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Biomedical subjects

H A Coleman

Publications and source records attributed to H A Coleman.

35 records · Page 2Linked to original sources
PubMed1994

Pilocarpine-induced relaxation of rat tail artery by a non-cholinergic mechanism and in the absence of an intact endothelium.

1. The partial muscarinic agonist, pilocarpine, evoked concentration-dependent relaxation with an EC50 of 2.4 x 10(-3) M in isolated segments of rat tail artery that were constricted with phenylephrine (10(-8) to 2 x 10(-7) M). Acetylcholine also evoked concentration-dependent relaxation but was more potent than pilocarpine (EC50, 6.5 x 10(-7) M). 2. The concentration-relaxation curves for pilocarpine were not affected by the muscarinic antagonists, atropine (10(-9) M) or pirenzepine (5 x 10(-7) M), while the concentration-relaxation curves for acetylcholine-evoked relaxation of the same tissues were shifted some 10 fold to the right by these concentrations of atropine and pirenzepine. 3. Acetylcholine failed to evoke relaxation following removal of the endothelium. The smooth muscle of the rat tail artery was some 10 fold more sensitive to the relaxing action of pilocarpine following denudation of the endothelium. 4. The effects of pilocarpine and acetylcholine on membrane potential were studied in tissues that were depolarized to -39 +/- 1 mV with phenylephrine (5 x 10(-8) to 2 x 10(-7) M). In intact tissues, pilocarpine caused hyperpolarization, an effect that persisted in the presence of muscarinic antagonists. Acetylcholine also evoked hyperpolarization. 5. Following removal of the endothelium, pilocarpine (10(-5) to 10(-3) M) evoked hyperpolarization in 6 of 15 preparations and a decrease in the frequency of action potentials in the remainder. Both of these responses were associated with relaxation. 6. The effects of pilocarpine were compared with other agents that evoke endothelium-independent relaxation. The concentration-relaxation curves in response to pilocarpine and nitroprusside were shifted to the right by ferricyanide (10-5 M) and methylene blue (10-5 M). Glibenclamide (10-6 M) was without effect on the hyperpolarization and relaxation evoked by pilocarpine (10' to 10- M).7. Thus, pilocarpine evokes relaxation of rat tail artery independently of the cholinergic system and it is suggested that this is achieved by decreasing the frequency of action potentials in the smooth muscle.

Acetylcholine↗
PubMed1993

Stretch revealed three components in the hyperpolarization of guinea-pig coronary artery in response to acetylcholine.

1. Membrane potential was recorded with intracellular microelectrodes from the smooth muscle of coronary arteries of guinea-pigs, and the responses to endothelium-derived relaxants were studied under a variety of conditions. 2. Stimulation of the endothelium with brief applications of acetylcholine or substance P evoked concentration-dependent hyperpolarizations that were complex in nature. A transient component, which is likely to result from endothelium-derived hyperpolarizing factor (EDHF), was followed by a slow component that resulted from the production of nitric oxide (NO) and a prostaglandin. 3. The ability of exogenous and endogenous NO and prostacyclin to hyperpolarize the membrane depended upon the smooth muscle being under stretch. Unstretched preparations responded to acetylcholine with only the transient component of hyperpolarization; NO and prostacyclin were without effect. 4. In stretched preparations exogenous NO and prostacyclin, and its synthetic analogue methyl prostacyclin (Iloprost), evoked hyperpolarization, and the slow component of the response induced by acetylcholine appeared. The amplitudes of these responses reached maximum when the tissues were stretched to the equivalent of approximately 50 mmHg. 5. From a resting membrane potential of -61 +/- 0.6 mV, exogenous NO and Iloprost hyperpolarized the smooth muscle to around -80 mV. The EC50 values for NO- and Iloprost-induced hyperpolarization were 2.6 x 10(-6) and 1.3 x 10(-8) M, respectively. 6. Coronary arterial smooth muscles from rats, rabbits and sheep also hyperpolarized in response to exogenous NO, although their sensitivities were less than those of preparations obtained from guinea-pigs. Iloprost hyperpolarized tissues from rabbits and sheep but not those obtained from rats. 7. It is concluded that the endothelial lining of coronary arteries can release three factors, EDHF, NO and prostacyclin, all of which can hyperpolarize the membrane of the smooth muscle. The relative proportions and significance of each factor depends on the amount of stretch, on the artery and on the species of animal.

Acetylcholine↗
PubMed1991

Response of the rat myometrium to phenylephrine in early pregnancy and the effects of 6-hydroxydopamine.

1. The contractile responses of the longitudinal and circular muscle layers of the rat uterus to the alpha 1-adrenoceptor agonist phenylephrine were measured on days 3-6 of gestation. There was a progressive increase in sensitivity to phenylephrine in both muscle layers between days 3 and 6 of gestation. Overall, this amounted to a 13 and 9 fold increase in sensitivity in longitudinal and circular muscles, respectively. In longitudinal muscle the slope of the Hill plot was 2 on day 3 of pregnancy and was decreased to 1 thereafter. 2. The sympathetic nerve terminals innervating the smooth muscle of the uterus were destroyed by administration of 6-hydroxydopamine (2 x 50 mg kg-1) 4-7 days before testing with phenylephrine. Following this treatment there was a significant increase in sensitivity to phenylephrine on day 3 in both muscle layers. After day 4, the longitudinal muscle was less sensitive to phenylephrine. 3. In the longitudinal muscle there was a progressive increase in the contractile response to maximal concentrations of phenylephrine and to high potassium (100 mM) between days 3 and 6 of pregnancy. In the circular muscle the responsiveness to both phenylephrine and potassium remained unchanged between days 3 and 6 of gestation. 6-Hydroxydopamine had no effect on the maximal responses to phenylephrine or high potassium in either muscle layer. 4. In conclusion, denervation supersensitivity of uterine smooth muscle following injection of 6-hydroxydopamine is observed only on day 3 of pregnancy and appears to be replaced by subsensitivity by day 6. The decrease in the slope of the Hill plot in longitudinal muscle after day 3 may be explained by changes in events between activation of alpha 1-adrenoceptors and contraction.

Animals↗
PubMed1990

Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium.

Stimulation of the endothelial lining of arteries with acetylcholine results in the release of a diffusible substance that relaxes and hyperpolarizes the underlying smooth muscle. Nitric oxide (NO) has been a candidate for this substance, termed endothelium-derived relaxing factor. But there are several observations that argue against the involvement of NO in acetylcholine-induced hyperpolarization. First, exogenous NO has no effect on the membrane potential of canine mesenteric arteries. Second, although haemoglobin (believed to bind and inactivate NO (refs 11-15)) and methylene blue (which prevents the stimulation of guanylate cyclase) inhibit relaxation, neither has an effect on hyperpolarization. Finally, nitroprusside, thought to generate NO in vascular smooth muscle, relaxes rat aorta without increasing rubidium efflux. Nevertheless, nitrovasodilators, nitroprusside and nitroglycerin cause hyperpolarization in some arteries. NO might therefore be responsible for at least part of the hyperpolarization induced by acetylcholine. We now report that hyperpolarization and relaxation evoked by acetylcholine are reduced by NG-monomethyl-L-arginine, an inhibitor of NO biosynthesis from L-arginine. Thus NO derived from the endothelium can cause hyperpolarization of vascular smooth muscle, which might also contribute to relaxation by closing voltage-dependent calcium channels. Our findings raise the possibility that hyperpolarization might be a component of NO signal transduction in neurons or inflammatory cells.

Acetylcholine↗
PubMed1990

Melatonin production by the guinea pig pineal gland in vitro.

The fluid bathing pineal glands isolated from guinea pigs was collected serially and its melatonin content was estimated. Production was found to be high (500 pg/5 min) soon after isolation of the gland: it declined exponentially to a maintained lower level (50 pg/5 min) with a half-time of 16-20 min. A rapid increase could be produced by exposure of the gland to the beta-adrenoceptor agonist orciprenaline or by stimulating it electrically. The time course and the extent of the responses to either form of stimulation were similar in glands that had been taken in the morning, at dusk or in mid-dark: the prestimulation peak was lower from glands taken at dusk. Thus the pineal gland of the guinea pig is capable of responding rapidly to stimulation of its beta-adrenoceptors at any time. These responses parallel the depolarization observed intracellularly in this species when the pineal gland is stimulated electrically or exposed to beta-adrenoceptor agonists.

Animals↗
PubMed1989

Passively propagated spikes from the soma of cells in pineal gland of guinea pigs.

The membrane properties of cells within the pineal gland of guinea pigs were studied using intracellular electrophysiological techniques. The electrotonic responses to intracellular current injection decayed with a single exponential in approximately 60% of cells but was preceded by a quicker component in the remainder. The membrane time constant was 2.8 ms. Depolarization beyond -29 mV activated an outward current that reversed at around the value of the resting potential. Hyperpolarization activated a slow inward current. Spikes occurred in response to activation of alpha-adrenoceptors. They were resistant to tetrodotoxin but were abolished by nifedipine and verapamil, suggesting that calcium carries the current during their upstroke. Spikes could not be evoked by depolarizing current pulses of 1-ms to 2-s duration. The responses to hyperpolarizing current steps or voltage-clamp steps applied during the peak of spikes evoked by nerve stimulation were indistinguishable from the responses to those applied between spikes. During nerve stimulation, fluctuations were observed in the current trace of cells under voltage clamp, indicating that the spikes could not be voltage clamped successfully. It is concluded that the spikes occurring in response to nerve stimulation are generated on the processes of the pinealocytes and are passive in the soma.

Animals↗
PubMed1988

Ionic mechanisms underlying action potentials in myometrium.

1. The ionic mechanisms underlying the simple spike action potential in longitudinal myometrium of pregnant rats and the complex action potential which occurs in the same layer of pregnant guinea-pigs are discussed. 2. The current during the upstroke of the simple spike is carried by calcium and repolarization results from inactivation of the calcium current and activation of a potassium current. 3. A slow inward current underlies the plateau component of the complex action potential and calcium is involved in carrying or regulating this current. 4. Single channel recordings from the longitudinal myometrium of pregnant guinea-pigs reveal large conductance (130-170 pS) potassium channels which are activated by depolarization of the membrane. The activation of these channels during the upstroke of the spike would contribute to the rapid termination of the spike. 5. The duration of the plateau component of the complex action potential closely correlates with the duration of contraction and it is suggested that sufficient calcium may enter the cell during the action potential to activate the contractile apparatus directly.

Action Potentials↗
PubMed1988

Gestational changes in the utilization of intracellularly stored calcium in the myometrium of guinea-pigs.

1. The ability of oxytocin and prostaglandin F2 alpha (PGF) to induce contraction in guinea-pig myometrium in calcium-free solution was studied in an attempt to assess the extent to which intracellular calcium stores could be released by these two agonists. Both longitudinal and circular muscle layers were studied separately and the effects of gestational age were also examined. 2. In longitudinal strips, the responses to oxytocin and PGF in the absence of external calcium decreased progressively throughout gestation. Responses of circular strips to both agonists were unchanged throughout pregnancy, until day 64, when no response to PGF could be elicited. 3. Pre-treatment with high potassium (and normal calcium) increased the responses to the agonists in calcium-free medium while pre-treatment with beta-adrenoceptor agonists had no effect on responses to oxytocin or PGF. 4. Responses to both agonists decreased with time in calcium-free solution suggesting a loss of calcium from stores with a half-time of 3 min. The rate of the decline in the responses was the same in both muscle layers and did not change with gestational age. 5. In the presence of lanthanum contractions evoked by oxytocin, but not PGF, were augmented 2-3-fold. This potentiation of the response to oxytocin occurred in both muscle layers and throughout gestation. 6. Each agonist evoked only one response in calcium-free solution containing EGTA. The response to PGF in longitudinal strips following a challenge with oxytocin was reduced, compared with the response to PGF when applied first while the response to oxytocin in these strips was unchanged following exposure to PGF. In circular strips neither oxytocin- nor PGF-induced contractions were altered following prior exposure to the other agonist. 7. It is concluded that oxytocin and PGF operate via two distinct mechanisms to release intracellularly stored calcium in both longitudinal and circular components of the guinea-pig myometrium and a hypothesis to explain the results is presented.

Animals↗
PubMed1988

Induction of prolonged excitability in myometrium of pregnant guinea-pigs by prostaglandin F2 alpha.

1. Electrical and mechanical responses to prostaglandin F2 alpha (PGF) were studied in circular myometrium, with or without endometrium, during the first 3 weeks of gestation of the guinea-pig. 2. Muscle strips from which endometrium had been removed became inexcitable within 30-40 min of isolation from the animal such that action potentials and contraction could not be initiated by depolarizing current steps. Raising the concentration of potassium in the perfusing solution resulted in a small contraction. 3. In these preparations PGF induced complex action potentials that consisted of spikes and a prolonged plateau of depolarization. Each action potential was associated with a large phasic contraction. 4. Contractions induced by PGF are unlikely to result predominantly from release of calcium from intracellular stores since the ability of the agonist to evoke a response was reduced by some 97% in the absence of external calcium or in the presence of calcium channel blockers. 5. When preceded by a brief exposure to PGF, the contractile response to high potassium was enhanced to equal that in response to PGF. Enhancement persisted for approximately 30 min after removal of PGF and was not dependent upon the presence of external calcium. 6. Muscle strips with intact endometrium contracted spontaneously for hours. Each contraction was associated with a complex action potential, both of which were abolished by indomethacin. 7. It is concluded that PGF transforms inexcitable calcium channels in the membrane of the smooth muscle cells of the circular myometrium into excitable ones. The study also suggests that endogenous prostaglandin of endometrial origin may prevent the 'run-down' of channels in vivo.

Action Potentials↗
PubMed1987

Single channel Cl- and K+ currents from cells of uterus not treated with enzymes.

Single channel currents were recorded from uterine smooth muscle cells of pregnant guinea-pigs. The cells were within small bundles of smooth muscle of low input resistance. Giga-ohm seals were formed between the patch clamp electrodes and the membrane of smooth muscle cells that had not been treated with enzymes. In cell-attached mode, outward current steps were observed that had a conductance of 130-170 pS, a reversal potential close to the potassium reversal potential, and the probability of a channel being in the open state increased e-fold per 8-11 mV depolarization. In the cell-free, inside-out patch mode, currents were recorded that had a large conductance, 420 pS, and smaller conductance levels. When the chloride concentration was changed the reversal potential shifted in a manner consistent with the Nernst equation indicating that the channels were permeable to chloride ions.

Action Potentials↗
PubMed1987

Multiple sites for the initiation of action potentials in neurons of the inferior mesenteric ganglion of the guinea-pig.

Responses to nerve stimulation were recorded with intracellular microelectrodes from neurons in the inferior mesenteric ganglion of the guinea-pig. An event was recorded which was subthreshold for a somatic action potential but which had a short rise time and a rapid initial repolarization that gave the event a small but well-defined peak. This event was termed a "partial spike." During repeated stimulation of the same nerve trunk, the fluctuations in the amplitude of the partial spike were small compared to those of evoked synaptic potentials. Stimulation of different nerve trunks evoked partial spikes of different amplitudes. When different nerve trunks were stimulated at short intervals between stimuli, one partial spike could occlude another partial spike. Antidromic responses could not be blocked by a preceding partial spike. This suggests that partial spikes are not initial segment spikes. Tubocurarine reversibly abolished partial spikes which is indicative of a synaptic origin. It is concluded that partial spikes result from action potentials initiated by synaptic potentials in the dendrites and which fail to generate somatic action potentials.

Action Potentials↗
PubMed1987

Two types of cells with central innervation in pineal gland of guinea pigs.

Cells within pineal glands isolated from young, male guinea pigs were impaled with intracellular microelectrodes and their responses to stimulate the nerve supply to the gland were studied. Two types of cells were identified. The response of cells of type I was a depolarization on which spikes were superimposed. Blockers of alpha-adrenoceptors abolished the spikes while beta-adrenoceptor blockers reduced the depolarization to 27%, leaving a small tetrodotoxin-sensitive depolarization. After bilateral removal of the superior cervical ganglia (SCG) the beta-mediated depolarization was not observed while the spikes and the smaller depolarization persisted. The response of cells of type II was an initial large, transient depolarization followed by a smaller depolarization. Both components were reversibly blocked by tetrodotoxin. The only agents found to have any effect on these cells were oxytocin, vasopressin, and vasotocin. These peptides caused depolarization similar in amplitude to the larger response to nerve stimulation, although more prolonged. The large depolarization was not observed following ganglionectomy, but the smaller one persisted. It is concluded that cells of type I and II both receive inputs from nerves whose cell bodies lie in the SCG. Cells of both types are also innervated through another pathway.

Action Potentials↗
PubMedDate not supplied

Pregnancy-induced decrease in evoked excitatory junction potentials in guinea pig uterine artery.

The effects of stimulating the intramural nerves on the membrane potential and tension in the uterine artery of virgin guinea pigs were compared with the responses during pregnancy. In all tissues the amplitude of the excitatory junction potential (EJP) increased as the stimulus voltage was increased. The rate of increase in EJP amplitude in tissues from virgin animals greatly exceeded that recorded in late pregnant tissues. EJPs were abolished by tetrodotoxin but were resistant to blockade by alpha-adrenoceptor antagonists. Stimulation of the nerves also evoked a slow depolarization and contraction which were abolished by both tetrodotoxin and alpha-adrenoceptor antagonists. The amplitudes of the depolarizations and contractions were not correlated. The role of EJPs and alpha-adrenoceptor activation in the control of vascular function is discussed. Fluorescence histochemistry revealed a decrease in the density of the catecholamine innervation that was correlated with a decrease in catecholamine content as pregnancy progressed. In addition, there appeared to be a difference in the arrangement of the fluorescent varicosities, with a shift from varicosities that were close to the outer layer of smooth muscle in virgin tissues to those that were more distantly dispersed in the adventitia during late pregnancy. The changes would be expected to reduce the effectiveness of vasoconstrictor drive to the uterine artery as pregnancy progresses.

Adrenergic alpha-Agonists↗