetrodotoxin, hexamethonium, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Inhibition of vasoactive intestinal peptide release by NG-nitro-L-arginine was reversed by L-arginine but not by D-arginine. Exogenous nitric oxide stimulated vasoactive intestinal peptide release whereas exogenous vasoactive intestinal peptide had no effect on L-[3H]citrulline production. The pattern of stimulation by nitric oxide and inhibition by NG-nitro-L-arginine implied that vasoactive intestinal peptide release is facilitated by and may be dependent on nitric oxide production. Consistent with this notion, vasoactive intestinal peptide release in response to either 1,1-dimethyl-4-phenylpiperizinium or nitric oxide was abolished by KT 5823, an inhibitor of cyclic GMP-dependent protein kinase activity and by LY83583, an inhibitor of soluble guanylate cyclase activity. The study provides the first direct evidence of nitric oxide production from enteric ganglia.

Myenteric 5-HT-containing neurones activate the descending cholinergic excitatory pathway to the circular muscle of guinea-pig ileum.

1. Participation of myenteric 5-hydroxytryptamine (5-HT)-containing neurones in the ascending and descending pathways of the guinea-pig isolated ileum was investigated in a new preparation. Transmural electrical stimulation of the longitudinal muscle-myenteric plexus (LM-MP) portion of the preparation caused ascending and descending contractions of circular or longitudinal muscle in the attached, intact segments situated orally or anally to the point of stimulation. 2. All contractions of LM-MP stimulation were abolished by tetrodotoxin (0.2 microM). The ascending and descending contractions of circular muscles were also abolished by atropine and inhibited to about 50% by hexamethonium. They were not affected by desensitization to substance P (SP) or by the SP antagonist, (D-Pro2,D-Trp7,9)-substance P. The contractions of longitudinal muscles were inhibited by about 45% by hexamethonium and abolished by a combination of atropine with SP desensitization or the SP antagonist, (D-Pro2,D-Trp7,9)-substance P. 3. Desensitization to 5-HT, ICS 205-930 (1 microM) or cocaine (1 microM) reduced the descending contraction of circular muscle by 80-90%, without significantly affecting the ascending contraction. Methysergide (0.2 microM) failed to alter either contraction. 4. 5-HT desensitization, ICS 205-930 and cocaine only partially reduced the descending contraction of longitudinal muscle. A similar reduction of the ascending contraction (20-30%) was also observed. Methysergide had no effects on either contraction. 5. Contractions of either circular or longitudinal muscle produced by field stimulation of the intact segment were not significantly affected by any of the 5-HT receptor antagonists tested. 6. The results imply that 5-HT-containing neurones, as interneurones, are involved mainly in the descending cholinergic excitatory pathway to the circular muscles.

Possible involvement of calcitonin gene-related peptide (CGRP) in non-cholinergic non-adrenergic relaxation induced by mesenteric nerve stimulation in guinea pig ileum.

Mesenteric nerve (MN) stimulation produced a biphasic response, i.e., a contraction followed by a prolonged relaxation in the isolated guinea pig ileum after complete adrenergic neuron blockade with guanethidine. This biphasic response mimicked the effect of capsaicin by itself. The latter relaxation response to MN stimulation was unaffected by hexamethonium, but was abolished by capsaicin in an irreversible fashion. Calcitonin gene-related peptide desensitization (CGRP-D) reduced the relaxation response to about 20% of the control. After pretreatment with atropine and guanethidine, MN stimulation provoked a pure relaxation, which was significantly reduced to about 20% of the control by CGRP-D. Therefore, it seems likely that the non-adrenergic non-cholinergic relaxation response to MN stimulation is partly mediated via a release of CGRP from sensory nerve endings.

Inhibitory effect of capsaicin on the ascending pathway of the guinea-pig ileum and antagonism of this effect by ruthenium red.

A segment of guinea-pig ileum, which was continuous with a strip of longitudinal muscle-myenteric plexus (LM-MP) at the anal end, was used to examine the effect of capsaicin on ascending excitatory pathways. Electrical field stimulation of the LM-MP caused an ascending contraction of the segment. After initially causing contraction capsaicin (3 microM) inhibited the ascending contraction. This inhibitory effect of capsaicin exhibited rapid desensitization and was abolished after extrinsic (mesenteric) denervation. Desensitization to calcitonin gene-related peptide (CGRP) prevented the capsaicin-induced inhibition without affecting the ascending contraction. Neither naloxone nor alpha- and beta-adrenoceptor antagonists affected the capsaicin-induced inhibition. CGRP (25 nM) also inhibited the ascending contraction, mimicking the inhibition induced by capsaicin. Ruthenium red (0.1-3 microM) antagonized the capsaicin-induced inhibition in a concentration-related manner, but did not affect the CGRP-induced inhibition. These findings suggest that the inhibitory effect of capsaicin on the ascending pathways might be mediated via the release of CGRP from extrinsic nerve terminals, and that the site of the antagonism of the action of capsaicin by ruthenium red is prejunctional.

Contractions of the guinea-pig ileum evoked by stimulation of the submucous plexus.

Neural pathways from the submucous plexus to the longitudinal muscle of an adjacent segment of isolated guinea-pig ileum were studied. It was found that electrical field stimulation of a strip of submucosa-submucous plexus produced frequency-dependent longitudinal contractions of an intact segment of intestine lying oral to the point of stimulation. The responses were reduced to less than 10% of control by tetrodotoxin, atropine, morphine and chymotrypsin and by desensitization to substance P (SP). The responses were only inhibited by one-third by hexamethonium and were not affected by desensitization to 5-hydroxytryptamine. The effect of desensitization to SP was reversible, but the effect of chymotrypsin was irreversible. SP-induced desensitization and chymotrypsin did not inhibit the twitch response produced by field stimulation of the whole ileal segment. The same results were observed with preparations made from ileal segments that had been extrinsically denervated. The results suggest that intrinsic neurons with processes in the submucous plexus can excite cholinergic and SP-containing neurons in the myenteric plexus, thereby causing the longitudinal muscle to contract.

Ruthenium red antagonism of the effect of capsaicin on the motility of the isolated guinea-pig ileum.

Ruthenium red (1 microM), an inorganic dye which blocks transmembrane calcium (Ca) fluxes in neural tissues, selectively reduced the capsaicin (1 microM)-induced contraction of the guinea-pig ileum and protected the sensory fibers from capsaicin-induced desensitization. The ruthenium red (0.5-1 microM) antagonism of capsaicin-induced inhibition of responses to mesenteric nerve stimulation or field stimulation in the isolated guinea-pig ileum was an example of a similar antagonism of the effect of capsaicin. In view of the known action of ruthenium red on the depolarization-coupled entry of Ca into synaptosomes and the release of transmitter, our results support the proposal that ruthenium red could antagonize the action of capsaicin on the peripheral terminals of sensory nerves by a similar mechanism, thereby suppressing transmitter release and preventing the establishment of desensitization.

Effects of piperine on the motility of the isolated guinea-pig ileum: comparison with capsaicin.

Piperine (1 microM), a congener of capsaicin, produced an initial contraction blocked the capsaicin-sensitive contractile response to mesenteric nerve stimulation and inhibited the twitch response induced by field stimulation in the isolated guinea-pig ileum. These three effects of piperine (1 microM) were rapidly desensitized and significantly antagonized by ruthenium red (0.5-1 microM), an inorganic dye known to antagonize the effects of capsaicin. The contractile effect of piperine was abolished by application of tetrodotoxin plus desensitization with substance P or by extrinsic denervation. The inhibitory effect of piperine (1 microM) on the twitch response was antagonized by desensitization with calcitonin gene-related peptide (CGRP). Moreover, cross-tachyphylaxis between piperine and capsaicin was observed, suggesting that a similar mechanism may be involved in the effects of these agents. The contractile effects induced by piperine (10 microM) and the subsequent inhibitory effects on the twitch response were not desensitized and largely persisted after extrinsic denervation. The contractile effects of piperine (10 microM) were not strongly inhibited by tetrodotoxin plus desensitization with substance P. It was concluded that the lower concentration of piperine caused contraction and inhibited the twitch responses by releasing substance P and CGRP, respectively, from sensory nerves, and blocked the response to mesenteric nerve stimulation by a mechanism similar to that of capsaicin. At higher concentrations, piperine had non-specific direct actions on the smooth muscle.

Bile salt potentiates the action of capsaicin on sensory neurones of guinea-pig ileum.

In the isolated guinea-pig ileum, exposure to the sensory stimulant drug capsaicin (1 microM) produced a contraction thought to involve substance P(SP) release from sensory nerves. Bile salt, sodium deoxycholate, potentiated the capsaicin-induced contraction in a concentration-dependent (0.03-10 microM) manner, without influencing contractions produced by exogenous SP or by electrical stimulation of efferent nerves. The bile salt-induced potentiation of the capsaicin response was not modified by hexamethonium or indomethacin. It was, however, abolished by concomitant incubation with Ruthenium Red, which was reported to block transmembrane calcium fluxes and then suppress the SP release from the capsaicin-sensitive sensory nerve terminals. We propose that bile salt, as a calcium ionophore, could activate or sensitize the action of capsaicin on the peripheral terminals of sensory nerves.

Ruthenium red prevents capsaicin-induced neurotoxic action on sensory fibers of the guinea pig ileum.

Capsaicin, a neurotoxin which impairs some primary afferent nerve fibers, was locally applied to the mesenteric nerve trunks of adult guinea pigs. The effect of capsaicin was studied on contractile responses of the ileum to mesenteric nerve stimulation (20 Hz). Exposure of the mesenteric nerve to capsaicin (1 microM) irreversibly abolished the contractile response to mesenteric nerve stimulation, without influencing the resting tension and spontaneous motility of the ileum. However, if the mesenteric nerve had been incubated in a Ca-free medium containing EGTA (0.1 mM) or pretreated with Ruthenium red (10 microM), capsaicin only partially inhibited (about 30%), but did not abolish, the contractile response to the mesenteric nerve stimulation, thus indicating protection from desensitization.

Polar innervation of enteric non-cholinergic and non-adrenergic neurons in the isolated guinea-pig ileum.

To study the polarity of the efferent pathway of the myenteric plexus, recordings were made of the mechanical activity of the longitudinal muscle of isolated guinea-pig ileal segments upon stimulation with an electrical field around the myenteric plexus contained within strips of longitudinal muscle (LM-MP) continuous with each end of ileal segment. The amplitude of the contractile response to stimulation of the anal LM-MP was always larger than that to the oral LM-MP. After cholinergic and adrenergic transmission was suppressed by atropine (10 microM) and guanethidine (1 microM), and the tone of the segment was enhanced by histamine (1 microM), the LM-MP stimulation produced non-cholinergic, non-adrenergic (NCNA) ascending contraction and NCNA descending relaxation. The NCNA contraction, but not the NCNA relaxation, was abolished or reduced by desensitization to substance P. The present results suggest that the NCNA innervation of the myenteric plexus participates in the polar effects observed in the guinea-pig ileum, that the NCNA excitatory response may be mediated at least in part by myenteric substance P neurons, and that the NCNA inhibitory response is mediated by non-adrenergic neurons.

Capsaicin-sensitive and hexamethonium-insensitive circular muscle responses to mesenteric nerve stimulation in the isolated guinea pig ileum.

Capsaicin-sensitive and hexamethonium-insensitive contractile and relaxatory motor responses of circular muscle induced by mesenteric nerve stimulation were studied. Desensitization to substance P or to neurokinin A, or the substance P antagonist, spantide largely reduced the initial contractile response. Desensitization to calcitonin gene-related peptide moderately reduced the late prolonged relaxation response. These results indicate that both responses of the circular muscle to mesenteric nerve stimulation may be attributed to a release of neuropeptides evoked by the 'efferent' stimulation of capsaicin-sensitive sensory nerves.

Effects of capsaicin on the circular muscle motility of the isolated guinea-pig ileum.

Effects of capsaicin on the circular muscle motility of the isolated guinea-pig ileum were investigated. Capsaicin produced a contraction followed by a relaxation of the circular muscle. Both responses were easily desensitized. As the late relaxation response was not sufficiently intense to be analyzed, the inhibitory effect of capsaicin on substance P-induced contractions was explored. Capsaicin abolished the substance P-induced contractions. This inhibitory effect was not affected by tetrodotoxin, and the effect was desensitized. Therefore, all effects of capsaicin on circular muscle motility seem to be due to the release of sensory neuropeptides, similarly to those elicited in the longitudinal muscle.

Slow hyperpolarizing action of tryptamine on myenteric neurons of the isolated guinea-pig ileum.

In the present study, tryptamine produced a slow hyperpolarization in a few neurons other than a slow depolarization in myenteric neurons of the isolated guinea-pig ileum. Neither the adrenergic neuron blocker, guanethidine nor the 5-hydroxytryptamine uptake inhibitor, zimelidine, which can inhibit the release of 5-hydroxytryptamine from enteric neurites induced by tryptamine (M. Takaki et al. (1985) Neuroscience 16, 223-240), affected this slow hyperpolarization. Therefore, it was concluded that the slow hyperpolarization induced by tryptamine in myenteric neurons was not mediated via the release of 5-hydroxytryptamine or noradrenaline. It might be possible that the hyperpolarization was induced by a direct action of tryptamine on myenteric neurons per se.

[Effect of superoxide dismutase for improvement of survival of ischemic reperfused island skin flap].

Using a rat model, we evaluated the effect of SOD on the survival of ischemic reperfused island skin flaps. In experiment 1, the oxygen free radical concentration in the flaps was measured by the technique of ESR. The results showed that the oxygen free radical concentration in ischemic reperfused flaps was significantly higher than in the corresponding control flaps (P less than 0.001). In experiment 2, the flaps were perfused with SOD (2000 U in 1 ml saline) before reperfusion after 8 hours of ischemia. Seven days after operation, the area of flap survived in the test group was significantly larger than in the control group (P less than 0.0005). The obtained data demonstrated that the generation of oxygen free radical increases with time during ischemia reperfusion in island skin flap and the role of oxygen free radical in tissue injury following ischemia and reperfusion. The use of SOD can enhance the survival of ischemic island skin flap.

Distinct populations of sensory neurons mediate the peristaltic reflex elicited by muscle stretch and mucosal stimulation.

Recent studies suggest that muscle stretch and mucosal stimulation elicit intestinal peristalsis by activating distinct populations of sensory neurons that converge on the same population of enteric motor neurons. The present study sought to characterize the origin and projections of these sensory neurons. The reflex was elicited by applying muscle stretch and mucosal stroking to the central compartment of a three-compartment flat-sheet preparation of rat colon while ascending contraction and descending relaxation were measured in the orad and caudad compartments, respectively. Identical graded responses were elicited by muscle stretch and mucosal stimulation: atropine (1 microM) and the tachykinin antagonist spantide (10 microM) inhibited ascending contraction when added to the orad compartment only, while the vasoactive intestinal peptide antagonist VIP10-28 (10 microM) and the NO synthase inhibitor NG-nitro-L-arginine (100 microM) inhibited descending relaxation when added to the caudad compartment only. Addition of capsaicin (1 microM) to the central compartment for 30 min abolished ascending contraction and descending relaxation elicited by muscle stretch and mucosal stimulation. Recovery of response was complete when capsaicin was applied to the mucosa of the colon in situ and measurements made 1 d after, implying that at this low concentration capsaicin depleted sensory nerve terminals of their transmitter content.(ABSTRACT TRUNCATED AT 250 WORDS)