Combination Of Hexamethonium Research Articles

The pressor effect of angiotensin-(1-7) in the rat rostral ventrolateral medulla involves multiple peripheral mechanisms

OBJECTIVE:In the present study, the peripheral mechanism that mediates the pressor effect of angiotensin-(1-7) in the rostral ventrolateral medulla was investigated.METHOD:Angiotensin-(1-7) (25 pmol) was bilaterally microinjected in the rostral ventrolateral medulla near the ventral surface in urethane-anesthetized male Wistar rats that were untreated or treated (intravenously) with effective doses of selective autonomic receptor antagonists (atenolol, prazosin, methyl-atropine, and hexamethonium) or a vasopressin V1 receptor antagonist [d(CH2)5 -Tyr(Me)–AVP] given alone or in combination.RESULTS:Unexpectedly, the pressor response produced by angiotensin-(1-7) (16±2 mmHg, n = 12), which was not associated with significant changes in heart rate, was not significantly altered by peripheral treatment with prazosin, the vasopressin V1 receptor antagonist, hexamethonium or methyl-atropine. Similar results were obtained in experiments that tested the association of prazosin and atenolol; methyl-atropine and the vasopressin V1 antagonist or methyl-atropine and prazosin. Peripheral treatment with the combination of prazosin, atenolol and the vasopressin V1 antagonist abolished the pressor effect of glutamate; however, this treatment produced only a small decrease in the pressor effect of angiotensin-(1-7) at the rostral ventrolateral medulla. The combination of hexamethonium with the vasopressin V1 receptor antagonist or the combination of prazosin, atenolol, the vasopressin V1 receptor antagonist and methyl-atropine was effective in blocking the effect of angiotensin-(1-7) at the rostral ventrolateral medulla.CONCLUSION:These results indicate that angiotensin-(1-7) triggers a complex pressor response at the rostral ventrolateral medulla that involves an increase in sympathetic tonus, release of vasopressin and possibly the inhibition of a vasodilatory mechanism.

Dual effects of lipophilic extract of Salvia miltiorrhiza (Danshen) on catecholamine secretion in cultured bovine adrenal medullary cells

Ethnopharmacological relevance Salvia miltiorrhiza (Danshen) is a well known traditional Chinese herb, which has been used widely in China for the treatment of cardiovascular diseases in clinic. Aim of this study The aim of the present study is to clarify the effects of lipophilic extract of Salvia miltiorrhiza (LESM) on catecholamine (CA) secretion, a traditional Chinese medicine used widely for the treatment of cardiovascular diseases in China. Materials and methods LESM was evaluated for its effects on CA secretion using HPLC-ECD method. The effects of LESM on 22Na + influx and intracellular calcium ([Ca 2+] i) were also investigated. Results Our results showed that LEMS directly stimulated basal CA secretion in an extracellular Ca 2+-dependent manner. And the stimulation was not affected by combination of hexamethonium (Hex), an inhibitor of nAChR. LESM also directly elevated [Ca 2+] i. In addition, using selective blockers of voltage-dependent Ca 2+ channels, such as nitrendipine (for L-type), ω-agatoxin-IVA (for P-type) and ω-conotoxin-GVIA (for N-type), it was found that nitrendipine suppressed the elevation of [Ca 2+] i induced by LESM, but not ω-agatoxin-IVA or ω-conotoxin-GVIA. Compared with acetylcholine (ACh) only, however, combination of LESM with ACh inhibited the raise of CA secretion, 22Na + influx and [Ca 2+] i in a concentration-dependent manner. Furthermore, LESM also inhibited CA secretion induced by veratridine (Ver), and 56 mM K + at concentrations similar to those for [Ca 2+] i rise. One of the lipophilic active compounds, cryptotanshione (Cryp), also had the same effects on CA secretion with LESM. Conclusions All these findings suggest that LESM exerts dual effects on CA secretion in cultured bovine adrenal medullary cells. LESM exerts antagonistic effects on nAChR, voltage-dependent Na + and Ca 2+ channels, whereas it is an agonist of L-type Ca 2+ channel when it used alone.

Short-Chain Fatty Acids Decrease the Frequency of Spontaneous Contractions of Longitudinal Muscle via Enteric Nerves in Rat Distal Colon

Short-chain fatty acids (SCFAs) produced by the bacterial fermentation of carbohydrates in the cecum and proximal colon are reported to modify colonic motility as a luminal factor. Besides the physical stimuli in the distal colon, SCFAs in the intestinal lumen also seem to affect colonic motility under physiological concentrations. This study therefore used fasted rats to investigate the effect of SCFAs on the spontaneous contractions of longitudinal muscle (LM) in rat distal colon, including mucosa in vitro. The frequency of spontaneous contractions of LM strips from the distal colon was 9.4 +/- 0.5 contractions/20 min. The exogenous addition of >5 mM SCFAs decreased the frequency of spontaneous contractions of the LM to 6.1 +/- 0.8 contractions/20 min. Among SCFAs, only acetate elicited this inhibitory response. TTX and the combination of hexamethonium and granisetron abolished SCFA-induced inhibitory response, suggesting that this inhibitory response is mediated via the ENS, including nicotinic and 5-HT(3) receptors. In conclusion, it is suggested that SCFAs in rat distal colon decrease the frequency of spontaneous contractions of the LM and that SCFAs may contribute to colonic motility, including the peristaltic reflex, by regulating the frequency of spontaneous contractions of the LM through the enteric nervous system (ENS).

Blockade of reflex venous capacitance responses in liver and spleen by hexamethonium, atropine, and surgical section

Since hexamethonium and surgical section have been used to prevent reflex splanchnic capacitance responses, we examined the effectiveness of these procedures in blocking responses to direct stimulation of preganglionic fibres in the splanchnic nerves. Liver blood volume was measured by plethysmography and splenic blood volume by weighing in cats anesthetized by pentobarbital. The cats were adrenalectomized to prevent adrenal catecholamine secretion in response to splanchnic nerve stimulation. Hexamethonium (10 and 20 mg/kg) alone or atropine (1 mg/kg) alone caused only a small variable block of the responses to preganglionic nerve stimulation. A combination of the two drugs essentially produced a complete block of the liver capacitance response, but a significant response still persisted in the spleen. Surgical section of the postganglionic nerve bundles around the hepatic and splenic arteries completely abolished the responses to preganglionic stimulation. It is concluded that a relatively complete block of reflex splanchnic capacitance responses requires either a combination of hexamethonium and atropine or surgical section of the postganglionic nerves.

Effect of α,β‐methylene ATP on distal colonic and rectal motility‐a possible involvement of P2‐purinoceptors in pelvic nerve mediated non‐adrenergic, non‐cholinergic contraction

The possible involvement of purinoceptors in the parasympathetic nervous control of large intestinal motility was investigated in cats anaesthetized with chloralose and treated with adrenolytics. Distal colonic and rectal motor responses to efferent pelvic nerve stimulation (PNS) and drugs injected close i.a., were recorded by a volumetric method. Single dose i.a. injections of alpha, beta-methylene ATP (mATP) induced colonic and rectal contractions which were resistant to atropine, hexamethonium and indomethacin, as well as to the nerve blocking agent tetrodotoxin. Repeated injections of mATP were followed by attenuated motor responses and eventually complete tachyphylaxis to the compound developed. In the presence of atropine, or a combination of hexamethonium and atropine, contractions elicited by PNS were inhibited during mATP tachyphylaxis. In contrast, prior to such anticholinergic drugs, or in the presence of hexamethonium alone, pelvic nerve mediated contractions persisted despite mATP tachyphylaxis, which did not affect the colonic and rectal contractions evoked by acetylcholine or histamine. The results suggest that P2-purinoceptors are involved in non-adrenergic, non-cholinergic large intestinal excitatory motor responses to PNS.

Potentiation of the inhibitory effect of a thromboxane A 2 antagonist (L-640,035) on arterial thrombosis formation in rabbit by the angiotensin converting enzyme inhibitor enalapril

The angiotensin converting enzyme inhibitor enalapril (0.5 mg/kg i.v.) potentiated significantly the inhibitor effect of the thromboxane A 2 antagonist L-640,035 (1 mg/kg i.v.) on electrically induced platelet accumulation in the rabbit in vivo. Enalapril had no effect upon platelet accumulation when given alone. The hypotensive effects of enalapril did not account for the potentiation because a combination of hexamethonium (5 mg/kg i.v.) and hydralazine (1 mg/kg i.v.), which decreased blood pressure similarly to enalapril, did not augment the effect of L-640,035. Determination by radioimmunoassay of plasma levels of immunoreactive 6-keto-PGF 1α, suggested that increases in PGI 2 levels after combined administration of enalapril and L-640,035 could explain the observed potentiation.

The mechanism of motilin excitation of the canine small intestine

Close intraarterial injections of motilin to the small intestine of the anaesthetized dog produce prolonged phasic contractions. Tetrodotoxin infused intraarterially blocked field stimulated contractions and abolished the response to motilin as did treatment with a combination of hexamethonium and atropine. Atropine alone increased the dose of motilin required to induce responses. Hexamethonium alone similarly increased the dose of motilin required in the jejunum, but not for the ileum. These results suggest that motilin acts to contract small intestine by stimulation of intrinsic excitatory nerves, some of which are post-ganglionic cholinergic and some of which are not, but are activated by a pathway with a nicotinic synapse. The ED 50 for ileal contractions was greater than that for the jejunum and the time to reach maximum contractions longer suggesting a decreased responsiveness of the lower small intestine to motilin as compared to the upper gastro-intestinal tract. These results and the lesser quantity of immunoreactive motilin in the ileum than in the jejunum may explain the lack of relationship of the activity front of the migrating motor complex in the lower small intestine to venous motilin concentrations.

Neural control of the lower esophageal sphincter in the cat: Studies on the excitatory pathways to the lower esophageal sphincter

Lower esophageal sphincter pressures were measured with a 6-lumen catheter anchored at the high pressure point by a metallic pin. Electrical stimulation (5–40 Hz) of both central ends of the cervical vagus caused contraction of the lower esophageal sphincter, which was antagonized by section of the spinal cord above the brachial plexus, by tetrodotoxin, by a combination of hexamethonium and atropine, by phentolamine, and by catecholamine depletion with reserpine. Stimulation (5–40 Hz) of peripheral or central ends of the left splanchnic nerves also caused contraction of the lower esophageal sphincter. This sphincter response was antagonized by tetradotoxin, a combination of hexamethonium and atropine, phentolamine, and catecholamine depletion with reserpine. It was not affected by atropine alone or by propranolol. Lower esophageal sphincter relaxation was not observed even after the contraction was blocked with pharmacologic antagonists. Stimulation (5–40 Hz) of the peripheral end of the periarterial nerves of the left gastric artery also caused contraction of the sphincter and was antagonized only by tetrodotoxin and phentolamine. Atropine and hexamethonium did not affect this sphincter response. Extrinsic denervation of the lower esophageal sphincter by sectioning of the cervical vagus nerves, the spinal cord, the left splanchnic nerves, or the left gastric artery did not affect basal sphincter pressures. Basal sphincter pressure was not affected by atropine alone, by a combination of hexamethonium and atropine, or by propranolol. There was, however, a 25%–28% reduction with tetrodotoxin and phentolamine. These findings suggest the existence of an excitatory reflex arc with an afferent vagal and efferent sympathetic pathway. It consists of preganglionic cholinergic fibers and postganglionic adrenergic neurons synapsing with α-receptors at the muscle fiber. These adrenergic neurons may contribute to the genesis of basal lower esophageal sphincter tone, or to its regulation in balance with tonic neural inhibitory influences.

Effect of cholecystokinin and the octapeptide of cholecystokinin on the feline sphincter of Oddi and gallbladder. Mechanisms of action.

We studied the effect of cholecystokinin (CCK) and the octapeptide of cholecystokinin (OP-CCK) on the feline gallbladder and sphinecter of Oddi. Both CCK caused a dose-dependent gallbladder contraction and sphincter of Oddi relaxation. The half-maximal responses of the sphincter of Oddi were 6 ng/kg for OP-CCK and 0.15 Ivy-dog U/kg for CCK, which were lower than those of the gallbladder with 28 ng/kg and 0.32 Ivy-dog U/kg, respectively. The effect of OP-CCK on the gallbladder was partially blocked by tetrodotoxin (P < 0.02), hexamethonium alone (P < 0.05), or a combination of hexamethonium and atropine (P < 0.01). The gallbladder response to CCK was not blocked by either atropine alone (P < 0.60) or adrenergic antagonists (P > 0.40). The sphincter of Oddi response to OP-CCK was blocked by tetrodotoxin (P < 0.001) but it was not blocked by cholinergic (P < 0.20) or adrenergic antagonists (P < 0.60). After complete denervation with tetrodotoxin, OP-CCK caused sphincter of Oddi contraction. These findings indicate that there are two excitatory receptors for CCK in the gallbladder, one at the cholinergic neurons and the other at the level of the gallbladder muscle. There are also two receptors for CCK in the sphincter of Oddi, one that is inhibitory, and present at the noncholinergic, nonadrenergic neurons, and the other, excitatory, at the circular muscle.

Effect of Glucagon Secretin, and Vasoactive Intestinal Polypeptide on the Feline Lower Esophageal Sphincter: Mechanism's of Action

We studied the effect of glucagon, secretin, and VIP on the feline LES as well as their mechanisms of action by pharmacologic analysis. Secretin and VIP caused relaxation, whereas glucagon caused LES contraction with all doses studied (1–80 μg/kg). The LES contraction in response to maximal doses of glucagon was two-thirds of the contraction after pentagastrin. Secretin was a weak LES inhibitor decreasing basal pressures by 25% and with relaxation only occurring after 4 and 8 clinical units/kg. In contrast, VIP was a potent inhibitor of LES pressures and its maximal dose (1 μg/kg) abolished basal pressures completely. The inhibitory action of secretin and VIP could not be antagonized by adrenergic (phentolamine and propranolol), or cholinergic (atropine and hexamethonium) antagonists or after complete LES denervation with tetrodotoxin. In contrast, the effect of glucagon was antagonized by a combination of hexamethonium and atropine, by phentolamine, by catecholamine depletion with reserpine, by TTX, or by surgical bilateral adrenalectomy. The dose of phentolamine needed to block the effect of a maximal dose of glucagon was onehalf of that required to antagonize the effect of a maximal dose of an alpha-adrenergic agonist (phenylephrine). These findings suggest that glucagon acts at the preganglionic level of the sympathetic pathway within the adrenal glands and its action appears to be mediated by humoral factors. Secretin and VIP appear to inhibit the LES circular muscle by direct action.

Evidence of 5-HT participation in vagal inhibitory pathway to opossum LES.

Studies were performed in anesthetized opossums to investigate the nature of vagal-stimulated sphincter relaxation, which is resistant to antagonism by a combination of hexamethonium and atropine. The sphincter pressures were measured with water-filled and continuously perfused catheters anchored in the lower esophageal sphincter. Neither increase in the doses of hexamethonium and atropine nor addition of diphenhydramine further modified the vagal response. However, administration of 5-methoxydimethyltryptamine in the presence of hexamethonium and atropine abolished vagally stimulated sphincter relaxation. In animals pretreated with parachlorophenylalanine, addition of atropine and hexamethonium also abolished vagally stimulated sphincter relaxation. In the experiments in which lower esophageal sphincter relaxation on vagal stimulation was abolished, the local stimulation of intramural neurons still produced normal lower esophageal sphincter relaxation. These studies suggest that 5-hydroxytryptamine may participate in the vagal inhibitory pathway to the lower esophageal sphincter.

Nature of the vagal inhibitory innervation to the lower esophageal sphincter.

The purpose of the present study was to investigate the nature of the vagal inhibitory innervation to the lower esophageal sphincter in the anesthetized opossum. Sphincter relaxation with electrical stimulation of the vagus was not antagonized by atropine, propranolol, phentolamine, or by catechloamine depletion with reserpine. A combination of atropine and propranolol was also ineffective, suggesting that the vagal inhibitory influences may be mediated by the noncholinergic, nonadrenergic neurons. To determine whether a synaptic link with nicotinic transmission was present, we investigated the effect of hexamethonium on vagal-stimulated lower esophageal sphincter relaxation. Hexamethonium in doses that completely antagonized the sphincter relaxation in response to a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), did not block the sphincter relaxation in response to vagal stimulation at 10 pulses per second, and optimal frequency of stimulation. A combination of hexamethonium and catecholamine depletion was also ineffective, but hexamethonium plus atropine markedly antagonized sphincter relaxation (P less than 0.001). Moreover, 4-(m-chlorophenyl carbamoyloxy)-2-butyltrimethylammonium chloride (McN-A-343), a muscarinic ganglionic stimulant, also caused relaxation of the lower esophageal sphincter. We suggest from these results that: (a) pthe vagal inhibitory pathway to the sphincter consists of preganglionic fibers which synapse with postganglionic neurons: (b) the synaptic transmission is predominantly cholinergic and utilizes nicotinic as well as muscarinic receptors on the postganglionic neuron, and; (c) postganglionic neurons exert their influence on the sphincter by an unidentified inhibitory transmitter that is neither adrenergic nor cholinergic.

Sympathetic ganglionic transmission and the cardiovascular changes of the defense reaction in the cat.

The effects of ganglionic blockade on the circulatory components of the defense reaction were studied in 25 anesthetized cats. Hexamethonium alone partially blocked the response; a combination of hexamethonium and atropine was necessary to block it completely. Vasodilation of skeletal muscle was reversed to vasoconstriction during hexamethonium infusion. Direct recording from pre- and postganglionic sympathetic nerves showed persisting ganglionic transmission during hexamethonium infusion that was subsequently blocked by atropine. Unit recordings showed that some ganglion cells were completely blocked by hexamethonium alone. Preganglionic discharge was unaffected. It is suggested that ganglion cells giving rise to cholinergic vasodilator fibers have fewer atropine-sensitive receptor sites than do cells from which adrenergic constrictor fibers arise.

Relationship Between Adrenergic Activity and Cardiac Actions of Quinidine

Unanesthetized dogs with complete heart block were used to explore the relationship between adrenergic activity and quinidine action on the heart. After vagolysis, quinidine still increased both the atrial and ventricular rates. Following reduction in adrenergic activity by reserpine, hexamethonium, or surgical sympathectomy, the atrial and ventricular pacemakers were depressed. After sympathetic activity had been reduced by a combination of hexamethonium and reserpine, quinidine caused profound pacemaker depression and sometimes ventricular asystole. Quinidine produced coupling and occasionally runs of ventricular tachycardia independent of the level of sympathetic activity. There was no significant prolongation of the QRS time by quinidine in doses of 5 and 10 mg./Kg. Both the development of ectopic pacemakers and the depression of pacemaker activity of quinidine were dose dependent.

Cardiovascular and renal responses to the combination of hexamethonium and 1-hydrazinophthalazine in hypertensive subjects

Cardiovascular and renal responses to the combination of hexamethonium and 1-hydrazinophthalazine in hypertensive subjects