This issue of JASH begins with Dr. Tadashi Inagami's review of the renin and pro-renin receptor in relation to end-organ damage. In experimental animals overexpressing the receptor they observed progressive glomerular abnormalities without differences in blood pressure (BP) that were independent of angiotensin II. Utilizing a blocker of the renin/pro-renin receptor, they also demonstrated the prevention of experimental diabetic nephropathy and amelioration of the effects of hypertension on both the kidney and the heart. These findings take the investigation of the renin-angiotensin cascade in hypertensive and diabetic end-organ disease to a new level and suggest that new therapeutic approaches may be in the offing. The second review in this issue, by Dr. Kailash Pandey, also utilized the genetic knock-out and overexpression techniques in mice to provide new information on the role of the natriuretic peptide receptors. These interesting studies also hold the promise of increasing our understanding of a variety of hemodynamic abnormalities in humans as well as new therapeutic approaches to hypertension and cardiovascular disorders.
Drs. Marchesi and Schiffrin provide an excellent review of the PPARs (alpha and gamma), focusing on their roles in the treatment of diabetes as well as their anti-oxidant and anti-inflammatory actions. In addition, they provide details of the impact of these transcription factors on fibrosis and remodeling, potentially beneficial cardiovascular effects. However, their review is tempered by the recognition of adverse cardiovascular effects reported in some patients receiving some agents of this class for the treatment of diabetes in whom an increased incidence of myocardial infarction has been reported. Obviously, much additional information will be needed to properly assign the appropriate use of these agents.
The next review examines BP as a component of the cardiometabolic syndrome and the myriad abnormalities that have been associated with it. The focus of this review by Drs. Melvin Hayden and James Sowers is on the function of the pancreatic islet and insulin sensitivity. After a detailed description of current knowledge in this area, the authors turn to a consideration of the effect of traditional antihypertensive agents on these factors. Several large trials have now provided clear evidence that thiazide diuretics and traditional beta-adrenergic blocking drugs worsen insulin sensitivity while angiotensin-converting enzyme inhibitors and angiotensin receptor blockers appear to protect hypertensive patients from the development of new diabetes mellitus. The role of the new direct renin inhibitor has not yet been clearly defined while older information indicated that alpha-adrenergic blocking drugs and, perhaps calcium channel entry blockers, may have a beneficial effect on insulin sensitivity. This review provides a summary of the current evidence in this area.
The increasing epidemic of obesity and hypertension in childhood is reviewed by Dr. Bonita Falkner. This emerging challenge augurs poorly for the cardiovascular health and well-being of our society for future decades. Alterations in lifestyle in childhood, particularly diet and exercise as well as leisure-time activities will likely be required to stem this tide.
An important series of research studies complete this issue. Gu and colleagues provide evidence that a high-salt diet raises BP after 6 or more weeks in an animal strain, the Sprague-Dawley rat, thought previously to be insensitive to this effect. In addition to the increase in BP, the investigators observed proteinuria and evidence of wide-spread renal histologic abnormalities. These findings indicate that the highly inbred strains of rats previously shown to be susceptible to the BP raising-effects of sodium intake and the manipulations of nephrectomy and DOCA administration, another technique used to invoke a hypertensive response to salt, are not the only ways in which this response can be demonstrated. Rather, in an unmanipulated and less highly inbred model, persistent intake of a high level of salt can raise BP and be associated with the typical renal abnormalities associated with it.
Morris and colleagues have extended their interest in naturally occurring inhibitors of 11 beta-hydroxysteroid dehydrogenase, a licorice (glycyrrhetinic acid)-like substance found in urine by comparing the effects of this compound in “low” and “high/normal renin” human hypertensive subjects. Their findings are interpreted as being consistent with increased renal sodium retention due to enhanced cortisol access to the renal mineralocorticoid receptor and increased vascular reactivity, presumably from stimulation of a putative vascular mineralocorticoid receptor, in high/normal renin subjects during a low sodium diet. These interesting preliminary findings are provocative.
The final research study, by Destro and colleagues, reports the efficacy and safety of amlodipine combined with valsartan in comparison to amlodipine alone in hypertensive humans. The combination was more effective in lowering BP than amlodipine alone and both regimens were well tolerated. The size of the study permitted evaluation of several hypertensive subgroups.
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