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Flipped learning has become a popular blended learning approach in higher education and is now being adopted in medical schools across Australia and internationally. There are a number of principal educational justifications for the introduction of this approach, primarily, that it fosters deeper student learning through active engagement in the classroom. As a pedagogical intervention however, what do the various stakeholders think about its introduction? This paper explores reactions to implementation of a flipped learning approach to pre-clinical medical education in a regional Victorian medical course, via a mixed method approach. A range of quantitative and qualitative data was collected concerning the implementation, including a student survey, student focus groups, a staff survey for both academic and professional staff members involved in the implementation of the approach, and an independent student-driven social media questionnaire conducted in the second year post implementation survey. These data provide critical feedback for refinement of the flipped learning approach, including more robust student and faculty development and support during implementation of this pedagogy. Taken together, our results provide a unique perspective of the introduction of the flipped approach through different stakeholder lenses, and over time.

We assessed the relative contributions of endothelium-derived relaxing factors to renal vasodilation in vivo and determined whether these are altered in established streptozotocin-induced diabetes. In nondiabetic rats, stimulation of the endothelium by locally administered ACh or bradykinin-induced transient renal hyperemia. Neither basal renal blood flow (RBF) nor renal hyperemic responses to ACh or bradykinin were altered by blockade of prostanoid production (indomethacin) or by administration of charybdotoxin (ChTx) plus apamin to block endothelium-derived hyperpolarizing factor (EDHF). In contrast, combined blockade of nitric oxide (NO) synthase, N[omega]-nitro-L-arginine methyl ester (L-NAME), and prostanoid production reduced basal RBF and the duration of the hyperemic responses to ACh and bradykinin and revealed a delayed ischemic response to ACh. Accordingly, L-NAME and indomethacin markedly reduced integrated (area under the curve) hyperemic responses to ACh and bradykinin. Peak increases in RBF in response to ACh and bradykinin were not reduced by L-NAME and indomethacin but were reduced by subsequent blockade of EDHF. L-NAME plus indomethacin and ChTx plus apamin altered RBF responses to endothelium stimulation in a qualitatively similar fashion in diabetic and nondiabetic rats. The integrated renal hyperemic responses to ACh and bradykinin were blunted in diabetes, due to a diminished contribution of the component abolished by L-NAME plus indomethacin. We conclude that NO dominates integrated hyperemic responses to ACh and bradykinin in the rat kidney in vivo. After prior inhibition of NO synthase, EDHF mediates transient renal vasodilation in vivo. Renal endothelium-dependent vasodilation is diminished in diabetes due to impaired NO function. kidney circulation; acetylcholine; bradykinin; endothelium-derived hyperpolarizing factor; nitric oxide

Vascular relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is important for resistance artery function and is underpinned by hyperpolarization of the smooth muscle cells of the blood vessel wall. Debate surrounds the identity of EDHF and its mechanism of action, with the consensus being that there is no universal EDHF. Regional differences in vascular function reflect the complex mechanisms of EDHF. Two primary mechanistic pathways are implicated: (i) myoendothelial gap junctions mediating the spread of endothelial cell hyperpolarization or small signaling molecules (or both) to the smooth muscle; and (ii) diffusible mediators released from the endothelium, including K* and epoxyeicosatrienoic acids. Here, we discuss the evidence for and against C-type natriuretic peptide (CNP), the latest candidate for a diffusible mediator.

The mechanisms underlying endothelium-dependent hyperpolarizing factor (EDHF) in the middle cerebral artery (MCA) remain largely unresolved. In particular, very little is known regarding the way in which the signal is transmitted from endothelium to smooth muscle. The present study tested the hypothesis that direct communication via myoendothelial gap junctions contributions to the EDHF response in the male rat MCA. EDHF-mediated dilations were elicited in rat MCAs by luminal application of ATP or UTP in the presence of [N.sup.[sigma]]-nitro-L-arginine methyl ester and indomethacin. Maximum dilation to luminal ATP ([10.sup.-4] M) was reduced significantly after incubation with a gap peptide cocktail (9 [+ or -] 4%, n = 6) compared with a scrambled gap peptide (99 [+ or -] 1%, n = 6, P < 0.005). A gap peptide cocktail had no effect on amplitude of endothelial cell hyper-polarization in response to 3 x [10.sup.-5] M UTP (22 [+ or -] 3 vs. 22 [+ or -] 1 mV, n = 4), whereas smooth muscle cell hyperpolarization was significant attenuated (17 [+ or -] 1 vs. 6 [+ or -] 1 mV, n = 4, P = 0.004). Connexin (Cx) 37 was localized to smooth muscle and Cx43 to endothelium, whereas Cx40 was found in endothelium and smooth muscle. Electron microscopy revealed the existence of frequent myoendothelial junctions. The total number of myoendothelial junctions per 5 [micro]m of MCA sectioned was 2.5 [+ or -] 0.5. Our results suggest that myoendothelial communication contributes to smooth muscle cell hyperpolarization and EDHF dilation in male rat MCA. connexins, endothelium-derived hyperpolarizing factor, vascular smooth muscle.

Glycyrrhetinic derivatives inhibit hyperpolarization in endothelial cells of guinea pig and rat arteries. Am J Physiol Heart Circ Physiol 282: H335-H341, 2002.--Glycyrrhetinic acid (GA) derivatives have been used to implicate gap junctions in vasorelaxation attributed to endothelium-derived hyperpolarizing factor (EDHF). The aim of this study was to assess whether GA compounds affect endothelial cell hyperpolarization. Membrane potentials were recorded from dye-identified endothelial and smooth muscle cells of guinea pig coronary and rat mesenteric arteries. GA derivatives had varied effects on the resting membrane potential: depolarization, hyperpolarization, or no effect, depending on the artery. 18[alpha]-GA (50 [micro]M) had a small variable effect on ACh-induced hyperpolarizations in endothelial cells. 18[beta]-GA (30 [micro]M) and carbenoxolone (100 [micro]M) significantly reduced ACh-induced hyperpolarizations in both endothelial and smooth muscle cells. Smooth muscle action potentials in rat tail arteries were smaller and slower in the presence of 18[beta]-GA. Nerve-induced excitatory junction potentials were inhibited by 18[beta]-GA and carbenoxolone, whereas the time course of their decay initially increased and then decreased. In conclusion, the GA compounds had a range of effects. Their inhibition of the EDHF hyperpolarization and relaxation in the smooth muscle may stem from the inhibition of endothelial cell hyperpolarization. gap junctions; glycyrrhetinic acid; action potentials; carbenoxolone; endothelium-derived hyperpolarizing factor

Background and Purpose: Endothelium-derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium-derived prostacyclin (PGI2 ) can cause contraction rather than relaxation. Relaxin is well known for its vasoprotective actions, but the possibility that this peptide could also reverse endothelium-derived vasoconstriction has never been investigated. We tested the hypothesis that short-term relaxin treatment mitigates endothelium-derived vasoconstriction in spontaneously hypertensive rats (SHR).Experimental Approach: Male Wistar Kyoto rats (WKY) and SHR were subcutaneously infused with either vehicle (20 mmol·L-1 sodium acetate) or relaxin (13.3 μg·kg-1 ·hr-1 ) using osmotic minipumps for 3 days. Vascular reactivity to the endothelium-dependent agonist ACh was assessed in vitro by wire myography. Quantitative PCR and LC-MS were used to identify changes in gene expression of prostanoid pathways and PG production, respectively.Key Results: Relaxin treatment ameliorated hypertension-induced endothelial dysfunction by increasing NO-dependent relaxation and reducing endothelium-dependent contraction. Notably, short-term relaxin treatment up-regulated mesenteric PGI2 receptor (IP) expression, permitting PGI2 -IP-mediated vasorelaxation. In the aorta, reversal of contraction was accompanied by suppression of the hypertension-induced increase in prostanoid-producing enzymes and reduction in PGI2 -evoked contractions.Conclusions and Implications: Relaxin has region-dependent vasoprotective actions in hypertension. Specifically, relaxin has distinct effects on endothelium-derived contracting factors and their associated vasoconstrictor pathways in mesenteric arteries and the aorta. Taken together, these observations reveal the potential of relaxin as a new therapeutic agent for vascular disorders that are associated with endothelium-derived vasoconstriction including hypertension. [ABSTRACT FROM AUTHOR]

Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery. Am J Physiol Heart Circ Physiol 281: H232-H240, 2001.--The hypothesis tested in this study is that diabetes has a different impact on an artery in which endothelium-dependent responses derive from both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) compared with responses in which NO predominates and EDHF is absent. The streptozotocin-treated rat model of diabetes was used, and the arteries were mounted on a wire myograph. In mesenteric arteries depolarized and constricted with phenylephrine, acetylcholine evoked hyperpolarization (31 [+ or -] 2 mV) and complete relaxation; these responses were attributed to EDHF and NO. In femoral arteries, acetylcholine evoked a small, NO-mediated hyperpolarization (5 [+ or -] 1 mV) and incomplete relaxation. Bradykinin evoked NO-dependent responses in mesenteric arteries. Whereas diabetes significantly impaired the EDHF-dependent hyperpolarization and relaxation in mesenteric arteries, NO-dependent responses in femoral and mesenteric arteries were preserved, 1-Ethyl-2-benzimidazolinone evoked hyperpolarization and relaxation in mesenteric arteries, and this was impaired in diabetes. In conclusion, NO-dependent responses are preserved in diabetes, whereas endothelial responses-dependent upon EDHF appear to be impaired. The putative channels responsible for mediating the EDHF response may be altered in diabetes. hyperpolarization and relaxation; nitric oxide; endothelium-derived hyperpolarizing factor; mesenteric artery; femoral artery

Endothelium-derived hyperpolarizing factor (EDHF)-attributed hyperpolarizations and relaxations were recorded simultaneously from submucosal arterioles of guinea pigs with the use of intracellular microelectrodes and a video-based system, respectively. Membrane currents were recorded from electrically short segments of arterioles under single-electrode voltage clamp. Substance P evoked an outward current with a current-voltage relationship that was well described by the Goldman-Hodgkin-Katz equation for a [K.sup.+] current, consistent with the involvement of intermediate- and small-conductance [Ca.sup.2+]-activated [K.sup.+] channels, 1-Ethyl-2-benzimidazolinone relaxed the arterioles and evoked hyperpolarizations that were blocked by charybdotoxin, but not by iberiotoxin. Application of [K.sup.+] induced depolarization under conditions in which EDHF evoked hyperpolarization. The [Ba.sup.2+]-sensitive component of the [K.sup.+]-induced current was inwardly rectifying, in contrast to the outwardly rectifying current evoked by substance P. EDHF-attributed hyperpolarizations in dye-identified smooth muscle cells were indistinguishable from those recorded from dye-identified endothelial cells in the same arterioles. These results provide evidence that EDHF is not [K.sup.+] but may involve electrotonic spread of hyperpolarization from the endothelial cells to the smooth muscle cells. calcium-activated potassium current; endothelium; gap junction; voltage clamp; 1-ethyl-2-benzimidazolinone