Activation of potassium channels is a major mechanism of cerebral vasodilatation. Alteration of activity of potassium channels and impairment of vasodilatation may contribute to the development or maintenance of cerebral ischemia or vasospasm.

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 03% NaCI diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137±3 mm Hg versus 119±3 mm Hg, p<0.05; plasma norepinephrine, 0.40±0.02 ng/ml versus 0.27±0.01 ng/ml, p<0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an or-blocker (bunazosin, 10 rag/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCI), Insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model. (Hypertension 1992^0:596-600) KEY WORDS • insulin • rats, Dahl salt-sensitive • sympathetic nervous system O besity and non-insulin-dependent diabetes mellitus are frequently accompanied by hypertension. 1 -2 In obese hypertensive patients, a loss of body weight is often associated with parallel decreases in blood pressure and insulin levels.3 An inverse relation between whole body glucose uptake and blood pressure in nonobese subjects has been reported. 4 -3 These observations have focused attention on the relation between hyperinsulinemia and hypertension, 6 but since hyperinsulinemia is not always accompanied by hypertension, it is not clear whether hyperinsulinemia increases the blood pressure.It is possible that insulin may increase the blood pressure of some subjects but not others. Data from several studies have suggested that the activation of the sympathetic nervous system and sodium retention may play roles in insulin-induced increases in blood pressure. -8 These two mechanisms have also been reported to be involved in salt-overload hypertension (salt-sensitive hypertension). 9 These observations suggest that hyperinsulinemia may affect salt sensitivity.We investigated the effects of chronic hyperinsulinemia on blood pressure and its mechanisms in Dahl salt-sensitive (DS) and salt-resistant (DR) rats.From the Department of Cardiology, Surugadai Nihon University Hospital, Tokyo, Japan.Address for reprints: Hirofumi Tonuyama, MD, PhD, Department of Cardiology, Surugadai Nihon University Hospital, 1-8-13, Kandasurugadai, Chjyoda-ku, Tokyo, Japan, 101.Received December 6, 1991; accepted in revised form July 17, 1992. MethodsFour-week-old male DS and DR rats were obtained from Brookhav...

The role of Ca(2+)-dependent potassium channels in mediating vascular responses to activation of adenylate cyclase in vivo is not known. The goal of this study was to examine the hypothesis that dilatation of cerebral arterioles in response to activation of adenylate cyclase is mediated by activation of Ca(2+)-dependent potassium channels. Diameters of cerebral arterioles were measured in vivo in anesthetized rabbits. Topical application of forskolin (1 and 10 mumol/L), a direct activator of adenylate cyclase, dilated cerebral arterioles by 40 +/- 8% (mean +/- SEM) and 71 +/- 9%, respectively, from a control diameter of 85 +/- 4 microns. Iberiotoxin (50 and 100 nmol/L), a selective inhibitor of Ca(2+)-dependent potassium channels, inhibited dilatation in response to both concentrations of forskolin by 45% to 60%. We obtained similar results by using charybdotoxin (50 nmol/L), another inhibitor of Ca(2+)-dependent potassium channels. Vasodilatation in response to dibutyryl cAMP (a cell-permeable cAMP analogue) was also inhibited by iberiotoxin. In contrast, dilatation of cerebral arterioles in response to sodium nitroprusside and acetylcholine (activators of guanylate cyclase) and aprikalim (activator of ATP-sensitive potassium channels) was not inhibited by iberiotoxin. These findings suggest that dilatation of cerebral arterioles in response to forskolin and increases in intracellular concentrations of cAMP are mediated by activation of Ca(2+)-dependent potassium channels. Thus, activation of Ca(2+)-dependent potassium channels may be a major mechanism of cerebral vasodilatation in response to activation of adenylate cyclase in vivo.

We tested the hypothesis that dilatation of cerebral arterioles during hypoxia is mediated by activation of ATP-sensitive K' channels. The diameter of pial arterioles was measured through a closed cranial window in anesthetized rabbits. Topical application of aprikalim (10`6 mol/L), a direct activator of ATP-sensitive K' channels, dilated pial arterioles by 18+3% (mean+SEM). Glibenclamide (10`6 mol/L), an inhibitor of ATP-sensitive K' channels, virtually abolished aprikalim-induced vasodilatation. When arterial P02 was reduced from 129±3 to 25±1 mm Hg, the diameter of cerebral arterioles increased by 66±9% (P<.05). Glibenclamide inhibypoxia produces relaxation of cerebral blood H vessels and marked increases in cerebral blood flow.1-4 The mechanism that mediates hypoxia-induced vasodilatation in the cerebral circulation is poorly defined, although several studies suggest that adenosine may play an important role.5-7Activation of ATP-sensitive K' channels appears to be a major mechanism that mediates vasodilatation.8-11 In the coronary circulation, dilatation in response to hypoxia appears to be mediated by activation of ATPsensitive K' channels.12 The first goal of the present study was to test the hypothesis that activation of ATP-sensitive K' channels mediates dilatation of cerebral arterioles during hypoxia in vivo. We attempted to determine whether dilatation of cerebral arterioles in response to hypoxia is attenuated by glibenclamide, a selective inhibitor of ATP-sensitive K' channels.9'10 Several lines of evidence suggest that adenosine may contribute to cerebral vasodilatation during hypoxia. In some blood vessels, adenosine may activate ATP-sensitive K' channels.12-14 Thus, the second goal of the present study was to determine whether vasodilatation in response to adenosine is attenuated by glibenclamide. ited dilatation of pial arterioles during hypoxia by 46+5% (P<.05). In contrast, vasodilatation in response to sodium nitroprusside was not altered by glibenclamide. Topical application of adenosine (10 mol/L) increased arteriolar diameter by 21+4%. Glibenclamide did not affect adenosine-induced vasodilatation. These findings suggest that dilatation of cerebral arterioles in response to hypoxia is mediated, in part, by activation of ATP-sensitive K' channels. (Circ Res. 1994; 74:1005-1008 Key Words * cerebral microcirculation * aprikalim . glibenclamide * adenosine * sodium nitroprusside additional pentobarbital was administered intravenously. A tracheotomy was performed, and the animals were mechanically ventilated with room air and supplemental oxygen. Skeletal muscle paralysis was produced with gallamine triethiodide (4 mg/kg IV). Materials and Methods Animal PreparationA catheter was placed in a femoral artery to measure blood pressure and obtain arterial blood samples. A femoral vein was cannulated for infusion of drugs. Arterial blood gases were monitored and maintained at normal levels, except during the experimental induction of hypoxia. Core body temperature was measured continuously ...

Cilnidipine has a blocking action against N-type calcium channels as well as L-type calcium channels. We studied the effect of morning and bedtime dosing on circadian variation of blood pressure (BP), heart rate (HR), and activity of the autonomic nervous system, using an open randomized crossover study in 13 essential hypertensive patients. An automated device allowed 24-hour monitoring of ambulatory BP and HR and the power spectrum of the R-R interval, at the observation period, the morning dosing regimen, and the bedtime dosing regimen. Morning dosing and bedtime dosing with cilnidipine reduced the average systolic BP over 24 hours, during daytime, and during nighttime. The average HR and the average LF/HF ratio over 24 hours, during daytime, and during nighttime, were similar for the three periods. Both morning and bedtime dosing reduced the maximum systolic BP in the early morning and suppressed the morning rise of BP, which were accompanied by partial inhibition of the increase in LF/HF ratio. Our results show that cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system.