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Biomedical subjects

S Rattan

Publications and source records attributed to S Rattan.

At least 55 records · Page 3Linked to original sources
PubMed1994

Role of hypogastric nerve activity in opossum internal anal sphincter function: influence of surgical and chemical denervation.

The exact role of the hypogastric nerve (HGN) in the regulation of basal internal anal sphincter pressures (IASP) and rectoanal reflex (RAR)-induced internal anal sphincter (IAS) relaxation is not known. The studies were performed to investigate the effect of electrical stimulation of HGN (HGNS) on IASP and RAR-induced fall in IASP, simultaneously record the HGN activity (HGNA) and IASP in response to different volumes of rectal balloon distension (RBD) to mimic RAR and determine the neural pathway involved in RBD-induced changes in HGNA. The recording of multifiber unit efferent HGNA was carried out after ipsilateral deafferentation in animals. HGNS produced a frequency-dependent rise in IASP and suppression of RBD-induced fall in IASP. Hexamethonium markedly attenuated the basal HGNA by 86% without causing a significant change in the basal IASP. Five cc of RBD caused a fall in IASP of 70.8 +/- 4.8% without any significant change in HGNA. Further increases in the RBD volume caused a volume-dependent increase in the basal HGNA and a biphasic systemic arterial pressure response (an initial fall followed by an elevation). These responses were suppressed by sympathectomy or sacral denervation. Sympathectomy plus sacral denervation caused complete obliteration of these responses. The data suggest that in the basal state, HGN may not play a significant role in the resting IASP and RAR-induced IAS relaxation. However, there was a significant sympathoexcitation in response to higher volumes of RBD (supramaximal stimulus for RAR). Hypogastric and sacral nerves may participate in the afferent pathways for the RBD-induced sympathoexcitation.

Anal Canal↗
PubMed1993

Role of nitric oxide in sympathetic neurotransmission in opossum internal anal sphincter.

BACKGROUND: The role of nitric oxide in the gut in response to sympathetic nerve stimulation has not been examined. The present study examined the influence of the NO synthase inhibitor L-NG-nitro-arginine (L-NNA) on responses to hypogastric nerve stimulation (HGNS) in the opossum internal anal sphincter (IAS). METHODS: Resting pressures in the IAS (IASP) were monitored using low-compliance continuously perfused catheters. RESULTS: The predominant response to HGNS was an elevation of the resting tone in the IAS. The other responses of infrequent nature were a decrease in the IASP and a biphasic response (an initial increase followed by a decrease in the IASP). beta-Adrenoceptor antagonist propranolol had no significant effect on the increase in the IASP by HGNS but almost abolished the decrease in the IASP caused by HGNS and unmasked the excitatory responses. The IAS responses to HGNS were frequency dependent and abolished by guanethidine (adrenergic blocker). L-NNA caused significant and stereoselective suppression of all IAS responses to HGNS. The suppressed HGNS responses were completely reversed by the NO precursor L-arginine stereoselectively. The NO synthase inhibitor and guanethidine had no effect on the increase in IASP by phenylephrine. CONCLUSIONS: NO may play a significant role in the facilitatory modulation of sympathetic responses in the IAS.

Adrenergic alpha-Antagonists↗
PubMed1993

Release of nitric oxide by activation of nonadrenergic noncholinergic neurons of internal anal sphincter.

The purpose of the present study was to investigate the direct release of nitric oxide (NO) in response to the stimulation of nonadrenergic noncholinergic (NANC) nerves. The studies were performed on isolated smooth muscle strips of the opossum (Didelphis virginiana) internal anal sphincter (IAS). Electrical field stimulation (EFS) using the appropriate parameters caused a frequency-dependent fall in the resting tone of the IAS. The release of NO was measured directly by the chemiluminescence method. The stimulation of NANC neurons by EFS and the nicotinic stimulant 1,1-dimethyl-4-phenylpiperazinium (DMPP) caused IAS relaxation with an accompanying release of NO. The release of NO and the fall in the resting tension of IAS in response to lower frequencies of EFS and DMPP were abolished by pretreatment of the smooth muscles with the neurotoxin tetrodotoxin and the NO-synthase inhibitor NG-nitro-L-arginine (L-NNA). The obliteration of the release of NO and the IAS relaxation in the presence of L-NNA reversed to control levels by the addition of the NO precursor L-arginine. The effect of L-NNA and L-arginine on NO release and IAS relaxation was stereoselective, since D-NNA and D-arginine had no significant effect. Vasoactive intestinal polypeptide also caused release of NO from IAS smooth muscle strips, which was abolished by L-NNA. However, isoproterenol and atrial natriuretic factor caused IAS relaxation without any increase in NO release. In conclusion, these studies demonstrate the direct release of NO in response to the stimulation of NANC inhibitory neurons of the gut.

Anal Canal↗
PubMed1993

Involvement of cAMP and cGMP in relaxation of internal anal sphincter by neural stimulation, VIP, and NO.

We examined simultaneous changes in resting tension and tissue levels of the two second messengers, adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), in the opossum internal anal sphincter (IAS). The influence of the nonadrenergic noncholinergic (NANC) nerve stimulation (NS) by electrical field stimulation (EFS) and the putative neurotransmitters nitric oxide (NO) and vasoactive intestinal peptide (VIP) on the above modalities was investigated. The fall in resting IAS tension in response to NS, NO, and VIP was accompanied by significant rises in both cGMP and cAMP. This fall and the levels of cAMP and cGMP were dependent on the intensity of EFS and the concentration of VIP and NO. EFS (2 Hz) caused a 63.5% fall of the resting tension with 61.7 and 118.2% rise of the tissue levels of cAMP and cGMP, respectively (P < 0.05). VIP (1 x 10(-6) M) caused an 81.5% fall of resting tension and 64.2 and 87.0% increases in cAMP and cGMP, respectively. Similarly, NO (1 x 10(-6) M) caused 69.6% fall in tension and an accompanying 93.4 and 415.9% rise of cAMP and cGMP, respectively. Although EFS, VIP, and NO all lowered IAS tension and raised both cyclic nucleotides, the changes in cAMP and cGMP in the IAS are otherwise stimulus specific, since fall in IAS tension by calcitonin gene-related peptide has been shown to be associated with an increase in cAMP without any change in cGMP, whereas the reverse was the case with atrial natriuretic factor. The common second messenger systems in IAS relaxation with NS, VIP, and NO suggest the involvement of VIP and NO as inhibitory neurotransmitters.

Anal Canal↗
PubMed1993

Inhibitory effect of CO on internal anal sphincter: heme oxygenase inhibitor inhibits NANC relaxation.

We examined the effect and role of CO in opossum internal anal sphincter (IAS) relaxation in response to nonadrenergic noncholinergic (NANC) nerve stimulation. Effects of NANC nerve stimulation on the IAS tension and second messengers (cAMP and cGMP) were examined before and after the selective heme oxygenase (HO) inhibitor zinc protoporphyrin IX (Zn PP-IX). The HO activity of the IAS smooth muscle was determined before and after NANC nerve stimulation. CO caused a concentration-dependent and tetrodotoxin-resistant fall in the resting tension of the IAS. The direct action of CO was confirmed by its relaxant action on the isolated smooth muscle cells. Furthermore, CO caused an increase in the tissue cGMP levels comparable to that observed with nerve stimulation. Zn PP-IX caused suppression of IAS relaxation caused by NANC nerve stimulation and vasoactive intestinal polypeptide (VIP) but not by peptide histidine-isoleucine and suppression of the increase in cGMP in response to NANC nerve stimulation. Zn PP-IX had no significant effect on the IAS responses to CO, nitric oxide (NO), and the beta-adrenoceptor agonist isoproterenol. The IAS responses to CO were not modified by the NO synthase inhibitor NG-nitro-L-arginine. Significant HO activity was detected in the IAS, which increased further in response to NANC nerve stimulation and VIP. The direct relaxant actions of CO and the suppression of NANC-mediated relaxation of the IAS by the HO inhibitor suggest the involvement of CO in the neurally mediated IAS relaxation.

Anal Canal↗
PubMed1993

Nitric oxide synthase inhibitor inhibits catecholamines release caused by hypogastric sympathetic nerve stimulation.

Recent studies suggest that nitric oxide (NO) plays a significant role in the parasympathetic inhibitory neurotransmission to the internal and sphincter (IAS). The role of NO in the sympathetic neurotransmission in the gut is not known. The resting intraluminal pressures of anesthetized opossum IAS (IASP) were monitored using low-compliance continuously perfused catheters. The plasma levels of catecholamines norepinephrine, epinephrine and dopamine were measured using a radioenzymatic assay. Parallel studies to determine the effects of hypogastric nerve stimulation (HGNS) on the resting IASP and catecholamine release were performed. The influence of NO in the sympathetic neurotransmission was determined by examining the effect of the NO synthase inhibitor L-NG-nitro-arginine (L-NNA) and the reversal of the effect by L-arginine. HGNS caused a frequency-dependent rise in the IASP accompanied by rises in norepinephrine, epinephrine and dopamine levels. The increases in the IASP and norepinephrine, epinephrine and dopamine levels were stereoselectively and significantly attenuated by L-NNA. Furthermore, the L-NNA-induced attenuation of rises in the resting IASP and catecholamine levels in response to HGNS was reversed stereoselectively by L-arginine. These studies for the first time (to the authors' knowledge) show that the NO synthase inhibitor causes specific suppression of sympathetic neurotransmitter release in the gut smooth muscle. It was concluded that, in the anorectum, NO has a facilitory role in the release of sympathetic neurotransmitters.

Amino Acid Oxidoreductases↗
PubMed1993

The entire vasoactive intestinal polypeptide molecule is required for the activation of the vasoactive intestinal polypeptide receptor: functional and binding studies on opossum internal anal sphincter smooth muscle.

UNLABELLED: Because no significant information exists regarding the structure-activity of vasoactive intestinal polypeptide (VIP) to gut smooth muscle, we performed functional studies in vitro on opossum internal anal sphincter (IAS) smooth muscle strips and supplemented them with binding studies to assess the ability of VIP, its fragments and analogs to inhibit [125I]VIP binding to IAS smooth muscle membranes. Binding of radiolabeled VIP to its receptor was specific, saturable and time- and temperature-dependent. Of all the substances tested, VIP was the most potent in causing a fall in the resting tension of the IAS and inhibiting [125I]VIP binding. VIP 2-28, VIP 10-28 and the putative VIP antagonists (1 x 10(-6) M) [4Cl-D-Phe6,Leu17]VIP (VIP analog) and (N-Ac-Tyr1, D-Phe2)-growth hormone-releasing factor [GRF] (1-29)-NH2 (GRF analog) caused significant inhibition of [125I]VIP binding, but had only minimal effect on the resting tension of the IAS. VIP 9-18 and VIP 1-12 had neither any significant effect nor inhibition of receptor binding. The rank order of potencies for inhibition of binding was VIP > VIP analog > VIP 10-28 = VIP 2-28 > GRF analog > peptide histidine isoleucine > VIP 9-18. The IC50 values for VIP, VIP analog, VIP 10-28, VIP 2-28, GRF analog and peptide histidine isoleucine were 9.6 x 10(-9), 1.6 x 10(-7), 5.5 x 10(-7), 6.2 x 10(-7), 1.2 x 10(-6) and 1.2 x 10(-5) M, respectively. CONCLUSION: the full action of VIP is critically dependent upon the integrity of the entire VIP molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Isolation and amino acid sequences of opossum vasoactive intestinal polypeptide and cholecystokinin octapeptide.

Evolutionary history suggests that the marsupials entered South America from North America about 75 million years ago and subsequently dispersed into Australia before the separation between South America and Antarctica-Australia. A question of interest is whether marsupial peptides resemble the corresponding peptides of Old or New World mammals. Previous studies had shown that "little" gastrin of the North American marsupial, the opossum, is identical in length to that of the New World mammals, the guinea pig and chinchilla. In this report, we demonstrate that opossum cholecystokinin octapeptide, like that of the Australian marsupials, the Eastern quoll and the Tamar wallaby, is identical to the cholecystokinin octapeptide of Old World mammals and differs from that of the guinea pig and chinchilla. However, opossum vasoactive intestinal polypeptide differs from the usual Old World mammalian vasoactive intestinal polypeptide in five sites: [sequence; see text].

Amino Acid Sequence↗
PubMed1992

Nitric oxide pathway in rectoanal inhibitory reflex of opossum internal anal sphincter.

The role of nitric oxide in relaxation of the internal anal sphincter (IAS) in response to the rectoanal reflex was studied in the opossum. Resting pressures in the IAS (IASP) were monitored using low-compliance continuously perfused catheters. The NO-synthase inhibitor L-NG-nitro-arginine (L-NNA) caused significant and dose-dependent suppression of the decrease in IASP in response to the reflex mimicked by the rectal balloon distention. NO-synthase inhibitor blocked IAS relaxation in response not only to rectoanal reflex but also to other neural stimuli such as sacral nerve stimulation, local intramural stimulation, and the nicotinic ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium. Suppression of the neurally mediated IAS relaxation by L-NNA was stereoselective; D-NNA had no effect on the relaxation. The suppression of the rectoanal reflex-induced IAS relaxation by L-NNA was completely reversed by NO precursor L-arginine stereoselectively as D-arginine failed to reverse the suppressed IAS relaxation. Sodium nitroprusside caused a decrease in IASP that was modified neither by the neurotoxin tetrodotoxin nor by L-NNA. Furthermore, the decrease in IASP by the direct-acting beta-adrenoceptor agonist isoproterenol was also not modified by the inhibitor of NO synthase. It is concluded that NO or an NO-like substance is an important mediator of IAS relaxation in response to noradrenergic, noncholinergic nerve stimulation.

Anal Canal↗
PubMed1992

Role of nitric oxide as a mediator of internal anal sphincter relaxation.

The studies were performed in in vitro to examine the role of nitric oxide (NO) in nonadrenergic noncholinergic (NANC) nerve-mediated relaxation of the internal anal sphincter (IAS) smooth muscle strips of opossums. NO caused a concentration-dependent fall in the resting tension of the IAS. The inhibitory action of NO may be exerted directly on the IAS smooth muscle since it was not modified by the neurotoxin tetrodotoxin (1 x 10(-6) M), which abolished the neurally mediated fall in the IAS tension. The inhibitor of NO synthesis NG-nitro-L-arginine (L-NNA) produced concentration-dependent suppression of the neurally mediated fall in the IAS tension. The suppression of the neurally mediated IAS relaxation was stereoselective because D-NNA had no effect on the control responses. The suppressant action of L-NNA was selectively reversed by L-arginine in a concentration-dependent manner. The reversal was complete with 3 x 10(-4) M L-arginine. D-Arginine on the other hand, at the same concentration had no effect on L-NNA-suppressed IAS relaxation. Interestingly, the fall in the IAS tension caused by vasoactive intestinal polypeptide (VIP) (an inhibitory neurotransmitter in the IAS) was also inhibited by L-NNA (3 x 10(-5) M). From these data we conclude that NO or NO-like substances serve as important inhibitory mediators for the NANC nerve-mediated IAS relaxation. A part of the inhibitory action of VIP on the IAS involves NO-synthase pathway. The exact site of formation and release of NO or NO-like substances in response to NANC nerve stimulation remain to be investigated.

Anal Canal↗
PubMed1992

Neurally mediated relaxation of opossum internal anal sphincter: influence of superoxide anion generator and the scavenger.

The present investigation was undertaken to examine the influence of super oxide anion generator hydroquinone and the superoxide anion scavenger superoxide dismutase (SOD) on the neurally mediated relaxation of the internal and sphincter (IAS). The studies were performed in vitro on IAS smooth muscle strips of opossums. Neural stimulation with appropriate parameters of electrical field stimulation is known to cause IAS relaxation by the activation of nonadrenergic noncholinergic inhibitory neurons. Hydroquinone caused a concentration-dependent suppression of IAS relaxation in response to neural stimulation. The suppression of the IAS relaxation was reversed by SOD in a concentration-dependent manner. The fall in the IAS tension by nitric oxide (NO) was also suppressed by hydroquinone and reversed by SOD. SOD alone caused an augmentation of the fall in the IAS tension by NO. The fall in the IAS tension in response to the candidate inhibitory neurotransmitter vasoactive intestinal polypeptide was not modified by SOD in the basal state. Hydroquinone, however, caused a significant suppression of vasoactive intestinal polypeptide-induced fall in the IAS tension which was reversed by SOD. The fall in the resting IAS tension by the directly acting smooth muscle relaxants, beta adrenoceptor agonist isoproterenol and atrial natriuretic factor were not significantly modified by hydroquinone or SOD. From the present data we conclude: NO or an NO-like factor plays a significant role in the nonadrenergic noncholinergic nerve-mediated IAS relaxation.

Anal Canal↗
PubMed1991

Effects of galanin on the opossum internal anal sphincter: structure-activity relationship.

The present study was carried out to investigate the effects of porcine galanin-(1-29), N-terminal fragment galanin-(1-10), C-terminal fragment galanin-(15-29), and the middle fragment galanin-(7-16) on the spontaneous tension of the opossum internal anal sphincter and on the decrease in the resting internal anal sphincter tension in response to neural stimulation by electrical field stimulation. Galanin and galanin-(1-10) caused a concentration-dependent decrease in the resting tension of internal anal sphincter and an augmentation of the percent decrease in the resting tension with electrical field stimulation. Galanin-(15-29), on the other hand, produced an increase in the resting tension of the internal anal sphincter and had no effect on the electrical field stimulation-induced decrease in the resting tension. Galanin-(7-16) produced no significant effect on the internal anal sphincter. The decrease in the internal anal sphincter tension by galanin and galanin-(1-10) was partially antagonized by tetrodotoxin, whereas the increase in the internal anal sphincter tension caused by galanin-(15-29) was not modified by tetrodotoxin. In contrast to its effect in the internal anal sphincter, galanin caused an increase in the resting tension and suppressed a decrease in the lower esophageal sphincter tension in response to electrical field stimulation. From these findings we conclude that (a) galanin exerts an inhibitory effect on the internal anal sphincter by activating galanin receptors both at the intramural inhibitory neurons and at the internal anal sphincter smooth muscle and that the N-terminal portion of galanin may be responsible for these actions; (b) the contractile action of galanin is produced by its action on the smooth muscle; and (c) the actions of galanin on the gastrointestinal tract are tissue specific.

Anal Canal↗
PubMed1991

CGRP and ANF cause relaxation of opossum internal anal sphincter via different mechanisms.

This investigation examined and compared the role of cyclic nucleotides in the mediation of internal anal sphincter (IAS) relaxation caused by the addition of neuropeptide calcitonin gene-related peptide (CGRP) and atrial natriuretic factor (ANF). The studies were performed in vitro on smooth muscle strips of opossum IAS. The relaxation produced by CGRP and ANF was examined before and after the addition of tetrodotoxin (TTX) (1 x 10(-6)M). At this concentration, TTX did not have any significant effect on the relaxation produced by either CGRP or ANF, suggesting that these peptides act directly on the smooth muscle. Addition of CGRP (3 x 10(-6) M) produced the maximal relaxation and significantly increased cAMP content without changing cGMP. On the other hand, addition of ANF (3 x 10(-6) M) caused a similar fall in IAS tension that was accompanied by a significant elevation in cGMP without any change in cAMP content. The rises in the levels of cyclic nucleotides preceded the onset of fall in the resting tension of IAS. Our results demonstrate that CGRP and ANF relax isolated strips of opossum IAS by their action directly at the smooth muscle and that this relaxation is associated with an increase in cAMP and cGMP, respectively. The studies suggest the presence of both cAMP and cGMP pathways in the IAS and that the relaxation of IAS smooth muscle in response to different peptides may occur via a specific intracellular biochemical pathway.

Anal Canal↗
PubMed1991

Antagonism of calcitonin gene-related peptide (CGRP) by human CGRP-(8-37): role of CGRP in internal anal sphincter relaxation.

We performed functional studies on the opossum internal anal sphincter (IAS) smooth muscle strips and receptor binding studies in the IAS smooth muscle membranes to examine the influence of: human calcitonin gene-related peptide (CGRP)-(8-37) on the fall in IAS tension caused by human CGRP I and CGRP II and on [125I]human CGRP I binding on the IAS smooth muscle membranes. We also compared the ability of [Tyr0]-rat CGRP 28-37 to displace the radioligand from the IAS membranes to that of human CGRP-(8-37). Human CGRP-(8-37) caused significant and dose-dependent right-ward shifts of the dose-response curves of both CGRP I and CGRP II on the IAS smooth muscle. The specific binding of [125I]human CGRP I to IAS smooth muscle membranes was time- and temperature-dependent. CGRP antagonists human CGRP-(8-37) and [Tyr0]-rat CGRP 28-37 and CGRP I and CGRP II caused dose-dependent displacement of the radioligand. Vasoactive intestinal polypeptide and calcitonin on the other hand had no significant effect on the radioligand binding. Tachyphylaxis and cross tachyphylaxis to the effects of CGRP I and CGRP II were observed. The CGRP antagonists and CGRP I and CGRP II tachyphylaxis failed to modify the fall in the IAS tension in response to neural stimulation by electrical field stimulation. From these studies we conclude: human CGRP-(8-37) and [Tyr0]-rat CGRP 28-37 may serve as potential antagonists of CGRP action; human CGRP I and CGRP II may act on the same receptor on the IAS smooth muscle; and CGRP may not play a significant role in the IAS relaxation in response to electrical field stimulation.

Anal Canal↗
PubMed1990

Role of neuropeptide Y in opossum internal anal sphincter.

The present investigation was undertaken to examine the effects and role of neuropeptide Y (NPY) on the internal anal sphincter (IAS). The studies were performed in alpha-chloralose-anesthetized opossums. Resting pressure in the IAS (IASP) was recorded using low-compliant continuously perfused catheters. The effect of NPY administered close intra-arterially on the resting IASP was examined before and after different neurohumoral antagonists and the neurotoxin tetrodotoxin (TTX). To examine the influence of sympathetic nerves, the ventral roots of lumbar sympathetic nerves were isolated in some experiments and stimulated electrically. The influence of NPY on the IAS relaxation in response to rectoanal reflex mimicked by rectal balloon distension (RD) was also examined. NPY caused dose-dependent rise in the IASP, which was not modified by different neurohumoral antagonists and TTX. The rise in IASP by electrical stimulation of ventral lumbar nerve root (L3) was suppressed but not abolished by phentolamine. However, guanethidine (which depletes both norepinephrine and NPY) caused complete obliteration of this response. The other effect of NPY on the IAS was significant antagonism of IAS relaxation caused by RD. From these results, we conclude that NPY exerts two different actions on the IAS. First, it causes a rise in IASP by its action directly at the IAS smooth muscle. Sympathetic nerve stimulation may cause a rise in IASP by its action directly at the IAS smooth muscle partially through release of NPY. Second, it inhibits IAS relaxation produced by rectoanal reflex. These findings would suggest an important regulatory role of NPY in rectoanal physiology.

Anal Canal↗
PubMed1990

Role of alpha adrenoceptors in opossum internal anal sphincter.

The purpose of the present investigation was to examine the role of alpha adrenoceptors in the internal anal sphincter (IAS). Studies wer performed on alpha-chloralose anesthetized opossums. Resting pressure in the IAS (IASP) was recorded using low compliant continuously perfused catheters. The effects of the alpha-1 adrenoceptor agonist phenylephrine and alpha-2 adrenoceptor agonist clonidine and their corresponding selective antagonists, prazosin and yohimbine, respectively, were examined on the resting IASP, and on rectal balloon distension (RBD)-mediated IAS relaxation. Phenylephrine caused a rise in the IASP that was blocked by prazosin and not by yohimbine. Phenylephrine had no effect on IAS relaxation caused by RBD. Clonidine on the other hand caused significant suppression of IAS relaxation in response to RBD, but caused minimal changes in the resting IASP. The suppression of IAS relaxation by clonidine was selectively antagonized by yohimbine but not by prazosin. From these studies we conclude that alpha-2 adrenoceptors exert important neuromodulatory influences on rectoanal inhibitory reflex, while alpha-1 adrenoceptors may exert modulatory effects on the resting IAS tone.

Anal Canal↗
PubMed1990

[Tyr0]-calcitonin gene-related peptide 28-37 (rat) as a putative antagonist of calcitonin gene-related peptide responses on opossum internal anal sphincter smooth muscle.

The effects of calcitonin gene-related peptide (CGRP) I(alpha) (human), CGRP II(beta) (human), CGRP (rat), and [Tyr0]-CGRP (rat) on the resting tone of opossum internal anal sphincter (IAS) were studied. Different CGRPs identified above produced a concentration-dependent fall in the resting tension of the IAS. CGRP II (human) was most potent, while [Tyr0]-CGRP (rat) was the least. The fall in IAS tension caused by CGRP II (human) was not modified by the neurotoxin tetrodotoxin, beta adrenoceptor antagonist propranolol and prostaglandin synthesis inhibitor indomethacin. In contrast to the other CGRP analogs, [Tyr0]-CGRP 28-37 (rat) produced no significant effects on the resting tension of the IAS. However, the fragment caused significant rightward shifts in the concentration-effect curves of different CGRP analogs examined on the IAS. [Tyr0]-CGRP 28-37 (rat) was found to be almost equipotent in antagonizing the inhibitory effects of CGRP (rat) and [Tyr0]-CGRP (rat), but was approximately 12 and 4 times more potent in antagonizing the responses of CGRP I (human) and CGRP II (human), respectively, as compared to that of CGRP (rat) and [Tyr0]-CGRP (rat). Calcitonin, on the other hand, caused a rise in the IAS tension by its action directly at the smooth muscle and this was not modified by [Tyr0]-CGRP 28-37. Thus, we conclude that: 1) CGRP causes a fall in the resting tension of IAS by its action directly at the smooth muscle; 2) [Tyr0]-CGRP 28-37 (rat) may serve as an antagonist of CGRP responses and 3) CGRP and calcitonin produce opposite actions on the resting IAS tension by the activation of their own receptors at the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Anal Canal↗