Effects of chronic ramipril treatment in streptozotocin-induced diabetic rats

The present investigation was undertaken to study the effects of chronic oral ramipril (1 mg/kg) treatment in streptozotocin (STZ) induced diabetic rats. Single tail vein injection of STZ (45 mg/kg, i.v.) produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinaemia and hyperglycaemia. The diabetic state was also found to be associated with bradycardia, hypothyroidism, cardiac depression and cardiomyopathy. Ramipril treatment prevented STZ-induced hypertension, bradycardia, hypothyroidism, hyperchosesterolaemia and partially the cardiomayopathy. Ramipril treatment could not, however prevent STZ-induced loss of body weight, polyuria, polydipsia, polyphagia, hyperglycaemia, hypoinsulinaemia, hypertriglyceridaemia and cardiac depression. Our data suggests that ramipril has a few beneficial effects in the STZ-treated diabetic rats.     

One-year Treatment of Streptozotocin-Induced Diabetic Rats with Vanadyl Sulphate

Streptozotocin-diabetic and non-diabetic rats were given various concentrations of vanadyl sulphate in drinking water for one year. It was found that vanadyl sulphate caused significant decreases in body weight gain and plasma insulin level in non-diabetic rats, but did not significantly alter fluid and food intakes or plasma levels of glucose, triglycerides, or cholesterol. In diabetic animals, vanadyl treatment significantly alleviated or prevented the occurrence of hyperglycaemia, hypoinsulinaemia, hyperphagia, polydipsia, hyperlipidaemia, or cataract formation, but the slower body weight gain was not improved. There were gradual decreases in the intake of the compound required to correct hyperglycaemia in the values of ED₅₀ with age of the rats. The beneficial effects of vanadyl treatment persisted 16 weeks following the withdrawal of the compound. It is concluded that vanadyl sulphate is an effective agent for chronic therapy of streptozotocin-induced diabetes in rats, and its prolonged use does not lead to the development of tolerance.     

Reversal of clonidine-induced hypotension by beta-adrenoceptor blocking drugs

The interaction between clonidine, propranolol and sotalol was investigated using conscious normotensive and spontaneously hypertensive rabbits as well as conscious normotensive and spontaneously hypertensive rats. Clonidine (20 micrograms/kg) administration into the marginal ear vein of rabbits produced persistent hypotension and bradycardia. In propranolol (0.5 mg/kg, i.v.)-pretreated animals, clonidine-induced hypotension was prevented. In rats, daily oral or subcutaneous clonidine as well as propranolol produced hypotension and bradycardia. Significant antagonism of the observed hypotensive effects resulted when clonidine was given to propranolol-pretreated animals or when propranolol was added to the treatment regimen of animals being maintained on clonidine. No antagonism between sotalol and clonidine was demonstrable. In view of the known central site of action of clonidine, and the failure of sotalol to antagonize clonidine-induced hypotension it would appear that the central nervous system is a possible site of the observed drug interaction.     

Anti-diabetic activity of Zingiber officinale in streptozotocin-induced type I diabetic rats

The fresh and dried rhizome of Zingiber officinale Roscoe (commonly known as ginger) is widely used in traditional medicine. We have studied the effect of the juice of Z. officinale (4 mL kg(-1), p.o. daily) for 6 weeks on streptozotocin (STZ)-induced type I diabetic rats with particular reference to the involvement of serotonin (5-hydroxytryptamine; 5-HT) receptors in glycaemic control. In normoglycaemic rats, 5-HT (1mg kg(-1), i.p.) produced hyperglycaemia and hypoinsulinaemia, which was significantly prevented by the juice of Z. officinale. STZ-diabetes produced a significant increase in fasting glucose levels that was associated with a significant decrease in serum insulin levels. Treatment with Z. officinale produced a significant increase in insulin levels and a decrease in fasting glucose levels in diabetic rats. In an oral glucose tolerance test, treatment with Z. officinale was found to decrease significantly the area under the curve of glucose and to increase the area under the curve of insulin in STZ-diabetic rats. Treatment with Z. officinale also caused a decrease in serum cholesterol, serum triglyceride and blood pressure in diabetic rats. Our data suggest a potential antidiabetic activity of the juice of Z. officinale in type I diabetic rats, possibly involving 5-HT receptors.     

Hypoglycaemic and anti-oxidant activity of Salacia oblonga Wall. extract in streptozotocin-induced diabetic rats

The petroleum ether extract of the root bark of S. oblonga Wall. (Celastraceae) (SOB) was studied in streptozotocin (STZ) diabetic rats and anti-lipid peroxidative activity of the same was studied in the cardiac tissue. SOB prevented significantly the streptozotocin-induced hyperglycaemia and hypoinsulinaemia. It also produced a significant decrease in peroxidation products viz. thiobarbituric acid reactive substances (P < 0.001), conjugated dienes (P < 0.05), hydroperoxides (P < 0.001). The activity of antioxidant enzymes such as superoxide dismutase (P < 0.001), catalase (P < 0.001), GSHPxase and GSSGRase was found to be increased in the heart tissue of diabetic animals treated with SOB. These results suggest that S. oblonga root bark extract possesses anti-diabetic and anti-oxidative activity in streptozotocin-diabetic rats.     

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Abstract: In the present study, we evaluated the effect of the α₂‐adrenoceptor agonist clonidine on tyrosine hydroxylase activity in adrenal medulla and brain of spontaneously hypertensive rats and Wistar Kyoto rats. Six‐week‐old animals were treated with clonidine (100 µg/kg body weight, daily, i.p.) for 4 weeks. Treatment with clonidine significantly reduced mean arterial blood pressure in spontaneously hypertensive rats to values similar to normotensive Wistar Kyoto rats. In the adrenal medulla of spontaneously hypertensive rats, clonidine treatment produced a significant increase in tyrosine hydroxylase activity with higher V_max values and no changes in K_M values. This effect was accompanied by a significant increase in tyrosine hydroxylase protein expression and of noradrenaline and adrenaline levels. In the brain of spontaneously hypertensive rats, treatment with clonidine produced a significant decrease in tyrosine hydroxylase activity with lower V_max values and no changes in K_M values accompanied by a significant decrease in tyrosine hydroxylase protein expression and of dopamine and noradrenaline levels. In Wistar Kyoto rats, clonidine treatment had no effect on tyrosine hydroxylase activity and protein expression or catecholamine levels in adrenal medulla or brain. Clonidine treatment significantly reduced noradrenaline and adrenaline plasma levels in spontaneously hypertensive rats and Wistar Kyoto rats. In conclusion, treatment with the α₂‐adrenoceptor agonist clonidine prevented the increase in mean arterial blood pressure in young spontaneously hypertensive rats. This effect was accompanied by opposite effects on tyrosine hydroxylase activity in spontaneously hypertensive rat adrenal medulla and brain: an increase in adrenal medulla and a decrease in brain, bringing sympathetic function to a similar profile found in normotensive Wistar Kyoto rats.     

Withdrawal syndrome upon cessation of chronic clonidine treatment in rats.

Clinical reports indicate that cessation of treatment with the antihypertensive agent clonidine is associated with a withdrawal syndrome which may include a hypertensive overshoot of critical proportions. We have attempted to produce an animal model of this syndrome in rats. Rats were treated with clonidine in the drinking water (5 microgram/ml; total dose 300-500 microgram/kg/day) which produced a significant (approx. 20%) decrease in heart rate and blood pressure. Within 24 h of cessation of treatment a significantly greater (approximately 100 beats/min) heart rate was seen in treated animals than in control animals when measurements were made in conscious animals. No hypertensive overshoot was observed. Cessation of treatment was associated with an increase in sympatho-adrenal tone as shown by a trans-synaptic induction of adrenal tyrosine hydroxylase activity. Adrenal denervation prevented the rise in adrenal tyrosine hydroxylase seen after cessation of treatment. Administration of clonidine to pregnant rats (10th day until term) did not alter the development of adrenal tyrosine hydroxylase in the offspring. The data indicate that a withdrawal syndrome is produced upon cessation of chronic clonidine treatment.     

The potential antidiabetic activity of some alpha-2 adrenoceptor antagonists.

The effect of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on the plasma glucose and insulin levels was studied in non-diabetic control, type-I (insulin-dependent) and type-II (non-insulin-dependent) diabetic rats. Pretreatment with either yohimbine or efaroxan potentiated glucose-induced insulin release in non-diabetic control rats and produced an improvement of the oral glucose tolerance and potentiated glucose-induced insulin release in type-II but not in type-I diabetic rats. Treatment with either yohimbine or efaroxan reduced the plasma glucose level and increased the plasma insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Effects of efaroxan were more marked. Pretreatment of non-diabetic control and type-II diabetic rats with either yohimbine or efaroxan inhibited clonidine-induced hyperglycaemia and suppressed or reversed clonidine-induced hypoinsulinaemia. Also, pretreatment of these animals with either yohimbine or efaroxan enhanced the hypoglycaemic and insulinotropic effects of glibenclamide. The combination of glibenclamide and efaroxan led to a synergistic increase in insulin secretion, while that of glibenclamide and yohimbine led to an additive increase. The hyperglycaemic effect of diazoxide in non-diabetic control and type-II diabetic rats was inhibited by pretreatment with either yohimbine or efaroxan. The hypoinsulinaemic effect of diazoxide in these animals was antagonized and reversed by pretreatment with yohimbine and efaroxan, respectively. In type-I diabetic rats, there was no change in the plasma glucose and insulin levels induced by the treatment of animals with each of clonidine or diazoxide alone or in combination with either yohimbine or efaroxan. Glibenclamide produced a slight decrease in the plasma glucose level of type-I diabetic rats, at the end of the 120 min period of investigation but there was no change in the plasma insulin level. Pretreatment of these animals with either yohimbine or efaroxan produced no change in glibenclamide effects. Additionally, bath application of efaroxan or glibenclamide inhibited the relaxant effects of different concentrations of diazoxide on the isolated norepinephrine-contracted aortic strips, while the application of yohimbine produced insignificant changes. The combination of glibenclamide and efaroxan led to complete inhibition of the relaxant effects of different concentrations of diazoxide, while that of glibenclamide and yohimbine did not produce such an effect. It is concluded that yohimbine, via blockade of postsynaptic alpha-2 adrenoceptors, and efaroxan, via blockade of postsynaptic alpha-2 adrenoceptors and adenosine triphosphate-sensitive potassium channels in the pancreatic beta-cell membrane, produce insulinotropic and subsequent hypoglycaemic effects.     

Effect of insulin treatment on long-term diabetes-induced alteration of myocardial function

Six months following the induction of diabetes by streptozotocin (50 mg/kg i.v.) diabetic rats exhibited elevated levels of plasma glucose and glycosylated hemoglobin. Plasma insulin levels were 50% of control and diabetic animals weighed significantly less than control. Using a working heart preparation it was found that (+) and (-) dP/dt and left ventricular pressure development (LVDP) was decreased in hearts from diabetic animals. Insulin treatment (9 U/kg/day s.c. of protamine zinc insulin) for 4 weeks prior to sacrifice restored body weight and plasma insulin to normal. Plasma glucose and glycosylated hemoglobin levels were significantly decreased towards normal in insulin treated diabetic rats. LVDP and (+) dP/dt was also partially returned to normal in insulin treated diabetic rats while (-) dP/dt was completely reversed to normal. Thus, 4 weeks of insulin treatment to rats previously diabetic for 5 months partially or totally reversed the changes produced by diabetes.     

Cardiovascular effects of 6-hydroxydopamine injected into a lateral brain ventricle of the rat

Summary 6-Hydroxydopamine (6-OH-DA) was injected into the left lateral brain ventricle of normotensive, DOCA/NaCl or spontaneously hypertensive rats, and its effect on heart rate and blood pressure was studied. A single injection of 250 g 6-OH-DA or 3 successive administrations of the same dose caused a reduction of noradrenaline content and tyrosine hydroxylase activity in several parts of the brain to 10–50% of the control values, indicating a considerable destruction of central adrenergic neurons. Heart rate and blood pressure decreased within 10 to 20 min after a single intraventricular injection of 6-OH-DA and both parameters returned to normal after 7 h. This effect was equally observed in normotensive and both types of hypertensive rats and regardless of whether the animals were conscious or anaesthetized. It was prevented by a prior intraventricular injection of phentolamine; this suggests that it is mediated by central alpha-adrenoceptors. The 6-OH-DA-induced bradycardia and hypotension were not influenced by a blockade of peripheral muscarinic receptors with scopolamine methylbromide; however, they were accompanied by a decrease of spontaneous discharges in the splanchnic nerve and, therefore, seem to be due to a reduction in peripheral sympathetic tone.The early cardiovascular effects of 6-OH-DA were sometimes followed by a second phase of bradycardia and hypotension. It occurred in normotensive rats 1–2 days after the second or third intraventricular injection of 6-OH-DA, and in spontaneously hypertensive rats already after a single injection. The hypotension of the second phase lasted 5–6 days, the bradycardia showed no recovery during the observation period which was limited to 3 weeks. Such long term cardiovascular effects of intraventricular 6-OH-DA were never observed in DOCA/NaCl hypertensive rats even after repeated administrations of the compound. The results provide evidence for the existence of a central adrenergic regulation of blood pressure and heart rate which seems to differ in normotensive and hypertensive rats.Preliminary results have been presented at the 11 th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, Gerold and Thoenen, 1970).     

Changes in vascular reactivity in experimental hypertensive animals following treatment with indapamide

Indapamide at doses of 8–16 mg kg^?1 day^?1, orally, lowered arterial blood pressure (9–26 mm Hg) in conscious renal hypertensive cats during a two week treatment period. The antihypertensive effect was sustained for 5–7 h after dosing and was not accompanied by reflex tachycardia. Antihypertensive responses to injection of clonidine (20 μg, i.c.v.) were significantly enhanced one week after the completion of indapamide treatment but had returned to normal two weeks later. In DOCA/saline hypertensive rats, administration of indapamide 10 mg kg^?1 day^?1, orally, or hydrochlorothiazide, 5 mg kg^?1 day^?1, intraperitoneally, for 10 days produced similar falls in blood pressure (40–45 mm Hg) as measured by an indirect method. Pressor responses to intravenous noradrenaline or tyramine or electrical stimulation of the sympathetic outflow in the pithed rat preparation were much reduced by pretreatment with indapamide (10 mg kg^?1, orally) for 10 days. However, cardiovascular reactivity was unaffected by hydrochlorothiazide pretreatment (5 mg kg^?1 day^?1, i.p.). Isolated perfused mesenteric artery***/preparations from indapamide-treated rats showed no changes in reactivity to noradrenaline, 5-hydroxytryptamine or adenosine-5′-triphosphate from those of control DOCA/saline hypertensive rats. Isolated portal veins from rats pretreated with indapamide showed contractile responses to noradrenaline similar to those of control animals although the frequency of spontaneous contractions was reduced in the former group. The results support a vascular site of action for indapamide and suggest a mode of action different from that of hydrochlorothiazide.     

Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine

Modification of clonidine-induced cardiovascular effects by endothelin-1 (ET-1) was studied in male Sprague-Dawley rats. A dose-dependent decrease in blood pressure and heart rate was produced by clonidine (100, 250 and 500 μg/kg i.v.). Lower doses produced only a fall in blood pressure (through central -adrenoceptors) while higher doses of clonidine produced an initial hypertensive response (through peripheral -adrenoceptors) and subsequent longer lasting hypotension and bradycardia. The hypotension and bradycardia induced by 100 and 250 μg/kg i.v. dose of clonidine were completely blocked by ET-1 (100 ng/kg i.v.) pretreatment. Conversely, the hypertensive response induced by high dose of clonidine (500 μg/kg i.v.) was significantly potentiated by ET-1 pretreatment. In cervical sectioned rats, i.v. administered clonidine failed to produce any hypotensive effect, indicating lack of central effect of clonidine. ET-1 significantly (P< 0.0005) potentiated the hypertensive response of a low dose (50μg/kg i.v.) of clonidine in cervical-sectioned rats. I.c.v administration of clodinine (1, 2, 4 and 6 μg) produced a dose-dependent decrease in blood pressure and heart rate. ET-1 pretreatment (25 ng i.c.v. transietly blocked the clonidine-induced decrease in blood pressure and heart rate for about 10 min but the hypotension and bradycardia was observed subsequently. Since the major site of action of clonidine is the ventral surface of medulla, clonidine was applied directly to the ventral surface of medulla and produced a decrease in blood pressure and heart rate. ET-1 pretreatment at the ventral surface of medulla blocked the clonidine-induced decrease in blood pressure and heart rate initially but the fall in blood pressure and heart rate was observed subsequently. To explore the possibility that transient antagonism of clonidine-induced effects is due to vasoconstriction, studies were performed with angiotensin II, a powerful vasoconstrictor. Angiotensin II (5 μg i.c.v.) pretreatment like ET-1 blocked the hypotensive and bradycardic effect of i.c.v. or i.v. administered clonidine. It is concluded that ET-1 blocks the hypotensive and potentiates the hypertensive effect of clonidine, possible mechanisms have been discussed.     

Effects of pentobarbitone and decerebration on the clonidine-induced circulatory changes.

Clonidine 5 and 15 mug/kg i.v. was given to conscious rats, to rats under pentobarbitone anaesthesia and to decerebrated rats. Clonidine 100 mug/kg was given to conscious and to decerebrated rats. Blood pressure and heart rate were recorded via indwelling catheters. The low dose of clonidine gave virtually no response in the conscious rats but produced hypotension and bradycardia in decerebrated and in anaesthetized rats. After clonidine 15 mug/kg the blood pressure of decerebrated rats decreased further, while conscious and anaesthetized rats showed a hypertensive response. The basal blood pressure and heart rate were significantly higher in the decerebrated rats than in the conscious rats. After the highest dose of clonidine, however, the blood pressure of the decerebrated rats decreased below the basal level of the conscious rats and the blood pressure of the conscious rats increased above the basal level of the decerebrated rats. The results suggest that the hypotensive response is caused by a mechanism located in the medulla oblongata. At higher concentrations clonidine may elicit a hypertensive effect by activating suprabulbar centers. The importance of this suprabulbar effect is attenuated by pentobarbitone anaesthesia.     

Protective effect of Melothria maderaspatana leaf fraction on electrolytes, catecholamines, endothelial nitric oxide synthase and endothelin-1 peptide in uninephrectomized deoxycorticosterone acetate–salt hypertensive rats

This study was designed to investigate the protective effect of ethyl acetate fraction of Melothria maderaspatana (EAFM) leaf on electrolytes, catecholamines, endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) peptide in uninephrectomized deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Administration of DOCA-salt significantly increased the systolic and diastolic blood pressure and treatment with EAFM significantly lowered the blood pressure. In DOCA-salt rats, the levels of sodium and chloride increased significantly while potassium level decreased and administration of EAFM brought these parameters to normality. The levels of epinephrine and norepinephrine increased significantly in DOCA-salt rats and administration of EAFM significantly decreased these parameters to normality. DOCA-salt hypertensive rats exhibited significantly decreased L: -arginine and nitrite + nitrate levels and administration of EAFM brought these parameters to normality. DOA-salt hypertensive rats showed down-regulation of eNOS and up-regulation of ET-1 protein expressions in heart and kidney, and treatment with EAFM prevented down-regulation of eNOS and significantly down-regulated the ET-1 protein expressions. In conclusion, EAFM provides good blood pressure control by enhancing potassium and decreasing sodium levels, decreasing levels of epinephrine and norepinephrine, and preventing down-regulation of eNOS and significantly down-regulating ET-1 protein expression.     

Antihypertensive activity of indolepyruvic acid: a keto analogue of tryptophan.

We studied the effect of indole-3-pyruvic acid (IPA) on systolic blood pressure of normotensive, spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive rats. Experiments were also carried out in order to investigate whether IPA may influence the development of hypertension in spontaneously hypertensive rats. Age-matched normotensive, spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive rats treated with N-methylglucamine, were used as controls. Acute oral (up to 50 mg/kg) and intravenous (5 mg/kg) administration of IPA did not change systolic blood pressure in any models of hypertension. By contrast, a repeated administration of IPA (100 mg/kg/day, by oral gavage for 10 days) significantly decreased systolic blood pressure in all models of hypertension, while it elicited no significant effect in normotensive rats. Moreover, when IPA was given daily to 5-week-old spontaneously hypertensive rats for 7 weeks, it partially inhibited the development of hypertension. In addition, chronic administration of IPA caused enhanced levels of tryptophan and 5-hydroxyindoleacetic acid in the cortex and diencephalon. Brainstem serotonin content in both normotensive and spontaneously hypertensive rats was also enhanced by IPA treatment. Our results suggest that IPA lowers blood pressure in different rat models of hypertension and this effect seems to be correlated with an increase in cerebral serotonin metabolism.     

Streptozotocin diabetes protects against arrhythmias in rat isolated hearts: role of hypothyroidism

We examined the contribution of hypothyroidism to streptozotocin diabetes-induced alterations in the arrhythmia susceptibility of ex vivo hearts to regional zero-flow ischaemia. Diabetic rats received either protamine zinc insulin (10 IU/kg/day, s.c.) or triiodothyronine (10 microg/kg/day, s.c.) for 8 weeks commencing 72 h after injection of streptozotocin (60 mg/kg, i.p.). Arrhythmias were determined in ex vivo Langendorff-perfused hearts, subjected to a 30-min main left coronary artery occlusion, followed by 30-min reperfusion. Serum free thyroxine concentrations, rectal temperature and ex vivo heart rate were significantly decreased in the 8-week diabetic group (P<0.001). These changes were prevented by administration of triiodothyronine or insulin. Ventricular fibrillation during reperfusion was abolished in hearts from diabetic rats. This protection was prevented by treatment with either triiodothyronine or insulin. Hearts from methimazole-hypothyroid rats also showed no ventricular fibrillation during reperfusion. The protection against ischaemia-reperfusion-arrhythmias observed in hearts from streptozotocin-diabetic rats may be due to diabetes-induced hypothyroidism.     

Effect of lesions of the nucleus tractus solitarii on the cardiovascular actions of clonidine in conscious rats.

Clonidine has been postulated to produce cardiovascular effects, the most noticeable of which are hypotension and bradycardia, by interaction with the nucleus tractus solitarii (NTS), a cranial nucleus in the dorsal medulla. The experiments reported herein, examined the effects of clonidine (30 μg/kg, i.v.) prior to and following bilateral electrolytic lesioning of the NTS. The studies were performed in conscious, spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Clonidine produced marked hypotension and bradycardia in conscious, NTS-intact SHR. Intact WKY exhibited a biphasic response to clonidine with an initial hypertension preceeding a moderate decrease in blood pressure. Heart rate responded similarly to the SHR. Lesioning of the NTS, in both SHR and WKY, induced hypertension. Virtual abolition of the hypotension and bradycardia to clonidine was noted in lesioned SHR upon subsequent administration of clonidine. Nucleus tractus solitarii lesioning in WKY did not significantly alter clonidine-induced hypotension; however, the initial hypertensive phase was abolished following lesioning and bradycardia was blunted. These results indicate that the NTS plays an important role in the mediation of both the hypotension and bradycardia seen with clonidine in SHR. The differing responses of SHR and WKY to clonidine after NTS lesions may also indicate altered functional roles for the NTS in these two strains.     

In vivo Study of Angiotensin II Tachyphylaxis in Freely Moving Normo- and Hypertensive Rats

In vivo tachyphylaxis to the angiotensin II-induced increase in mean arterial blood pressure was studied in conscious freely moving rats by telemetry blood pressure monitoring. The animals studied were the normotensive Sprague Dawley rats (SD), the spontaneously hypertensive rats (SHR), and two models of experimentally-induced hypertensive rats, namely, the left renal artery stenosed SD hypertensive rat (LRAS) and the deoxycorticosterone acetate/salt SD hypertensive rat (DOCA). Two consecutive dose-response curves to angiotensin II in each rat were obtained. The increase in mean arterial pressure (MAP) at each bolus dose of the first dose-response curve was found not to be significantly different from the corresponding value of the second dose-response curve in the four models of rat studied (i.e. no significant difference in the intra-rat response to AII). In addition, the slope of the dose-response curve is similar for each model of rat indicating that there was no inter-model variation to the response of AII. The results show that the response to AII in the SD and the three models of hypertensive rats was remarkably similar and that they did not develop tachyphylaxis to the pressor response of AII at concentrations ranging from circulating level of 0.0005 nmoles/kg (10^?11 M) to 10 nmoles/kg (2 × 10^?7 M). This was despite the fact that the SD had normal blood pressure and the genesis of hypertension in each model of the hypertensive rats was different. These findings support our earlier suggestion that the development of tachyphylaxis to the concentration range of AII in in vitro preparations is prevented from occurring in the intact animal by circulating spasmogens.     

Essential oil of Croton nepetaefolius decreases blood pressure through an action upon vascular smooth muscle: studies in DOCA-salt hypertensive rats

Experiments tested the hypothesis that hypotensive effects of intravenous (i.v.) treatment with the essential oil of Croton nepetaefolius (EOCN) result from its vasodilatory effects directly upon vascular smooth muscle. In both deoxycorticosterone-acetate (DOCA)-salt hypertensive and uninephrectomised control, conscious rats, i.v. bolus injections of EOCN (1 to 50 mg/kg) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-related manner. Treatment with DOCA-salt significantly enhanced EOCN-induced decreases in MAP without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. hexamethonium (30 mg/kg), a ganglion blocker, were significantly greater in DOCA-salt hypertensive than in control rats. In DOCA-salt hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg) reduced the bradycardia elicited by EOCN (50 mg/kg) without affecting the enhancement of EOCN-induced hypotension. In isolated thoracic aorta preparations from DOCA-salt hypertensive rats, EOCN (1-300 micrograms/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction. Arteries from DOCA rats showed increased sensitivity to EOCN, as evidenced by the significant decrease in the IC50 for EOCN-induced reduction of phenylephrine-induced contraction (16.4 +/- 3.6 vs. 112.9 +/- 23.4 micrograms/ml in uninephrectomized controls). These results show that i.v. treatment with EOCN dose-dependently decreases blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement appears to be related mainly to an increase in EOCN-induced vascular smooth muscle relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model. Thus, the hypothesis that EOCN may be a direct vasorelaxant agent is supported by the results of the present study.     

Hypothalamic responsiveness in DOCA hypertensive rats augmented by streptozotocin-induced diabetes

In rats with deoxycorticosterone acetate (DOCA) salt hypertension, induction of diabetes with streptozotocin did not aggravate the elevation in blood pressure, but pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were enhanced. Along with glycosuria and hyperglycemia, the other effects of streptozotocin-induced diabetes were: reduced body weight, increased fluid intake, and bradycardia. Despite enhanced responsiveness to hypothalamic stimulation, blood pressure increases produced by intravenous injections of norepinephrine, tyramine, or vasopressin were unaltered. When pressor responses were compared in diabetic rats drinking either tap water or isotonic saline solution, no appreciable differences occurred. It was considered possible that hypothalamic responsiveness was enhanced in diabetic-DOCA hypertensive rats by increases not only in sympathetic nerve firing but also in release of endogenous norepinephrine.