Translating Pharmacogenetics and Pharmacogenomics to the Clinic: Progress in Human and Veterinary Medicine.

As targeted personalized therapy becomes more widely used in human medicine, clients will expect the veterinary clinician to be able to implement an evidence-based strategy regarding both the prescribing of medicines and also recognition of the potential for adverse drug reactions (ADR) for their pet, at breed and individual level. This review aims to provide an overview of current developments and challenges in pharmacogenetics in medicine for a veterinary audience and to map these to developments in veterinary pharmacogenetics. Pharmacogenetics has been in development over the past 100 years but has been revolutionized following the publication of the human, and then veterinary species genomes. Genetic biomarkers called pharmacogenes have been identified as specific genetic loci on chromosomes which are associated with either positive or adverse drug responses. Pharmacogene variation may be classified according to the associated drug response, such as a change in (1) the pharmacokinetics; (2) the pharmacodynamics; (3) genes in the downstream pathway of the drug or (4) the effect of "off-target" genes resulting in a response that is unrelated to the intended target. There are many barriers to translation of pharmacogenetic information to the clinic, however, in human medicine, international initiatives are promising real change in the delivery of personalized medicine by 2025. We argue that for effective translation into the veterinary clinic, clinicians, international experts, and stakeholders must collaborate to ensure quality assurance and genetic test validation so that animals may also benefit from this genomics revolution.

Neutering affects urinary bladder function by different mechanisms in male and female dogs.

Acquired urinary incontinence is a significant, incurable problem, prevalent in neutered bitches but rarely seen in entire bitches or males. Decreased urethral closure pressure has been proposed as a causative factor for altered detrusor contractility in the neutered bitch. In post menopausal women, acquired urinary incontinence is associated with acquired urinary incontinence and changes in collagen deposition within the bladder wall. The aim of this study was to determine effects of neutering on smooth muscle in the canine urinary bladder. Tissue bath studies were used to assess contractile function and morphometric analysis to determine percentage of collagen in the bladder wall from male and female, neutered and entire canines. Maximal response to both carbachol and neurogenic stimulation was significantly lower in bladder strips from neutered animals of both sexes. Sensitivity to carbachol was also significantly reduced by neutering in both sexes. The percentage of collagen was significantly higher in the bladder wall from neutered vs. entire females, which were similar to that of both neutered and entire males. Neutering a canine decreases urinary bladder responsiveness to muscarinic stimulation in vitro, in both sexes, but only increases the percentage of collagen in the bladder wall in females. While increased percentage collagen may predispose bitches to acquired urinary incontinence, the sex difference in this parameter indicates that more than one mechanism underlies the changes in bladder responsiveness seen following neutering. This alternative effect of neutering may be in the muscarinic receptor effector pathway and act as a therapeutic target for acquired urinary incontinence treatment.

Requirement for flow in the blockade of endothelium-derived hyperpolarizing factor (EDHF) by ascorbate in the bovine ciliary artery.

We previously reported that ascorbate inhibits endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine perfused ciliary circulation and rat perfused mesentery, but not in rings of bovine or porcine coronary artery. In this study, we have compared the ability of ascorbate to inhibit EDHF-mediated vasodilatation in a single vessel, the bovine long posterior ciliary artery, when perfused and when mounted as rings in a myograph. Both in segments perfused at a flow rate of 2.5 ml min(-1) and in rings mounted in a myograph, bradykinin and acetylcholine each induced vasodilator responses that were mediated jointly by EDHF and nitric oxide, as revealed by their respective blocking agents, apamin/charybdotoxin, and L-NAME. Ascorbate (50 and 150 microm) induced a time (max at 2-3 h)-dependent inhibition of the EDHF-mediated component of vasodilatation to bradykinin or acetylcholine in perfused segments, but not in rings. Ascorbate (50 microm) failed to inhibit bradykinin-induced vasodilatation at a flow rate of 1.25 ml min(-1) or below, but produced graded blockade at the higher flow rates of 2.5 and 5 ml min(-1). Furthermore, using a pressure myograph where pressure and flow were independently controlled, it was confirmed that the inhibitory action of ascorbate (150 microm) was directly related to flow per se and not any associated changes in pressure. Thus, we have shown in the bovine ciliary artery that ascorbate inhibits EDHF-mediated vasodilatation under conditions of flow but not in a static myograph. The mechanism by which flow renders EDHF susceptible to inhibition by ascorbate remains to be determined.

Differential effects of ascorbate on endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation in the bovine ciliary vascular bed and coronary artery.

1. The ability of ascorbate to inhibit endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation was compared in the bovine perfused ciliary vascular bed and isolated rings of coronary artery. 2. Acetylcholine-induced, EDHF-mediated vasodilatation of the ciliary circulation was blocked following inclusion of ascorbate (50 micro M, 120 min) in the perfusion fluid. The blockade was highly selective since ascorbate had no effect on the vasodilator actions of the K(ATP) channel opener, levcromakalim, nor on the tonic vasodepressor action of basally released nitric oxide. 3. The possibility that concentration of ascorbate by the ciliary body was a prerequisite for blockade to occur was ruled out, since EDHF was still blocked when the anterior and posterior chambers were continuously flushed with Krebs solution or when both the aqueous and vitreous humour were drained. 4. Ascorbate at 50 micro M failed to affect bradykinin- or acetylcholine-induced, EDHF-mediated vasodilatation in rings of bovine coronary artery. Raising the concentration to 3 mM did produce blockade of EDHF, but this was nonselective, since vasodilator responses to endothelium-derived nitric oxide were also inhibited. 5. Thus, ascorbate (50 micro M) is not a universal blocker of EDHF. Whether its ability to block in the bovine ciliary circulation, but not in the coronary artery, is due to differences in the nature of EDHF at the two sites, differences in vessel size (resistance arterioles versus conduit artery), the presence or absence of flow, or to some other factor remains to be determined.