BACKGROUND: One of prominent cardiovascular effects of imipramine is postural hypotension. The present study was to verify whether imipramine has a central hypotensive action and futher to investigate its mechanism of action. METHODS: Rats(male, Sprague-Dawley) weighing 250-300g were anesthetized with pentobarbital sodium(50mg/kg, ip). Imipramine was administered into the left lateral cerebral ventricle. Mean arterial pressure(MAP) and heart rate(HR) were continuously monitored from the right femoral artery. RESULTS: Intracerebroventricular(icv) imipramine(3micromol/kg) caused decrease in MAP without significant alterations in HR, of which safety dose-range was very narrow. 1micromol/kg did not affect MAP and 10micromol/kg caused deaths of animals within 10min. Intravenous infusion of the same dose(3micromol/kg) of imipramine caused only a transient hypotension within 5min. Hexamethonium-treated(1mg/kg/min) rats did not respond to icv imipramine. Regitine pretreatment(2mg/kg, iv) prevented the hypotensive response to icv imipramine. Yohimbine pretreatment(500microg/kg, icv) not only blocked the hypotensive effect, but it caused a transient pressor response to icv imipramine. CONCLUSIONS: These results indicate that imipramine has a separate hypotensive effect which is mediated through central alpha2-adrenoceptors.
Animals ; Blood Pressure ; Cerebral Ventricles ; Femoral Artery ; Heart ; Hypotension ; Hypotension, Orthostatic ; Imipramine* ; Infusions, Intravenous ; Pentobarbital ; Phentolamine ; Rats* ; Yohimbine

BACKGROUND: Prostaglandin system is known to participate in manifestation of the renin-angiotensin system. However, role of prostaglandins on the renin-angiotensin system in development of hypertension is not well established. This study was to examine whether the role of prostaglandins is altered in experimental hypertension. METHODS: Two-kidney, one-clip(2KIC) renal hypertension was made by clipping the left renal artery with a silver clip(internal gap of 0.2mm) and deoxycorticosterone acetate (DOCA)-salt hypertension by subcutaneous implantation of DOCA(200mg/kg) strip plus saline(1%) drinking. They were used 3 weeks later. Age-matched normal rats served as a control. Femoral artery was cannulated and arterial blood pressure and heart rate were monitored continuously. RESULTS: 1) In normotensive rats, saralasin infusion(20 microg/kg/min, IV) caused a decrease in mean arterial pressure without significant alterations in heart rate. Indomethacin-pretreatment(10mg/kg, IP) abolished the depressor response to saralasin. 2) The depressor response to saralasin was more marked in renal hypertensive rats than in normotensive rats. The magnitude of maximum decrease in blood pressure, however, was comparable between the hypertensive and normotensive rats. Indomethacin-pretreatment did not affect the depressor response to saralasin in renal hypertensive rats. 3) In DOCA-salt hypertensive rats, saralasin infusion rather caused an increase in mean arterial pressure without significant alterations in heart rate. The pressor response to saralasin was not affected by indomethacin-pretreatment. CONCLUSION: These results indicate that prostaglandin system may modify renin-angiotensin system in normotensive rats. It is suggested that mechanisms other than prostaglandin system participate in the full-blown manifestation of renin-angiotensin system in 2KIC renal hypertensive rats.
Animals ; Arterial Pressure ; Blood Pressure ; Desoxycorticosterone ; Drinking ; Femoral Artery ; Heart Rate ; Hypertension ; Hypertension, Renal ; Prostaglandins I ; Prostaglandins* ; Rats* ; Renal Artery ; Renin-Angiotensin System* ; Saralasin ; Silver

BACKGROUND: Aside from its well known peripheral antihypertensive effects, calcium also lowers blood pressure, when administered into the cerebral ventricle. The present study was aimed to determine whether the central depressor response to calcium is mediated by a stimulation of endogenous L-arginine-nitric oxide (NO) pathway. METHODA: Mean arterial pressure (MAP) and heart rate (HR) were continuously recorded from the femoral artery in anesthetized rats. Administration of calcium was performed into the right lateral cerebral ventricle. The effects of N G-nitro-L-arginine methyl ester (L-NAME) on the cardiovascular response to calcium were examined. RESULTS: Intracerebroventricular (ICV) injection of calcium consistently produced a decrease in MAP and HR. The depressor and bradycardiac responses to calcium showed a dose-dependent fashion. Pretreatment with a calcium channel blocker, diltiazem (1 micromol, ICV), attenuated cardiovascular responses to calcium. ICV infusion (1 microl/min) of L-NAME (200 microgram/kg and 20 microgram/kg/min for 60 min) increased MAP without significant changes in HR. Chronic ingestion of L-NAME (5 mg/100 ml in drinking water, 4 weeks) also increased the systolic blood pressure as compared with control. The depressor effect of ICV calcium was significantly diminished in acute or chronic L-NAME treated rats. CONCLUSION: These findings suggest that the central depressor response to calcium, at least in part, is NO-dependent.
Animals ; Arterial Pressure ; Blood Pressure ; Calcium Channels ; Calcium* ; Cerebral Ventricles ; Diltiazem ; Drinking Water ; Eating ; Femoral Artery ; Heart Rate ; NG-Nitroarginine Methyl Ester ; Nitric Oxide* ; Rats

It has been known that activation of tyrosine kinases is involved in signal transduction. Role of the tyrosine kinase in vascular smooth muscle contraction was examined in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Male Sprague-Dawley rats underwent uninephrectomy, one week after which they were subcutaneously implanted with DOCA (200 mg/kg) and supplied with 1% NaCl and 0.2% KCl drinking water for 4-6 weeks. Control rats were treated the same except for that no DOCA was implanted. Helical strips of carotid arteries were mounted in organ baths for measurement of isometric force development. Genistein was used as a tyrosine kinase inhibitor. Concentration-response curves to 5-hydroxytryptamine (5-HT) shifted to the right by genistein in both DOCA-salt hypertensive and control rats. Although the sensitivity to genistein was similar between the two groups, the maximum force generation by 5-HT was less inhibited by genistein in arteries from DOCA-salt hypertensive rats than in those from controls. Genistein-induced relaxations were attenuated in arteries from DOCA-salt rats. Genistein affected the contraction to phorbol 12, 13-dibutyrate (PDBu) neither in DOCA-salt nor in control arteries. These observations suggest that tyrosine kinase is involved in 5-HT-induced vascular contraction, of which role is reduced in DOCA-salt hypertension.
Animals ; Arteries ; Baths ; Carotid Arteries ; Desoxycorticosterone Acetate ; Desoxycorticosterone* ; Drinking Water ; Genistein ; Humans ; Hypertension ; Male ; Muscle, Smooth, Vascular ; Phosphotransferases* ; Protein-Tyrosine Kinases ; Rats* ; Rats, Sprague-Dawley ; Relaxation ; Serotonin ; Signal Transduction ; Tyrosine*

Endogenous nitric oxide(NO) plays an important role in the regulation of blood pressure. It has been known that the evoked NO-dependent dilator system may be impaired in various hypertensive models. The effects of NG-nitro-L-arginine(L-NNA), lipopolysaccharide(LPS) and tempol on mean arterial pressure(MAP) and the effects of L-NNA on isolated aorta tone were studied in order to elucidate potential alterations in resting vasodilator tone of NO in two-kidney, one clip(2K1C) hypertension. Plasma nitrite/nitrate levels were measured by colorimetric assay, and the expression of endothelial and inducible NO synthases(eNOS, iNOS) was determined by Western blot analysis. L-NNA caused an increase of MAP, while LPS produced a hypotensive effect in both 2K1C and control rats. The magnitude of the pressor or depressor response to L-NNA and LPS was comparable in the two groups. Tempol induced a sustained decrease in MAP in 2K1C rats, while it had no effects on MAP in control rats. Plasma concentrations of NO metabolites were significantly increased following the LPS-treatment in both 2K1C and control rats, while they were not affected by tempol-treatment. In endothelium-intact aortic rings precontracted with 25 mM KCl, L-NNA caused a dose-dependent contraction. The magnitude of the maximal contraction was attenuated in 2K1C rats as compared with control. An inhibition of contractile responses to L-NNA in the hypertensive group was also shown in rubbed rings, although the magnitude of contractions was markedly reduced. The vascular expression of both eNOS and iNOS was significantly decreased in 2K1C rats as compared with control. These results indicate that 2K1C hypertension is associated with a reduced basal vasodilator tone of NO and a decrease in the vascular expression of NOS isozymes.
Animals ; Aorta ; Blood Pressure ; Blotting, Western ; Hypertension ; Isoenzymes ; Nitric Oxide* ; Plasma ; Rats*

BACKGROUND AND OBJECTIVES: Protein tyrosine kinases appear to be involved in the signal transduction mechanisms, which result in vascular smooth muscle contraction, as well those required in cell growth. The present study was conducted to examine the role of tyrosine kinases in the norepinephrine-induced vascular smooth muscle contraction of isolated aortae from two-kidney, one clip (2K1C) hypertensive rats. MATERIALS AND METHODS: 2K1C hypertension was made by clipping the left renal artery of the rats, with age-matched rats receiving a sham treatment serving as controls. Thoracic aortae denuded of endothelium were mounted in tissue baths to measure the isometric tension. RESULTS: The putative tyrosine kinase inhibitors, genistein and tyrphostin 25, significantly inhibited the contractile responses of the aorta to norepinephrine in the control rats, but not in the 2K1C rats. The protein tyrosine phosphatase inhibitor, sodium orthovanadate, selectively potentiated the contractile response to norepinephrine, but only in the controls. Genistein, tyrphostin 25 and sodium orthovanadate did not affect KCl-induced vascular contractions in either the 2K1C or the controls. The vascular contraction elicited by phorbol 12, 13 dibutyrate, in the presence and absence of genistein, did not alter in either the 2K1C or the controls. CONCLUSION: These findings indicate that protein tyrosine kinases participate in the norepinephrine-induced contraction of rat aortic smooth muscle, where the role is attenuated in 2K1C renal hypertension.
Animals ; Aorta ; Aorta, Thoracic ; Baths ; Endothelium ; Genistein ; Hypertension ; Hypertension, Renal ; Muscle, Smooth ; Muscle, Smooth, Vascular ; Norepinephrine ; Phosphotransferases* ; Placebos ; Protein Tyrosine Phosphatases ; Protein-Tyrosine Kinases ; Rats* ; Renal Artery ; Signal Transduction ; Sodium ; Tyrosine* ; Vanadates

BACKGROUND: An increase of the extracellular K+concentrations up to about 8 mM in the isolated vessels causes relaxation in pre-contracted state. In order to elucidate the mechanisms of K+induced relaxation and compare with that of 2-kidney, 1 clip (2K1C) renal hypertensive rats, we recorded aortic vascular tension using an organ bath study. METHOD: 2K1C hypertension was made by clipping the left renal artery and age-matched control rats received a sham treatment. Thoracic aortic rings were mounted in tissue baths for measurement of isometric contractile force. RESULTS: Exposure to K+(from 2 to 8 mM) relaxed a phenylephrine (2 x 10-6 M)-induced contraction in K+free Krebs-Ringer solution, dose-dependently. Ouabain (10-5 M) enhanced the K+induced relaxation in above 2 mM K+ The K+induced relaxation was still induced in endothelium-denuded condition. Incubation with the K+channel blockers such as tetraethylammonium (TEA, 1 mM), glibenclamide (10-5 M), 4-aminopyridine (3 mM), barium (5 mM) and cesium (2 mM) did not affect on the K+induced relaxation. In renal hypertensive rats, the K+induced relaxation was markedly suppressed and ouabain enhanced it. CONCLUSIONS: These results suggest that the K+induced relaxation in aorta be mediated by Na-pump independent mechanisms, and the decrease of the K+induced relaxation in the renal hypertensive rats may be a possible mechanism of hypertension.
4-Aminopyridine ; Animals ; Aorta ; Barium ; Baths ; Cesium ; Glyburide ; Hypertension ; Muscle, Smooth* ; Ouabain ; Phenylephrine ; Placebos ; Rats* ; Relaxation ; Renal Artery ; Tetraethylammonium ; Vasodilation*

BACKGROUND: An increase of the extracellular K+concentrations up to about 8 mM in the isolated vessels causes relaxation in pre-contracted state. In order to elucidate the mechanisms of K+induced relaxation and compare with that of 2-kidney, 1 clip (2K1C) renal hypertensive rats, we recorded aortic vascular tension using an organ bath study. METHOD: 2K1C hypertension was made by clipping the left renal artery and age-matched control rats received a sham treatment. Thoracic aortic rings were mounted in tissue baths for measurement of isometric contractile force. RESULTS: Exposure to K+(from 2 to 8 mM) relaxed a phenylephrine (2 x 10-6 M)-induced contraction in K+free Krebs-Ringer solution, dose-dependently. Ouabain (10-5 M) enhanced the K+induced relaxation in above 2 mM K+ The K+induced relaxation was still induced in endothelium-denuded condition. Incubation with the K+channel blockers such as tetraethylammonium (TEA, 1 mM), glibenclamide (10-5 M), 4-aminopyridine (3 mM), barium (5 mM) and cesium (2 mM) did not affect on the K+induced relaxation. In renal hypertensive rats, the K+induced relaxation was markedly suppressed and ouabain enhanced it. CONCLUSIONS: These results suggest that the K+induced relaxation in aorta be mediated by Na-pump independent mechanisms, and the decrease of the K+induced relaxation in the renal hypertensive rats may be a possible mechanism of hypertension.
4-Aminopyridine ; Animals ; Aorta ; Barium ; Baths ; Cesium ; Glyburide ; Hypertension ; Muscle, Smooth* ; Ouabain ; Phenylephrine ; Placebos ; Rats* ; Relaxation ; Renal Artery ; Tetraethylammonium ; Vasodilation*

Bradykinin has been known to elicit a pressor effect when administered centrally, and a depressor effect when administered peripherally. The present study was aimed at investigating whether the blood pressure response to bradykinin is dependent on the endogenous generation of nitric oxide (NO). Effects of NG-nitro-L-arginine methyl ester (L-NAME) on the pressor and depressor responses to intracerebroventricularly and intravenously injected bradykinin (5nmol/rat), respectively, were examined in anesthetized rats. Neither the pressor response nor the depressor response was affected by acute parenteral treatment with L-NAME. The pressor and depressor effects of bradykinin were also noted in rats chronically supplemented with L-NAME in drinking water for 4 weeks. Bradykinin caused a relaxation of the isolated thoracic aorta in vitro, which was not affected in the presence of L-NAME. However, bradykinin failed to cause a relaxation of the aorta isolated from rats chronically treated with L-NAME. These findings suggest that endogenous generation of NO may not completely account for the blood pressure responses to bradykinin in rats.
Animals ; Aorta ; Aorta, Thoracic ; Blood Pressure* ; Bradykinin* ; Drinking Water ; NG-Nitroarginine Methyl Ester ; Nitric Oxide* ; Rats* ; Relaxation

BACKGROUND: Calcium plays a key role in vascular contraction and regulates receptor sensitivity to certain neurotransmitters. Calcium channel blockers are useful in the treatment of both clinical and experimental hypertension. The present study was designed to examine whether there is an alteration of the activity of calcium channels in association with the development of hypertension. METHODS: Deoxycorticosterone acetate(DOCA)-salt hypertension was made by subcutaneous implantation of DOCA(200mg/kg)strip plus saline drinking(1%) and 2-kidney, 1 clip(2KIC)hypertension by clipping the left renal artery with a silver clip(internal gap of 0.2mm). They were used 4 weeks later. Age-matched normal rats served as a control. Mean arterial pressure(MAP) and heart rate(HR) were continuously recorded from the right femoral artery. The drugs were administered intravenously. RESULTS: Vehicle alone was without effect on MAP or HR. In normotensive rats, nifedipine infusion(5 and 10ug/kg/min)caused a dose-dependent decrease in MAP without significant changes in HR, while Bay k 8644(Bay K, 5 and 10 ug/kg/min) increased MAP transiently. Both the depressor response to nifedipine and the pressor response to Bay k were more marked in DOCA-salt hypetensive rats than in normotensive rats. The maximal changes in MAP indced by nifedipine(5 and 50 ug/kg) or Bay K(5 and 50 ug/kg) were also enhanced in 2KIC hypertensive rats as compared with control rats. CONCLUSION: These results indicate that calcium channel inhibitors and activators can affect on the regulation of blood pressure in an opposite fashion. It is also suggested that the activity of calcium channels might be altered in the developement of experimental hypertension.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester* ; Animals ; Bays* ; Blood Pressure ; Calcium ; Calcium Channel Blockers ; Calcium Channels ; Desoxycorticosterone ; Femoral Artery ; Heart ; Hypertension ; Neurotransmitter Agents ; Nifedipine* ; Rats* ; Renal Artery ; Silver