Changes in plasma glucose and lactate evoked by α and β2-adrenoceptor stimulation in conscious fasted rabbits

In conscious fasted rabbits, the iv infusion of salbutamol (3 micrograms/kg per min) and clonidine (2 micrograms/kg per min) induced a blood glucose increase amenable to blockade, respectively by ICI 118551 (1 micrograms/kg per min) and idazoxan (20 micrograms/kg per min). Amidephrine (10 micrograms/kg per min) and salbutamol mediated an increase in plasma lactate which was attenuated by prazosin (50 micrograms/kg, sc) and ICI 118551 respectively. Clonidine did not alter basal plasma lactate. The iv infusion of adrenaline (0.3 micrograms/kg per min) evoked an increase in plasma lactate more sensitive to blockade by ICI 118551 than by prazosin. ICI 118551 also shortened the hyperglycaemic response to adrenaline, 3-Mercaptopicolinic acid (25 mg/kg) reduced salbutamol- and adrenaline-mediated hyperglycaemia and increased at the same time the lactate/glucose ratio. Our data show that plasma lactate levels may be regulated by alpha 1- and beta 2-excitatory adrenoceptor stimulation. However, only the increase in blood lactate derived from beta 2-adrenergic stimulation seems to contribute to the overall catecholamine-mediated hyperglycaemia.     

Mechanism of opioid-induced atrial natriuretic peptide release in conscious rats

To examine the role of atrial stretch and vasopressin in opiate-induced atrial natriuretic peptide (ANP) release, we studied the effects of a mu receptor agonist fentanyl on plasma immunoreactive ANP (IR-ANP) and hemodynamics (mean arterial pressure, heart rate and right atrial pressure) in the conscious, chronically cannulated Wistar, Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Infusion of fentanyl (3 and 10 micrograms/kg i.v.) produced an immediate decrease in heart rate in conscious Wistar rats, whereas mean arterial pressure did not change significantly. Heart rate returned to control levels within 2 min of the injection, except after the largest dose of fentanyl when heart rate remained decreased for 5 min. Administration of 10 micrograms/kg of fentanyl caused a marked increase in right atrial pressure (3.9 +/- 0.3 mm Hg, n = 9, P less than .001) associated with 3.5-fold increase in the plasma IR-ANP concentration (168 +/- 17 pg/ml vs. 567 +/- 116 pg/ml, n = 9, P less than .01). In contrast, right atrial pressure decreased by 0.8 +/- 0.3 mm Hg (P less than .05) in response to infusion of 3 micrograms/kg of fentanyl with a slight increase (34%) in plasma IR-ANP. One microgram per kilogram i.v. of fentanyl had no effect on hemodynamic variables and plasma IR-ANP levels. Infusion of V1 antagonist (5 micrograms/kg/min for 25 min) did not affect basal or fentanyl-stimulated changes in hemodynamics or plasma IR-ANP concentration in Wistar rats. Infusion of fentanyl (3 and 10 micrograms/kg) in the LE and DI rats produced similar short-lasting heart rate reductions as seen in Wistar rats. Furthermore, injection of 10 micrograms/kg of fentanyl decreased blood pressure and increased plasma IR-ANP and right atrial pressure in both strains. The analysis of changes in plasma IR-ANP and right atrial pressure in response to fentanyl showed that for a given increase in right atrial pressure, a smaller amount of IR-ANP was released in the DI than in the LE rats. These results demonstrate that at higher fentanyl doses, the increased ANP release is mediated primarily by elevation of right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of quinpirole, a specific dopamine DA2 receptor agonist on the sympathoadrenal system in dogs

The effects of quinpirole, a specific dopamine DA2 receptor agonist, were investigated on both cardiovascular responses in conscious dogs and catecholamine release from the adrenal medulla in anesthetized dogs. In conscious normal dogs, i.v. quinpirole (30 micrograms/kg) elicited a decrease in blood pressure and a marked increase in heart rate associated with a rise in plasma catecholamine levels. The increase in heart rate is due to both baroreflex and central mechanisms because a slight but significant positive chronotropic effect persists in sinoaortic denervated dogs (i.e., animals deprived of baroreflex pathways). The central origin of this excitatory effect was confirmed by two subsequent protocols: intracisterna magna injection of quinpirole (5 micrograms/kg) increased blood pressure, heart rate and plasma catecholamines; i.v. domperidone reversed the hypotensive effect of i.v. quinpirole into a pressor response. The rise in plasma catecholamines was associated with an increase in plasma vasopressin levels. In anesthetized dogs, i.v. quinpirole (10 micrograms/kg/min during 12 min), which also decreased blood pressure, failed to modify epinephrine (and norepinephrine) release from the adrenal medulla whatever the stimulation frequencies (1, 3 and 5 Hz) of the sectioned splanchnic nerve. Similar results were obtained with apomorphine (5 micrograms/kg/min during 12 min). These results show that two mechanisms are involved in the action of quinpirole: first, a peripheral depressor action (which elicits the decrease in blood pressure) and secondly, a central pressor component involving an increase in both sympathetic tone and vasopressin release. They also demonstrate clearly that peripheral DA2 receptors are not involved in the control of catecholamine release from the adrenal medulla under in vivo conditions.     

Calcium channel blockers reverse the sustained elevation of blood pressure induced by chronic infusion of endothelin in conscious rats

To determine whether endothelin could act as a circulating hormone in the regulation of blood pressure and sodium-water excretion, we assessed the chronic effects of synthetic endothelin on systolic blood pressure, urine volume and urinary sodium excretion in conscious rats, and also evaluated the effects of benidipine or nilvadipine, newly developed calcium channel blockers, in rats infused chronically with synthetic endothelin. Continuous infusion of endothelin at a rate of 60 micrograms/kg/day into the jugular vein via osmotic minipumps induced a significant increase in systolic blood pressure, but did not induce any significant changes in urine volume and urinary sodium excretion, compared to those in vehicle-infused rats. On the contrary, the infusion of endothelin at a rate of 6 micrograms/kg/day did not induce any significant changes in systolic blood pressure, urine volume and urinary sodium excretion, compared to those in vehicle-infused rats. When 6 mg/kg/day of benidipine or 10 mg/kg/day of nilvadipine was administered simultaneously with 60 micrograms/kg/day of endothelin, the systolic blood pressure rose on Day I to only 137.0 +/- 2.4 mmHg (p less than 0.05) and 119.7 +/- 5.9 mmHg (p less than 0.05) compared to the rise to 163.8 +/- 4.7 mmHg when endothelin alone was infused. The antihypertensive effect of benidipine or nilvadipine was sustained for the entire experimental period and was not associated with any significant changes in urine volume and urinary sodium excretion. The present results suggest that endothelin can act as a circulating hormone and might be involved in the regulation of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of galanin on plasma glucose,insulin and pancreatic glucagon in dogs

The effect of synthetic galanin on plasma glucose, insulin and pancreatic glucagon levels in dogs was studied. Infusion of galanin caused a rapid, reversible and dose-dependent reduction in basal insulin level. A maximal increase in blood glucose level accompanying the insulin decrease was observed when galanin was administered at a dose of 4 micrograms/kg per h. Pancreatic glucagon levels showed little change compared with basal secretion. These results indicate that galanin is involved in the regulation of glucose through control of insulin secretion.     

Reduction in biliary excretion of ceftriaxone by diclofenac in rabbits.

The effects of diclofenac, a nonsteroidal anti-inflammatory drug, on biliary excretion of ceftriaxone were evaluated in rabbits. In a previous study, we demonstrated that diclofenac increased the extravascular diffusion and antibacterial efficacy of ceftriaxone without any effect on serum protein binding and urinary excretion of this antibiotic. We perfected a surgical procedure that allowed the study of biliary secretion in conscious rabbits with a stable hemodynamic state. The kinetic study was carried out on the fourth day of treatment with ceftriaxone alone (30 mg/kg per day given intramuscularly; group 1) or combined with diclofenac (1.5 mg/kg per 12 h given intramuscularly; group 2). Cumulative biliary excretion of ceftriaxone over 6 h was significantly reduced in group 2 (5,291.6 +/- 2,017.5 micrograms in group 1 versus 1,379.1 +/- 567.1 micrograms in group 2). This phenomenon occurred without any change in biliary flow. Indocyanine green clearance (20 mg/kg) increased in animals treated with ceftriaxone alone compared with the saline-treated control group (55.04 +/- 4.68 versus 33.29 +/- 7.52 ml/min per kg, respectively). Diclofenac alone caused a significant decrease in indocyanine green clearance compared with clearance in controls (25.05 +/- 4.74 versus 33.29 +/- 7.52 ml/min per kg), and indocyanine green clearance appeared not significantly different from control values in animals receiving ceftriaxone plus diclofenac. These results suggest that (i) ceftriaxone could increase hepatic blood flow and (ii) reduction of the hepatic clearance of ceftriaxone by diclofenac may be due to hepatic hemodynamic variations involving diclofenac inhibition of prostaglandin synthesis, although an interaction of diclofenac with hepatic uptake of ceftriaxone cannot be ruled out.     

Dopamine1 receptor agonist and alpha-2 adrenoceptor antagonist effects of fenoldopam in rabbits

Neurochemical and circulatory effects of fenoldopam were studied in pithed rabbits with electrically stimulated sympathetic outflow and in strips of the rabbit pulmonary artery. In pithed rabbits, fenoldopam (1-30 micrograms/kg/min) decreased the arterial blood pressure. Fenoldopam (3-30 microgram/kg/min) also increased the norepinephrine spillover rate (the rate at which endogenous norepinephrine enters into the plasma after having been released from postganglionic sympathetic nerves) and decreased the [3H]norepinephrine plasma clearance. The selective dopamine (DA)1 antagonist SCH 23390 (bolus injection of 10 micrograms/kg followed by infusion of 2 micrograms/kg/hr) antagonized markedly and the DA2-selective antagonist domperidone (bolus injection of 200 micrograms/kg followed by infusion of 50 micrograms/kg/hr) antagonized slightly the hypotensive effect. The increase in the norepinephrine spillover rate was enhanced after treatment with desipramine. Clonidine (0.3 microgram/kg/min) reduced the spillover of norepinephrine, and this effect was abolished by fenoldopam (30 micrograms/kg/min). In pulmonary artery strips preincubated with [3H]norepinephrine, fenoldopam (10(-7) and 10(-6) M) increased the electrically evoked overflow of tritium. The effect of fenoldopam (10(-6) M) was prevented in the presence of a supramaximal concentration of clonidine (10(-5) M). The results suggest that fenoldopam lowers blood pressure mainly by activation of vascular smooth muscle DA1 receptors. In addition, however, it blocks prejunctional alpha-2 autoreceptors at postganglionic sympathetic axons.     

Effects of octopamine on renal function in anaesthetized dogs

Increased levels of octopamine in adrenergic nerve terminals and plasma have been implicated in the circulatory and renal disturbances of chronic hepatic failure. Little is known about its renal actions in normal animals. In the present study, DL-octopamine was administered both i.v. and into one renal artery of anaesthetized dogs in doses ranging between 25-200 micrograms/min (1.6-20 micrograms/kg/min). Octopamine was hypertensive in doses of 100 micrograms/min and more and this change was associated with a significant decrement in GFR and renal perfusion. This amine also exerted a direct tubular effect since decreased excretion of sodium and water occurred in the absence of blood pressure or renal perfusional changes when given i.v. When given into one renal artery octopamine produced only an ipsilateral antidiuresis and antinatriuresis, in the absence of any change to GFR or renal perfusion. Lithium clearances suggest that octopamine acts beyond the proximal tubule in altering the tubular reabsorption of salt and water. Because octopamine was found to increase blood pressure in the presence of a hypertensive infusion of noradrenaline, it is likely that this amine exerts a primary pharmacological effect rather than liberating noradrenaline from nerve terminals. Saline expansion (7% body weight), acute biliary obstruction, chronic cirrhosis with ascites, and chronic thoracic caval constriction with the production of ascites all abolish the effect of octopamine when administered at 100 micrograms/min. Though octopamine may directly influence renal perfusion, its possible role in liver disease remains uncertain.     

Low oral bioavailability of dihydroergotamine and first-pass extraction in patients with orthostatic hypotension

The relative importance of the effect of absorption and first-pass extraction in bioavailability and clinical effectiveness of oraldihydroergotamine (DHE) was examined in six subjects with orthostatic hypotension. Maximum increases in systolic blood pressure of standing subjects occurred within 15 min of intravenous administration (10 micrograms/kg); after 30 min pressure declined linearly with respect to time over the ensuing 3 hr. Plasma DHE concentrations declined biexponentially with respect to time. Mean plasma half-life was 2.15 hr and plasma clearance averaged 862 ml/min. There was no rise in "standing" systolic blood pressure on oral administration (200 to 600 micrograms/kg). Peak plasma concentrations ranged from less than 0.1 to 2 ng/ml. Apparent oral absorption for DHE ranged from 19.5% to 53.3% while systemic bioavailability varied from less than 0.1% to 1.5%. when glyceryl trinitrate was taken orally with DHE, the bioavailability of the latter increased between 56% and 370% over the 0.1% to 1.5% without any apparent alteration in DHE absorption. Standing systolic blood pressure increased 27% (P less than 0.05) 2 hr after the same doses of DHE with glyceryl trinitrate. These findings suggest that the extent of first-pass extraction by the liver is the prime determinant of DHE bioavailability after oral administration and that factors that alter gastrointestinal and portal vein flow to the liver affect its bioavailability.     

Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis.

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min, respectively, P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.     

Lack of effect of naloxone in a moderate dosage on the exercise-induced increase in blood pressure, heart rate, plasma catecholamines, plasma renin activity and plasma aldosterone in healthy males

There is evidence that opioid peptides influence blood pressure and heart rate in animals and man. In the present investigation the effect of naloxone on the exercise-induced increase in blood pressure, heart rate, plasma catecholamines, plasma renin activity (PRA) and plasma aldosterone was investigated in nine healthy men. A submaximal work test was performed on two occasions. The test consisted of ergometer bicycling for 10 min on 50% of maximal working capacity immediately followed by 10 min on 80% of maximal working capacity. Ten minutes before exercise the subjects received in a randomized manner a bolus dose of naloxone (10 micrograms/kg) or a corresponding volume of saline followed by a slow infusion (15 ml/h) of naloxone (5 micrograms h-1 kg-1) or saline, respectively. After exercise systolic blood pressure, heart rate, plasma catecholamines, PRA and plasma aldosterone increased during both saline and naloxone infusion. The changes were similar in both studies. Accordingly, opiate receptors sensitive to naloxone in a moderate dosage seem not to be involved in the cardiovascular response and the increase in plasma catecholamines, PRA and plasma aldosterone induced by exercise.     

Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase.

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.     

Nicardipine versus nitroprusside infusion as antihypertensive therapy in hypertensive emergencies

This prospective study compared the efficacy of nicardipine and nitroprusside for treating hypertensive emergencies by measuring haemodynamic indices and serum catecholamine levels. Patients admitted to the emergency department with a hypertensive crisis and acute pulmonary oedema received intravenous infusions of nitroprusside (starting dose 1 microgram/kg per min, n = 20) or nicardipine (starting dose 3 micrograms/kg per min, n = 20). Both groups experienced significant declines in systolic and diastolic blood pressure after treatment, but there were no significant time-dependent differences between the groups. Heart rate decreased in the nicardipine group and increased in the nitroprusside group, but neither change was significant. Respiration rate decreased and capillary oxygen saturation rate increased after treatment in both groups. Adrenaline and noradrenaline levels decreased significantly after treatment in both groups; noradrenaline levels were significantly decreased in the nicardipine-treated group compared with the nitroprusside-treated group. Injectable nicardipine is easy to use and as effective as nitroprusside for treating hypertensive crisis with acute pulmonary oedema.     

Effects of intracerebroventricular administration of adrenoceptor-agonists on the regulation of renal water and electrolytes handling through endocrine, renal and hemodynamic function

In order to assess the roles of central adrenoceptors in the release of atrial natriuretic peptide (ANP), aldosterone (ALD), vasopressin (AVP) and renin as well as in the regulation of renal and cardiovascular functions, either norepinephrine (NE; 0.07 microgram/kg/min), guanabenz (GB; alpha 2-agonist; 0.4 microgram/kg/min), methoxamine (MET; alpha 1-agonist; 0.4 microgram/kg/min), or isoproterenol (ISO; beta-agonist; 0.07 microgram/kg/min), dissolved in the artificial cerebrospinal fluid (ACSF), was intracerebroventricularly (i.c.v.) administered at a rate of 10 microliters/min for 30 min in anesthetized dogs. In the control study, the drugs were omitted. NE decreased mean arterial pressure (MAP), urinary osmolality (Uosm) and plasma ALD and AVP concentrations, and increased urine flow (UF). GB increased UF and urinary K excretion without any changes in urinary Na excretion, but decreased plasma ALD and AVP, heart rate, and Uosm without changes in MAP. ISO decreased MAP and plasma ALD, and increased Na and K output, renal plasma flow and UF with decreased Uosm. MET and ACSF failed to affect any of these parameters. Glomerular filtration rate, plasma ANP concentration and renin activity did not change in any of the studies. The present results suggest that central alpha 2- and beta-adrenoceptors may attenuate ALD and/or AVP release without changes in ANP and renin release, and decrease blood pressure, thereby causing a diuresis and natriuresis.     

Effect of synthetic ovine corticotropin-releasing factor. Dose response of plasma adrenocorticotropin and cortisol

Synthetic ovine corticotropin-releasing factor (CRF) was administered to normal male volunteer subjects as an intravenous bolus or 30-s infusion. Doses of CRF ranging from 0.001 to 30 micrograms/kg body wt were administered, and plasma immunoreactive (IR)-ACTH and IR-cortisol concentrations were measured. The threshold dose appeared to be 0.01-0.03 micrograms/kg, the half-maximal dose 0.3-1 micrograms/kg, and the maximally effective dose 3-10 micrograms/kg. Basal concentrations of IR-ACTH and IR-cortisol were 14 +/- 7.6 pg/ml (mean +/- SD) and 5.6 +/- 2.2 micrograms/dl, respectively. IR-ACTH rose as early as 2 min after CRF injection, reached peak levels in 10-15 min, and declined slowly thereafter. IR-cortisol rose at 10 min or later and reached peak levels in 30-60 min. At a dose of 30 micrograms/kg, neither IR-ACTH nor IR-cortisol fell from peak levels of 82 +/- 21 pg/ml (mean +/- SE) and 23 +/- 1.4 micrograms/dl, respectively, during the 2-h course of the experiment, indicating that CRF has a sustained effect on ACTH release and/or a prolonged circulating plasma half-life. There was little or no increase in the levels of other anterior pituitary hormones. At doses of 1 microgram/kg and higher, facial flushing, tachycardia, and, in some subjects, a 15-29-mmHg decline in systemic arterial blood pressure were observed, even though blood volume was replaced and the subjects remained supine. These data indicate that synthetic ovine CRF is a very potent and specific ACTH secretagogue in man. Administered with caution until its vasomotor effects are more fully defined, CRF promises to be a safe and very useful investigative, diagnostic, and, possibly, therapeutic agent in man.     

Exogenous insulin augments in healthy volunteers the cardiovascular reactivity to noradrenaline but not to angiotensin II.

Hyperinsulinemia has been implicated in the pathogenesis of the blood pressure elevation in patients with noninsulin-dependent diabetes mellitus, obesity, but also essential hypertension. In these conditions an increased cardiovascular reactivity to noradrenaline (NA) and angiotensin II (AII) can be observed. Using the euglycemic clamp technique, we determined the cardiovascular reactivity to graded infusions of NA and AII in nine healthy males before (Bas), and 1 and 6 h after infusion of insulin (50 mU/kg per h) was started. On separate days control experiments were carried out to control for any circadian variation. Insulin led to a decrease of the amount of circulating NA necessary to increase the diastolic blood pressure (DBP) 20 mmHg (actual experiment [mean +/- SEM]: Bas, 23.1 +/- 5.0; 1 h, 14.8 +/- 3.0; and 6 h, 12.3 +/- 3.1; and control experiment: Bas, 20.7 +/- 5.0; 1 h, 18.6 +/- 3.5; and 6 h, 17.3 +/- 3.3 nmol/liter; Bas vs. 1 and 6 h: P less than 0.05). Although the amount of NA infused to raise DBP 20 mmHg showed a similar decline after 1 h of insulin infusion, no such change from baseline could be observed at 6 h. This appeared to be due to an increase in NA clearance with more prolonged insulin infusion. Insulin exerted no effect on the amount of AII infused to increase DBP 20 mmHg (actual experiment: Bas, 27.6 +/- 6.4; 1 h, 28.8 +/- 10.0; and 6 h, 21.2 +/- 5.3; and control experiment: Bas, 33.6 +/- 5.7; 1 h, 34.2 +/- 6.1; and 6 h, 23.4 +/- 4.7 ng/kg/min; NS). We did observe a circadian variation in AII reactivity. Whether the increase in cardiovascular responsiveness to NA after administration of insulin contributes to the elevation in blood pressure frequently observed in patients with insulin resistance remains to be proven.     

Cardiovascular and renal effects of dopamine and dobutamine in healthy, conscious piglets

The pharmacologic effects of dopamine and dobutamine (2 to 32 micrograms/kg.min) were evaluated in 12 1 to 2-month-old piglets. Dopamine increased cardiac output at 16 to 32 micrograms/kg.min (p less than .05) and increased heart rate (HR) at 4 to 32 micrograms/kg.min (p less than .05). Dobutamine produced an increased cardiac output at doses of 16 to 32 micrograms/kg.min (p less than .05), and increased HR at 32 micrograms/kg.min (p less than .05), decreased systemic arterial pressure and systemic vascular resistance at 16 to 32 micrograms/kg.min (p less than .05), decreased renal vascular resistance at 16 to 32 micrograms/kg.min, and increased renal blood flow at 4.8 and 32 micrograms/kg.min (p less than .05). We conclude that dopamine and dobutamine increase cardiac output in healthy, conscious piglets primarily by increasing HR. Neither agent was effective in increasing stroke volume, although a positive inotropic effect obscured by tachycardia cannot be ruled out. Dobutamine was the superior agent for renal vasodilation, whereas neither agent produced significant pulmonary vasodilation.     

Blood pressure dependency on vasopressin and angiotensin II in prazosin-treated conscious normotensive rats

The role of the sympathetic nervous system, angiotensin II and vasopressin in limiting the hypotensive effect of prazosin (0.25 mg i.v.) was investigated in conscious normotensive rats. Within 45 min, mean blood pressure fell from 120 +/- 1 to 98 +/- 1 mm Hg (mean +/- S.E.M., P less than .001) while pulse rate rose from 463 +/- 9 to 500 +/- 9 beats/min (P less than .01). The blood pressure response to prazosin tended to be most pronounced in the rats with the smallest increase in heart rate (r = 0.58, P less than .001). Plasma norepinephrine and epinephrine levels were higher in prazosin-treated rats than in the controls (P less than .001). In the animals receiving prazosin, plasma renin activity was 4 times (P less than .001) and plasma vasopressin 7 times (P less than .01) higher than in the controls. Blockade of angiotensin II with saralasin (10 micrograms/min) further decreased blood pressure of the prazosin-treated rats by 22 +/- 4 mm Hg (P less than .001). In contrast, dPVDAVP (25 micrograms), a vasopressin antagonist, had no effect. Prazosin decreased the pressor response to methoxamine (10 micrograms) by 80% (P less than .001) but not to angiotensin II (60 ng). However, prazosin enhanced the reflex bradycardia induced by angiotensin II (P less than .001). These data demonstrate that both the sympathetic and the renin angiotensin system are markedly stimulated by prazosin; they both appear to limit its acute hypotensive action. In contrast, although plasma vasopressin is also increased, its pressor action is effectively buffered, probably due to enhanced baroreflex sensitivity.     

Renal actions of a new adenosine agonist, CGS 21680A selective for the A2 receptor

This study compares the renal actions of the A2 selective adenosine agonist, CGS 21680A, with the A1 selective adenosine agonist, N6-cyclopentyladenosine (CPA), and the nonselective agonist, 5'-N-ethylcarboxamide adenosine (NECA), in the anesthetized dog. Initial receptor binding studies in dog brain demonstrated that CPA and CGS 21680A were selective for the A1 and A2 adenosine receptor, respectively, whereas NECA displayed slightly greater affinity for A1 than A2 adenosine receptors in the canine brain. Intravenous infusion of CGS 21680A (0.25 and 2.5 micrograms/kg/min) decreased blood pressure (BP) and increased heart rate (HR). CGS 21680A transiently increased renal blood flow (RBF) and either did not change or, at the highest dose infused, decreased glomerular filtration rate (GFR). Both urine volume (UV) and urinary sodium excretion (UNaV) also were decreased by CGS 21680A. At the lowest infusion rate (0.025 micrograms/kg/min) CGS 21680A produced a slowly developing increase in RBF, no change in GFR and a significant decrease in sodium excretion. Intravenous infusion of CPA (15 micrograms/kg/min) lowered BP and HR RBF and GFR. UNaV, UV and renin release also were inhibited by CPA. At a lower infusion rate (2.5 micrograms/kg/min), CPA markedly inhibited UNaV in the absence of a significant change in either BP or renal hemodynamic parameters. Infusion of NECA (0.01 and 0.1 micrograms/kg/min) lowered BP but did not change HR. Furthermore, RBF was increased by NECA, whereas UV and UNaV were inhibited in the absence of a change in GFR. These results may be explained by the relative selectivity of each analog for A1 or A2 adenosine receptors.     

A forskolin derivative, colforsin daropate hydrochloride, inhibits the decrease in cortical renal blood flow induced by noradrenaline or angiotensin II in anesthetized rats

A forskolin derivative, colforsin daropate hydrochloride (CDH), acts directly on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate levels which produce a positive inotropic effect and a lower blood pressure. However, little is known about the effects of CDH on the renal function. We used laser Doppler flowmetry to measure the cortical renal blood flow (RBF) in male Wistar rats given a continuous intravenous infusion of CDH and evaluated the effects of CDH on the noradrenaline (NA) and angiotensin II (AngII) induced increases in blood pressure and reductions in RBF. Continuous intravenous administration of CDH at 0.25 microg/kg/min did not affect the mean arterial pressure (MAP), but increased heart rate and RBF. Continuous intravenous administration of CDH at high doses (0.5-0.75 microg/kg/min) decreased the MAP, with little effect on the RBF. The administration of exogenous NA (1.7 microg/kg) increased the MAP and decreased the RBF. However, a bolus injection of NA did not decrease the RBF during continuous intravenous administration of CDH, and CDH did not affect the NA-induced increase in MAP. The administration of exogenous AngII (100 ng/kg) increased MAP and decreased RBF and heart rate, but a bolus injection of AngII did not decrease RBF during continuous intravenous administration of CDH. These results suggest that CDH plays a protective role against the pressor effects and the decrease in RBF induced by NA or AngII.