Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a broad-spectrum antiviral agent whose molecular mode of action remains remarkably controversial. This antiviral agent was approved by the U.S. Food and Drug Administration in 1986 for use as an aerosol for infants with serious infections due to respiratory syncytial virus. Ribavirin is and has been under clinical investigation for activity against a variety of viral illnesses, including those due to influenza virus, Lassa fever virus, Hantaan virus, and human immunodeficiency virus (HIV). There has been a great deal of clinical interest in the utilization of ribavirin for treatment of infections due to HIV. It has been reported to slow the development of AIDS in HIV-infected patients. We describe here the major mechanisms of action of this newly licensed antiviral agent.

Bunyaviridae↗

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Mechanisms of action of CO 2 on pial precapillary vessels.

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Acidosis↗

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Detailed description of a cranial window technique for acute and chronic experiments.

Methods for implatation of cranial windows for the direct observations of the pial microcirculation in experimental animals are described in detail. These techniques are suitable for both acute experiments in anesthetized animals and chronic implantation permitting several months of observation in awake animals. Experience over several years shows that these techniques have an acceptably low rate of failure, are low in cost and can easily be mastered in most laboratories. They make possible observation of the microcirculation and accurate measurement of the diameter of pial vessels, and permit study of the effects on the microcirculation of a variety of maneuvers and vasoactive agents which can be studied by direct application as well as by intravascular administration. Because they preserve the intergrity of the skull, the techniques permit study of the cerebral microcirculation under conditions closely approximating the normal environment of these vessels.

Animals↗

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Determinants of response of pial arteries to norepinephrine and sympathetic nerve stimulation.

Feline pial arteries larger than 100 mu in diameter constricted in response to cervical sympathetic nerve stimulation suggests or in response to topical application of norepinephrine. Smaller pial arteries were unresponsive to norepinephrine. This unresponsiveness persisted when norepinephrine was dissolved in CSF with high calcium ion concentration, or in CSF with both high calcium ion and zero magnesium ion concentration, or when it was dissolved in the acid fluid used by Wahl et al. and applied by constant infusion or by intermittent application. Comparison of the responses of the larger pial vessels to norepinephrine and to sympathetic nerve stimulation that maximal activation of sympathetic nerves achieves a concentration of released norepinephrine equal to 5.9 x 10(-6) M. The constriction of the larger pial vessels in response to sympathetic nerve stimulation could account for modest reductions in cerebral blood flow.

Animals↗

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Local mechanism of CO2 action of cat pial arterioles.

The effect of local hypercapnic acidosis or local hypocapnic alkalosis on pial arterioles were studied in anesthetized cats equipped with a cranial window for the direct observation of the pial microcirculation of the parietal cortex. Changes in PCO2 and pH of the extracellular fluid were induced by perfusing the space under the cranial window with artificial cerebrospinal fluid equilibrated with different concentrations of CO2, while PaCO2 was maintained constant. Hypercapnic acidosis dilated and hypocapnic alkalosis constricted pial arteioles markedly. The results indicate that a basis exists for considering CO2 as a mediator for local regulation of brain blood flow. The vasodilation associated with arterial hypercapnia was abolished by a reduction in CSF PCO2 equal in magnitude to the rise in arterial blood PCO2, suggesting that the action of CO2 is entirely local.

Animals↗

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Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels.

The mechanism by which the local effect of CO2ON pial arterioles is exerted was examined in anesthetized cats equipped with a cranial window for the direct observation of the microcirculation of the parietal cortex. The dilation of pial arterioles in response to application of artificial cerebrospinal fluid with low pH was the same whether or not the PCO2 of the solution was maintained in the normal range or markedly increased. The constriction of pial arterioles in response to application of artificial cerebrospinal fluid with high pH was the same whether or not the PCO2 of the solution was maintained in the normal range or markedly decreased. Finally, pial arterioles did not change their caliber in response to application of cerebrospinal fluid with unchanged pH but markedly increased or decreased Pco, or bicarbonate ion concentration. These results show that the action of CO2 on cerebral vessels is exerted via changes in extracellular fluid pH and that molecular CO2 and bicarbonate ions do not have independent vasoactivity on these vessels.

Animals↗

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Vasoconstrictor effect of angiotensin on pial arteries.

The effect of topical application of angiotensin on pial arterioles was examined in anesthetized cats equipped with a cranial window for the direct observation of the pial microcirculation of the parietal cortex. Angiotensin in a dose of 0.01 to 1 microgram/ml constricted pial arterioles and arteries strongly. The response of the smaller vessels was greater than that of the larger ones. Intravenous administration of angiotensin in a dose of 0.04--3.8 microgram/min raised arterial blood pressure and constricted the larger pial arteries. While the infusion of angiotensin was continued at the same dose, the blood pressure was then reduced to the control level via bleeding into a reservoir. This abolished the vasoconstriction of the larger pial arteries, showing that this effect was due to autoregulatory adjustments to the rise in blood pressure and not due to a direct effect of angiotensin. We conclude that, despite the strong constrictor effect of angiotensin on pial arteries, intravenous angiotensin can be used to study the effects of arterial hypertension on the cerebral circulation.

Administration, Topical↗

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Overview of the Leishmaniavirus endoribonuclease and functions of other endoribonucleases affecting viral gene expression.

Leishmaniaviruses (LRV) are double-stranded RNA viruses that persistently infect some strains of the protozoan parasite Leishmania. The identification of a short viral RNA transcript led to our discovery of an endoribonuclease activity of the LRV capsid protein. Other known endoribonucleases serve a variety of diverse roles in the regulated balance of processing and degradation of both cellular and viral RNAs, thus determining the amount and functionality of specific RNA molecules in a cell at any given time. The consequence of LRV RNA cleavage on the LRV life cycle has not yet been determined. Here we review the LRV endoribonuclease and discuss potential roles for this endoribonuclease activity in the context of the involvement of other endoribonucleases in regulating viral gene expression and replicative capacity.

Animals↗