Endogenous calcitonin gene-related peptide suppresses vasoconstriction mediated by adrenergic nerves in rat mesenteric resistance blood vessels

The role of perivascular calcitonin gene-related peptide (CGRP)-containing nerves in the modulation of adrenergic nerve-mediated vasoconstrictions was studied in the rat perfused mesenteric vascular bed. A frequency-dependent vasoconstriction induced by periarterial nerve stimulation (1-6 Hz) of the bed was significantly potentiated by perfusion of 1 microM CGRP-(8-37) (CGRP receptor antagonist) or to a similar extent after treatment with 500 nM capsaicin. In the preparations treated with capsaicin, CGRP-(8-37) caused a small potentiation of periarterial nerve stimulation-induced vasoconstriction. Exogenous CGRP (0.1-1 nM) concentration-dependently attenuated the augmented vasoconstriction in response to periarterial nerve stimulation after treatment with capsaicin. However, exogenous CGRP (1 nM) did not attenuate the periarterial nerve stimulation-induced vasoconstriction in the bed untreated with capsaicin. These results suggest that endogenous CGRP, which is released from CGRP-containing nerves, suppresses the adrenergic nerve function involved in mechanisms regulating the tone of resistant blood vessels.     

Effects of repeated infusions of substance P and vasoactive intestinal peptide on the weights of salivary glands subjected to atrophying influences in rats.

1. The long-term influence of substance P (SP) and vasoactive intestinal peptide (VIP) on rat salivary gland weight was investigated after parasympathetic denervation or on feeding soft food. 2. The parotid gland lost about one-third of its weight within 4-5 days following parasympathetic post-ganglionic denervation or change in dietary regimen, from pellets to liquid diet, thought to reduce nerve reflex activity. 3. Daily i.v. infusions with SP or VIP diminished or largely prevented the fall in parotid gland weight, whereas infusions with pentagastrin, bethanechol and saline had no effect. The infusions were preceded by administration of alpha- and beta-adrenoceptor antagonists; these antagonists were also given to the control animals. 4. The effect of SP and VIP on the parotid gland weight appeared to be related to cell size rather than to cell number, as judged by measurements of RNA and DNA. 5. Observations on the two other major salivary glands underlined the fact that different gland types in the same animal behave differently. Parasympathetic preganglionic denervation (decentralization) lowered the weights of the sublingual and submandibular glands, whereas liquid diet only reduced the weight of the sublingual gland. SP and VIP did not affect the weights of the submandibular glands, but VIP prevented the slight fall in sublingual gland weight induced by liquid diet. 6. The present results suggest a trophic role in rats for SP and VIP on parotid glands and for VIP on sublingual glands. Such an influence may be exerted naturally as a result of their release from nerves containing these peptides around acini.     

Tachykinin involvement in parasympathetic nerve-evoked salivation of the ferret.

1. The tachykinin antagonist (D-Arg1, D-Cl2Phe5, Asn6, D-Trp7.9, Nle11)-substance P, injected intravenously, blocked salivary secretion from the ferret parotid and submandibular glands in response to subsequent i.v. injections of the tachykinins, substance P and neurokinin A. 2. The tachykinin antagonist reduced the parasympathetic nerve-evoked secretion of parotid and submandibular saliva by 15-20% and 35-40%, respectively. Atropine abolished the remaining secretory response. 3. The 'atropine-resistant' parasympathetic nerve-evoked secretion of saliva from the parotid and submandibular glands (about 5 and 30%, respectively, of that before administration of atropine) was abolished by the tachykinin antagonist. 4. The tachykinin antagonist was without effect on the protein concentration of parotid and submandibular saliva secreted in response to parasympathetic nerve stimulation. Parotid and submandibular saliva lacked amylase. 5. Atropine reduced the protein concentration of the submandibular saliva secreted in response to parasympathetic nerve stimulation by 50%; this was the protein concentration of substance P-evoked saliva. 6. The secretory response to methacholine and to stimulation of preganglionic sympathetic nerve fibres, tested in rats, was unaffected by the tachykinin antagonist, contra-indicating an unspecific action of the antagonist. 7. The results suggest that the neuronal release of tachykinins is probably important in the nerve-evoked secretory response of the parotid and submandibular glands.     

Visceromotor responses to calcitonin gene-related peptide (CGRP) in the rat lower urinary tract: evidence for a transmitter role in the capsaicin-sensitive nerves of the ureter

Either intra-arterial or topical administration of calcitonin gene-related peptide (CGRP) had little effect on motility of the urinary bladder in urethane-anaesthetized rats. Only a high concentration (50 microM) of topical CGRP activated the micturition reflex and potentiated the response to exogenous substance P (SP). In the isolated rat bladder CGRP had inconsistent effects on spontaneous or field-stimulated contractions. CGRP neither produced any significant plasma extravasation (Evans blue leakage) in the rat lower urinary tract, nor potentiated the response to exogenous SP. CGRP inhibited motility in the rat isolated proximal urethra and ureters and counteracted the contractile response to neurokinins. An inhibitory effect of capsaicin on stimulated motility of the urethra was observed in all preparations and a small contractile response was evident in about 40% of cases. Lack of desensitization to the action of CGRP prevented the study of its interaction with capsaicin. The inhibitory effect of CGRP in the ureter exhibited a specific desensitization: if the preparations were pre-exposed to exogenous CGRP, the inhibition of motility produced by antidromic activation of the capsaicin-sensitive nerve terminals (field stimulation) as well as the response to capsaicin (1 microM) was prevented but the inhibitory response to isoprenaline was unaffected. These findings indicate that CGRP is able to influence markedly the motility of the rat lower urinary tract, but exhibits marked regional differences in its action. Endogenous CGRP could be the inhibitory transmitter which, when released from capsaicin-sensitive fibers, participate in the control of ureteral motility.     

Cutaneous vasodilatation induced by nitric oxide-evoked stimulation of afferent nerves in the rat.

1. The site of action at which nitric oxide (NO) may contribute to neurogenic vasodilatation in the hindpaw skin of urethane-anaesthetized rats was examined by the use of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. 2. Skin blood flow was measured by laser Doppler flowmetry, and neurogenic vasodilatation was evoked either by topical application of mustard oil (5%) or antidromic electrical stimulation of the saphenous nerve (antidromic vasodilatation). 3. L-NAME (60 mumol kg-1, i.v.) attenuated the hyperaemia evoked by mustard oil in an enantiomer-specific manner but failed to reduce antidromic vasodilatation and the vasodilatation due to i.v. injected calcitonin gene-related peptide (CGRP) and substance P (0.1-1 nmol kg-1 each), two proposed mediators of neurogenic vasodilatation. 4. Pretreatment of rats with capsaicin (125 mg kg-1, s.c. 2 weeks beforehand), to defunctionalize afferent neurones, reduced the hyperaemic response to mustard oil and prevented L-NAME from further decreasing the vasodilatation evoked by mustard oil. 5. Intraplantar infusion of sodium nitroprusside (SNP, 0.15 nmol in 1 min), a donor of NO, induced hyperaemia which was significantly diminished by the CGRP antagonist CGRP8-37 (50 nmol kg-1, i.v.) and by capsaicin pretreatment. The ability of CGRP8-37 to inhibit the vasodilator response to SNP was lost in capsaicin-pretreated rats. 6. Taken together, these data indicate that NO does not play a vasorelaxant messenger role in neurogenic vasodilatation but can contribute to activation of, and/or transmitter release from, afferent nerve fibres in response to irritant chemicals.     

Co-existence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin

Immunohistochemical studies showed that substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactivity co-exist in capsaicin-sensitive primary sensory neurons. Varicose SP- and CGRP-immunoreactive nerve fibres with a similar distribution pattern were seen in the lower airways and heart. The functional analysis revealed that CGRP caused cardiac stimulation and had, together with SP and neurokinin A, potent hypotensive effects. Vascular permeability was increased by SP and neurokinin A, and the bronchial smooth muscle was particularly sensitive to neurokinin A. Thus, multiple peptides stored in an possible released from the same nerve endings by capsaicin may exert differential effects in various target tissues.     

Involvement of substance P present in primary afferent neurones in modulation of cutaneous blood flow in the instep of rat hind paw.

1. The participation of small-diameter afferent fibres in the microcirculatory haemodynamics of cutaneous tissue was examined by studies on the effects of antidromic stimulation of primary afferent neurones on cutaneous blood flow (CBF) and tachykinin release into the subcutaneous space in the instep of the hind paw of rats. 2. Antidromic stimulation of the sectioned sciatic nerve induced a biphasic flow response, an initial transient decrease followed by an increase, with no alteration in the blood pressure. 3. Neither phase was affected by pretreatment with phentolamine (0.1 mg kg-1, i.a.), propranolol (0.5 mg kg-1, i.a.), atropine (0.5 mg kg-1, i.a.), methysergide (0.5 mg kg-1, i.a.) or mepyramine (10 mg kg-1, i.a.) plus cimetidine (10 mg kg-1, i.a.), but both were significantly inhibited by pretreatment with capsaicin (50 mg kg-1, s.c.). 4. Spantide (1-2 mumol kg-1, i.a.), a substance P (SP) antagonist, reduced the basal CBF, and also inhibited both phases of the biphasic flow response evoked by antidromic stimulation of the sectioned sciatic nerve. 5. Intra-arterial infusion of SP (0.5 mumol kg-1, i.a.) induced a biphasic flow response similar to that elicited by antidromic stimulation of the sectioned sciatic nerve. 6. Antidromic stimulation of the sectioned sciatic nerve caused a marked increase in SP release into the subcutaneous perfusate of the instep of the rat hind paw, but no detectable increase in neurokinin A release.(ABSTRACT TRUNCATED AT 250 WORDS)     

EVIDENCE AGAINST THE INVOLVEMENT OF VASOACTIVE INTESTINAL PEPTIDE IN OVINE PAROTID SECRETION AND BLOOD FLOW

1. The proposition that stimulation of the secretomotor nerve to the ovine parotid gland might involve co-release of vasoactive intestinal peptide (VIP) was tested by studying responses to infusion of VIP directly into the gland's arterial blood supply and by assay of VIP in parotid venous blood. 2. In unstimulated glands, an arterial blood concentration of 1.5 - 2.5 X 10(-9) mol/L VIP did not evoke fluid secretion but it increased K+ and phosphate secretion and glandular blood flow. The same blood concentration of VIP potentiated the stimulation of salivary flow rate caused by intraarterial infusion of bethanechol but nerve stimulation was not potentiated. VIP increased glandular blood flow in both conditions of stimulation. 3. Atropine blocked neurally stimulated salivary secretion but an increase in glandular blood flow was still detectable. There was therefore no evidence for a non-cholinergic neural mechanism for salivary secretion. 4. Furthermore, VIP concentrations in glandular venous blood were not increased by nerve stimulation. 5. The results indicate that exogenous VIP can affect the flow and composition of ovine parotid secretion but was not involved in the response to secretomotor nerve stimulation.     

Effect of adrenomedullin on adrenergic vasoconstriction in mesenteric resistance arteries of the rat

Adrenomedullin (AM) is a hypotensive peptide that belongs to a family of peptides structurally related to calcitonin gene-related peptide (CGRP). The present study examined the effect of AM on adrenergic nerve-mediated vasoconstriction in rat perfused mesenteric vascular beds without endothelium. Perfusion of AM at 0.1 nM but not 10 nM increased vasoconstrictor responses to periarterial nerve stimulation (PNS) (1-4 Hz), while AM at 10 nM significantly attenuated vasoconstriction induced by bolus injection of norepinephrine (NE). In preparations treated with capsaicin (a CGRP depletor), pressor responses to both PNS and NE injection were markedly attenuated by AM. Perfusion of CGRP(8-37) (a CGRP-receptor antagonist) significantly potentiated the PNS- but not the NE-induced vasoconstriction. Combined perfusion of CGRP(8-37) and AM had no effect on the PNS-induced response and antagonized the inhibitory effect of AM on the NE-induced response. AM(2-52) (an AM-receptor antagonist) did not influence the effect of AM. These findings suggest that AM facilitates adrenergic vasoconstriction by inhibiting neurotransmission of CGRP-containing nerves, which counteract adrenergic nerve-mediated vasoconstriction.     

Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback

The concept that NK₁ receptors are located pre-junctionally on substance P (SP)-containing nerves, acting as autoreceptors to inhibit SP release, has been suggested, but remains a controversial issue. To further investigate the existence of this receptor on central and peripheral terminals of primary afferent fibres, NK₁ receptor knockout mice and an NK₁ receptor antagonist were used in nerve-attached tissue preparations. These were the isolated dorsal horn of the spinal cord with dorsal roots attached, and the hairy skin of the hind paw with attached saphenous nerve. The results reveal that in the dorsal horn preparation, basal release of SP is significantly higher in NK₁^−/− mice than NK₁^+/+ mice (P<0.05, n=7 mice/strain). However, a difference in SP release evoked in the dorsal horn by electrical stimulation of the dorsal roots or capsaicin application was not observed. In contrast, antidromic electrical stimulation of the saphenous nerve caused a substantially greater release of SP in the skin of NK₁^−/− mice than in NK₁^+/+ mice (P<0.05, n=5 to 6 mice/strain). These results provide evidence for the existence of NK₁ autoreceptors on sensory nerves in skin, which may be relevant to the modulation of their peripheral pathophysiological effector functions.     

Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig

The systemic anti-inflammatory effect induced by antidromic sensory nerve stimulation was investigated in rats and guinea-pigs. In atropine-pretreated rats, bilateral antidromic stimulation of vagal afferent fibres (8 Hz, 20 min, at C-fibre strength) inhibited plasma extravasation induced by 1% mustard oil on the acutely denervated hindlegs by 36.45+/-3.95%. Both the prevention of this inhibitory effect by cysteamine pretreatment and the stimulation-evoked rise of plasma somatostatin-like immunoreactivity in the two species suggest a mediator role of neural somatostatin. Since this response was blocked by systemic capsaicin pretreatment and slightly reduced after subdiaphragmal vagotomy, participation of thoracic capsaicin-sensitive afferents is indicated. In guinea-pigs pretreated with guanethidine and pipecuronium, antidromic sciatic nerve stimulation induced 45.46+/-5.08% inhibition on the contralateral leg and increased plasma somatostatin-like immunoreactivity. It is concluded that somatostatin released from the activated vagal capsaicin-sensitive sensory nerve terminals of the rat and somatic nerves of the guinea-pigs exerts a systemic humoral function.     

EFFECTS OF CHRONIC ADMINISTRATION OF ANTIHYPERTENSIVE DRUGS ON VASODILATION MEDIATED BY CALCITONIN GENE-RELATED PEPTIDE-CONTAINING VASODILATOR NERVES IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The effects of chronic administration of antihypertensive drugs on the vasodilator response mediated by calcitonin gene-related peptide (CGRP)-containing nerves were investigated in spontaneously hypertensive rats (SHR). 2. A 7 week period of antihypertensive treatment with captopril, nicardipine or propranolol during the developmental phase (8-15 weeks of age) significantly lowered the mean blood pressure of SHR when compared with non-treated SHR. 3. The mesenteric vascular beds isolated from SHR, which were chronically administered with captopril, propranolol or nicardipine, were perfused with Krebs' solution containing 7 mumol/L methoxamine to produce active tone and 5 mumol/L guanethidine to block adrenergic neurotransmission. 4. In the mesenteric vascular bed with active tone, perivascular nerve stimulation (PNS; 0.5-8 Hz) caused a frequency-dependent vasodilator response that was abolished by 100 nmol/L tetrodotoxin (neurotoxin) or 1 mumol/L CGRP (8-37), a CGRP receptor antagonist. 5. CGRP-containing nerve-mediated vasodilator responses were significantly greater in captopril-treated SHR and significantly smaller in nicardipine-treated SHR than in non-treated SHR. There was no difference between the response between propranolol-treated SHR and non-treated SHR. 6. These results suggest that chronic treatment with captopril reverses the reduced neurogenic vasodilation mediated by CGRP-containing nerves in SHR.     

The pharmacology of salivary myoepithelial cells in dogs

1. Pressure changes in the submaxillary and parotid ducts of dogs, induced by nerve stimulation or intravenous injection of drugs, were studied.2. Pressure rises could be elicited by parasympathetic stimulation and by acetylcholine and methacholine, even when no secretion was evoked. These effects were abolished by atropine.3. Similarly, sympathetic stimulation, adrenaline, noradrenaline and phenylephrine raised the pressure in both glands, also in the absence of secretion. Dihydroergotamine abolished these effects. Isoprenaline increased the pressure in the submaxillary duct, but only when it caused secretion. This effect was abolished by propranolol. In the parotid gland isoprenaline caused neither secretion nor pressure rise. It is concluded that the myoepithelial cells of the two glands are supplied with alpha-adrenoceptors.4. Doses of histamine, bradykinin, kallidin and physalaemin which caused no salivary secretion raised the duct pressure even when dihydroergotamine, propranolol and atropine had been given.5. Angiotensin and 5-hydroxytryptamine increased the pressure only in some experiments. Oxytocin caused very little or no pressure rise. Vasopressin had no effect of its own but reduced the pressure raising effects of nerve stimulation or drugs.     

Calcitonin gene-related peptide but not substance P mimics capsaicin-induced coronary vasodilation in the pig

The vasodilator effects of the human calcitonin gene-related peptides alpha (hCGRP alpha) and beta (hCGRP beta) were studied in vitro and in vivo in relation to the effects of substance P (SP) and capsaicin on coronary vascular tone in the pig. Both hCGRP alpha and -beta induced a concentration-dependent, long-lasting relaxation of precontracted small (diameter 0.5 mm) pig coronary arteries in vitro. SP was slightly more potent but caused a transient relaxation with a smaller maximal response than CGRP. The relaxation induced by hCGRP alpha and -beta as well as SP was resistant to propranolol and atropine. Capsaicin also induced a long-lasting relaxation of potassium and PGF2 alpha-precontracted coronary arteries. After tachyphylaxis to SP had developed the relaxant effects of CGRP and capsaicin were unchanged. Rubbing the vessels to remove the endothelium completely abolished the relaxant effects of SP while the vasodilation induced by hCGRP alpha as well as capsaicin remained unchanged. Injections of hCGRP alpha, SP or capsaicin into the constantly perfused left anterior descending coronary artery of the pig in vivo caused a dose-dependent decrease in perfusion pressure, suggesting coronary vasodilation. In conclusion, the vasodilator effects of SP in vitro differ from the response to CGRP both with regard to their transient nature, the development of tachyphylaxis and endothelium dependence. The capsaicin-induced coronary vasodilation is therefore more likely to depend on release of CGRP rather than tachykinins from sensory nerves since neither endothelium removal nor SP-tachyphylaxis influenced the capsaicin and CGRP responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphological and functional in vitro and in vivo characterization of the mouse corpus cavernosum

1. In normal mice, the distribution of adrenergic, cholinergic, some peptidergic, and neuronal nitric oxide synthase (nNOS)-containing nerves were investigated. Functional in vitro correlates were obtained. An in vivo model was developed in which erectile haemodynamics in response to drugs or nerve-stimulation were studied. 2. Immunoreactivities for vesicular acetylcholine transporter protein (VAChT), nNOS-, and vasoactive intestinal polypeptide (VIP), co-existed in nerve fibres and terminal varicosities. Immunoreactivities for neuropeptide Y (NPY) and tyrosine hydroxylase (TH) were found in the same nerve structures. 3. Chemical sympathectomy abolished TH- and NPY-IR nerve structures in cavernous smooth muscle bundles. The distribution of calcitonin gene-related peptide (CGRP)-, nNOS-, VAChT- and VIP-IR nerve structures was unchanged. 4. In endothelial cells of the central and helicine arteries, veins and venules, intense immunoreactivity for endothelial NOS (eNOS) was observed. No distinct eNOS-IR cells were found lining the cavernous sinusoids. 5. In vitro, nerve-induced relaxations were verified, and endothelial NO/cyclic GMP-mediated relaxant responses were established. VIP and CGRP had small relaxant effects. A functioning adenylate cyclase/cyclic AMP pathway was confirmed. 6. Neuronal excitatory responses were abolished by prazosin, or forskolin. VIP and CGRP counteracted contractions, whereas NPY and scopolamine enhanced excitatory responses. 7. In vivo, erectile responses were significantly attenuated by L-NAME (50 mg kg(-1)) and facilitated by sildenafil (200 microg kg(-1)). 8. It is concluded that the mouse is a suitable model for studies of erectile mechanisms in vitro and in vivo.     

Calcitonin gene-related peptide (CGRP) and capsaicin-induced stimulation of heart contractile rate and force

The effects of calcitonin gene-related peptide (CGRP) on guinea-pig heart contractility were investigated in vitro in relation to the response of capsaicin and noradrenaline (NA). Synthetic rat CGRP (greater than 10(-8) M) caused a long-lasting, positive inotropic and chronotropic effect on the spontaneously beating right atrium. The response to CGRP mimicked the effects of capsaicin and was resistant to beta-adrenoceptor blockade using metoprolol. Furthermore, CGRP did not change basal efflux or the release of 3H-NA induced by transmural nerve stimulation, suggesting an action independent of sympathetic mechanisms. Mepyramine and cimetidine did not reduce the response to CGRP. After tachyphylaxis to the effects of CGRP (5 X 10(-7) M) which developed within 15-20 min, the positive inotropic and chronotropic atrial response to capsaicin was abolished. The effects of NA, however, were not influenced by CGRP tachyphylaxis. In the isolated perfused whole heart, CGRP had more pronounced stimulatory effects on ventricular contractile rate than on force compared to NA. The CGRP response was resistant to metoprolol and still present in capsaicin-pretreated animals. Capsaicin caused a slight initial inhibition of ventricular contractility, which was followed by a marked stimulatory action. As for CGRP, the cardioexcitatory response to capsaicin was more pronounced on rate than on force. The stimulatory responses to capsaicin were absent 2 weeks after systemic capsaicin pretreatment. In conclusion, CGRP mimics the non-adrenergic, cardioexcitatory effects of capsaicin, and the capsaicin response is absent after CGRP tachyphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of capsaicin-sensitive neurons in catecholamine secretion from rat adrenal glands

Sensory fibres innervate the adrenal medulla but their function is not known. In the present study, we have used the sensory neurotoxin capsaicin to evaluate the effect of capsaicin sensitive sensory fibres on catecholamine (CA) secretion from isolated perfused rat adrenal glands. CA secretion in response to 1 and 10 min electrical field stimulation of adrenal nerve terminals was significantly attenuated in the adrenal glands of adult rats pretreated as neonates with capsaicin and was frequency dependent, being more pronounced at the higher frequencies of stimulation (5 to 30 Hz) than at the low (0.3, 1 Hz) frequencies. Perfusion of control rat adrenal glands with capsaicin did not evoke CA secretion, but did increase CA secretion in response to perfusion with nicotine. Perfusion with capsaicin for 30 min (but not for 4 min) reduced the CA secretory response to subsequent nerve stimulation. The results suggest that capsaicin sensitive sensory neurons innervating the adrenal medulla are involved in the regulation of adrenal CA secretion evoked by electrical stimulation of adrenal nerve terminals.     

Substance P and calcitonin gene-related peptide: immunohistochemical localisation and microvascular effects in rabbit skeletal muscle

Summary 1. The distribution and microvascular effects of substance P (SP) and calcitonin gene-related peptide (CGRP) were studied in the rabbit tenuissimus muscle using immunohistochemistry and intravital microscopy. 2. Individual fibers within nerve bundles and along blood vessels in the muscle were found to be immunoreactive (IR) for both SP and CGRP, thus showing an apparently complete coexistence for these peptides. In dorsal root ganglia most SP-positive cells were also CGRP-IR, but the latter cells were somewhat more numerous than SP-IR cells. 3. When applied topically to the muscle, both SP and CGRP increased blood flow in a dose-dependent manner, but CGRP was more potent and caused responses of longer duration. Both SP and CGRP dilated transverse arterioles, but they had little or no effect on the smaller terminal arterioles. This resulted in a redistribution of blood flow to the connective tissue adjacent to the muscle. 4. SP, but not CGRP, elicited vigorous vasomotion in larger arterioles and caused the formation of aggregates of platelets and leukocytes in the venules. Neither flow increase, nor vasomotion or aggregate formation were influenced by pretreatment of the animals with mepyramine, cimetidine or indomethacin. Capsaicin (1 M) had a powerful effect on transverse arterioles resembling that of both SP and CGRP. 5. It is concluded that some of the vascular effects hitherto ascribed to SP on the basis of nerve stimulation and application of capsaicin might, at least in part, be due to release of CGRP. Send offprint requests to: A. Ohlen, Department of Physiology, Karolinska Institutet, S-104 01 Stockholm, Sweden     

Assessment of the effects of vasoactive intestinal peptide (VIP) on blood flow through and salivation of the dog salivary gland in comparison with those of secretin, glucagon and acetylcholine.

1. The vascular bed of the submandibular gland in situ was perfused with blood through the glandular artery at a constant pressure in anesthetized dogs. All drugs were administered intra-arterially. 2. Vasoactive intestinal peptide (VIP), secretin and acetylcholine produced a dose-dependent increase in blood flow through the artery (vasodilatation) but glucagon was almost ineffective. 3. Dose-blood flow response curves for VIP and secretin were parallel, and VIP was about 100 times as potent as secretin on a molar basis. Dose-blood flow response curves for acetylcholine were flatter than those for VIP and secretin. Acetylcholine was approximately as potent as secretin on a molar basis. 4. No tachyphylaxis developed to the vasodilator action of VIP. 5. The vasodilator responses to VIP and to electrical stimulation of the chordolingual nerve were scarcely modified by (-)-hyoscyamine in doses that fully antagonized the vasodilator response to acetylcholine. 6. VIP, secretin and glucagon were ineffective in eliciting salivary secretion. 7. The possibility that VIP is released from parasympathetic vasodilator nerves and mediates the atropine-resistant vasodilatation in the dog submandibular gland is discussed.     

创伤愈合中降钙素基因相关肽对表皮干细胞迁移 趋化作用的研究

目的探讨创伤愈合中降钙素基因相关肽(CGRP)对表皮干细胞迁移、趋化作用的影响。方法将实验鼠随机分为CGRP组、P物质(SP)组、辣椒素组和对照组,4组均致背部全层皮肤缺损,CGRP组和SP组致伤当天开始创面给予CGRP和SP(1次/d),辣椒素组致伤前1周皮下预注射辣椒素,利用核标记物BrdU作为表皮干细胞的示踪剂,观察4组创面愈合速度和表皮干细胞的迁移特征。结果CGRP组与SP组的创面愈合速度最快,创缘BrdU阳性细胞率最高,峰值出现最早;辣椒素组愈合速度最慢,BrdU阳性细胞率最低,峰值出现晚;CGRP组和SP组除创缘外,在创面肉芽组织中也出现了BrdU阳性细胞,另2组未出现。结论CGRP能明显加速创面愈合速度,并具有诱导表皮干细胞向创缘集中和向创面肉芽组织中迁移的作用。