Neurophysiologic evaluation of lower motor neuron damage in tetraplegia.

We quantitatively investigated the extent of damage to motor neurons in tetraplegic subjects. Numbers of motor units in the patients were significantly lower for thenar, wrist extensor, and biceps brachii as compared to controls. Reduction in counts occurred even when M-response amplitudes were normal. Standard electromyography suggested a surprising frequency of lower motor neuron dysfunction below the level of injury. These results confirm previous reports and add data on motor units in the biceps brachii.

Early onset of antidepressant action of venlafaxine: pattern analysis in intent-to-treat patients.

Pattern analysis has been used to distinguish between the true effect of an antidepressant and a placebo effect. The placebo effect constitutes clinical improvement that is attributable to the caregiver, treatment setting, or placebo substance. Pattern analysis allows identification of patients who have early persistent responses, delayed persistent responses, or no responses to a drug. In our study, we used this method to assess the onset and persistence of antidepressant activity of high daily doses of venlafaxine. Our analysis considered scores on the Global Improvement item of the Clinical Global Impressions scale for intent-to-treat patients in two double-masked, placebo-controlled studies of at least 6 weeks' duration. Dosages in both studies were rapidly titrated upward so patients received at least 200 mg/d within the first week of treatment. Improvement within the first 2 weeks was considered early, and improvement not followed by a relapse through the scheduled end of treatment was considered persistent. Significantly greater percentages of patients in the venlafaxine group (27% and 20% in study 1 and study 2, respectively) than in the placebo group (9% and 2%, respectively) had a clinically meaningful drug response within the first 2 weeks of treatment. This early response persisted for the duration of each trial. We concluded that venlafaxine in dosages of at least 200 mg/d demonstrates an early and persistent onset of efficacy compared with placebo.

Venlafaxine: measuring the onset of antidepressant action.

Venlafaxine, a new antidepressant, inhibits reuptake of norepinephrine and serotonin without appreciable effects on histaminergic, alpha-adrenergic, or cholinergic systems. Pharmacologically the drug is unique: the half-life is short and it exerts both rapid and prolonged beta-adrenergic desensitization after single doses in a rodent model. Venlafaxine has been thought to possess a rapid onset of clinical antidepressant action. Accordingly, two clinical studies in which moderate amounts of venlafaxine were given aggressively were reviewed to examine aspects of the drug's onset of action. Three statistical methodologies were employed--traditional analysis of depression scale scores, pattern analysis based on timing and persistence of response, and survival analysis of sustained response. All three methods showed venlafaxine to have significant effects early in the course of therapy. In addition, venlafaxine is the first drug to meet criteria for early onset using the pattern analysis methodology. Depressed patients aggressively treated with venlafaxine show significant benefit on or before Day 7 of treatment using traditional methods of analysis as well as survival analysis of sustained response.

Age-related changes in thoracic aorta of obese Zucker rats.

Studies were performed on the ontogeny of arterial blood pressure and functional properties of the thoracic aorta in lean (L) and obese (O) male Zucker rats at ages of 6-36 wk. Body weight was larger in the O than the L at all ages, with differences reaching values of 200-250 g at ages over 24 wk (at 33-36 wk: L = 510 +/- 9 and O = 730 +/- 15 g). Systolic blood pressure was lower in young O compared with L (6-15 wk) but increased with age at a rate seven times greater in O than in L. For ages of 33-36 wk, systolic pressure was significantly higher in O compared with L (O = 132 +/- 2 vs. L = 122 +/- 2 mmHg). Total serum cholesterol (at 36 wk: L = 278 +/- 31 and O = 354 +/- 12 mg/dl) and triglycerides (at 36 wk: L = 493 +/- 71 and O = 1,618 +/- 220 mg/dl), as well as glucose levels, increased with age in both groups and were significantly higher in O at all ages. Serum levels of thyroxine but not triiodothyronine were significantly lower in O at all ages. No differences were found in passive mechanics at any age. Values of maximum active stress with smooth muscle activation by 75 mM K+ plus 10 microM norepinephrine were significantly higher at 24 and 36 wk in O (at 36 wk: L = 573 +/- 42 and O = 821 +/- 89 x 10(3) dyn/m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Development of hypertension in rats during chronic exposure to cold.

Resting systolic, diastolic, and mean blood pressures (MBP), as well as heart rates, of unanesthetized, unrestrained, cold-acclimated (CA, 4 wk, 6 degrees C) rats were measured by direct arterial cannula and compared with those of controls maintained at 25 degrees C. Exposure to cold increased all these measurements significantly. Mean heart weight of CA rats was also increased significantly above that of controls. The responsiveness of MBP and heart rate to administration of the beta-adrenergic agonist, isoproterenol (3, 5, and 8 micrograms/kg ip), to unanesthetized, unrestrained, CA rats during exposure to air at 6 degrees C was similar to, and possibly less than, that of warm-acclimated (WA) rats measured at 25 degrees C. Acute administration of the alpha-adrenergic agonist, phenylephrine (100 micrograms/kg ip), to CA rats while in air at 6 degrees C induced less of a change in MBP from pretreatment level than was observed in WA rats. However, no differences were observed between groups when changes in heart rate from pretreatment level were compared. A similar statement may be made for a higher dose of phenylephrine (150 micrograms/kg ip), although MBP were elevated to higher levels in both groups with the higher dose. Abrupt exposure of WA rats to cold (6 degrees C) resulted in a sharp increase in heart rate and a more gradual increase in MBP over a period of 1 h. Removal of CA rats from 6 to 25 degrees C resulted in a gradual decrease in heart rate with no significant change in MBP during the ensuing hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracranial hemorrhages due to phenylpropanolamine.

We describe 2 patients with intracranial hemorrhage after ingestion of diet pills containing phenylpropanolamine (PPA) in combination with caffeine. The first patient had bilateral simultaneous intracerebral hemorrhages, and the second had a subarachnoid hemorrhage. PPA is widely used most often without prescription and causes intracranial hemorrhage more often than has been realized. The mechanism may be induction of a transient hypertensive crisis.

Effect of chronic treatment with captopril on reactivity of aortic smooth muscle from normotensive and renal hypertensive rats.

Acute administration of the angiotensin I converting enzyme inhibitor, captopril (2 X 10(-4) M), was shown in an earlier study to attenuate the contractile responses of aortic rings of rats to alpha-adrenergic agonists in vitro. The objective of the present study was to determine the effect of chronic treatment with captopril on reactivity of aortic rings from both normotensive and renal hypertensive rats when captopril was no longer present. Four groups of rats were used: (1) normotensive, untreated; (2) normotensive, captopril-treated (48 mg/kg b.w. per day for five weeks); (3) hypertensive (bilateral renal encapsulation for five weeks), untreated and (4) hypertensive, captopril-treated. Renal encapsulation was associated with a significant increase in systolic blood pressure, which was prevented by concomitant treatment with captopril. At the end of the five weeks treatment aortic rings, 4 mm in length, were washed for 2 h to remove the captopril, following which contractile responses to various vasoactive agents were studied in vitro. Chronic treatment with captopril attenuated significantly contractile responses to both norepinephrine (10(-9) to 10(-5) M) and phenylephrine (10(-8) to 10(-4) M) but had no effect on isoproterenol-induced relaxation of KCl-depolarized tissue in the presence of 10(-5) M phentolamine. Contractile responses to angiotension I (10(-10) to 10(-7) M) did not differ statistically among the four groups. Following addition of captopril (2 X 10(-4) m) to the bath for 30 min, contractile responses to angiotensin I were attenuated in all four groups of rings.(ABSTRACT TRUNCATED AT 250 WORDS)

On the mechanism of serotonin-induced dipsogenesis in the rat.

Subcutaneous administration of l-5-hydroxytryptophan (5-HTP), the precursor of serotonin, to female rats induces copious drinking accompanied by activation of the renin-angiotensin system. Neither a reduction in blood pressure nor body temperature accompanied administration of 5-HTP. The objective of the present study was to determine whether serotonin-induced dipsogenesis, like that of 5-HTP, is mediated via the renin-angiotensin system. Serotonin (2 mg/kg, SC)-induced drinking was inhibited by the dopaminergic antagonist, haloperidol (150 micrograms/kg, IP), which also inhibits angiotensin II-induced drinking. Both captopril (35 mg/kg, IP), an angiotensin converting enzyme inhibitor, and propranolol (6 mg/kg, IP), a beta-adrenergic antagonist, blocked serotonin-induced dipsogenesis. The alpha 2-adrenergic agonist, clonidine (6.25 micrograms/kg, SC), which suppresses renin release from the kidney, attenuated serotonin-induced water intake. The dipsogenic responses to submaximal concentrations of both serotonin (1 mg/kg, SC) and isoproterenol (8 micrograms/kg, SC) were additive rather than interactive suggesting that similar pathways mediate both responses. The serotonergic receptor antagonist, methysergide (3 mg/kg, IP), inhibited serotonin-induced drinking but had no effect on isoproterenol (25 micrograms/kg, SC)-induced dipsogenesis. However, neither serotonin (2 mg/kg, SC) nor isoproterenol (25 micrograms/kg, SC)-induced drinking was inhibited by cinanserin (25 micrograms/kg, IP). These data indicate that serotonin induces drinking in rats via the renin-angiotensin system. However, the results of the studies using methysergide suggest that serotonin appears to act at a point prior to activation of beta-adrenoceptors in the pathway leading to release of renin from the kidneys.

Effects of chronic administration of mestranol on alpha and beta adrenergic responsiveness in female rats.

Several alpha and beta adrenergic responses were studied in female rats after treatment with a low dose of the synthetic estrogen, mestranol (15 micrograms i.p. biweekly), for 4 to 6 weeks and compared with untreated controls. The response of blood pressure to exogenously administered norepinephrine was measured in conscious rats by means of an indwelling catheter in the femoral artery. Basal systolic blood pressure was not different between control and treated groups, or was any difference observed in peak systolic pressure after acute i.v. administration of l-norepinephrine in concentrations of 0.0625, 0.125, 0.250 and 0.625 micrograms. In contrast, the half-time of the blood pressure response was significantly prolonged after administration of the various concentrations of norepinephrine to mestranol-treated rats. The half-time of the pressor response observed in control animals administered 0.625 micrograms of norepinephrine was elicited in mestranol-treated animals by only 0.250 micrograms of norepinephrine. Analysis of the time course of the pressor response indicates that mestranol treatment altered the duration of the blood pressure increase without an apparent change in the onset of the pressor response. No differences between groups were observed in beta adrenergic responsiveness measured in terms of the isoproterenol-induced increase in either heart rate (beta-1 response) or water intake (beta-2 response). Finally, the contractile response of aortic rings from mestranol-treated rats to both l-norepinephrine (10(-9) to 10(-5) M) and l-phenylephrine (10(-8) to 10(-4) M) was significantly less than that of aortic rings from control rats. These data indicate, therefore, that in vivo cardiovascular responsiveness to norepinephrine does not reflect the attenuated vascular reactivity of isolated aortic rings. Insofar as the dominant feature of the in vivo adrenergic response appears to be prolongation of pressor action, the present study suggests that processes involved in the inactivation of circulating norepinephrine may be altered by chronic treatment with a low-dose of mestranol.

Bethanechol-induced water intake in rats: possible mechanisms of induction.

Acute administration of the parasympathomimetic agent, bethanechol, at 2, 4, 8 and 12 mg/kg body wt, IP, induced drinking and increased urine output of rats in a dose-dependent fashion. The first significant increases in both water intake and urine output above that of controls occurred when 4 mg/kg was administered. The drinking and increased urine output in response to administration of 8 mg bethanechol/kg was inhibited by atropine sulfate (3 and 6 mg/kg, IP). In addition, the beta-adrenergic antagonist, propranolol (6 mg/kg, IP, administered 30 min prior to treatment with bethanechol), inhibited bethanechol (8 mg/kg, IP)-induced drinking. Urine output, however, was unaffected by propranolol. Further, the angiotensin I converting enzyme inhibitor, captopril, inhibited significantly the drinking response, but not the increased urine output, accompanying administration of bethanechol (8 mg/kg). The effect of bethanechol and the beta-adrenergic agonist, isoproterenol (25 micrograms/kg) separately and in combination, on water intake was also studied. Both compounds increased water intake but they exerted no interactive effect when administered simultaneously. Administration of bethanechol (8 mg/kg) to conscious rats was also accompanied by a significant reduction in both mean blood pressure and heart rate that reached minimal levels within 10 min after treatment. Both responses had returned to control level by one hr after treatment. These results suggest that bethanechol induces drinking in rats by way of the renin-angiotensin system.

Effect of in vitro administration of captopril on vascular reactivity of rat aorta.

The effect of acute administration of captopril, an angiotensin converting enzyme inhibitor, on vascular responses of rings of rat aortic smooth muscle was tested in vitro. Dose-response curves for various vasoactive agents were obtained before and after exposure to captopril (2 x 10(-4) M) for 30 minutes. In the presence of captopril, contractile responses to angiotensin I (5 x 10(-10) to 5 x 10(-8) M) were attenuated significantly, probably as a result of decreased local conversion of angiotensin I to angiotensin II. Contractile responses to angiotensin II (10(-11) to 5 x 10(-9) M) were not affected by captopril. All responses to norepinephrine (10(-9) to 10(-4) M) and phenylephrine (10(-8) to 10(-4) M) were attenuated significantly from control in the presence of captopril. In the presence of the alpha-adrenergic antagonist, phentolamine, captopril did not affect either the contractile responses to KCl (30 to 100 mM) or the isoproterenol-induced (10(-8) to 10(-5) M) relaxation of KCl-depolarized tissue. These results suggest that captopril decreased vascular responsiveness to alpha-adrenergic agonists but not to beta-adrenergic agonists. Low concentrations of bradykinin (10(-10) to 10(-8) M) induced contraction in KCl-depolarized tissue while higher concentrations (10(-7) and 10(-6) M) induced relaxation. In the presence of captopril, relaxation occurred at all concentrations of bradykinin (10(-10) to 10(-6) M), probably as a result of decreased degradation of the bradykinin. These data suggest depression of alpha-adrenergic responsiveness in vascular smooth muscle as another potential antihypertensive action of captopril.

Thoracic root pain in diabetes: the spectrum of clinical and electromyographic findings.

Diabetic thoracic radiculopathy has been reported rarely. Fifteen new cases, seen in an equal number of patients over a 3-year period and confirmed by electromyographic findings, have been analyzed. All patients presented with severe abdominal or chest pain, which often was not radicular in character. The presence of dysesthesias and an abnormal sensory examination of the trunk aided diagnosis. The pain was frequently associated with marked weight loss but carried a good prognosis for recovery. Six additional patients with negative electromyographic examinations were considered to have the disorder. Diabetic thoracic radiculopathy produces a distinct syndrome and may be more common than is generally recognized.

Peripheral conversion of L-5-hydroxytryptophan to serotonin induces drinking in rats.

Female rats administered serotonin (0.25 to 4.0 mg/kg, s.c.) showed a dose-dependent increase in water intake. The dipsogenic response was nearly maximal when 2 mg/lg was administered s.c. and plateaued by 2 hr after treatment. l-5-Hydroxytryptophan (5-HTP), the precursor of serotonin, is also a potent dipsogen which induces drinking by way of the renin-angiotensin system. The possibility that the dipsogenic activity of 5-HTP is dependent on decarboxylation to serotonin was the objective of these studies. Either benserazide (30 mg/kg. s.c.), a central and peripheral decarboxylase inhibitor, or carbidopa (6.5 mg/kg, s.c.), a peripheral decarboxylase inhibitor, was administered 15 min prior to the dipsogen. Both decarboxylase inhibitors attenuated the dipsogenic response to 5-HTP (25 mg/kg, s.c.) but not to serotonin (2 mg/kg, s.c.). The peripheral serotonergic receptor antagonist, methysergide (3 mg/kg, i.p.), blocked the dipsogenic responses to both 5-HTP (25 mg/kg, s.c.) and serotonin (2 mg/kg, s.c.). There was no interaction between 5-HTP (18 mg/kg, s.c.) and serotonin (1 mg/kg, s.c.) when administered simultaneously with respect to their dipsogenic effects. Thus, the drinking response accompanying administration of 5-HTP occurs following peripheral conversion to serotonin which, in turn, activates peripheral serotonergic receptors. The mechanisms(s) by which activation of peripheral serotonergic receptors increases water intake is not known, but appears to involve release of renin from the kidney.

Effects of serotonin and L-5-hydroxytryptophan on plasma renin activity in rats.

The effects of dipsogenic doses of l-5-hydroxytryptophan (5-HTP) and serotonin on plasma renin activity (PRA), blood pressure, and body temperature were determined in unanesthetized female rats. Both serotonin (2 mg/kg, s.c.) and 5-HTP (25 mg/kg, s.c.) induced six-fold increases in PRA measured 1 hr after drug administration. The central and peripheral decarboxylase inhibitor, benserazide (30 mg/kg, s.c.), as well as the peripheral decarboxylase inhibitor, carbidopa (6.5 mg/kg s.c.), prevented the increase in PRA associated with administration of 5-HTP. This suggests that 5-HTP must be converted to serotonin peripherally to increase PRA. At the doses used, serotonin decreased mean blood pressure and colonic temperature of unanesthetized rats while 5-HTP was without effect. The increase in PRA induced by 5-HTP does not appear, therefore, to be a response to either hypotension or a decrease in colonic temperature. Since 5-HTP must be converted to serotonin to initiate both a drinking response and an increase in PRA, the results suggest that the decrease in blood pressure and colonic temperature following administration of serotonin may not be important in induction of the drinking response and the increase in PRA. The mechanism by which activation of the renin-angiotensin system occurs following peripheral administration of either 5-HTP or serotonin remains for further study.

L-5-Hydroxytryptophan-induced drinking in rats: possible mechanisms for induction.

Administration of L-5-hydroxytryptophan (25 mg/kg body weight, SC) to female rats resulted in copious drinking. The dipsogenic response to administration of L-5-hydroxytryptophan (5-HTP) was blocked by propranolol (6 mg/kg body weight, IP), a beta-adrenergic antagonist, and captopril (35 mg/kg body weight, IP), an angiotensin converting enzyme inhibitor. In addition, clonidine (12.5 and 25 microgram/kg body weight, IP), a central alpha-adrenergic agonist known to inhibit renin release, attenuated drinking during 1, 2 and 3 hours after 5-HTP was administered. These results suggest that 5-HTP-induced drinking is mediated by way of the renin-angiotensin system. Haloperidol (150 microgram/kg body weight, IP), a dopaminergic antagonist, also attenuated the dipsogenic response to administration of 5-HTP. In addition, incremental reductions in 5-HTP-induced drinking with increasing doses of spiperone (37.5 to 150 microgram/kg body weight, IP), a more potent dopaminergic antagonist, were demonstrated. Thus, the dipsogenic response to administration of 5-HTP to rats is dependent on both the renin-angiotensin system and an intact dopaminergic pathway.

Dipsogenic effect of L-5-hydroxytryptophan in rats.

The precursor of serotonin, l-hydroxytryptophan (5HTP), is a potent dipsogen in the rat. Peripheral administration of increasing doses of this compound increased water intake in a dose-dependent fashion. Peripheral administration of other analogs of tryptophan, including d-tryptophan, l-tryptophan and acetyltryptophan, failed to affect water intake at a dose at which 5HTP induced maximal drinking (25 mg/kg, SC). The dipsogenic effect of melatonin, one of the metabolites of serotonin, was also tested. At any of 6 different doses (0.5 to 50 mg/kg, SC), melatonin failed to affect water intake in the rat. The mechanism by which 5HTP induces drinking is not known with certainty but could involve its conversion to serotonin, a known dipsogenic agent.