Genetic hypertension results from numerous phenotypic expressions. We hypothesized that increased calcium current in vascular smooth muscle of genetically hypertensive animals is partly responsible for observed increases in agonist sensitivity, contractility, and calcium influx. Using adult, spontaneously hypertensive stroke-prone rats (SHRSP) and normotensive Wistar-Kyoto (WKY) controls from an inbred colony, we characterized calcium current in smooth muscle cells isolated from cerebral arteries. The cerebral arterial circulation is an important regional vascular bed in the end-stage pathology of hypertension. In the cerebral arterial circulation, changes in

Abstract-Dietary fat contributes to the elevation of blood pressure and increases the risk of stroke and coronary artery disease. Previous observations have shown that voltage-gated Ca 2ϩ current density is significantly increased in hypertension and can be affected by free fatty acids (FAs). We hypothesized that a diet of elevated fat level would lead to an increase in blood pressure, an elevation of L-type Ca 2ϩ current, and an increase in saturated FA content in vascular smooth muscle cell membranes. Male Osborne-Mendel rats were fed normal rat chow or a high-fat diet (Ob/HT group) for 8 weeks. Blood pressures in the Ob/HT group increased moderately from 122.5Ϯ0.7 to 134.4Ϯ0.8 mm Hg (PϽ0.05, nϭ26). Voltage-clamp examination of cerebral arterial cells revealed significantly elevated L-type Ca 2ϩ current density in the Ob/HT group. Voltage-dependent inactivation of the Ob/HT L-type channels was significantly delayed. Total serum FA contents were significantly elevated in the Ob/HT group, and HPLC analyses of fractional pools of FAs from segments of abdominal aorta revealed that arachidonic acid levels were elevated in the phospholipid fraction in Ob/HT. No differences in vascular membrane cholesterol contents were noted. Plasma cholesterol was significantly elevated in portal venous and cardiac blood samples from Ob/HT rats. These findings suggest that an elevation of plasma FAs may contribute to the development of hypertension via a process involving the elevation of Ca 2ϩ current density and an alteration of channel kinetics in the vascular smooth muscle membrane. (Hypertension. 2000;35:832-837.)

Abstract-Linoleic acid, a polyunsaturated C 18 fatty acid, is one of the major fatty acids in the coronary arterial wall. Although diets rich in linoleic acid reduce blood pressure and prevent coronary artery disease in both humans and animals, very little is known about its mechanism of action. We believed that its beneficial effects might be mediated by changes in vascular tone. We investigated whether linoleic acid induces relaxation of porcine coronary artery rings and the mechanism involved in this process. Linoleic acid and two of its metabolites, 13-hydroxyoctadecadienoic acid (13-HODE) and 13-hydroperoxyoctadecadienoic acid (13-HPODE), induced dose-dependent relaxation of prostaglandin (PG) F 2␣ -precontracted rings that was not affected by indomethacin (10 Ϫ5 mol/L), a cyclooxygenase inhibitor, or cinnamyl-3,4-dihydroxy-␣-cyanocinnamate (CDC; 10 Ϫ5 mol/L), a lipoxygenase inhibitor. Removal of endothelial cells had no effect on vasorelaxation, suggesting a direct effect on the vascular smooth muscle cells (VSMC). When rings were contracted with KCl, linoleic acid failed to induce relaxation. Although tetrabutylammonium (5ϫ10 Ϫ3 mol/L), a nonselective K ϩ channel blocker, slightly inhibited the relaxation caused by linoleic acid, glibenclamide (10 Ϫ6 mol/L), an ATP-sensitive K ϩ channel blocker, and charybdotoxin (7.5ϫ10-activated K ϩ channel blockers, had no effect. However, relaxation was completely blocked by ouabain (5ϫ10 Ϫ7 mol/L), a NaIn addition, linoleic acid (10 Ϫ6 mol/L) caused sustained hyperpolarization of porcine coronary VSMC (from -49.5Ϯ2.0 to -60.7Ϯ4.2 mV), which was also abolished by ouabain. We concluded that linoleic acid induces relaxation and hyperpolarization of porcine coronary VSMC via a mechanism that involves activation of the Na Key Words: linoleic acid Ⅲ nitric oxide Ⅲ prostaglandins Ⅲ endothelium-derived hyperpolarizing factorinoleic acid, a polyunsaturated C 18 fatty acid (18:2n-6), is one of the main essential fatty acids, and is one of the major fatty acids in the arterial wall, 1 which can be liberated by phospholipase activity.2,3 Linoleic acid is the principal precursor of arachidonic acid (20:4n-6), which is the substrate for synthesis of prostaglandins and thromboxane A 2 . Structurally related derivatives of arachidonic acid and linoleic acid have been demonstrated in blood vessels and related tissues. Linoleic acid can be enzymatically or nonenzymatically 4 converted to 13-HPODE, which can be further reduced to 13-HODE. Production of these hydro(per)oxy metabolites has been reported in aortas from rats, rabbits, and cows, 1 and unlike the fetal calf aorta 5 their formation is independent of cyclooxygenase activity. Lipoxygenation of linoleic acid resulted in 13-HODE formation in endothelial cells.6 Linoleic acid metabolites are formed in larger quantities than the corresponding arachidonic acid metabolites, 1 suggesting that they may be of biological significance.Several studies have suggested that hypertension and cardiovascular disease are caused in part by a relat...

Introduction Limited efficacy and safety data exist from open-label clinical trials of phosphodiesterase 5 inhibitors in men with erectile dysfunction (ED) and multiple comorbid (MCM) conditions, historically a difficult group to treat. Aim A multicenter study (Multiple Observations in Men with Erectile Dysfunction in National Tadalafil Study in the US) assessed efficacy and safety of tadalafil in men with ED and MCM conditions. Main Outcome Measures The primary end point was change from baseline in the erectile function (EF) domain of the International Index of Erectile Function. Secondary end points included the Sexual Encounter Profile, Global Assessment Questions, and Sexual Self-Confidence and Spontaneity Domains of the Psychological and Interpersonal Relationship Scales. Methods This was an open-label, multicenter study in men with ED. Tadalafil 20 mg was administered as needed prior to sexual activity, up to once/day, for 12 weeks following a 4-week ED-treatment-free period. The MCM group was 155 of 1,911 men enrolled in this study. Men in the MCM group met eligibility criteria but could not be included in other predefined groups: (i) Caucasian; (ii) Black American; (iii) Hispanic (groups 1–3, ≤65 years, no diabetes or depression); (iv) depression, ≤65 years, no diabetes; (v) diabetes, ≤65 years, no depression; (vi) >65 years, no diabetes or depression; and (vii) ED subsequent to traumatic spinal cord injury. Results Mean baseline EF domain score in MCM (mean age 65 ± 9 years) was 12.2 ± 6.5; 52% of subjects had severe ED; 72% diabetes mellitus; 67% cardiovascular disease (including hypertension); 49% hyperlipidemia; 38% depression; 84% had two or more comorbidities. At end point, there was a significant (P <0.001) mean change of 7.6 from baseline in mean EF domain score. Among men with severe ED, 22% achieved an EF domain score ≥26. Most common adverse events were headache 5.2%; flushing 3.9% and nasal congestion 3.2%; 3% discontinued use because of an adverse event. Conclusion In this open-label clinical trial of older men with ED and MCMs, tadalafil 20 mg significantly increased all efficacy end points and was well-tolerated.