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Extensive research has provided few therapeutic agents for the treatment of septicemia. Bradykinin, an endogenous vasodepressor hormone, is a key mediator in the hypotension seen with septicemia. The present investigation shows that a stable metabolic fragment of bradykinin, arginine-proline-proline-glycine-phenylalanine (RPPGF), prevents the deleterious effects of endotoxin [lipopolysaccharide (LPS); a component of the membrane of Gram negative bacteria], the signaling agent responsible for the effects of septicemia, in both anesthetized rats and in isolated rat aortic segments. Survival time of rats treated with LPS (12 mg/kg) was significantly (p < 0.05) prolonged by pretreatment with RPPGF [140.3 +/- 16 min (n = 10)] compared with rats receiving saline and LPS [93.2 +/- 8 min (n = 39)]. Prolongation of survival was not seen when rats were pretreated with either bradykinin or with PRGFP (proline-arginine-glycine-phenylalanine-proline). Isolated aortic segments treated with LPS (30 microg/ml) showed a significantly reduced ability to contract in response to phenylephrine compared with control segments not receiving LPS. Pretreatment of the segments with RPPGF significantly reversed the LPS-induced reduction in contractile response of the segments. Removal of the endothelial layer did not alter the protection provided by RPPGF. These results demonstrate the ability of a stable metabolic fragment of bradykinin, RPPGF, to protect against the deleterious effects produced by LPS. The findings presented here may provide the basis for a new developmental area for novel therapeutic agents in the treatment of septicemia.

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Microinjections of kallikrein, 0.5-2.0 units, in the rostral ventrolateral medulla (RVLM) of brain increased arterial pressure in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). This effect was significantly greater in SHR. The kinin B2 receptor antagonist icatibant (Hoe 140) blocked the hypertensive responses to kallikrein in both groups and caused greater hypotension and bradycardia in SHR. These results suggest that local kinins in the RVLM act to alter cardiovascular function and may be involved in the maintenance of blood pressure in the SHR.

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The objective of the present study was to determine whether the brain kallikrein-kinin system differs between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and if so, whether any detected differences occur before the development of hypertension in SHR. We measured cerebrospinal fluid levels of various components of the system in adult and young prehypertensive SHR and WKY. Cerebrospinal fluid kinin concentration and appearance rate were higher in SHR. Cerebrospinal fluid active kallikrein level and kininogenase activity were also higher in adult SHR. In addition, cerebrospinal fluid kinin concentration and appearance rate were higher in prehypertensive, 5- to 6-week-old SHR compared with age-matched WKY. However, no differences in cerebrospinal fluid kallikrein or kininogenase activity were observed between the two strains of young rats. Cerebrospinal fluid kinin concentration was higher in young versus adult rats of the same strain. In WKY, cerebrospinal fluid kallikrein also decreased with age although cerebrospinal fluid kallikrein concentration did not decrease in young and adult SHR. Together, these data suggest that there is a hyperactive kallikrein-kinin system in the brain of SHR that may contribute to the hypertensive state in this animal model.

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In the present study, we focused on the rostral ventrolateral medulla as a possible site of action for kinins because of its established importance in the central regulation of the cardiovascular system. Unilateral microinjections of 100 pmol to 4 nmol bradykinin into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure in Sprague-Dawley (SD) rats, Wistar-Kyoto (WKY) rats, and spontaneously hypertensive rats (SHR). The dose-response curves for the hypertensive responses to bradykinin in SD and WKY rats were essentially the same, whereas the hypertensive effect of bradykinin was significantly greater in SHR than in either SD or WKY rats. The kinin B2 receptor antagonists D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin and Hoe 140 inhibited the hypertensive responses to bradykinin in both SHR and WKY rats. The hypertensive effect of 500 pmol bradykinin was reduced 65 +/- 5% after 4 nmol of D-Arg0, Hyp3,Thi5,8,D-Phe7-bradykinin in SHR and 50 +/- 16% in WKY rats, whereas 1 nmol Hoe 140 abolished the hypertensive effect of 500 pmol bradykinin injected into the rostral ventrolateral medulla. Microinjection of D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin produced prolonged dose-dependent decreases in mean arterial pressure and heart rate. Blood pressure decreased 70 +/- 8 mm Hg and heart rate decreased 49 +/- 9 beats per minute in SHR, whereas in WKY rats mean arterial pressure decreased 12 +/- 4 mm Hg, with no change in heart rate. In a similar fashion, Hoe 140 caused a 51 +/- 7 and 17 +/- 3 mm Hg reduction in blood pressure in SHR and WKY rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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OBJECTIVE: To determine whether immunoreactive tissue kallikrein levels in cerebrospinal fluid (CSF) of spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)--salt-treated hypertensive rats are elevated compared with normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats. DESIGN: The present study was designed to test the hypothesis that the activity of the brain tissue kallikrein-kinin system is enhanced in hypertensive states. METHODS: Age-matched 18- to 19-week-old SHR and WKY rats, and Sprague-Dawley rats treated for 6 weeks either with 2 mg/kg per day DOCA subcutaneously and 0.9% saline in the drinking water, or with vehicle and tap water to drink, were studied. CSF was collected from a cannula inserted into the cisterna magna, and was frozen until the tissue kallikrein in the samples was measured by radioimmunoassay. Arterial pressure in the SHR and WKY rats was measured directly via a cannula inserted in the femoral artery or by tail-cuff plethysmography. RESULTS: In adult 18- to 19-week-old SHR the CSF kallikrein concentration was higher than in WKY rats. The CSF flow rate in SHR was also higher than in WKY rats. The rate of appearance of kallikrein in the CSF of SHR was twice that in WKY rats. Moreover, CSF kininogenase activity in SHR was significantly higher than that in age-matched WKY rats. In DOCA--salt hypertensive rats the CSF kallikrein concentration was higher than in vehicle-treated control rats. Acute elevation of blood pressure with a 120-min intravenous phenylephrine infusion did not change the CSF kallikrein concentration in 50 rats compared with vehicle-treated control rats. This is the first study to quantitate immunoreactive tissue kallikrein in the CSF of rats and to show elevated levels of CSF kallikrein in hypertensive rats compared with normotensive rats. CONCLUSION: The present data suggest that higher brain kallikrein activity in hypertensive rats may play a role in the development of elevated blood pressure.

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The present study was undertaken to localize and characterize bradykinin (BK) binding sites in 10 microns serial sections of guinea pig brain by in vitro quantitative receptor autoradiography. Specific binding of [125I-Tyr8]bradykinin ([125I]BK) was localized in the medulla oblongata to the regions of the nucleus of the solitary tract (nTS), the area postrema (AP), the dorsal motor nucleus of the vagus (X) and the caudal subnucleus of the spinal trigeminal nucleus. No significant specific [125I]BK binding was seen in other brain regions. The specific binding (85-90% of total binding) was of high affinity and saturable with a KD of 73.5 +/- 9.9 pM and a Bmax of 27.8 +/- 1.9 amol per mm2 of tissue. In competition studies, the rank order of potencies was: BK greater than Met-Lys-BK greater than Lys-BK much greater than Des-Arg9-BK. The B2 receptor antagonist D-Arg0-Hyp3-Thi5,8-D-Phe7-BK inhibited [125I]BK binding with a Ki value of 3.5 +/- 1.5 nM while Des-Arg9-[Leu8]-BK, a B1 receptor antagonist did not significantly inhibit [125I]BK binding in concentrations up to 10 microM. Our finding of specific high affinity [125I]BK binding sites in the nTS, AP and the X is important because these brain areas are known to be involved in central cardiovascular regulation. Moreover, our results suggest that the specific [125I]BK binding sites in the guinea pig medulla are of the bradykinin B2 receptor type.

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Previous studies have demonstrated that propranolol can lower arterial pressure through an action within the central nervous system. The purpose of this study was to determine 1) whether the hydrophilic beta blocking drug atenolol which is devoid of membrane stabilizing activity can reduce arterial pressure through a central action and 2) whether this action is stereoselective for the (-)-, or beta receptor blocking enantiomer. Studies were conducted in the anesthetized spontaneously hypertensive (SH) rats in which the cardiovascular effects of (-)- and (+)- atenolol were compared after i.v. or intracisternal administration. Intravenous injection of 100 micrograms/kg of (-)-atenolol reduced mean arterial pressure 25 +/- 5 mm Hg (P less than .02) and lowered heart rate 58 +/- 7 bpm (P less than .02). The same dose of (+)-atenolol i.v. produced no significant changes in either mean arterial pressure or heart rate. Similarly, intracisternal (-)-atenolol, 66 micrograms/kg, significantly (P less than .05) reduced mean arterial pressure and heart rate whereas the same dose of the (+)-isomer was without effect. When the i.v. dose of (-)-atenolol was lowered to 33 micrograms/kg, heart rate was decreased markedly but mean arterial pressure was not reduced. In contrast, 33 micrograms/kg of intracisternal (-)- atenolol significantly reduced mean arterial pressure 17 +/- 6 mm Hg and reduced heart rate. These results suggest that atenolol possesses a central hypotensive action that is selective for the (-)-, beta receptor blocking enantiomer.

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Only limited information is available on the stereochemistry of the in vivo distribution of beta-receptor-blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium-labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminal t1/2 of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10-fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50-fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)-vs. (-)-propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (-)-propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue or CSF distribution.

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Previous studies suggest that the hypotensive response to centrally administered propranolol results from a drug-induced release of norepinephrine which then stimulates central alpha adrenergic receptors and, as a consequence, arterial pressure is lowered. Inasmuch as the C1 area of the rostral ventrolateral medulla is known to contain noradrenergic nerve terminals and participate in arterial pressure regulation, we determined whether this medullary region is a site mediating the hypotensive response to centrally administered propranolol. Bilateral microinjections (0.1 microliter) of dl-propranolol (0.25-2 nmol) into the C1 area of urethane-anesthetized rats resulted in a gradual reduction in mean arterial pressure which was sustained throughout the 120-min experimental period. The injection site was verified pharmacologically at the end of each experiment by bilateral microinjection of 10 nmol of tyramine and observing a further decrease in mean arterial pressure and a reduction in heart rate. Pretreatment of the C1 area bilaterally with reserpine 24 hr earlier significantly reduced the hypotensive responses to microinjections of both propranolol and tyramine whereas the hypotensive response to the direct acting agonist clonidine was unchanged. These results demonstrate that the C1 area of the rostral ventrolateral medulla is a site for a central hypotensive action of propranolol. Moreover, the data provide further evidence that the hypotensive action of centrally administered propranolol results from a drug-induced release of norepinephrine from central noradrenergic neurons.

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The effects of afferent vagal stimulation, cerebroventricular vasopressin, and intravenous nitroprusside on cerebrospinal fluid (CSF) kinin levels, mean arterial pressure (MAP), and heart rate (HR) were determined in anesthetized dogs in which a ventriculocisternal perfusion system (VP) was established. Following bilateral vagotomy, stimulation of the central ends of both vagi for 60 min significantly increased MAP and CSF perfusate levels of kinin and norepinephrine (NE). MAP was increased a maximum of 32 +/- 4 mmHg, and the rates of kinin and NE appearance into the CSF perfusate increased from 4.2 +/- 1.4 to 22.1 +/- 6.9 and from 28 +/- 5 to 256 +/- 39 pg/min, respectively. A significant correlation was found between CSF kinin and NE levels in these experiments. In other experiments the addition of arginine vasopressin to the VP system caused a significant increase in CSF perfusate kinin without affecting MAP or HR. Intravenous infusion of nitroprusside lowered MAP without affecting kinin levels in the CSF. However, on cessation of nitroprusside infusion, CSF kinin increased significantly in association with the return in MAP to predrug level. Collectively the data are consistent with the hypothesis that central nervous system kinins have some role in cardiovascular regulation, and furthermore that this role may involve an interaction between brain kinin and central noradrenergic neuronal pathways.

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Ventriculocisternal perfusion of propranolol (25 micrograms/kg/min for 30 min) throughout the entire brain ventricular system in anesthetized dogs decreased arterial pressure and increased cerebrospinal fluid (CSF) norepinephrine. Localized perfusion of propranolol into the fourth ventricle produced increased CSF norepinephrine levels and a hypotensive response comparable to that seen with whole-brain ventriculocisternal perfusion. In comparison, perfusion of propranolol through the forebrain (lateral-third) ventricles resulted in changes in CSF norepinephrine comparable to those observed with the administration of the drug into the fourth ventricle but resulted in a reduced hypotensive response. Increased CSF norepinephrine levels and a hypotensive response were also observed after peripheral i.v. infusion of propranolol (100 micrograms/kg/min for 45 min). Collectively, these results support the hypothesis that an interaction of propranolol at noradrenergic nerve terminals in the hindbrain area results in a hypotensive effect which may contribute to the antihypertensive action of the drug.

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The effects of angiotensin-converting enzyme inhibitor captopril on infarct size and cardiovascular hemodynamics were studied in 35 conscious dogs subjected to 24 h of coronary occlusion. Following occlusion of the left anterior descending coronary artery, 10 dogs were infused with captopril 0.25 mg/kg/h i.v. (group 1), eight dogs received captopril 0.5 mg/kg/h i.v. (group 2), and 17 dogs served as saline-infused controls. All infusions were started 10 min following occlusion and continued for 15 h. Eighty-eight percent of untreated dogs and 80% of group 1 captopril dogs survived the 24-h duration of the study. No experimental deaths occurred in group 2 captopril dogs. Arterial blood pressure had decreased 10-12 mm Hg in both captopril groups by 4 h and remained relatively stable for the remainder of the study period. In untreated dogs, blood pressure was unchanged for 6 h, then began a gradual decline. There were no significant differences in infarct size among the groups. When infarct size is expressed as percent of left ventricle at risk the values were: control, 39.9 +/- 5.6; captopril group 1, 44.8 +/- 4.9; and captopril group 2, 43.8 +/- 7.8%. Creatine kinase levels were not different among the groups. Heart rate and incidence of arrhythmias also did not differ among the groups. These data show that captopril had no detrimental or beneficial effects on infarct size or on cardiovascular hemodynamics associated with myocardial infarction in conscious dogs.

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Three patients with brainstem tumors had orthostatic hypotension as the major presenting manifestation. Two patients had primary tumors that involved the dorsal medulla, pons, and rostral spinal cord; one was a malignant astrocytoma and the other a hemangioblastoma. The third patient had an oat cell carcinoma of the lung with subependymal spread to the medulla, pons, hypothalamus, and thalamus. Evaluation of baroreceptor function in the patient with the malignant astrocytoma showed a defect in the efferent sympathetic limb of the baroreceptor reflex arc.

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Biochemical and histochemical studies have identified components of the kallikrein-kinin system in the brain. The present study was designed to determine whether kinins could be detected in cerebrospinal fluid (CSF) and if these levels could be altered. Endogenous CSF samples were taken from the cisterna magna of pentobarbital-anesthetized mongrel dogs (n = 11) and were shown to contain 13 +/- 3 pg/ml (mean +/- SE) of immunoreactive kinin ( ikinin ) measured by RIA. The ( ikinin ) samples showed complete parallelism to standard synthetic bradykinin. Ventriculocisternal perfusion of the anesthetized dog brain with artificial CSF alone at a rate of 0.191 ml/min for 240 minutes had little or no effect on basal levels of CSF ( ikinin ), mean arterial pressure (MAP), or heart rate (HR). Melittin (20 microM), an activator of membrane-bound kallikrein, added to the perfusion system for 60 minutes caused a significant and sustained elevation in CSF ( ikinin ) levels from 19 pg/ml up to a maximum of 194 pg/ml (p less than 0.01). This change was accompanied by a prolonged increase in MAP of up to 22 mm Hg (p less than 0.01) and a transient increase in HR of 14 bpm (p less than 0.05). Melittin (2 microM) had no significant effect on CSF ( ikinin ) levels or MAP, but resulted in a sustained increase in HR of 17 to 25 bpm (p less than 0.01). The cardiovascular responses to centrally administered melittin (20 microM) were attenuated by concomitant administration of aprotinin (2000 KIU/ml). This study establishes the existence of ( ikinin ) in the CSF, shows that such levels can be manipulated, and suggests that central kinins may be involved in the modulation of cardiovascular function.

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Length-contractile force curves and dose-response curves of heart rate, blood pressure, and contractile force were recorded from the left ventricle of six anesthetized dogs in a control state. These measurements were repeated at an average of 56 days following creation of an atrioventricular fistula when signs of heart failure were present. The fistula was then closed and the dogs restudied after an additional 57 days. Heart failure was associated with a shift up the ascending limb of a depressed length-contractile force curve and a depressed contractile response to isoproterenol. For instance, 0.1 micrograms/kg of isoproterenol produced a 173 +/- 8% increase in contractile force in control and 42 +/- 7% in failure. The contractile response to ouabain (30 micrograms/kg) was unchanged in heart failure, i.e., 36 +/- 5% in control vs. 39 +/- 4% in heart failure. When the dogs were restudied following fistula closure, the length-contractile force curve was still depressed as was the contractile response to isoproterenol, whereas the response to ouabain was again unchanged from control. Plasma norepinephrine and renin levels increased 5- and 10-fold, respectively, during heart failure and then returned to control following closure of the fistula. The data support the view that myocardial dysfunction associated with volume-overload heart failure is not reversible within the same time frame as its onset.

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Previous studies in our laboratory have demonstrated that the acute sympathomimetic effects of isopropylamine are due to stimulation of autonomic ganglia. The present studies were designed to determine whether isopropylamine produced ganglionic blockade after its initial stimulation of autonomic ganglia. Infusion of isopropylamine (2.5 mg/kg/min) produced an initial increase in arterial pressure and heart rate which was followed by a prolonged hypotension and bradycardia; lower doses produced only a hypotensive response. After infusion of isopropylamine, the positive chronotropic responses to preganglionic cardioaccelerator nerve stimulation were significantly reduced, whereas the responses to postganglionic nerve stimulation were essentially unchanged. Similarly, the negative chronotropic responses to peripheral vagal stimulation were significantly reduced after isopropylamine administration. Moreover, isopropylamine reduced the cardiovascular responses to i.v. injections of the ganglion nicotinic stimulant, dimethylphenylpiperazinium iodide. Studies on the disposition of isopropylamine indicated that there was significant cumulation of isopropylamine in all tissues as compared to plasma. When the relationship between plasma isopropylamine and the decreases in mean arterial pressure was examined, a significant positive correlation (r = 0.87) was found. These results indicate that isopropylamine has both ganglion stimulating and blocking properties and is similar in its action to the classical nicotinic ganglion stimulant drugs such as dimethylphenylpiperazinium iodide and tetramethylammonium.

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