Oral contraceptive progestins and angiotensin-dependent control of the renal circulation in humans

Oral contraceptive (OC) use is associated with increased intra-renal renin-angiotensin-aldosterone system (RAA System) activity and risk of nephropathy, though the contribution of progestins contained in the OC in the regulation of angiotensin-dependent control of the renal circulation has not been elucidated. Eighteen OC users (8 non-diabetic, 10 Type 1 diabetic) were studied in high salt balance, a state of maximal RAA System suppression. Progestational and androgenic activity of the progestin in each OC was standardized to that of the reference progestin norethindrone. Renal plasma flow (RPF) was measured by paraaminohippurate clearance at baseline and in response to angiotensin converting enzyme (ACE)-inhibition. There was a positive correlation between OC progestational activity and the RPF response to ACE-inhibition (r=0.52, p=0.03). Similar results were noted with OC androgenic activity (r=0.54, p=0.02). On subgroup analysis, only non-diabetic subjects showed an association between progestational activity and angiotensin-dependent control of the renal circulation (r=0.71, p=0.05 non-diabetic; r=0.14, p=0.7 diabetic; p=0.07 between groups). Similar results were noted with respect to androgenic activity (r=0.88, p=0.005 non-diabetic; r=−0.33, p=0.3 diabetic; p=0.002 between groups). Our results suggest that the OC progestin component is a significant influence on the degree of angiotensin-dependent control of the renal circulation, though these findings may not apply to women with diabetes

Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans

Farzaneh A Sorond1,2, Lewis A Lipsitz2,4, Norman K Hollenberg3,5, Naomi DL Fisher31Department of Neurology, Stroke Division; 2Institute for Aging Research, Hebrew SeniorLife, Boston, MA; 3Department of Medicine, Endocrine-Hypertension Division; 4Department of Medicine, Gerontology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 5Department of Radiology, Brigham and Women’s Hospital, Boston, MABackground and Purpose: Cerebral ischemia is a common, morbid condition accompanied by cognitive decline. Recent reports on the vascular health benefits of flavanol-containing foods signify a promising approach to the treatment of cerebral ischemia. Our study was designed to investigate the effects of flavanol-rich cocoa (FRC) consumption on cerebral blood flow in older healthy volunteers.Methods: We used transcranial Doppler (TCD) ultrasound to measure mean blood flow velocity (MFV) in the middle cerebral artery (MCA) in thirty-four healthy elderly volunteers (72 ± 6 years) in response to the regular intake of FRC or flavanol-poor cocoa (FPC).Results: In response to two weeks of FRC intake, MFV increased by 8% ± 4% at one week (p = 0.01) and 10% ± 4% (p = 0.04) at two weeks. In response to one week of cocoa, significantly more subjects in the FRC as compared with the FPC group had an increase in their MFV (p < 0.05).Conclusions: In summary, we show that dietary intake of FRC is associated with a significant increase in cerebral blood flow velocity in the MCA as measured by TCD. Our data suggest a promising role for regular cocoa flavanol’s consumption in the treatment of cerebrovascular ischemic syndromes, including dementias and stroke.Keywords: cerebral blood flow, flavanol, cocoa, transcranial Doppler ultrasoun

ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus

ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus.BackgroundThe enormous contribution of renin-angiotensin system (RAS) interruption with ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers (ARB) in the treatment of diabetic nephropathy has led to interest in the factors involved in angiotensin II (Ang II) generation. In normal subjects, RAS interruption using an ARB produced a 50% greater renal plasma flow (RPF) rise than with an ACE inhibitor, suggesting a substantial contribution of non-ACE pathways. Moreover, immunohistochemistry studies in kidneys of overtly proteinuric diabetic subjects showed up-regulation of chymase, an alternative Ang II-generating enzyme. Our aim was to determine the degree to which the non-ACE pathways contribute to RAS activation in type 1 diabetes mellitus (DM).MethodsType 1DM patients (N = 37, 14 M/23 F; age 31 ± 2 years; DM duration 16 ± 1.7 years; HbA1c 7.7.0 ± 0.3%) were studied on a high-salt diet. They received captopril 25mg po one day and candesartan 16mg po the next day. RPF and glomerular filtration rate (GFR) were measured before and up to 4 hours after drug administration.ResultsBoth captopril and candesartan induced a significant rise in RPF (baseline vs. peak <0.0001 for both), and the rise was concordant for the 2 drugs (r = 0.77,P < 0.001). However, the RPF responses were not significantly different between the 2 drugs (captopril 72 ± 11mL/min/1.73m2, candesartan 75 ± 12,P = 0.841).ConclusionIn predominantly normoalbuminuric, normotensive type 1 DM, activation of the intrarenal RAS reflects a mechanism involving primarily the classic ACE pathway

Angiotensin-Converting Enzyme Inhibition and Renal Protection: An Assessment of Implications for Therapy

The role of hypertension in the pathogenesis of renal damage is a subject of both historical interest and current investigation. Because of the difficulty associated with studying the pathophysiologic role of glomerular injury in systemic hypertension, experimental models have provided much of the data in this field. The mechanisms leading to glomerular injury are complex and not fully elucidated. Mesangial and endothelial cell injury are thought to be important pathophysiologic mechanisms in the renal injury associated with hypertension. One hypothesis suggests that glomerular hypertension (ie, a hemodynamic event) is the primary pathogenetic mechanism, but another supports the notion that glomerular hypertrophy (ie, abnormal growth-related events) contributes to injury. The intrarenal renin-angiotensin system may play an important pathogenetic role in end-stage renal disease. Angiotensin-converting enzyme (ACE) inhibition has been shown to arrest the progression of renal injury in animal models. Although the clinical database is incomplete, the findings of anecdotal reports and short-term studies suggest that ACE inhibition may preserve renal function in patients with scleroderma renal crisis, reduce proteinuria in patients with diabetic nephropathy, and normalize renal hemodynamics in patients with a variety of renal diseases. The beneficial effects of ACE inhibition may be due to both hemodynamic (eg, reduction in glomerular capillary and intraglomerular pressures) and nonhemodynamic (eg, potassium-sparing and reduction in mesangial proliferation) mechanisms. The precise role of ACE inhibitors in the prevention of renal damage awaits the results of ongoing long-term, double-blind clinical studies. Nevertheless, ACE inhibition may be an appropriate therapeutic alternative in the hypertensive patient whose renal injury is progressing despite aggressive antihypertensive therapy.(Arch Intern Med. 1993;153:2426-2435