Role of protein kinase C in angiotensin II-induced constriction of renal microvessels

Role of protein kinase C in angiotensin II-induced constriction of renal microvesselsBackgroundAlthough angiotensin II (Ang II) exerts its action through multiple vasomotor mechanisms, the contribution of phosphoinositol hydrolysis products to Ang II-induced renal vasoconstriction remains undetermined.MethodsThe role of protein kinase C (PKC) in Ang II-induced afferent (AFF) and efferent (EFF) arteriolar constriction was examined using the isolated perfused hydronephrotic rat kidney.ResultsAng II (0.3 nmol/L)-induced EFF constriction was refractory to inhibition of voltage-dependent calcium channels by pranidipine (1 μmol/L, 19 ± 2% reversal) but was completely reversed by a PKC inhibitor, chelerythrine (1 μmol/L, 96 ± 2% reversal). Furthermore, direct PKC activation by phorbol myristate acetate (PMA; 1 μmol/L) caused prominent EFF constriction, and this constriction was inhibited by manganese and free calcium medium. In contrast, Ang II-induced AFF constriction was completely abolished by pranidipine (98 ± 4% reversal) and was partially inhibited by chelerythrine (55 ± 3% reversal). Although PMA elicited marked AFF constriction, this constriction was insensitive to the calcium antagonist, but was totally inhibited by manganese or free calcium medium.ConclusionsPKC plays an obligatory role in Ang II-induced EFF constriction that requires extracellular calcium entry through nonselective cation channels. In contrast, in concert with our recent findings demonstrating a complete dilation by thapsigargin, Ang II-induced AFF constriction is mainly mediated by inositol trisphosphate (IP3) and voltage-dependent calcium channel pathways, but could not be attributed to the PKC-activated calcium entry pathway (for example, nonselective cation channels). Rather, Ang II-stimulated PKC may cross-talk to the IP3/voltage-dependent calcium channel pathway and could modulate the vasoconstrictor mechanism of the AFF. Thus, the role of PKC during Ang II stimulation differs in AFF and EFF, which may constitute segmental heterogeneity in the renal microvasculature

Height Constitutes an Important Predictor of Mortality in End-Stage Renal Disease

Aim. Height is an important determinant of augmentation index (AI) that anticipates cardiovascular prognosis. There is a scanty of the data whether short height predicts survival in patients with end-stage renal diseases, a high risk population. Methods. Fifty two hypertensive patients with type 2 diabetic nephropathy receiving hemodialysis and 52 patients with nondiabetic nephropathy were enrolled. In addition to AI estimated with radial artery tonometry, classical cardiovascular risk factors were considered. Patients were followed for 2 years to assess cardiovascular prognosis. Results. Cox hazards regression revealed that both smoking and shortness in height independently contributed to total mortality and indicated that smoking as well as the presence of left ventricular hypertrophy predicted cardiovascular mortality. Our findings implicated that high AI, the presence of diabetes, and low high-density lipoprotein cholesterol were significant contributors to cardiovascular events. Conclusions. Our findings provide new evidence that shortness in height independently contributes to total mortality in hemodialysis patients

Inferred systolic blood pressure levels to switch from lifestyle modifications to antihypertensive medications: a success-rate oriented simulation

Objective: This simulation study attempted to infer the systolic blood pressure (SBP) levels at which subjects with hypertension, health nurses, and primary physicians should switch their preference of their treatment policies from lifestyle modifications to antihypertensive medications in virtual Japanese sample populations. Methods: We assumed that SBP levels were normally distributed and that the incidence rate of cardiovascular disease (IRCVD, events/year) increased exponentially according to SBP. The total IRCVD was calculated by the definite integral for the product of the distribution of SBP multiplied by IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. We deduced the hypothetical SBP levels by solving differential equations of ∆(IRCVD)/ ∆(SBP) = 0 using numerical analysis. Results: In the realistic situations where the subjects were not affirmative to antihypertensive medications, the inferred SBP level to switch from lifestyle modifications to antihypertensive medications should be around 150 mmHg. If the subjects are affirmative to antihypertensive medications, the SBP level should be lowered to 140 mm Hg. Conclusion: This success rate-oriented simulation proposes that the SBP level to switch from lifestyle modifications to antihypertensive medications can be modulated according to the behavioral propensity for taking antihypertensive medications. Abbreviations: The following abbreviations are used in this manuscript: CVD: cardiovascular disease; LM: lifestyle modifications; AM: antihypertensive medications; IRCVD: incidence rate of cardiovascular disease (events/year); SBP: systolic blood pressure; ∆IRCVD: the improvements in the incidence rate of cardiovascular disease by lifestyle modifications and/or by antihypertensive medications

A medaka model of cancer allowing direct observation of transplanted tumor cells in vivo at a cellular-level resolution

The recent success with small fish as an animal model of cancer with the aid of fluorescence technique has attracted cancer modelers\u27 attention because it would be possible to directly visualize tumor cells in vivo in real time. Here, we report a medaka model capable of allowing the observation of various cell behaviors of transplanted tumor cells, such as cell proliferation and metastasis, which were visualized easily in vivo. We established medaka melanoma (MM) cells stably expressing GFP and transplanted them into nonirradiated and irradiated medaka. The tumor cells were grown at the injection sites in medaka, and the spatiotemporal changes were visualized under a fluorescence stereoscopic microscope at a cellular-level resolution, and even at a single-cell level. Tumor dormancy and metastasis were also observed. Interestingly, in irradiated medaka, accelerated tumor growth and metastasis of the transplanted tumor cells were directly visualized. Our medaka model provides an opportunity to visualize in vivo tumor cells "as seen in a culture dish" and would be useful for in vivo tumor cell biology

Characterization of the Renal Microvascular Effects of Angiotensin II Antagonist, DuP 753

The renal microvascular effects of DuP 753, an orally active imidazole angiotensin II (ANG II) receptor antagonist were assessed directly in isolated perfused hydronephrotic rat kidneys. Unilateral hydronephrosis was induced to facilitate direct visualization of renal microvessels. Hydronephrotic kidneys were perfused in vitro and microvessel diameters were measured by automated computer-assisted image processing. The administration of 0.3 nmol/L ANG II decreased afferent arteriolar (AA) and efferent arteriolar (EA) diameters by 34 ± 3% (from 17.9 ± 0.6 to 11.9 ± 0.6 µm, P < .001, n = 11) and 28 ± 3% (from 17.1 ± 1.3 to 12.3 ± 1.3 µm, P < .001, n = 11), respectively. The subsequent administration of 0.1,1.0, and 10 µmol/L DuP 753 reversed ANG II-induced vasoconstriction of the AA by 39 ± 10%, 81 ± 8%, and 103 ± 9%, and of the EA by 22 ± 7%, 51 ± 6%, and 87 ± 13%, respectively. These observations indicate that DuP 753 completely blocks both the renal afferent and efferent arteriolar actions of ANG II. In light of the pathogenetic role of ANG II in mediating the deranged renal hemodynamics associated with hypertension, conjestive heart failure, and some forms of renal insufficiency, our findings provide a theoretical framework for future studies assessing the potential therapeutic applicability of DuP 753 in reversing ANG II-mediated renal vasoconstriction. Am J Hypertens 1991;4:309S-314