Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene.

Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality.

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Recent studies have indicated that chronic administration of iV"-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, produces marked hypertension. Although the mechanism of this form of hypertension is not well understood, several studies have demonstrated that sympathetic nerve activity is at least acutely elevated after L-NAME administration. To evaluate the potential role of the renal sympathetic nerves in L-NAMEinduced hypertension, we compared the blood pressure response to L-NAME in four groups of Sprague-Dawley rats (n=8 each): (1) sham-operated vehicle-treated, (2) shamoperated L-NAME-treated, (3) denervated vehicle-treated, and (4) denervated L-NAME-treated. After renal denervation or sham surgery, L-NAME was added to the drinking N itric oxide (NO) is now known to be an important participant in a variety of physiological processes, including several that influence arterial pressure.1 Acute administration of substituted arginine analogues that inhibit NO synthesis, including /V°'-nitro-Larginine methyl ester (L-NAME), results in a prompt increase in arterial pressure.2 -3 The immediate increase in arterial pressure may be principally due to an increased vascular smooth muscle tone as a consequence of decreased endothelial synthesis of NO. Increases in sympathetic nerve activity have been described after acute NO synthesis inhibition, 46 suggesting that neurogenic mechanisms may also contribute to the acute increase in arterial pressure.Several laboratories have recently reported that continued administration of inhibitors of NO synthesis induces a sustained hypertension.79 Although a precise mechanism by which continued NO synthesis inhibition may induce chronic hypertension remains to be identified, renal control of fluid and electrolyte balance is thought to play a dominant role in the long-term control of arterial pressure in both normal and pathophysiological states.10 ' 11 Renal sympathetic nerve activity is known to be increased at least acutely after administration of NO synthesis inhibitor, 46 and activation of the renal sympathetic nerves is known to inhibit renal sodium excretion and promote renal renin secretion. 12 Thus, we hypothesized that chronic L-NAME-induced hypertension may be, in part, the result of a sustained activation of the renal sympathetic nerves and the resultant resetting of renal fluid and electrolyte balance water (70 rngVlOO mL) for 4 weeks, and arterial pressure was measured weekly by the tail-cuff method. L-NAME treatment caused a progressive increase in arterial pressure in shamoperated rats, rising to 154±6 mm Hg by week 4 of treatment compared with 115±2 mm Hg in the vehicle-treated shamoperated group (P<.005). In contrast, the development of hypertension was significantly delayed and attenuated in renaldenervated rats treated with L-NAME. The results of our study suggest that L-NAME-induced hypertension may be partly mediated by or is at least dependent on the integrity of the renal nerves. Key Words • blood pressure • end...

Nitric oxide inhibits proliferation and migration of vascular smooth muscle cells and contractility of cardiomyocytes in vitro. In spontaneously hypertensive rats (SHR), evidence suggests intrinsic abnormalities of the L-arginine-nitric oxide axis, such as low cGMP-dependent protein kinase in the heart and abnormal L-arginine metabolism. To investigate the in vivo effect of L-arginine on cardiac hypertrophy, 30 SHR and 30 Wistar-Kyoto rats (WKY) were randomly grouped to receive L-arginine (7.5 g/L in drinking water) or vehicle for 12 weeks. L-Arginine treatment did not affect body weight or arterial pressure in either strain. In vehicle-treated animals, the heart/body weight ratio was significantly higher in SHR than in WKY (P < .01). L-Arginine treatment decreased the heart/body weight ratio in SHR (P < .05) but did not affect it in WKY. Expression of skeletal alpha-actin mRNA, known to be expressed in the hypertrophied myocardium, was attenuated in L-arginine-treated SHR compared with vehicle-treated SHR. Cardiac cGMP content and nitrate/nitrite content were less in SHR than WKY. L-Arginine treatment increased these levels only in SHR, suggesting enhanced nitric oxide production. Thus, chronic L-arginine administration attenuated cardiac hypertrophy independently of blood pressure and increased myocardial content of cGMP and nitrate/nitrite. Our results suggest that abnormality of the cardiac L-arginine-nitric oxide axis may play an important role in the pathogenesis of cardiac hypertrophy in SHR.