Interaction of propranolol with central serotonergic neurons

Central monoaminergic mechanisms are believed to be involved in cardiovascular regulation. The present study was designed to evaluate the involvement of central serotonergic pathways in the antihypertensive action of propranolol in pentobarbital anesthetized mongrel dogs. Ventriculocisternal perfusion of propranolol (25 ug/kg/min for 30 min) decreased serotonin turnover as indicated by a significant decrease in cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA). This effect was accompanied by a significant reduction in mean arterial pressure and heart rate. These results indicate that propranolol decreases central serotonergic activity and suggests a possible role for central serotonergic pathways in the antihypertensive action of propranolol. Several studies have indicated that central serotonergic pathways participate in the regulation of blood pressure. Brainstem regions including the nucleus tractus solitarius, the raphe nucleus and the anterior hypothalamic preoptic region are involved in cardiovascular control and contain a dense population of serotonergic neurons. A centrally-mediated hypotensive effect of propranolol has been demonstrated. Centrally administered propranolol increases cerebrospinal fluid (CSF) levels of norepinephrine and reduces blood pressure possibly due to decreased peripheral sympathetic nerve activity. Central serotonergic pathways may also be involved in the antihypertensive action of some beta-adrenoceptor antagonists. Destruction of central serotonergic neurons with 5,7-dihydroxytryptamine and desipramine abolished the antihypertensive effect of intracisternal propranolol in sinoaortic denervated dogs. Acute administrations of (-)-propranolol and (-)-pindolol decreased the synthesis rate of serotonin, while acute administration of salbutamol, a beta 2-adrenoceptor agonist, increased 5-HIAA levels in rat brain structures. The present study was designed to evaluate the involvement of central serotonergic pathways in the antihypertensive action of propranolol.     

Adrenergic reactivity of the myocardium in hypertension

Adrenoceptor-mediated inotropic and chronotropic responses have been studied in isolated atria from a younger and an older group of spontaneously hypertensive (SHR) and age-matched normotensive rats (NR). The isoproterenol/phenylephrine potency ratios were significantly lower in the older SHR than in age-matched NR. Exposure of left atria to cocaine, iproniazid and tropolone to inhibit major pathways of agonist inactivation significantly enhanced the potency of both agonists in NR but did not influence agonist potencies in SHR and the agonist potency ratios remained different in the two groups. Inotropic responses to phenylephrine were blocked by metoprolol less effectively and by phentolamine more effectively in older SHR than in NR. Atrial sensitivity to isoproterenol was significantly higher in the younger than in the older SHR. Chronic treatment of SHR with propranolol, 5–20 mg/kg/day i.p. from age 4 to 14 weeks and stopped 2 days before the experiment, limited the increase in blood pressure and increased the potency of isoproterenol and decreased the potency of phenylephrine to or beyond levels in NR. The effectiveness of adrenoceptor antagonists in SHR did not significantly change with age or after propranolol treatment. The results were interpreted to indicate that 1) mechanisms of agonist inactivation are impaired or non-functional in the SHR myocardium; 2) there is a shift in the balance of cardiac inotropic adrenoceptors from β toward α between normotensive and hypertensive rats, and 3) β-adrenoceptors are subsensitive in adult SHR, but become supersensitive to isoproterenol after chronic treatment with propranolol.     

Norepinephrine turnover in the heart and blood vessels of rats subjected to bilateral renal infarction

The total norepinephrine (NE) content, the uptake of [3H]NE, the turnover rate and the synthesis rate of the neurotransmitter at the heart and blood vessels have been studied during the development of hypertension in rats subjected to bilateral renal infarction. Normal and sham-operated rats were used as controls. Fifty percent of the rats with renal infarction became hypertensive. The weight of the hearts and blood vessels of the experimental animals was significantly increased 15 days after renal infarction. Changes were greater in hypertensive animals. NE concentration in the heart was slightly decreased without achieving statistical significance, while total NE content was unchanged. In the artery wall NE concentration was significantly decreased in normotensive and hypertensive operated rats. [3H]NE uptake in the heart and blood vessels was similar in experimental and control animals. In relation to NE turnover, in both the heart and blood vessels, normal and sham-operated animals behaved as one population while normotensive and hypertensive rats behaved as another population. The rate constant of NE turnover was increased in both tissues of operated experimental animals without achieving statistical significance in the case of the heart. NE synthesis rate was unchanged in the cardiac muscle but was significantly increased in the blood vessels of operated animals. Present data indicate that results describing NE dynamics in the heart cannot be extrapolated for the blood vessels level; on the other hand changes in the neurotransmitter do not seem to be related to the development of high blood pressure after renal infarction in the rat.     

Effects of propranolol, nalorphine and haloperidol on the breathing and on the metabolism of PGI2 and TXA2 of normotensive and spontaneously hypertensive rats

The influence of propranolol, nalorphine and haloperidol on the breathing pattern and on the blood levels of cyclooxygenase products of anaesthetized spontaneously-breathing normotensive Wistar rats (WR) and of spontaneously hypertensive rats (SHR) were investigated. The respiratory rate was higher and the effective lung resistance was smaller in the SHR than in the WR. Breathing frequency decreased after nalorphine in both groups, while only in SHR after haloperidol. Propranolol augmented the dynamic lung resistance in both groups. The blood 6-keto-PGF1 alpha level was higher and the TXB2 level was lower in the SHR than in the WR. The central inspiratory activity as well as the levels of peripherally acting substances involved in the regulation of respiration and in the control of bronchial smooth muscle tone are different in the SHR and WR.     

Comparison of the effect of hypoxia on the secretion of the atrial natriuretic factor in spontaneously hypertensive and normotensive rats.

The effect of short lasting hypoxia on blood pressure, plasma atrial natriuretic peptide level and number of specific atrial granules were studied in 26 male spontaneously hypertensive and 24 normotensive Wistar rats. A great difference occurred in ANP secretion between hypertensive and normotensive rats. In the hypertensive animals elevated plasma ANP concentration (130 +/- 27 pg/ml) and decreased granularity in the right atria (73 +/- 2) were found on the first day of hypoxia with a slight elevation in urinary sodium content versus normotensive controls. The blood pressure also decreased although not significantly (190 +/- 14 mm Hg). In Wistar rats increased plasma ANP (130 +/- 34 pg/ml) and decreased atrial granularity versus normotensive controls (72 +/- 10 in the left and 113 +/- 16 in the right atrium) were observed only on the third day of hypoxia without changes in blood pressure and natriuresis. In SHR the rapid but short timed ANP release might be of right atrial origin and probably the consequence of a continuous and perhaps increased secretion of the peptide in normoxic conditions too. In Wistar rats the plasma ANP elevation could be secondary due to the increased plasma level of different vasoactive hormones to hypoxia. In the altered effect of ANP in hypertensive and normotensive hypoxic animals, structural and functional changes in the vascular bed may play a role.     

Role of autonomic nervous system on heart rate in experimental hypertension

Heart rate and the role of the autonomic nervous system in hypertensive conscious rats by subtotal nephrectomy were studied. Heart rate is significantly higher in the hypertensive rats. Sympathetic blockade with an intravenous injection of propranolol produces a higher decrease in heart rate of hypertensive rats than in control rats. Intravenous injection of atropine produces an increase in heart rate in both groups of animals. It is significantly higher in the control rats than in hypertensive animals. When the autonomic nervous system is blocked with atropine and propranolol, intrinsic heart rate is similar in both groups of animals. Similar results are obtained after blocking ganglionic transmission with hexamethonium. No significative differences are observed in heart rate after intracerebroventricular injection of hemicholinium-3 between both groups of rats. Results show an increased cardiac sympathetic tone, reduced parasympathetic activities, no alterations in the pacemaker activity and implications of central acetylcholine. These alterations in the autonomic nervous system have an important role in the maintenance of elevated heart rate in this experimental model of arterial hypertension.     

Uptake of serotonin by human platelets and its relevance to CNS involvement in hypertension.

The central serotonergic neurones seem to have important regulatory function on the cardiovascular system. Since human blood platelets and serotonin (5-HT) containing neurones in the central nervous system have numerous similarities, the uptake of serotonin by human platelets was investigated in normal subjects and in patients of essential hypertension. The 5-HT content of platelets as well as 5-HT uptake by the platelets were significantly reduced in hypertensive subjects as compared to control. It appears that a deficiency of serotonin centrally may lead to disinhibition of the serotonergic mechanisms leading to hypertension. Moreover, a decreased activity of serotonergic neurones may co-exist with an over-activity of catecholaminergic neurones in essential hypertension, which is discussed. This is probably the first report of altered serotonin mechanism in clinical hypertension.     

Hemodynamic and renal effects of ProANF31-67 in hypertensive rats.

It has been demonstrated previously that the atrial natriuretic factor prohormone fragment 31-67 (ProANF31-67) circulates in animals and possesses natriuretic and vasodilating actions. Although the plasma levels of the peptide are reportedly elevated in patients with high blood pressure, its role and actions in hypertension are unknown. In the present study, synthetic human ProANF31-67 was infused intravenously at doses of 0, 10, 30, and 100 ng/kg/min into respective groups of anesthetized normotensive and spontaneously hypertensive rats. Mean arterial pressure (MAP), urine flow rate (UV), and sodium excretion (UNaV) were measured during two consecutive 30-min periods. In both strains of rats, reductions in MAP with ProANF31-67 were similar in magnitude and dose-related. Sodium excretion responses to the peptide infusions also were remarkably similar in both normotensive and hypertensive rats, and the responses demonstrated 3- to 5-fold (P < 0.05) increments compared to control at the doses of 10 and 30 ng/kg/min. However, in the two strains of rats, attenuation of natriuresis occurred with the highest infusion dose of 100 ng/kg/min and was probably related to the large decreases in MAP of 17-23 mmHg at this dose of the peptide. The present results indicate the ProANF31-67 has important hemodynamic and renal effects in hypertension and may represent one compensatory mechanism involved in this disease.     

Moderate exercise training does not worsen left ventricle remodeling and function in untreated severe hypertensive rats.

Exercise training and hypertension induced cardiac hypertrophy but modulate differently left ventricle (LV) function. This study set out to evaluate cardiac adaptations induced by moderate exercise training in normotensive and untreated severe hypertensive rats. Four groups of animals were studied: normotensive (Ctl) and severe hypertensive (HT) Wistar rats were assigned to be sedentary (Sed) or perform a moderate exercise training (Ex) over a 10-wk period. Severe hypertension was induced in rat by a two-kidney, one-clip model. At the end of the training period, hemodynamic parameters and LV morphology and function were assessed using catheterism and conventional pulsed Doppler echocardiography. LV histology was performed to study fibrosis infiltrations. Severe hypertension increased systolic blood pressure to 202 +/- 9 mmHg and induced pathological hypertrophy (LV hypertrophy index was 0.34 +/- 0.02 vs. 0.44 +/- 0.02 in Ctl-Sed and HT-Sed groups, respectively) with LV relaxation alteration (early-to-atrial wave ratio = 2.02 +/- 0.11 vs. 1.63 +/- 0.12). Blood pressure was not altered by exercise training, but arterial stiffness was reduced in trained hypertensive rats (pulse pressure was 75 +/- 7 vs. 62 +/- 3 mmHg in HT-Sed and HT-Ex groups, respectively). Exercise training induced eccentric hypertrophy in both Ex groups by increasing LV cavity without alteration of LV systolic function. However, LV hypertrophy index was significantly decreased in normotensive rats only (0.34 +/- 0.02 vs. 0.30 +/- 0.02 in Ctl-Sed and Ctl-Ex groups, respectively). Moreover, exercise training improved LV passive filling in Ctl-Ex rats but not in Ht-Ex rats. In this study, exercise training did not reduce blood pressure and induced an additional physiological hypertrophy in untreated HT rats, which was slightly blunted when compared with Ctl rats. However, cardiac function was not worsened by exercise training.     

Dietary fish oils reduce plasma levels of platelet activating factor precursor (lyso-PAF) in rats

The object of this study was to develop an assay for platelet activating factor (PAF) in rat plasma, and to utilise this to determine the effects of dietary fish oil on PAF in normotensive and spontaneously hypertensive rats. Measurement of platelet activating factor in blood plasma has proved difficult because of its rapid hydrolysis in vivo to lyso PAF. We describe here a method based on the prior acetylation of lyso PAF extracted from plasma to PAF before bioassay using 14C-serotonin labelled platelets. The active material found in acetylated plasma extracts was characterized as PAF by its chromatographic mobility, the action of phospholipases A2, C and D and by cross-desensitization studies with rabbit platelets. Rats fed dietary fish oil ('max EPA') had significantly decreased plasma lyso-PAF levels compared to control animals fed hydrogenated coconut oil (HCO). Serum thromboxane B2 (TXB2) levels were also significantly lower in animals fed the 'max EPA' diet. Spontaneously hypertensive rats (SHR) had significantly lower plasma lyso-PAF levels than their normotensive Wistar Kyoto (WKY) controls maintained on the same diets. It is proposed that dietary alterations in PAF synthesis may influence platelet behaviour in addition to the well described effects of dietary fish oil on the proaggregatory prostanoid TXA2. Rat strain differences in lyso-PAF synthesis occur, but are unlikely to be related to the maintenance of hypertension in SHR.     

Vervet monkey (Cercopithecus aethiops sabaeus) whole blood serotonin level is determined by platelet uptake sites

Whole blood serotonin levels in adult male vervet monkeys living in social groups are sensitive to the animals' social environment. The mechanisms that translate different behavioral and environmental cues into altered whole blood serotonin levels are unknown. In this study, we have measured platelet number, size, serotonin content, and serotonin uptake, as well as the serum concentrations of tryptophan, Mg+2 and Ca+2. Results showed that whole blood serotonin levels, platelet serotonin content, and the serotonin uptake parameter Vmax were stable within animals on repeated sampling. The whole blood serotonin level was highly positively associated with platelet serotonin content, and the platelet serotonin content was highly positively associated with Vmax. These findings suggested that whole blood serotonin levels were a function of the number of platelet uptake sites.     

Abnormal regulation of the sympathoadrenal system in deoxycorticosterone acetate-salt hypertensive rats

With the use of circulating norepinephrine (NE) and epinephrine (E) levels, the sympathoadrenal activity as well as its local modulation by adrenoceptors were studied in normotensive (NT) and DOCA-salt hypertensive (HT) rats. In anesthetized hypertensive rats, plasma NE levels were higher, whereas in conscious animals both NE and E levels were found to be increased, suggesting an increased basal sympathoadrenal tone in these animals. The finding of a close correlation between blood pressure levels and NE levels suggests that the elevation of blood pressure may be linked to sympathetic system activity in this experimental model of hypertension. The reactivity of the sympathoadrenal system was also found to be increased in DOCA HT rats. Following a bilateral carotid occlusion of 1 min, which specifically activates the adrenal medulla, the elevation of E levels was found to be potentiated in intact or vagotomized HT rats. Moreover, in response to prolonged or acute hypotension in anesthetized and conscious animals, the elevation in plasma NE and E levels was found to be markedly potentiated in DOCA HT rats. The local modulating adrenoceptor-mediated mechanisms of the sympathoadrenal system appeared to be altered in this model of hypertension. Although it was possible to demonstrate that the E response to carotid occlusion can be greatly potentiated by administration of an alpha2-antagonist (yohimbine) and completely abolished by an alpha2-agonist (clonidine) in NT rats, the E response was found to be unaffected by the same treatments in HT rats, suggesting a reduced sensitivity in the alpha2-mediated inhibitory modulation of the adrenal medulla. Moreover, the acute treatment with a beta-blocker (sotalol) lowered circulating NE levels and blood pressure only in HT rats, suggesting the possibility of a more sensitive beta-receptor-mediated presynaptic facilitatory mechanism on sympathetic fibers of these animals. Finally, it was observed that the functional balance which exists between the activities of sympathetic fibers and the adrenal medulla in normotensive animals appears to be impaired in DOCA HT rats. In conclusion, the present studies suggest that the increased sympathoadrenal tone and reactivity may be due, in part, to a variety of dysfunctions in local adrenoceptor modulatory mechanisms of the sympathoadrenal system in DOCA hypertensive rats.     

Increased plasma level of asymmetric dimethylarginine in hypertensive rats facilitates platelet aggregation: role of plasma tissue factor

This study was designed to explore the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in platelet aggregation in hypertension and its possible mechanisms. Spontaneously hypertensive rats (SHR) and L-NAME-induced hypertensive rats were orally administered with L-arginine (1 g/(kg·day) for 14 days. Systolic blood pressure, platelet aggregation, and plasma tissue factor (TF) level and activity were measured. The plasma concentration of ADMA in SHR was determined. In vitro, platelet-rich plasma isolated from Wistar rats was prepared in order to observe the effect of exogenous ADMA on platelet aggregation and TF level and (or) activity in platelet-rich plasma. In both types of hypertensive rats, systolic blood pressure, platelet aggregation, and the level and activity of plasma TF were elevated compared with corresponding control animals. Plasma ADMA level was also increased in SHR. Treatment with L-arginine, a competitor of ADMA, lowered blood pressure and inhibited platelet aggregation concomitantly with a decrease in plasma TF level and activity in both types of hypertensive rats. We also found that exogenous ADMA promoted platelet aggregation and increased TF level and (or) activity in platelet-rich plasma, an effect that was inhibited by pretreatment with L-arginine. Importantly, the enhanced platelet aggregation induced by exogenous ADMA was reduced by pretreatment with anti-TF antibody. The results suggest that endogenous ADMA may be involved in platelet hyperaggregation status in hypertension, and the facilitation of platelet aggregation by ADMA is related to upregulation of the level and activity of plasma TF.     

Adrenaline-induced damage to the myocardium in rats with genetically determined arterial hypertension

Genetically hypertensive and normotensive rats were subjected to acute myocardial injury by a single subcutaneous injection of adrenaline (0.5 mg/100 g bw). The animals were sacrificed one day later. The lesions showed the signs of focal coagulative necrosis and intracellular myocytolysis. The damaged cardiomyocytes with high sarcolemmal permeability for blood plasma proteins were more widespread in the hypertensive versus normotensive rats. Intracellular myocytolysis, which is not associated with alterations in the cell membrane, was found in both experimental groups at an equal rate. The data agree with the concepts of alterations in biological membranes in genetically determined arterial hypertension.     

Influence of ovariectomy on cardiac oxidative stress in a renovascular hypertension model

The aim of this study was to evaluate the potential influence of endogenous ovarian hormones on cardiac oxidative stress in renovascular hypertension. Female Wistar rats (N = 10 per group) were divided among 4 groups: (i) normotensive control; (ii) hypertensive control; (iii) normotensive ovariectomized; and (iv) hypertensive ovariectomized rats. To induce hypertension, 2-kidney 1-clip (2K1C) Goldblatt's method was followed. Blood pressure (BP) was enhanced (25%) in 2K1C and it was not further altered in hypertensive ovariectomized animals. Lipid peroxidation (measured by thiobarbituric acid reactive substances; TBARS) increased in heart homogenates after ovariectomy (253%) and was additionally augmented when associated with hypertension (by 28%). Superoxide dismutase and catalase activities were similar in both hypertensive groups. Hypertension enhanced glutathione peroxidase activity (75%), but the association with ovariectomy prevented this change. Total radical trapping antioxidant potential (TRAP) decreased in hypertensive rats (34%) and was recovered when associated with ovariectomy. However, this adaptation seems not to be sufficient to avoid the increased oxidative damage in ovariectomized hypertensive animals. These results suggest a protective role for physiological ovarian hormones in the cardiac oxidative stress induced by 2K1C hypertension.     

Antihypertensive profile of the angiotensin-converting enzyme inhibitors CI-906 and CI-907

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.     

Minerals in renal and SHR hypertensive rats

References to individual trace minerals in hypertensive rats have been made; however, data on multiple minerals in SHR hypertensive rats is lacking. The purpose of this study was to investigate five trace minerals in normotensive, chronic renal and SHR hypertensive rats. Blood samples were drawn to measure serum levels of Ca, Fe, K, Mg, and Na. Serum K values were elevated in the chronic renal hypertensive animals. Iron levels were decreased in both the renal and SHR hypertensive animals. No difference was observed in levels of Ca, Mg, and Na between normotensive and chronic renal or SHR hypertensive rats. Further study of multiple trace minerals in experimental hypertension is recorded in order to extend these deviations.     

Effect of ketanserin and prazosin on blood pressure and cardiovascular reactivity to vasopressor agents during the development of two kidney-two clip renal hypertension in the conscious rat

The present experiment was performed in order to evaluate some of the actions of ketanserin, a blocking agent active at the serotonin 2 (S2) receptors. Male rats were divided into: 1. Two kidney-two clip (2K-2C) renal hypertensive: a silver clip (0.25 mm width) was placed in both renal arteries. 2. Sham-operated: a similar operation without placing the clip was performed. Blood pressure (BP), heart rate and pressor responses to tyramine, angiotensin II and norepinephrine (NE), and the hypotensive effect of prazosin (Pz) and ketanserin (Kt) were recorded in the conscious animals 8 weeks later. Results showed that Pz produced a similar decrease in BP in hypertensive and sham animals while Kt lowered BP much more in hypertensive than in normotensive rats. Prazosin abolished the pressor response to tyramine while ketanserin only diminished tyramine effect. Both hypotensive agents shifted the dose-response curve to NE to the right. Present data have shown that ketanserin and prazosin are effective hypotensive agents in 2K - 2C renovascular hypertension in the rat. They also suggest that both hypotensive compounds have an alpha 1-blocking effect, somehow they seem to have some differences in their pattern of pharmacological action.     

Growth hormone responses to clonidine and GRF in spontaneously hypertensive rats: neuroendocrine evidence for an enhanced responsiveness of brain alpha 2-adrenoceptors in genetical hypertension

Clonidine induces growth hormone (GH) release in rat. According to previous investigations this effect is mediated by postsynaptic alpha 2-adrenoceptors in the hypothalamus exerting a stimulatory influence on the recently discovered GH releasing factor (GRF). In the present study it is demonstrated that spontaneously hypertensive rats (SHR) of the Wistar-Kyoto strain display enhanced GH responses to clonidine as compared to normotensive Wistar-Kyoto control rats. In contrast, the GH responses to GRF are similar in hypertensive and normotensive animals. These findings indicate that brain alpha 2-adrenoceptors are more responsive in SHR than in normotensive controls. Since the enhanced GH responses to clonidine were observed also in young, prehypertensive SHR they are probably not secondary to the elevated blood pressure. The possible importance of an altered alpha 2-adrenergic neurotransmission for the development of elevated blood pressure in SHR is discussed.     

Effects of chronic L-NAME treatment on rat focal cerebral ischemia and cerebral vasoreactivity.

Nitric oxide has been shown to be involved in the regulation of cerebral blood flow and the consequences of cerebral ischemia. Short-term inhibition of its synthesis induces hypertension and increases the cortical infarct volume in focal ischemia. Our purpose was to investigate the influence of the long-term inhibition of nitric oxide synthase on infarct volume due to middle cerebral artery (MCA) occlusion and on the reactivity of cerebral arteries. Sprague Dawley rats were given N(omega)-nitro-L-arginine methyl ester (L-NAME) for 2 or 6 weeks and compared to untreated normotensive rats and untreated spontaneously hypertensive rats (SHRs). Brain nitric oxide synthase activity was measured by the 14C-L-arginine assay. Arterial blood pressure was measured in each group. Independently, the reactivity of MCA trees was studied in vitro by a perfusion technique. Cortical infarct volume was not significantly modified by either 2-week or 6-week L-NAME treatment, despite induced hypertension, whereas it was significantly higher in SHRs than in normotensive rats. The reactivity of the MCA tree was significantly affected by the treatment with a clearcut time-dependency. Compared to normotensive controls, contractility to noradrenaline and serotonin was reduced, more severely at 6 weeks, and while dilatation to acetylcholine and nitroprusside was moderately reduced at 6 weeks, dilatation to papaverine was then increased. A major difference of treated animals compared to SHRs was the decreased response to 5-hydroxytryptamine. We conclude that infarct expansion may be limited in treated animals by a progressive reduction in cerebral artery response to vasoconstrictory neurotransmitters, concomitant with augmented non-guanylate cyclase dilator responses (cf. papaverine) and some recovery of dilatation to acetylcholine.