Regional vasodilation is a prominent feature of the haemodynamic response to endothelin in anaesthetized, spontaneously hypertensive rats.
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Anesthesia↗
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Further studies on the mechanism of the cardiovascular effects of L-tyrosine.
Tyrosine is the precursor amino acid of catecholamines. Low doses of tyrosine produce tachycardia and hypertension, while higher doses induce bradycardia and hypotension in anaesthetised rats. The mechanism and site of action of L-tyrosine are not fully understood. Eight groups of Wistar rats received different pretreatments in order to study the influence of blockade of various receptor mechanisms on the cardiovascular effects of L-tyrosine. The effects mediated by the autonomic nervous system were inhibited by ganglion blockade (hexamethonium), by alpha 1- and beta 1-adrenoceptor blockade (prazosin and atenolol) and by parasympathetic acetylcholine receptor blockade (atropine). The possible role of histamine receptors was studied by inducing H1 and H2-receptor blockade (diphenhydramine and cimetidine, respectively). The effect of inhibition of prostaglandin synthesis by indomethacin was also studied. The L-tyrosine-induced tachycardia was completely blocked by atenolol. Both atenolol and prazosin partly inhibited the hypertensive effects of low doses of tyrosine. The tyrosine-induced bradycardia was not inhibited, and the hypotension was only partly blocked by the pretreatments. Therefore, adrenergic mechanisms seem to mediate the stimulatory cardiovascular effects of tyrosine. The depressant effects of high doses of tyrosine do not appear to be mediated by cholinergic activation, histamine receptor activation, or prostaglandin synthesis.
Adrenergic alpha-Antagonists↗
Effects of human ANF-(99-126) on sympathetic nerve function, hemodynamic parameters and plasma cGMP levels in anesthetized, ganglion-blocked dogs.
The ability of human ANF-(99-126) (ANF) to affect neuronal function, plasma cGMP levels or various hemodynamic parameters was tested in anesthetized dogs subjected to ganglionic blockade which prevented reflex changes in sympathetic tone. In each group of dogs, heart rate changes due to electrical stimulation of the cardioaccelerator nerve at 0.5, 1, 3 and 10 Hz were measured before and after ANF or vehicle infusion. A possible direct effect of ANF on the beta-adrenoceptor mechanisms was assessed by evaluating changes in heart rate after i.v. administration of isoproterenol (a beta-adrenoceptor agonist). The results showed that i.v. infusion of ANF (200 pmol/kg per min for 60 min), but not vehicle, produced significant inhibition of heart rate responses to low frequency nerve stimulation (0.5-1 Hz) when compared to vehicle 30 min after the end of infusion; high frequency (10 Hz) responses remained unaffected. A significant (P less than 0.05) enhancement in isoproterenol responses was evident in ANF-treated animals at the end of infusion, and 30 min afterward. ANF increased plasma cGMP from pretreatment levels of 28 +/- 4 to 149 +/- 1 pmol/ml at the end of infusion, and falling to 63 +/- 7 pmol/ml 30 min later (t 1/2 = 25.1 +/- 2.2 min). Cardiac output also tended to fall during infusion and remained significantly reduced (-18%) 30 min after infusion's end; blood pressure fell without a decrease in total peripheral resistance. Thus, ANF produced a direct, frequency-dependent depressant action on sympathetic nerve function, reduced both cardiac output and blood pressure, and enhanced chronotropic responses to beta-adrenoceptor stimulation. These persistent changes in hemodynamic parameters and neuronal function may contribute to the mechanism of action of ANF.
Anesthesia↗
Ganglion-blocking agents enhance neurally mediated bronchoconstriction in the guinea-pig: possible role of sensory neuropeptides.
The effect of ganglion blockade by hexamethonium bromide (0.1-100 mumol.kg-1) and pentolinium tartrate (0.01-3 mumol.kg-1) on the bronchoconstriction induced by vagal nerve stimulation (15 Hz, 0.2 ms, 3 s, 7-20 V) was evaluated in the anaesthetized guinea-pig. Both ganglion-blocking agents potentiated this response dose dependently. When the neural bronchoconstriction was suppressed by atropine, hexamethonium restored this response dose dependently. Hexamethonium produced inhibitory effects on vagally induced bronchoconstriction in capsaicin-desensitized and in propranolol- or reserpine-pretreated guinea-pigs. Propranolol (0.03-3 mumol.kg-1) produced a marked dose-dependent increase of neural bronchoconstriction (which was markedly reduced, about 10 times) in capsaicin-desensitized animals. Our results show that ganglion-blocking agents potentiate neural bronchoconstriction in the guinea-pig and that sensory neuropeptides may have a role in this effect. Moreover, beta-adrenergic modulation of the release of neuropeptides from vagal sensory fibers is suggested.
Anesthesia↗
Does enhanced sympathetic tone contribute to angiotensin II hypertension in rats?
To determine whether enhanced sympathetic tone contributes to the maintenance of chronic angiotensin II (A II, 10 ng/min i.v. for 10 days) hypertension in rats, sympathetic activity was assessed in hypertensive and control rats by measuring norepinephrine (NE) turnover (alpha-methyl-p-tyrosine) in peripheral organs and by measuring depressor responses to ganglionic blockade in conscious rats. Pressor responses to methoxamine (1-8 micrograms/min) and arginine vasopressin (0.5-4 ng/min) were also obtained in rats with ganglionic blockade. Chronic A II infusion produced significant hypertension (mean +/- S.E. tail cuff pressure: 176 +/- 5 vs. 134 +/- 2 mm Hg in controls; n = 23 each group) but there were no significant differences in NE turnover in heart, kidney, skeletal muscle, or intestine in hypertensive rats compared with controls. Ganglionic blockade produced a significantly larger decrease in mean arterial pressure in A II-treated rats when compared with controls (73 +/- 7 vs. 38 +/- 2 mm Hg, n = 18 for each group). Dose-response curves for methoxamine and vasopressin were not significantly different between groups. The results suggest that the maintenance of chronic A II hypertension does not involve postsynaptic interactions between A II and the sympathetic system. The NE turnover data do not support the hypothesis that rats with chronic A II hypertension have enhanced sympathetic tone.
Adrenergic alpha-Agonists↗
Big endothelin-3-induced hypertension and its inhibition by phosphoramidon in anaesthetized rats.
Intravenous injection of big endothelin-3 (big ET-3, 1-41 amide) at 3 nmol/kg to ganglion-blocked anaesthetized rats produced a long-lasting hypertensive action, but the action was less potent than that seen with the same dose of ET-3-(1-21). The pressor effect induced by big ET-3 was markedly attenuated by pretreatment with phosphoramidon, 5 mg/kg i.v., a dose which had no effect on the hypertensive action induced by ET-3. These results strongly suggest that big ET-3 is converted to mature ET-3 by a phosphoramidon-sensitive metalloproteinase in vivo, in a manner similar to the conversion of big ET-1 to ET-1.
Anesthesia↗
Intracisternally applied angiotensin II does not excite reticulospinal vasomotor neurons in anesthetized rats.
We examined whether vasomotor neurons in the rostroventrolateral reticular nucleus of the medulla oblongata might be responsible for an acute increase in arterial pressure, elicited by application of angiotensin II in the central nervous system, as suggested by others. In urethane-pentobarbital-anesthetized and ventilated rats, intracisternal administration of angiotensin II (1-30 nmol, infused over a period of 30 s) produced a dose-dependent pressor response, which was abolished by intracisternal application of [Sar1, Thr8]angiotensin II (100 nmol), an angiotensin II receptor antagonist. The pressor response, however, was neither preceded by nor associated with increased discharges of vasomotor neurons with slow- and fast-conduction axons in the rostroventrolateral reticular nucleus and of lumbar sympathetic chain and renal sympathetic nerves. Intravenous injections of [beta-mercapto-beta, beta-cyclopentamethylenepropinyl1,-O-Et-Tyr2, Val4, Arg8]vasopressin, a vasopressin receptor antagonist, largely abolished the central angiotensin II-induced pressor response, while a blockade of ganglionic transmission with hexamethonium and disruption of descending sympathoexcitatory output were ineffective. We conclude that central administration of angiotensin II, under the experimental conditions and at the doses, evokes an acute pressor response largely through the release of vasopressin, not by exciting vasomotor and sympathetic neurons.
Angiotensin II↗
Influence of vascular tone on vasoconstrictor responses to the 5-HT 1-like receptor agonist sumatriptan in anaesthetised rabbits.
The cardiovascular profile of the 5-HT1-like receptor agonist sumatriptan has been studied in anaesthetised rabbits pretreated with chlorisondamine (0.5 mg kg-1 i.v.) and enalapril (0.3 mg kg-1 i.v.) to eliminate autonomic reflexes and minimise endogenous vasoconstrictor tone. Under these conditions sumatriptan (2-100 micrograms kg-1 i.v.) produced modest increases in carotid vascular resistance but had no significant influence on heart rate, blood pressure or mesenteric vascular resistance. In a similarly pretreated group of animals in which vasoconstrictor tone was elevated by infusion of angiotensin (100 ng kg-1 min-1 i.v.) sumatriptan caused moderate increases in blood pressure (55 +/- 5 to 65 +/- 5 mm Hg after 25 micrograms kg-1 i.v.) and mesenteric vascular resistance (1.4 +/- 0.2 to 1.6 +/- 0.2 mm Hg min ml-1 after 25 micrograms kg-1 i.v.) and tended to produce a greater carotid vasoconstriction (3.6 +/- 0.5 to 4.7 +/- 0.7 mm Hg min ml-1 after 25 micrograms kg-1). These effects were antagonised by methiothepin 0.3 mg kg-1 i.v. implying the involvement of 5-HT1-like receptor stimulation. Hence, the presence of angiotensin produces a modest amplification of the vasoconstrictor effects of sumatriptan and, in particular, unmasks a constriction of the mesenteric vascular bed. The degree of synergy observed between these two vasoconstrictors was, however, less marked than might have been expected on the basis of previous isolated tissue studies.
Angiotensin II↗
Central choline reverses hypotension caused by alpha-adrenoceptor or ganglion blockade in rats: the role of vasopressin.
The effect of intracerebrovenricularly (i.c.v.) injected choline on blood pressure was investigated in rats made hypotensive by blocking peripheral alpha-adrenoceptors or autonomic ganglionic transmission. Choline (50-150 micrograms; i.c.v.) increased blood pressure in a dose-dependent manner and 150 micrograms of choline restored blood pressure to the resting level. The pressor response to choline was associated with an increase in plasma vasopressin levels. Pretreatment with mecamylamine (50 micrograms; i.c.v.), but not atropine (10 micrograms; i.c.v.), blocked both the pressor and vasopressin responses to i.c.v. choline. The vasopressin receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylene-propionyl1,O-Me-T ry2,Arg8] vasopressin (10 micrograms/kg; i.v.), given 5 min after i.c.v. choline (150 micrograms), abolished the pressor effect of choline and blood pressure returned to the pre-choline levels. It is concluded that the precursor of acetylcholine, choline, can increase blood pressure and reverse hypotension in alpha-adrenoceptor or ganglionic transmission blocked rats, by increasing plasma vasopressin.
Adrenergic alpha-Antagonists↗
Characteristics of uveal vasodilation produced by facial nerve stimulation in monkeys, cats and rabbits.
The effect of electrical stimulation of the facial nerve on ocular blood flow and intraocular pressure (IOP) was studied in monkeys, cats and rabbits. Ocular blood flow was determined with radioactive microspheres or by direct measurement of uveal blood flow from a cannulated vortex vein in rabbits. Frequency-response relationships were determined in monkeys (intraocular pressure) and rabbits (uveal blood flow). Stimulation of the facial nerve produced a marked increase (greater than 100%) in choroidal blood flow in all three species. The effect in the anterior uvea appeared the same, but less pronounced. Retinal blood flow was not affected by the stimulation in any of the species. In cats, local blood flow in the optic nerve was significantly increased by the stimulation. As there was no significant change in mean arterial blood pressure, the increase in blood flow must have been due to decreased vascular resistance. The uveal vasodilation was resistant to muscarinic blockade in all three species, excluding acetylcholine as the principal peripheral transmitter. Stimulation of the facial nerve also caused a moderate increase in IOP (range 1-11 cmH2O), only investigated in monkeys. This increase in IOP seems to be secondary to the intraocular vasodilation. The maximal increase in intraocular pressure, in monkeys, and vasodilation, in rabbits, was obtained at 15-20 Hz. At these frequencies, the vasodilation was always abolished by ganglionic blockade. In rabbits, stimulation at high frequencies (greater than 40 Hz) sometimes produced uveal vasodilation even after ganglionic blockade. This vasodilation was always less pronounced than before the ganglionic blockade and could be abolished by muscarinic blockade. The increase in uveal blood flow, in rabbits, was not affected by administration of indomethacin, indicating that prostaglandins are not critically involved in the vasodilation produced by facial nerve stimulation. The vasodilatory nerve fibers in the facial nerve are likely to be involved in regulation of choroidal blood flow to control the environmental temperature for the retina. The present study establishes the existence of efferent vasodilatory nerve fibers of facial nerve origin to the uvea. The peripheral transmitter causing the vasodilation is suggested to be vasoactive intestinal polypeptide (VIP).
Animals↗
Parasympathetic nervous control of intraocular pressure.
Electrical or chemical activation of the oculomotor nucleus (ONC) was performed in pentobarbital anesthetized cats to determine the role of parasympathetic nervous input to the eye in modulating intraocular pressure (IOP). In all animals, the vagosympathetic nerve trunks were sectioned bilaterally at the mid-cervical level. Intracranial stimulation of the ONC produced miosis and a bilateral sustained rise in IOP with little or no cardiovascular response. During stimulation, IOP increased by approximately 35-40%, with an additional small rise seen when the current was turned off. The secondary rise in IOP probably represents the actual pressure level reached which was otherwise masked by intense accommodation due to stimulation. The rise in IOP was not antagonized with gallamine triethiodide. However, both IOP and pupillary responses were blocked by either hexamethonium (1.5 mg kg-1, i.v.) or atropine (0.5 mg kg-1, i.v.). These results provide evidence for a neural parasympathetic mechanism for increasing IOP in cats. In another group, activation of ONC following electrolytic lesion of the preganglionic parasympathetic nerve to one eye, produced a rise in IOP and miosis only on the side with intact oculomotor nerve indicating that the rise in IOP is in part mediated by nerve fibers that travel to the eye along the oculomotor nerve trunk. Microinjection of L-glutamate (2.5 x 10(-7) M) into the ONC produced a bilateral rise in IOP that lasted for more than 15 min. This increase in IOP was greater than 50% of control levels and was accompanied with miosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Denervation effects on the presumed de novo synthesis of muscle cholinesterase and the effects of acetylcholine availability on retinal cholinesterase.
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Acetylcholine↗
Identification of neurotransmitters regulating intestinal peristaltic reflex in humans.
The components of the intestinal peristaltic reflex in humans were examined and the neurotransmitters responsible for them identified for the first time i isolated flat sheet segments of intestine. Increasing radial stretch to the caudad end elicited increasing ascending contraction only, whereas increasing radial stretch to the orad end elicited increasing descending relaxation only. Both components were abolished by hexamethonium, implying the participation of cholinergic interneurons in each component. Atropine inhibited ascending contraction only, abolishing the response to low grades of stretch and partially inhibiting the response to high grades of stretch (69% +/- 17%, p less than 0.01). The substance P antagonist [D-Pro2, D-Trp7,9] substance P partially inhibited ascending contraction induced by high grades of stretch only (40% +/- 12%, p less than 0.02). The vasoactive intestinal peptide antagonist [4-Cl-D-Phe6, Leu17]vasoactive intestinal peptide inhibited descending relaxation, abolishing the response to low grades of stretch and partially inhibiting the response to high grades of stretch (40% +/- 4%, p less than 0.001). Release of vasoactive intestinal peptide increased significantly by 91% during descending relaxation only, whereas release of both substance P and substance K increased significantly by 107% during ascending contraction only, supporting the participation of vasoactive intestinal peptide motor neurons in descending relaxation and tachykinin motor neurons as well as cholinergic motor neurons in ascending contraction. The components of the human peristaltic reflex and transmitters regulating them were identical to those found in rat and guinea pig intestine.
Atropine↗
Mechanism of cholecystokinin-induced contraction of the opossum gallbladder.
The present study evaluated the mechanism of cholecystokinin-induced gallbladder contraction in awake opossums. Each of 19 chronic animal preparations had an indwelling gallbladder cannula for monitoring changes in gallbladder volume and a jugular catheter for administration of cholecystokinin octapeptide and drugs. An intraduodenal catheter allowed intraduodenal infusion of Isocal (Mead Johnson Laboratories, Evansville, Ind.). Bipolar electrodes in the stomach, duodenum, and jejunum enabled monitoring of the duodenal migratory myoelectric complex cycle. One-hour infusions of cholecystokinin octapeptide (10 ng/kg/min), intraduodenal Isocal (0.4 ml/min), or feeding were started 20 min after cessation of phase 3 duodenal migratory myoelectric complex activity. Bolus intravenous doses of potential pharmacological antagonists were given 10 min before and 20 min after the onset of cholecystokinin octapeptide infusion, Isocal infusion, or feeding. Each test challenge induced about 60% gallbladder emptying at 30 min and 70% at 60 min. Cholecystokinin octapeptide-induced gallbladder emptying was converted to filling by hexamethonium and nearly abolished by atropine. Similar results were obtained for gallbladder emptying induced by feeding or duodenal infusion of Isocal. Phentolamine caused a modest decrease of cholecystokinin octapeptide-induced gallbladder contraction at 30 min, whereas postprandial or Isocal-induced gallbladder contraction was unaffected. Cholecystokinin octapeptide-induced gallbladder contraction was not affected by pirenzepine, 4-diphenylacetoxy-N-methylpiperidine methiodide, prazosin, pyrilamine, cimetidine, methysergide, naloxone, or propranolol. In acute studies of anesthetized animals, gallbladder contraction induced by a D100 intravenous bolus of cholecystokinin octapeptide (800 ng/kg) was not antagonized by hexamethonium, atropine, or tetrodotoxin. It is concluded (a) that cholecystokinin-induced physiologic contraction of the opossum gallbladder occurs through neural mechanisms rather than by a direct action of cholecystokinin on gallbladder smooth muscle, and (b) that studies using pharmacologic bolus doses of cholecystokinin octapeptide and tetrodotoxin indicate that cholecystokinin receptors exist on the gallbladder smooth muscle which do not seem to have any physiological role in gallbladder emptying.
Animals↗
Laparotomy-induced gastric protection against ethanol injury is mediated by capsaicin-sensitive sensory neurons.
Laparotomy significantly attenuates ethanol-induced gastric mucosal lesions in the rat. The effects of sensory denervation by capsaicin, indomethacin, atropine, guanethidine, and hexamethonium on laparotomy-induced protection were studied in the rat. Gastric mucosal injury was induced by the intragastric instillation of 1 mL of 75% ethanol. The laparotomy-induced protection against ethanol injury was abolished by sensory denervation by capsaicin (total dose, 125 mg/kg, SC) and also by pretreatment with indomethacin (5 mg/kg, SC). In contrast, pretreatment with atropine (0.5 mg/kg, IP), guanethidine (total dose, 20 mg/kg, SC), or hexamethonium (20 mg/kg, IP) had no significant effect on laparotomy-induced protection. These data indicate that capsaicin-sensitive sensory afferent neurons, but not cholinergic or adrenergic autonomic neurons, mediate laparotomy-induced protection against ethanol injury. The hypothesis is put forward that the protective response to laparotomy arises from a somatovisceral and/or viscerovisceral axon reflex of capsaicin-sensitive afferent neurons. Prostaglandins might play a mediator role in the activation by laparotomy of somatic and/or visceral branches of the afferent neurons.
Animals↗
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↗
Arginine vasopressin inhibits phasic contractions and stimulates giant contractions in monkey colon.
Abdominal cramps and urgent defecation are common side effects of clinical doses of arginine vasopressin, indicating that the drug may have stimulating effects on colonic motor activity. Four strain-gauge transducers were implanted on the colon in six monkeys. A blood flow probe was fixed on the inferior mesenteric artery. After a 1-hour control recording, vasopressin, 0.13, 1.3, or 13.0 ng.kg-1.min-1, was infused intravenously for 90 minutes. The frequency of basal colonic contractions was reduced with increasing doses of vasopressin, but their mean amplitude and duration were not altered. Giant migrating contractions associated with defecation were initiated by the highest dose of vasopressin. Atropine had no effect on these giant migrating contractions but completely inhibited normal phasic contractions. Hexamethonium completely inhibited both giant migrating contractions and phasic contractions. Parasympathetic denervation of the colon did not inhibit giant migrating contractions initiated by vasopressin. Our findings suggest that the physiological concentrations of serum vasopressin present perioperatively may transiently inhibit spontaneous colon contractions but are unlikely to be the major cause of postoperative ileus. The giant migrating contractions initiated by vasopressin may account for the defecation associated with pharmacological doses of vasopressin. The initiation of giant migrating contractions by vasopressin may be mediated through a neural pathway.
Animals↗
Increased total vascular capacity in conscious cirrhotic rats.
The purpose of the present study was to determine the role of the systemic venous circulation in the hemodynamic alterations of the cirrhotic disease. Cardiac output (thermodilution; n = 8), mean circulatory filling pressure (balloon technique; n = 6), and blood volume (Evans blue dye; n = 7) were investigated in a rat model of liver cirrhosis without ascites induced by a 12-week individualized CCl4/phenobarbital treatment. Compared with control rats, conscious cirrhotic rats showed a hyperdynamic circulation characterized by normotension, high cardiac output (51 +/- 4.8 vs. 28.6 +/- 1.3 mL.min-1.100 g-1; P less than 0.01), and expanded blood volume (6.5 +/- 0.15 vs. 5.4 +/- 0.22 mL.100 g-1; P less than 0.05). There were no significant differences between control and cirrhotic rats in mean circulatory filling pressure (6.40 +/- 0.27 vs. 5.99 +/- 0.22 mm Hg, respectively) or in the pressure gradient for venous return (6.17 +/- 0.19 vs. 5.8 +/- 0.21 mm Hg, respectively). To further examine the venous tone, effective vascular compliance was estimated with the vascular filling-blood volume relationship by measuring the vascular filling before and after rapid changes in volume (+/- 8 mL.kg-1). Compliance was similar in both control and cirrhotic rats (3.15 +/- 0.26 and 3.41 +/- 0.21 mL.mm Hg-1), but the vascular filling-total blood volume relationship of the cirrhotic rats was displaced toward the volume axis. In conclusion, the increase in blood volume without changes in mean circulatory filling pressure (or venous tone) of the cirrhotic rats indicates a situation with venodilation and elevated total venous capacity; this is likely to be an important mechanism that could explain the hyperdynamic circulation of the cirrhotic disease.
Animals↗