Antioxidant treatment with alpha-tocopherol improves erectile function in hypertensive rats.

There is no known treatment for erectile dysfunction (ED) in hypertensive patients. We tested whether or not antioxidative therapy improves ED in the setting of hypertension. Spontaneously hypertensive rats (SHRs) were treated with a control chow or an alpha-tocopherol-enriched chow (12 or 24 mg/100 g chow) for 8 weeks. The isometric tension of corpus cavernosum strips from these SHRs was recorded. nNOS and HO-2 gene expression and NOx, cGMP, thiobarbituric acid-reacting substance (TBARS), and superoxide dismutase (SOD) activity levels were determined in serum and tissue. Relaxation in response to electrical field stimulation (EFS) in the corpus cavernosum increased after the administration of alpha-tocopherol at a dose of 24 mg/100 g chow. This effect was inhibited by a nitric oxide synthase (NOS) inhibitor and by a heme oxygenase (HO) inhibitor, nNOS and HO-2 gene expression and NOx concentrations in the corpus cavernosum were similar between 24 mg alpha-tocopherol-fed SHRs and controls. Tissue cGMP levels were greater in alpha-tocopherol-fed SHRs than in controls. Treatment with 24 mg alpha-tocopherol decreased TBARS levels and increased SOD activity in the serum and corpus cavernosum. Relaxation in response to acetylcholine chloride in the corpus cavernosum was improved with alpha-tocopherol treatment at each dose. These results suggest that alpha-tocopherol treatment increases the diminished relaxation in the corpus cavernosum of SHRs by improving neuronal or endothelial function related to nitric oxide and carbon monoxide. This, in turn, indicates that antioxidant therapy may play a role in treatment for ED in hypertensive patients.

Is renoprotection by angiotensin receptor blocker dependent on blood pressure?: the Saitama Medical School, Albuminuria Reduction in Diabetics with Valsartan (STAR) study.

To explore the effects of various antihypertensive regimes on microalbuminuria, an angiotensin II receptor blocker (ARB), valsartan, was substituted for or added to treatment with a calcium channel blocker (CCB). After a 6-month CCB baseline period, 28 Japanese hypertensive patients with incipient diabetic nephropathy (defined as a urinary albumin excretion [UAE] of 30-300 mg/g creatinine), were assigned to two groups according to their blood pressure (BP) levels: in patients with a BP of more than 130/85 mmHg (n=17), valsartan was added to the CCB (Group A), while in patients with a BP <130/85 mmHg, valsartan alone was given (Group B: n=11) for 12 months. UAE was determined before and at 3, 6 and 12 months after the initiation of ARB. Although the initial BP was significantly higher in Group A (150/83 mmHg) than Group B (127/77 mmHg), BP was decreased to 141/78 mmHg in Group A and slightly, but not significantly, increased to 130/82 mmHg in Group B. In both groups, UAE was significantly decreased after ARB treatment (to 89% of the basal value in Group A and to 40.5% of the basal value in Group B) and did not differ each other and the amount of decrease did not differ significantly between the two groups. These results suggest that combination therapy with an ARB and CCB is very effective in lowering BP and UAE in cases in which BP is not well controlled, while, even in patients with a sufficient BP control of <130/85 mmHg, the use of ARB singly resulted in a significant decrease in UAE without a further decrease in BP, implying that the ARB had a renoprotective action independent of changes in BP.

Erectile dysfunction in hypertensive rats results from impairment of the relaxation evoked by neurogenic carbon monoxide and nitric oxide.

Erectile dysfunction (ED) with aging and diabetes mellitus is caused by impairment of the relaxation evoked by nitric oxide (NO) of penile cavernous smooth muscles and arterioles. However, the mechanism of ED in hypertension is unknown. Carbon monoxide (CO), which is produced by heme oxygenase (HO)-2 in the neuronal system is a neurotransmitter and a vasodilator. We examined the neurogenic role of CO in penile erection and the neurogenic mechanisms of ED in hypertension, using spontaneously hypertensive rats (SHR) or Wistar-Kyoto rats (WKY). The isometric tension of corpus cavernosum tissues from both strains was recorded after guanethidine and atropine treatment. Relaxation in response to electrical field stimulation (EFS) in WKY was suppressed dose-dependently by HO inhibitors both in the absence and presence of an NO synthase (NOS) inhibitor. Reverse transcription-polymerase chain reaction (RT-PCR) showed that the HO-2 gene was expressed in the corpus cavernosum. CO-saturated solution induced a concentration-dependent relaxation in WKY. The neurogenic relaxation to EFS in SHR was impaired as compared with that in WKY after the age of 5 weeks, when blood pressure began to be elevated, due to the attenuated relaxation in response to neurogenic NO and CO. In the corpus cavernosum of SHR, expression of the HO-2 and nNOS genes was similar, and NOx levels after EFS were similar to those of WKY. cGMP levels after EFS and the relaxation evoked by the NO donor was lower in SHR than WKY. Thiobarbituric acid-reacting substance (TBARS) levels were increased, and superoxide dismutase (SOD) activity was suppressed in SHR, as compared with those in WKY, suggesting that the increasing oxidative stress partially causes the impairment of NO-dependent relaxation. These findings suggest that CO regulates the relaxation evoked by EFS in the rat corpus cavernosum, and that ED in hypertension in rats results from an impairment of the relaxation induced by neurogenic CO and NO.

Effects of a low dose of indapamide, a diuretic, given daily or every-other-day on blood pressure and metabolic parameters.

To investigate the effects of the diuretic, indapamide, on blood pressure (BP) and metabolic parameters, thirty hypertensive patients were treated with 1 mg of indapamide either every day or every other day. BP, fasting plasma glucose, lipids, serum potassium and uric acid were determined at baseline and after 3 months of a stable regimen of the drug. At the termination of the study, 48-h ambulatory blood pressure monitoring (ABPM) was performed. Three patients received only indapamide, while other patients were treated in combination with additional antihypertensive medications. Patients treated with daily indapamide showed a BP reduction from 162 +/- 2.9/85 +/- 2.4 mmHg to 134 +/- 2.4/71 +/-2.6 mmHg (p < 0.001). The BP reduction was similar in those patients receiving the drug every other day (137 +/- 3.4/71 +/- 3.6 mmHg). While plasma lipids and serum potassium did not differ significantly with the intervention, uric acid increased significantly with daily treatment and normalized with every-other-day treatment. Glycosylated hemoglobin A1c (HbA1c) was not altered (5.6 +/- 0.1% vs. 5.4 +/- 0.2%), and did not differ between patients with and without diabetes mellitus. ABPM revealed an average 24-h BP of 134 +/- 3.3/75 +/- 1.7 mmHg on days in which patients received the medication and 139 +/- 4.9/78 +/- 2.6 mmHg on the intervening day without indapamide (no significant difference). These results suggest that a low dose of indapamide given every day or every other day is effective in lowering BP and does not result in metabolic derangements.

Combined treatment with an AT1 receptor blocker and angiotensin converting enzyme inhibitor has an additive effect on inhibiting neointima formation via improvement of nitric oxide production and suppression of oxidative stress.

Accumulating evidence shows that inhibition of the vascular renin-angiotensin system results in suppression of injury-elicited neointima formation. We attempted to determine whether or not combined treatment with an angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) has an additive inhibitory effect on balloon-injury-elicited neointima formation in the carotid artery. Male Sprague-Dawley rats were treated with an ARB (valsartan: 3 mg/kg/day) and/or an ACEI (benazepril: 0.3 mg/kg/day) from 1 week before until 2 weeks after balloon injury. Experiments were also conducted with one-third of the dose combination used in the original experiments. Both ARB and ACEI inhibited neointima formation without any blood pressure changes. The full-dose combination lowered blood pressure and suppressed neointima formation significantly compared with the levels in the groups treated with either ACEI or ARB alone. The low-dose combination without blood pressure reduction also inhibited neointima formation to a similar extent as the full-dose combination. We measured 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a marker of oxidative stress, and nitrite and nitrate (NOx), an index of nitric monoxide production, in media conditioned by the injured artery. NOx production was lower and 8-iso-PGF2alpha was higher in the media of the injured artery, compared with those in the normal artery. ACEI restored NOx production more dramatically than ARB, and ARB suppressed 8-iso-PGF2alpha markedly compared with ACEI. These results suggest that the combination of an ARB and an ACEI exerts an additive inhibitory effect, presumably through an increase in production and bioavailability of NO from the endothelium.

Effect of cilnidipine on insulin sensitivity in patients with essential hypertension.

To clarify the effect of cilnidipine, a long-acting dihydropyridine Ca-antagonist that blocks both L- and N-type Ca(2+)-channels, on insulin sensitivity, cilnidipine at 5 to 10 mg/day was administered to ten patients with essential hypertension for 12 weeks. Mean age and body mass index (BMI) were 57.7 +/- 5.0 (SEM) years old and 27.1 +/- 1.5, respectively. Blood pressure, serum levels of catecholamines, glucose and lipid were determined before and after the treatment. Insulin sensitivity was also measured by a euglycemic hyperinsulinemic clamp method using an artificial pancreas (STG-22; Nikiso, Tokyo, Japan) before and after the treatment. Cilnidipine administration significantly lowered blood pressure from 154/96 to 137/84 mmHg (p<0.05). The glucose infusion rate was significantly increased by 20.8%, from 3.27 +/- 0.36 to 3.95 +/- 0.55 mg/kg/min (p<0.05). HbA1C and serum lipid levels such as total cholesterol and triglyceride were not altered. In addition, cilnidipine treatment did not significantly increase serum norepinephrine levels (278 +/- 25.2 vs. 332 +/- 33.6 pg/ml). Our results suggest that cilnidipine improves insulin sensitivity, possibly due to its exerting a vasodilatory action without stimulating sympathetic nervous activity.

Effect of p53 deficiency on external vascular cuff-induced neointima formation.

The p53 tumor suppressor gene may act as an inhibitor of vascular neointima formation in response to injury and in the present study the effects of p53 deficiency on external vascular cuff-induced neointima formation were evaluated. Vascular neointima formation was induced by an external vascular cuff; a polyethylene tube placed around a 2 mm segment of the left femoral artery ensheathed the adventitia, but avoided direct intraluminal injury. Two weeks after cuff placement, the cuff-sheathed and contralateral control arteries without cuff from wild-type (n=10) and p53 deficient (n=8) mice were harvested and analyzed by quantitative morphometry. The areas of the lumen, intima, and media were measured in 10 cross-sections from one edge to the other of the cuffed portion, and in the corresponding 2-mm segment of the contralateral control artery. The volume ratio of the intima to media (I/M) was calculated. The contralateral control arteries without a cuff did not have intima in either wild-type or p53 deficient mice. In the cuff-sheathed arteries, neointima formation of p53 deficient mice with an I/M of 93% was significantly greater than that of wild-type mice with an I/M of 50% (P=0.001). The absence of p53 is associated with increased neointima formation in response to cuff injury.