Abstract-Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (nϭ458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (nϭ421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, PϽ0.0017; Kumamoto: 0.120 versus 0.058, PϽ0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.(Hypertension. 1998;32:3-8.)Key Words: genes Ⅲ nitric oxide synthase Ⅲ hypertension, essential Ⅲ polymorphism Ⅲ genetics W ith a genetic contribution of from 25% to 60%, human essential hypertension has a genetic basis. Among persons younger than age 50 years, essential hypertension occurs 3.8 times more often in those having two or more first-degree relatives who developed high blood pressure before age 55.1 NO synthesis by the vascular endothelium is important for the regulation of vasodilator tone and the control of blood pressure in humans.2 A recent study using mice with disrupted eNOS gene revealed that eNOS function is required for vascular and hemodynamic responses to acetylcholine and that the disruption of the eNOS gene leads to hypertension. 3 Moreover, recent reports demonstrate that whole-body NO production in patients with essential hypertension is diminished under basal conditions, as established by measurement of urinary and plasma nitrate. 4 In addition, the offspring of hypertensive patients exhibit a reduced response to acetylcholine linked to a defect in the NO pathway.5...

IntroductionWe previously demonstrated that brain natriuretic peptide (BNP) is a cardiac hormone mainly produced in the ventricle, while the major production site of atrial natriuretic peptide (ANP) is the atrium. 1. Abbreviations used in this paper: ANP, atrial natriuretic peptide; BNP, brain NP; ET-1, endothelin-1; HP-GPC, high performance gel permeation chromatography; -LI, like immunoreactivity; MLC-2, myosin light chain-2; PKC, protein kinase C.The identification of atrial natriuretic peptide (ANP)' in the cardiac atrium (1, 2) uncovered a new functional role of the heart as an endocrine organ regulating body fluid homeostasis and blood pressure control (3-5). ANP is mainly produced in and released from the atrium, and the plasma ANP concentration elevates in volume-overloaded states including congestive heart failure (6-8). In addition, the gene expression of ANP in the ventricle is markedly induced during the process of cardiac hypertrophy upon ventricular overload, and significantly contributes to the increase in the plasma ANP concentration in various cardiovascular disorders (9-11).Brain natriuretic peptide (BNP), originally isolated from the porcine brain (12), is a second member of natriuretic peptide family (3-5). We previously demonstrated that BNP is predominantly synthesized in and secreted from the cardiac ventricle (13-15). We have further shown that the ventricular gene expression of BNP is substantially augmented in response to ventricular overload in congestive heart failure, idiopathic cardiomyopathy, or hypertensive heart disease with cardiac hypertrophy (14-17). Although the plasma BNP concentration is approximately one-sixth of the plasma ANP concentration in healthy men, it markedly elevates in patients with congestive heart failure in parallel with its severity and surpasses the plasma ANP concentration in severe cases (14,(18)(19)(20). Furthermore, we have recently demonstrated that the plasma BNP concentration increases rapidly and tremendously, in contrast to the modest change of the plasma ANP concentration, in the early clinical course of acute myocardial infarction (21,22). These findings indicate that the biosynthesis and secretion of BNP are distinctly regulated from those of ANP in response to ventricular overload, and suggest that BNP may have a discrete pathophysiological role in the maintenance of cardiovascular homeostasis.The augmented productions of BNP and ANP in the hypertrophied myocardium can be considered as a compensation mechanism against ventricular overload, since BNP and ANP serve to reduce both cardiac preload and afterload by their natriuretic, diuretic, and vasodilatory actions (23)(24)(25). It will be of great importance to characterize the gene expressions of BNP and ANP during the development of cardiac hypertrophy, which also constitutes one of the principal adapting mechanisms against increased ventricular workload (26). The cellular mechanisms of the cardiac adaptations to ventricular overload, especially the expressions of various cardiac-spe...

These results demonstrate the rapid induction of ventricular BNP gene expression in rats with AMI compared with ANP and suggest that BNP gene expression in the ventricle is regulated distinctively from ANP gene expression against acute ventricular overload. They also suggest that the BNP gene can be one of the acutely responsive cardiac genes for the ventricular overload and suggest a possible pathophysiological role of BNP distinct from ANP in AMI.

Receptor-mediated activation of both adenylate cyclase and phosphatidylinositide hydrolysis systems occurs through guanine nucleotide regulatory proteins and ultimately leads to specific activation of either cyclic AMP-dependent protein kinase A or Ca2+/phospholipid-dependent protein kinase C. Given the remarkable diversity of agents that influence cellular metabolism through these pathways and the similarities of their components, interactions between the two signalling systems could occur. In fact, stimulation of cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA), a phorbol ester that activates protein kinase C, influences hormone-sensitive adenylate cyclase. In some cells TPA induces desensitization of receptor-mediated stimulation of adenylate cyclase, whereas in others, such as frog erythrocytes, phorbol ester treatment results in increased agonist-stimulated as well as basal, guanine nucleotide- and fluoride ion-stimulated adenylate cyclase activities. We show here that TPA produces phosphorylation of the catalytic unit of adenylate cyclase in frog erythrocytes. Moreover, purified protein kinase C can directly phosphorylate in vitro the catalytic unit of adenylate cyclase purified from bovine brain. These results suggest that phosphorylation of the catalytic unit of adenylate cyclase by protein kinase C may be involved in the phorbol ester-induced enhancement of adenylate cyclase activity. In addition to providing the first direct demonstration of a covalent modification of the catalytic unit of adenylate cyclase, these results provide a potential biochemical mechanism for a regulatory link between the two major transmembrane signalling systems.