Among the multrple mechanisms postulated for the increased risk of hypertensive left ventrrcular hypertrophy (LVH), coronary hemodynamrc alterations remam a strong possrbrhty Thts study was designed to compare the effects of treatment with an ACE mhlbrtor (enalapnl) and an angrotensm AT, receptor antagonist (losartan) on systemic and coronary hemodynamics and to determine whether the combmatlon of these two renm-angrotensm system (RAS) mhlbrtors would be as or more effectrve m reducing mean arterial pressure (MAP), left ventncular (LV) mass, and tmprovmg coronary hemodynamtcs than etther regimen alone Thus, 23 week old spontaneously hypertensive rats (SHR) were treated (12 weeks) with tap water (C), enalaprd (30 mg kg-' d-l), losartan (30 mg kg-' d-'), or then combmatron (15 mg kg-' d-') Age-matched Wtstar-Kyoto (WKY) rats served as normotenslve controls After 12 weeks, systemic and coronary hemodynamtcs were determmed (15 pm radrolabeled microspheres) at baseline, durmg maximal treadmill exerctse, and durmg maximal ddatton (drpyndamole) Enalapnl and losartan equally reduced MAP and LV mass m association with a decreased total peripheral resistance The RAS combmanon reduced MAP and LV mass more than either drug alone Resting cardiac index and coronary blood flow (CBF) per umt of LV mass did not differ among the groups. Although enalaprd dtd not improve coronary flow reserve (CFR), tt drmunshed muumal coronary vascular resistance (MCVR), losartan improved both However, the combmatton was more effective than either agent alone, reaching values close to normotenslve WKY controls In concluslon, these data demonstrated sigmficantly impaired maximal CBF, CFR, and MCVR m untreated SHR, but losartan alone and m combmatron with enalapnl improved systemic and coronary hemodynamtcs more than enalaprtl alone (Hypertension. 1997;29[part 21519-524.) Key Words l left ventricular hypertrophy [reversal] l angrotensm II [antagonism and mhtbrtron] l drug synergism l losartan l enalapnl l coronary circulation l spontaneously hypertensive rats L eft ventricular hypertrophy resultmg from hypertension IS an independent rusk factor for premature cardtovascular morbidity and mortality, t-3 although LVH reversal has not ye@een shown to reduce that risk 4 LVH has been associated with impaired coronary hemodynamrcs m expenmental animal+ and patients 7-9 Among the postulated mechanisms offered to explain the increased risk are altered coronary hemodynamrcs, including decreased CBF and CFR, increased resting and MCVR, and altered vrscostty; cardtac arrhythmias, cardiac failure, and accelerated atherosclerosis of epicardial arteries. 10 Current goals of antthypertenstve therapy have been directed toward optimal control of arterial pressure, although reversal of LVH and rmprovement of the compromtsed coronary hemodynamrcs are the SubJect of intense investrgatron directed toward reducing LVH risk.4 Accordmgly, this study was designed to determine whether treatment wrth an ACE inhibitor (enalapnl), an AT, receptor antagomst (losar...

Both aging and hypertension adversely affected the coronary circulation; furthermore, these effects appeared to be additive. Cardiac fibrosis, but not hypertrophy, might play a role in progressive deterioration of coronary hemodynamics in aging and hypertension and could provide an explanation for the diastolic dysfunction encountered clinically in older patients with hypertension.

Abstract-Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues. We have cloned and sequenced the genomic DNA encoding the human AM gene and have determined that the gene is located in the short arm of chromosome 11. The 3Ј-end of the gene is flanked by the microsatellite marker of cytosine adenine (CA) repeats. In this study, we investigated the association between DNA variations in AM gene and the predisposition to hypertension. Genomic DNA was obtained from 272 healthy normotensive subjects (NT) age 57Ϯ5 years and 266 patients with essential hypertension (EH) age 53Ϯ11 years. The DNA was subject to PCR using a fluorescence-labeled primer, and the number of CA repeats were determined by poly-acrylamide gel electrophoresis. The averaged blood pressure was 117Ϯ13/73Ϯ9 mm Hg in NT and 170Ϯ23/104Ϯ12 mm Hg in EH. In Japanese, there existed 4 types of alleles with different CA-repeat numbers: 11, 13, 14, and 19. The frequencies of these alleles were significantly different between NT and EH ( 2 ϭ9.43, Pϭ0.024). Namely, 13.5% of EH carried the 19-repeat allele, whereas the frequency was 6.2% in NT ( 2 ϭ7.62, Pϭ0.007). In NT, plasma AM concentrations were not significantly different between the genotypes. In conclusion, microsatellite DNA polymorphism of AM gene may be associated with the genetic predisposition to EH, although the gene expression is not likely to be affected by the genotypes. Key Words: adrenomedullin Ⅲ polymorphism Ⅲ hypertension, essential Ⅲ microsatellite repeats Ⅲ genetics A drenomedullin (AM) is a hypotensive peptide produced in cardiovascular tissues such as the heart, lung, kidney, and vascular wall. 1,2 Besides the potent vasodilator action, AM has also been shown to cause natriuresis in the kidney and to inhibit growth of cardiovascular cells. Moreover, a significant level of AM has been identified in human plasma, and AM is supposed to be a circulating hormone. 1,3 We have previously reported that plasma AM levels are increased in patients with cardiovascular diseases such as hypertension, renal failure, and heart failure. 4,5 These findings suggest that AM has implications in pathophysiology of the cardiovascular system.We have cloned and sequenced the genomic DNAencoding human AM gene and have determined that the gene is located in the short arm of chromosome 11. 6 Nucleotide sequencing of genomic DNA adjacent to the AM gene revealed that the 3Ј-end of the gene is flanked by the microsatellite marker with a variable number of cytosine adenine (CA)-repeats. This microsatellite marker is located approximately 4 kb downstream of the AM gene. Considering the possible implications of AM in the cardiovascular system, it seems of interest to elucidate whether this gene variation has any relation to the etiology of cardiovascular diseases. In the present study, we investigated the relationship between the microsatellite polymorphism adjacent to the AM gene and genetic predisposition to essential hypertension. Subjects and Methods Study SubjectsA group...

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