The Contractility of the Portal Vein: Role of Oxygen and Calcium

Fasehun, Olufunmilayo Abosede (1987) The Contractility of the Portal Vein: Role of Oxygen and Calcium. PhD thesis, University of Glasgow.

Abstract

The effects of PO2 and [Ca2+]o in the isolated rat portal vein have been investigated. 1. PO2 tensions from a supraphysiological level (95%O2) to normoxic levels (16%O2) did not affect the spontaneous phasic contractile activity of the portal vein. In fact, levels down to 50mm Hg (8%O2) did not statistically significantly affect it. On the other hand, drug induced contraction to NA, amidephrine and phenylephrine was sensitive to O2 over this range. Responses induced by these drugs changed from being monophasic in supraphysiological O2 to biphasic in normoxia. In general, drugs that induced an increase in the spontaneous activity without a concomitant increase in baseline tension were less sensitive to O2 change from 95%O2 to 16%O2. Examples of such drugs were UK14304, xylazine and (+) m-synephrine, while clonidine was the only exception to this rule, being sensitive to O2 changes. 2. The tonic component of the biphasic response to NA at normoxia became progressively smaller as PO2 was lowered from 32%O2, while the phasic component was quite resistant to PO2 changes. Consequently the phasic component became more prominent as O2 was lowered. However, the nature of this biphasic response at normoxia O2 in this tissue is different from that obtained in the aorta which is considered to involve the release of intracellular Ca2+. (i). The biphasic contraction is rapidly lost in nominally "Ca2+-free" saline, (ii). The Ca2+ threshold of the phasic component is at 1. 25mM. (iii). The phasic response was also susceptible to blockade by the Ca2+ chelators EGTA + NTA, and the Ca2+ antagonist nifedipine and to facilitation by Bay K 8644. All these results suggest that both components require influx of extracelullar Ca2+. 3. Assessment of the facilitating effect of Bay K 8644 (InM - 0.3muM) at the [Ca2+] (2.5mM) normally employed in pharmacological experiments and over a wide range of PO2 (95%O2 - 4%O2) showed that while spontaneous activity was increased in a concentration related manner, there was little effect on responses to NA or KCl. On the other hand Bay K 8644 could facilitate responses to these activators at low [Ca 2+]. Under such conditions the preparation provided a highly sensitive assay for drugs which facilitate Ca 2+ channel opening such as Bay K 8644 and CGP 28392. 4. Assay of Bay K at different O2 tensions indicated similar potency versus responses induced by NA and KCl suggesting that both might be acting via voltage-operated channels (VOCs). 5. At hypoxia, NA-induced responses were depressed. On the other hand KCl-induced responses were resistant and in some cases were bigger than they were in normoxia. Investigation into the hypoxia- resistant KCl-induced responses showed that they were relatively resistant to Bay K 8644 and CGP 283 92 when compared to those in normoxia. This could mean that these hypoxia resistant KCl -induced responses may have already been facilitated as a result of endogenous accumulation of some metabolites such as long chain acyl carnitines, which is known to occur in hypoxia/ ischaemia. Palmitoyl carnitine, an acyl carnitine, has been shown to activate Ca2+ channels directly (Spedding & Mir, 1987). In the present study it has been shown that the effects of palmitoyl carnitine, mimic those of Bay K and CGP in, both normoxic and hypoxic conditions. The resistance to Ca2+ facilitators occurs because there is less scope for further facilitation by these Ca2+ facilitators since the channels are fully facilitated in hypoxia. 6. KCl-induced response was more susceptible to POCA, a carnitine acyl transferase in hypoxia than in normoxia suggesting that POCA can block the accumulation of acyl carnitines in hypoxia, thereby reducing their facilitating effects. The relative resistance of KCl response to POCA in normoxia suggest that acyl carnitines do not accumulate in normoxic conditions. 7. The hypoxia-resistant response was also relatively resistant to nifedipine. Such a situation could be predicted since palmitoyl carnitine acts at the dihydropryridine sites to oppose the effects of nifedipine (Spedding & Mir, 1987) and my experiments add evidence for this, showing that it may occur with endogenous PC under hypoxic conditions. 8. Despite several experimental manipulations, hypoxic vasodilatation was not reversed by Ca2+ facilitators Bay K and CGP, supporting the hypothesis that these compounds may be relatively ineffective in hypoxic conditions. 9. The implications of the relative ineffectiveness of the dihydropyridine compounds in patho-physiological conditions of hypoxia/ischaemia are (i) these compounds would be ineffective in alleviating ischaemic conditions, (ii) they cannot be employed in the treatment of hypoxic vasodilatation.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Physiology
• Date of Award: 1987
• Depositing User: Enlighten Team
• Unique ID: glathesis:1987-77564
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Jan 2020 11:53
• Last Modified: 14 Jan 2020 11:53
• URI: https://theses.gla.ac.uk/id/eprint/77564