Responsiveness of α2-adrenoceptor/I1-imidazoline receptor in the rostral ventrolateral medulla to cardiovascular regulation is enhanced in conscious spontaneously hypertensive rat.

Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Switching therapy from variable-dose multiple pill to fixed-dose single-pill combinations of angiotensin II receptor blockers and thiazides for hypertension.

The efficacy and tolerability of switching therapy from free combinations of angiotensin II receptor blocker (ARB) and thiazide (A/T) to a fixed-dose of losartan and hydrochlorothiazide (L/H) has not been evaluated in Japan. We examined effects of switching therapy from variable-dose multiple-pill A/T to a fixed-dose L/H on blood pressure (BP) along with medication adherence and the degree of satisfaction in 91 hypertensive outpatients (mean age, 65.2 ± 9.6 years). After 6 months, a significant BP reduction (132 ± 9/76 ± 10 vs. 126 ± 12/72 ± 11 mm Hg), along with an improvement of attaining target BP (44.0 vs. 61.5%) and that of adherence, were observed. The magnitude of BP reduction in the participants increased their degree of satisfaction more significantly than in the participants who worsened their degree of satisfaction. The estimated glomerular filtration rate and the serum uric acid (UA) level decreased slightly but significantly. The hemoglobin A1c of participants with diabetes mellitus increased slightly but significantly. In conclusion, a switch in therapy from variable-dose, multiple-pill A/T combinations to a fixed-dose, single-pill L/H was effective in decreasing BP and serum UA in Japanese clinical practice. Metabolic side effects of L/H in patients with diabetes mellitus remain to be investigated.

Pioglitazone, a thiazolidinedione derivative, attenuates left ventricular hypertrophy and fibrosis in salt-sensitive hypertension.

Thiazolidinediones, which stimulate peroxisome proliferator-activated receptor gamma, have been shown to prevent cardiovascular injury. However, little is known about their effects on salt-sensitive hypertension. We thus investigated whether or not pioglitazone affects left ventricular (LV) hypertrophy in Dahl salt-sensitive rats, then compared its effects to those of an angiotensin II receptor blocker, candesartan. Rats were used at 16 weeks of age after they had been fed either a low-salt (0.3%; DSL) or high-salt (8%; DSH) diet for 10 weeks; some of the DSH rats were treated with pioglitazone (10 mg/kg/day) or candesartan (4 mg/kg/day). Both drugs decreased the elevated blood pressure in DSH rats, although it was still higher than in DSL rats. Both drugs decreased plasma insulin levels, but neither affected plasma glucose levels. The thiobarbituric acid reactive substance level in the LV was decreased by both drugs. LV hypertrophy evaluated by echocardiography in DSH rats was nearly normalized by both drugs, whereas only candesartan decreased LV diameter. In histological analysis, both drugs ameliorated LV fibrosis and myocardial cell hypertrophy. Both drugs decreased elevated gene expression levels of transforming growth factor-beta1 and collagen type I, although the pioglitazone action was slightly modest. The metalloproteinase activity was increased in DSH rats, but both drugs decreased this level. Taken together, these findings indicate that pioglitazone reduced LV hypertrophy and fibrosis in salt-sensitive hypertension. Improvement in blood pressure, insulin level, and oxidative stress may be associated with this beneficial action of pioglitazone.

Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats.

Beneficial effects of thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, on cardiovascular injuries have been reported. However, the effects of these agonists on left ventricular (LV) hypertrophy have not been clarified. To investigate whether pioglitazone improves LV hypertrophy, we used 32-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) that had been treated or not treated with pioglitazone (10 mg/kg/day) for 8 weeks, and Wistar Kyoto rats (WKY). We evaluated LV geometry by echocardiography; myocyte hypertrophy, tissue fibrosis, and appearance of myofibroblasts by histological examination; mRNA expression by real-time polymerase chain reaction (PCR); protein expression by Western blot; activities of matrix metalloproteinase (MMP) by zymography; and production of reactive oxygen species (ROS) by electron spin resonance spectroscopy or thiobarbituric acid reactive substances (TBARS). SHR-SP showed concentric hypertrophy of the LV, but WKY did not. The myocyte diameter, fraction of tissue fibrosis, and number of myofibroblasts were greater in SHR-SP. mRNA expressions of collagen type I and type III, tissue growth factor (TGF)-beta1, and brain natriuretic peptide (BNP); protein expression of connective tissue growth factor (CTGF); activities of MMP2 and MMP9; and ROS were increased in SHR-SP. Pioglitazone did not decrease blood pressure, but partially normalized LV geometry in addition to decreasing myocyte diameter, interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen type I and BNP; MMP2 activity; and protein level of CTGF. However, the mRNA level of collagen type III and TGF-beta1, MMP9 activity, and ROS production were not improved. In conclusion, pioglitazone reversed the concentric LV remodeling independently from blood pressure or oxidative stress in chronic hypertension.

Azelnidipine attenuates cardiovascular and sympathetic responses to air-jet stress in genetically hypertensive rats.

Azelnidipine is a new dihydropyridine calcium channel blocker that causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. In the present study, we examined the effects of oral or intravenous administration of azelnidipine on cardiovascular and renal sympathetic nerve activity (RSNA) responses to air-jet stress in conscious, unrestrained stroke-prone spontaneously hypertensive rats. Oral administration of high-dose azelnidipine (10 mg/kg per day) or nicardipine (150 mg/kg per day) for 10 days caused a significant and comparable decrease in blood pressure, but low-dose azelnidipine (3 mg/kg per day) did not. Air-jet stress increased mean arterial pressure (MAP), heart rate (HR) and RSNA. High-dose azelnidipine significantly attenuated the increases in MAP, HR and RSNA in response to air-jet stress while nicardipine did not. Low-dose azelnidipine significantly attenuated the pressor response with a trend of decrease in RSNA. Intravenous injection of azelnidipine induced a slowly developing depressor effect. To obtain a similar time course of decrease in MAP by azelnidipine, nicardipine was continuously infused at adjusted doses. Both drugs increased HR and RSNA significantly, while the change in RSNA was smaller in the azelnidipine group. In addition, intravenous administration of azelnidipine attenuated the responses of MAP, HR, and RSNA to air-jet stress; by comparison, the inhibitory actions of nicardipine were weak. In conclusion, oral or intravenous administration of azelnidipine inhibited cardiovascular and sympathetic responses to air-jet stress. This action of azelnidipine may be mediated at least in part by the inhibition of the sympathetic nervous system.

Sympathetic hyperreactivity to air-jet stress in the chromosome 1 blood pressure quantitative trait locus congenic rats.

A chromosome 1 blood pressure quantitative trait locus (QTL) was introgressed from the stroke-prone spontaneously hypertensive rats (SHRSP) to Wistar-Kyoto (WKY) rats. This congenic strain (WKYpch1.0) showed an exaggerated pressor response to both restraint and cold stress. In this study, we evaluated cardiovascular and sympathetic response to an air-jet stress and also examined the role of the brain renin-angiotensin system (RAS) in the stress response of WKYpch1.0. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to air-jet stress in WKYpch1.0, WKY, and SHRSP. We also examined effects of intracerebroventricular administration of candesartan, an ANG II type 1 receptor blocker, on MAP and HR responses to air-jet stress. Baseline MAP in the WKYpch1.0 and WKY rats were comparable, while it was lower than that in SHRSP rats. Baseline HR did not differ among the strains. In WKYpch1.0, air-jet stress caused greater increase in MAP and RSNA than in WKY. The increase in RSNA was as large as that in SHRSP, whereas the increase in MAP was smaller than in SHRSP. Intracerebroventricular injection of a nondepressor dose of candesartan inhibited the stress-induced pressor response to a greater extent in WKYpch1.0 than in WKY. Intravenous injection of phenylephrine caused a presser effect comparable between WKYpch1.0 and WKY. These results suggest that the chromosome 1 blood pressure QTL congenic rat has a sympathetic hyperreactivity to an air-jet stress, which causes exaggerated pressor responses. The exaggerated response is at least partly mediated by the brain RAS.