Evidence for prostaglandin-independent mechanisms in renin release mediated by alpha adrenoceptors during renal nerve stimulation in anesthetized dogs

We investigated alpha adrenoceptor-mediated renin release in relation to renal prostaglandin production in anesthetized dogs. The effects of intrarenally infused phentolamine (5 micrograms/kg/min) on renin and prostaglandin E2 release induced by renal nerve stimulation (RNS, 2.5-5 Hz) were studied in indomethacin (5 mg/kg i.v.)-treated and untreated dogs. In the control group, RNS reduced renal blood flow and increased both renin and prostaglandin E2 secretion rates. Phentolamine inhibited the blood flow response and attenuated the renin response; it did not affect the prostaglandin E2 response. In the indomethacin-treated group, the renal venous plasma prostaglandin E2 concentration was not changed, the renin secretion rate was increased during RNS. Phentolamine also attenuated the renin response in this prostaglandin-depleted state. These results suggest that alpha adrenoceptors participate in renin release induced by RNS and that some of the alpha adrenoceptor-mediated renin release is independent of renal prostaglandins. Prostaglandin release induced by RNS may be mediated by mechanisms other than alpha adrenoceptors.     

Undifferentiated effects of calcium antagonists on pressor responses to selective alpha-1 and alpha-2 adrenoceptor agonists in anesthetized, spinal dogs

Whether pressor responses mediated by alpha-2 adrenoceptors are more susceptible to calcium antagonists than those mediated by alpha-1 adrenoceptors was investigated in anesthetized, spinal dogs. All drugs were administered i.v. Methoxamine (3-100 mu/kg) or xylazine (3-300 micrograms/kg) produced a sustained increase in mean arterial pressure but almost no effect on heart rate. Both the initial and the sustained phase of the pressor response to methoxamine were selectively antagonized by prazosin, whereas those to xylazine were selectively antagonized by yohimbine. These results indicate that the peripheral arterial bed of the dog comprises alpha-1 and alpha-2 adrenoceptors and that both the initial and sustained phases of the pressor response to methoxamine are predominantly mediated by alpha-1 adrenoceptors, whereas those to xylazine are mediated by alpha-2 adrenoceptors. The calcium antagonists, i.e., nifedipine (0.3-3 micrograms/kg), diltiazem (10-100 micrograms/kg) and KB-944 (10-100 micrograms/kg), administered during the sustained phase of the pressor responses to equieffective doses of methoxamine (100 micrograms/kg) and xylazine (1000 micrograms/kg), lowered mean arterial pressure. The three calcium antagonists in these doses also lowered the baseline mean arterial pressure but to a lesser extent than the elevated one. These results altogether indicate that the calcium antagonists were more effective in lowering mean arterial pressure elevated by either an alpha-1 or alpha-2 adrenoceptor agonist than the base-line mean arterial pressure and that the sustained phase of the pressor response mediated by alpha-1 adrenoceptors would involve Ca++ influx as much as or more than those mediated by alpha-2 adrenoceptors.     

Renal nerve stimulation induces alpha2-adrenoceptor-mediated antinatriuresis under inhibition of prostaglandin synthesis in anesthetized dogs

The interaction between prostaglandins and alpha-adrenoceptors in neural control of tubular sodium reabsorption was examined in anesthetized dogs. Renal nerve stimulation (RNS; 0.5-1.0 Hz, 10 V, 1.0-milliseconds duration) reduced fractional excretion of Na+ (FENa) with minimal changes in hemodynamics and glomerular filtration. Intrarenal arterial infusion of prazosin (0.7 microg x kg(-1) x min(-1)), an alpha1-adrenoceptor antagonist, inhibited the RNS-induced reduction in FENa. However, the RNS-induced reduction in FENa was resistant to prazosin under pretreatment with indomethacin (5 mg/kg, i.v.), a cyclooxygenase inhibitor. Intrarenal arterial infusion of yohimbine (1 microg x kg(-1) x min(-1)), an alpha2-adrenoceptor antagonist, failed to inhibit the RNS-induced reduction in FENa in the absence or presence of indomethacin, but combined infusion of prazosin and yohimbine abolished the RNS-induced reduction in FENa in the presence of indomethacin. These results suggest that both alpha1- and alpha2-adrenoceptors mediate the RNS-induced antinatriuresis, but the alpha2-adrenoceptor-mediated portion is impaired by prostaglandins.     

Effects of alpha adrenoceptor blockade on renal nerve stimulation-induced norepinephrine release and vasoconstriction in the dog kidney

Effects of alpha-antagonists on renal norepinephrine (NE) release and vasoconstriction induced by renal nerve stimulation (RNS) were examined in pentobarbital-anesthetized dogs. RNS at 1,2 and 3 Hz (1 msec duration, 10-20 V) for 1 min decreased renal blood flow (RBF) and increased both the renal venous NE concentration (NEC) and calculated renal NE efflux (NEE). The RBF responses to 2 and 3 Hz RNS and NEC responses to 1, 2 and 3 Hz RNS during intrarenal arterial infusion of yohimbine (1.0 micrograms/kg/min) were greater than those observed during the control period. The NEE responses to 1 and 2 Hz RNS, but not to 3 Hz RNS, were also potentiated by the yohimbine infusion. Prazosin treatment (0.2 mg/kg i.v.) attenuated the RBF responses. Subsequent infusion of yohimbine potentiated both the NEC and NEE responses to 1, 2 and 3 Hz RNS in this alpha-1 adrenoceptor-blocked state. These results suggest that an alpha-2 adrenoceptor-mediated inhibitory mechanism of neural NE release exists in the dog kidney, which can be activated by endogenously released catecholamines to modulate the neural control of renal hemodynamics. Alpha-1 adrenoceptor-mediated renal vasoconstriction may affect the evaluation of neural NE release by NEE when high-frequency RNS is applied during inhibition of the alpha-2 adrenoceptor-mediated mechanism.     

Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine

The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. The depressor and antinociceptive effects of 3.2 micrograms of clonidine were antagonized by pretreatment with yohimbine (30.0 micrograms i.t.) but not by prazosin (30.0 micrograms i.t.) or by yohimbine (0.1 mg/kg i.v.). Thus, these effects of clonidine are mediated by spinal alpha-2 adrenoceptors. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was accompanied by marked bradycardia, and similar cardiovascular effects were observed when this dose of clonidine was administered either i.v. or to the cervical level of the spinal cord. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was not reduced significantly by i.t. pretreatment with yohimbine (30.0 micrograms) or prazosin (30.0 micrograms), but was diminished significantly by i.v. pretreatment with yohimbine (1.0 mg/kg), prazosin (0.1 mg/kg) or phentolamine (2.0 mg/kg). Neither chlorisondamine (2.5 mg/kg i.v.) or the V1-vasopressin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]Arg8-vasopressin (10.0 micrograms/kg i.v.) reduced the clonidine-produced pressor response. After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.     

Comparison of the cardiovascular actions of dopamine and epinine in the dog

The effects of i.v. infusions of 3 and 6 micrograms/kg/min of dopamine (DA) and epinine on heart rate, arterial blood pressure, regional blood flows and vascular resistances in the renal, mesenteric and femoral vascular beds were compared in pentobarbital-anesthetized dogs. At the 3 micrograms/kg/min infusion rate, neither DA nor epinine changed blood pressure, whereas at the higher infusion rate both increased blood pressure by about 20 mm Hg. DA increased renal blood flow significantly at both infusion rates; whereas, epinine did not change renal blood flow. After administration of phenoxybenzamine, both epinine and DA decreased blood pressure; upon adding propranolol, the vasodepressor effect of epinine, but not of DA, was abolished. However, propranolol did not inhibit epinine-mediated vasodilation in the renal or mesenteric vascular beds, but a marked increase in femoral vascular resistance was observed. The addition of (R)-sulpiride, a DA antagonist, abolished DA and epinine-induced vasodilation in the mesenteric and renal vascular beds. Experiments in animals treated with hexamethonium to block ganglion transmission and propranolol to block beta adrenoceptors revealed that both selective alpha-1 (terazosin) and alpha-2 (rauwolscine) adrenoceptor antagonists inhibited the vasopressor response to DA to a greater degree than the responses to epinine. Thus, although DA and epinine possess significant DA1 activity, the consistent increase in renal blood flow observed with DA is not seen with epinine because of the more potent alpha adrenoceptor activity of the latter, which is mediated by both alpha-1 and alpha-2 adrenoceptors.     

Inhibitory effects of AE0047, a new dihydropyridine Ca(2+) channel blocker, on renal nerve stimulation-induced renal actions in anesthetized dogs

The effects of AE0047, a newly developed dihydropyridine Ca(2+) channel blocker, and nicardipine on changes in the renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS at a low frequency (0. 5-2.0 Hz) caused significant decreases in the urine flow, urinary excretion of sodium, and fractional excretion of sodium, while also inducing increases in the NE secretion rate (NESR), without affecting the renal hemodynamics. RNS at a high frequency (2.5-5.0 Hz), which diminishes the renal blood flow, glomerular filtration rate, and filtrate fraction, elicited more potent decreases in urine formation and increases in NESR than those seen for the low-frequency RNS. When AE0047 (10 and 50 ng/kg/min) was administered intrarenally, increases in the basal renal blood flow and urine formation were observed. During AE0047 (50 ng/kg/min) infusion, low-frequency RNS-induced antidiuretic action and increase in NESR were markedly attenuated. Qualitatively similar results were observed for high-frequency RNS. In addition, high-frequency RNS-induced renal vasoconstriction was significantly suppressed by AE0047 infusion at higher doses. Lower doses of AE0047 (10 ng/kg/min) tended to attenuate the low- and high-frequency RNS-induced antidiuretic actions, although neither of the RNS-induced increases in NESR were suppressed by lower doses of AE0047. Nicardipine (50 ng/kg/min) also increased the level of basal urine formation, but the RNS-induced changes in renal function and increases in NESR were not affected by this drug. These results suggest that AE0047 suppresses the RNS-induced NE overflow from renal nerve endings, which is probably involved in the inhibitory effects of the drug on the antidiuretic action elicited by RNS.     

Neural activation of alpha-2 adrenoceptors in cat cutaneous vasculature.

The present study was designed to assess the relative contribution of postjunctional alpha-1 and alpha-2 adrenoceptors in neurally evoked cutaneous vasoconstrictor responses in anesthetized cats. Preganglionic stimulation of the thoracic sympathetic nerve trunk produced an intensity-related decrease of digital skin blood flow as measured by laser-Doppler flowmetry. Sympathetic-cholinergic sudomotor (electrodermal) responses were recorded simultaneously as an additional index of neuronal activation. Vasoconstrictor responses were not altered by pretreatment with i.v. propranolol (1 mg/kg) or atropine (1 mg/kg) and were refractory to low doses (2 mg/kg) of hexamethonium. As expected, atropine abolished evoked skin potential responses which were also sensitive only to higher doses (20 mg/kg) of hexamethonium. Pretreatment with either phentolamine (1 mg/kg i.v.), yohimbine (0.5 mg/kg i.v.) or prazosin (0.3 mg/kg i.v.) produced significant reduction of sympathetic vasoconstriction with blockade by phentolamine and yohimbine being far greater than that seen with prazosin. In animals previously given prazosin (0.3 mg/kg), subsequent administration of yohimbine (0.5 mg/kg) almost totally blocked the remaining evoked cutaneous vasoconstriction. These results demonstrate that both alpha-1 and alpha-2 adrenoceptors are present in the cutaneous bed of the cat with the predominant effect mediated by innervated alpha-2 adrenoceptors.     

Inhibitory effects of norepinephrine, methoxamine and phenylephrine on renin release from rat kidney cortical slices

We attempted to determine whether the inhibition of renin release from rat kidney cortical slices by alpha adrenoceptor agonists is mediated by activation of alpha-1 and/or alpha-2 adrenoceptors, and to investigate the role of calcium in the mechanisms of this inhibition. Norepinephrine (NE), methoxamine (ME) and phenylephrine (PE) produced a concentration-dependent inhibition of renin release from rat kidney cortical slices, whereas clonidine was without effect. NE-, ME- and PE-induced inhibition of renin release was blocked by prazosin, which was 2 or 3 orders of magnitude more potent than yohimbine. The inhibitory effects of NE, ME and PE on renin release from the slices were abolished by removal of calcium from the incubation medium. Calcium antagonists, verapamil and nifedipine, attenuated the responses of renin release to NE, ME and PE, in a concentration-dependent manner. The inhibitory effects of NE, ME and PE on renin release were blocked significantly by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, a calmodulin antagonist, but not by N-(6-aminohexyl)-1-naphthalenesulfonamide, which has virtually no calmodulin antagonistic activity. These findings suggest that alpha adrenoceptor agonists inhibit renin release from rat kidney cortical slices mainly via alpha-1 adrenoceptors and that calcium influx followed by the activation of the calcium-calmodulin system is involved in the above inhibition.     

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.     

Autoregulatory vasodilation enhances renal prostaglandin E2 and associated renin release during arachidonic acid infusion in dogs

To examine whether autoregulatory dilation of preglomerular vessels enhances prostaglandin (PG)E2 and renin release during arachidonic acid infusion, the ureter was occluded or the renal artery constricted in anesthetized dogs. Intrarenal arachidonic acid infusion (40 micrograms X kg-1 X min-1) increased PGE2 release by 41 +/- 17 pmol/min at control pressures and by 149 +/- 60 pmol/min during ureteral occlusion. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) increased PGE2 release by 149 +/- 60 pmol/min at control pressures, by 505 +/- 211 pmol/min during ureteral occlusion and by 581 +/- 201 pmol/min during renal arterial constriction. Thus, PGE2 release during arachidonic acid infusion was trebled by autoregulatory dilation. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) raised renin release by 6 +/- 2 micrograms of angiotensin I per min at control pressures, by 25 +/- 9 micrograms of angiotensin I per min during renal arterial constriction and during ureteral occlusion by 16 +/- 4 micrograms of angiotensin I per min, which was not significantly higher than induced by the lower rate of infusion. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) raised renal blood flow by 54 +/- 5% at control pressures but exerted no vasoactive effect during ureteral occlusion and renal arterial constriction. We conclude that autoregulatory dilation enhances the stimulatory effects of arachidonic acid on renal PG synthesis. Both increased intrarenal PG concentration and autoregulatory dilation may contribute to enhancement of renin release. The stimulatory effects of arachidonic acid on PG synthesis and renin release are independent of the vasoactive effects of arachidonic acid.     

Effects of epinephrine, isoproterenol and IPS-339 on sympathetic transmission to the dog heart: evidence against the facilitatory role of presynaptic beta adrenoceptors

The autoregulation of norepinephrine (NE) release mediated by presynaptic alpha and beta adrenoceptors on sympathetic nerve terminals in the heart of pentobarbital-anesthetized dog was studied. NE overflow elicited by left cardiac sympathetic nerve stimulation was determined from the coronary sinus blood, by using high-performance liquid chromatography with electrochemical detection. Intracoronary infusion of epinephrine (1,3 and 10 micrograms/min) into the left circumflex artery increased basal left ventricular dp/dt maximum (LV dp/dt max) and coronary sinus blood flow. The epinephrine infusion decreased coronary sinus output of NE (NE output) during left cardiac sympathetic nerve stimulation. Intracoronary infusion of isoproterenol (0.03, 0.1 and 0.3 microgram/min) increased the basal LV dp/dt max and coronary sinus blood flow, whereas the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow were not altered by its infusions. Intravenous injection of IPS-339 (0.03, 0.1 and 0.3 mg/kg), a selective beta-2 adrenoceptor antagonist, diminished the stimulation-induced increases in LV dp/dt max and coronary sinus blood flow in a dose-dependent manner, whereas it did not decrease the stimulation-induced increase in NE output. Intracoronary infusion of yohimbine (10, 30 and 100 micrograms/min), a preferentially selective alpha-2 adrenoceptor antagonist, facilitated the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow. There was no significant difference in the facilitation of the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow between intracoronary infusion of both isoproterenol (0.1 microgram/min) and yohimbine (100 micrograms/min) and the infusion of yohimbine alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for two subtypes of alpha adrenergic receptors in canine airway smooth muscle

The contractile response of canine tracheal muscle to i.a. phenylephrine, clonidine and norepinephrine was studied isometrically in situ in 32 dogs after beta adrenergic and ganglionic blockade. Intra-arterial phenylephrine caused dose-related tracheal contraction which was not altered by yohimbine (5 microgram/kg i.a.). Prazosin (4 mg/kg i.v.) caused a 77 +/- 3% decrease in tracheal response to i.a. phenylephrine. Clonidine also caused dose-related tracheal contraction, which was not altered by prazosin (4 mg/kg i.v.) but was 95 +/- 2% blocked by 5 microgram/kg i.a. of yohimbine. Norepinephrine caused tracheal muscle contraction which was greater than both phenylephrine (P less than .05) and yohimbine (P less than .001). Prazosin (4 mg/kg i.v.) caused 53 +/- 6% blockade and yohimbine (5 microgram/kg i.a.) caused 76 +/- 2% blockade of the response to i.a. norepinephrine; prazosin plus yohimbine caused greater than 98% blockade of the response to i.a. norepinephrine. The dose-response curve to i.a. acetylcholine was not altered by treatment with prazosin (4 mg/kg i.v.) plus yohimbine (5 microgram/kg i.a.). These results demonstrate that tracheal contraction induced by sympathomimetic amines is mediated by two subtypes of alpha adrenergic receptors on tracheal muscle, alpha-1 for phenylephrine, alpha-2 for clonidine and both alpha-1 and alpha-2 for norepinephrine.     

Pharmacological characterization of the postsynaptic alpha adrenoceptors in vascular smooth muscle from canine and rat mesenteric vascular beds

Postsynaptic alpha adrenoceptors have been characterized in rat superior mesenteric artery and branches of canine mesenteric artery. l-Phenylephrine, naphazoline and clonidine were used as agonists and prazosin and yohimbine were used as antagonists. The pA2 values for prazosin and yohimbine were determined against these agonists in canine and rat mesenteric arteries. The pA2 values for either prazosin or yohimbine were similar when l-phenylephrine and naphazoline were used as the agonists. The slope of the Schild plot was less than unity for prazosin and yohimbine acting as antagonists to l-phenylephrine in canine mesenteric artery whereas in the rat mesenteric artery, the slopes obtained for either phenylephrine or naphazoline against the antagonists were not significantly different from unity. In rat mesenteric artery, the pA2 value for yohimbine against clonidine was not statistically different from values obtained with the other agonists; however, in the presence of prazosin the dose-response curve to clonidine was biphasic, suggesting that the action of clonidine is mediated through two distinct sites to which prazosin has different affinities. However, these results do not provide definitive support for the concept of functionally independent subtypes of postsynaptic alpha adrenoceptors in rat and canine mesenteric artery.     

Pharmacological characterization of alpha-2 adrenergic receptor subtype involved in the release of insulin from isolated rat pancreatic islets

Alpha-2 adrenoceptors are involved in the inhibition of insulin release induced by sympathetic nerve stimulation. To test the possibility that one of the postulated subtypes of alpha-2 adrenoceptors is differentially implicated in the inhibition of insulin release, we compared the effects of several agonists and antagonists with preferential selectivity for the alpha-2 adrenoceptor subtypes on the release of insulin induced by glucose in rat isolated islets. Similar to the inhibition of glucose-evoked release of insulin by the alpha-2 agonist (nonsubtype selective) UK 14.304, the alpha-2A preferential agonist oxymetazoline, concentration-dependently inhibited the release of insulin. Glucose-evoked insulin release was similarly inhibited by other alpha-2 adrenoceptor agonists such as clonidine, p-aminoclonidine, epinephrine and norepinephrine. However, neither the alpha-1 selective agonist cirazoline, nor the beta adrenoceptor agonist isoproterenol affected glucose-evoked insulin release, thus suggesting that this inhibitory effect is mediated by alpha-2 adrenoceptors, possibly of the alpha-2A subtype. The inhibition of glucose-evoked insulin release induced by the alpha-2 adrenoceptor agonists was concentration-dependently inhibited by the alpha-2 antagonists yohimbine, phentolamine, rauwolscine and idazoxan. However, neither the alpha-1 selective antagonist prazosin, nor the beta selective antagonist propranolol attenuated the inhibition of insulin release induced by alpha-2 adrenoceptor agonists. Furthermore, the inhibition of insulin release induced by UK 14.304 was concentration-dependently antagonized by the alpha-2A preferential antagonist WB-4101.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological, hemodynamic and biochemical mechanisms involved in the blood pressure lowering effects of pergolide, in normotensive and hypertensive dogs

In pentobarbital-anesthetized normotensive dogs, clonidine (20.0 micrograms/kg i.v.), in contrast to pergolide (30.0 micrograms/kg i.v.), reduced significantly both aortic blood pressure and plasma concentration of norepinephrine. However, in dogs that had been made hypertensive by sectioning the vagi and carotid sinus nerves, pergolide, like clonidine, lowered the blood pressure and plasma concentrations of epinephrine and norepinephrine that were enhanced markedly by deafferentation. Furthermore, in this preparation pergolide decreased the calculated resistance in vascular regions supplied by the upper abdominal aorta and the innervated femoral and renal arteries, but it increased vascular resistance in the denervated hind leg. Pergolide (1.0 microgram/kg) injected intracisternally (i.c.m.) induced a fall in blood pressure of comparable magnitude to that produced by a 30 times higher i.v. dose. Intravenously and i.c.m. administered pergolide lowered blood pressure by acting at distinct anatomical sites inasmuch as i.v. sulpiride blocked the effects of i.v. but not i.c.m. pergolide. The combination of sulpiride plus yohimbine injected i.c.m. was necessary to abolish the decrease in blood pressure evoked by i.c.m. pergolide. In atropinized spinal dogs, i.v. pergolide inhibited the vasoconstriction elicited by electrical stimulation of the lumbar sympathetic chain, an effect which was antagonized by sulpiride. Similarly, pergolide (30.0 micrograms/kg i.v.) like clonidine, reduced the heart rate and coronary venous plasma norepinephrine concentration raised by sustained electrical stimulation of the cardioaccelerator nerve. Sulpiride, but not phentolamine, antagonized this pergolide-induced inhibition of sympathetic nerve function. In chlorisondamine-pretreated dogs, pergolide produced a transient pressor response due to stimulation of postsynaptic vascular alpha-2 adrenoceptors. In conclusion, the failure of i.v. pergolide to decrease aortic blood pressure in pentobarbital-anesthetized normotensive dogs is presumably due to the inability of pergolide to produce a significant inhibition of the vascular sympathetic tone in this preparation. However, in neurogenic hypertensive dogs which are characterized by an elevated level of sympathetic drive, i.v. pergolide reduced blood pressure and aortic plasma norepinephrine concentration. These effects of pergolide are compatible with a DA-2 dopamine receptor stimulation on peripheral sympathetic nerve fibers. In contrast, the antihypertensive effects of i.c.m. pergolide would appear to be mediated by both alpha-2 adrenoceptors and DA-2 dopamine receptors located within the central nervous system.     

Dose selective dissociation of water and solute excretion after renal alpha-2 adrenoceptor stimulation

In vitro studies have demonstrated an antagonism of the renal effects of vasopressin after alpha-2 adrenoceptor stimulation. Whether the effect of alpha-2 adrenoceptor stimulation in relation to sodium and water excretion in vivo is mediated through independent mechanisms is unclear. The dose-response relationship between renal alpha-2 adrenoceptor stimulation (clonidine) and water and electrolyte excretion was evaluated in anesthetized rats. Rats were nephrectomized unilaterally 7 to 10 days before the experimental day to allow isolation of renal function. A base-line level of sodium and water excretion was established by the infusion of saline (0.097 ml/min i.v.). In separate groups of rats, clonidine was infused directly into the renal artery at 0 (vehicle), 0.1, 0.3, 1 or 3 micrograms/kg/min at 0.0034 ml/min. The lower doses (0.1, 0.3 and 1 microgram/kg/min) produced a dose-related increase in urine volume and free water clearance and a decrease in urine osmolality. Electrolyte or solute excretion was not altered at these infusion rates even though urine volume increased 4-fold. The highest dose investigated (3 micrograms/kg/min) increased urine volume (9-fold) and sodium excretion (4-fold). Free water clearance and osmolar clearance were also increased. The effects of clonidine were attenuated by yohimbine but not prazosin indicating these effects were mediated by alpha-2 adrenoceptor stimulation. These results demonstrate a dose-related selectivity of alpha-2 adrenoceptor stimulation for water and sodium excretion. The increase in water excretion at the lower infusion rates would be consistent with the antagonism of the renal effects of vasopressin. The potent natriuresis observed only at higher doses indicates another mechanism may be involved.     

Existence of two types of postjunctional alpha adrenoceptors in the isolated canine intermediate auricular artery

Four alpha adrenergic agonists (phenylephrine, xylazine, clonidine and norepinephrine) and two antagonists (prazosin and yohimbine) were used to investigate the characteristics of the postjunctional alpha adrenoceptors involved in contraction of the isolated and perfused canine intermediate auricular artery. All agonists showed almost equal potencies for inducing vasoconstriction in the perfused arterial preparations (i.e., all agonists caused strong vasoconstrictor responses in a dose-related manner; the threshold dose of each agonist was within a dose range of 0.003 to 0.01 micrograms and 0.3 to 1.0 micrograms of each agent caused approximately 200 mm Hg increase in perfusion pressure). Prazosin inhibited phenylephrine-induced vasoconstriction in a competitive manner, but yohimbine did not significantly influence phenylephrine-induced responses. Xylazine-induced responses were inhibited by both prazosin and yohimbine, but the former was less potent than the latter at a low dose and the antagonistic property of prazosin against xylazine was not competitive. The pA2 values of prazosin against phenylephrine, xylazine and clonidine were 7.10, 6.82 and 6.99, respectively, and that of yohimbine against xylazine was 7.16. These results support the theory that not only alpha-1 but also alpha-2 adrenoceptors are involved in the contractile responses of the isolated and perfused canine intermediate auricular artery.     

Conditions for augmentation of renin release by theophylline

Isoproterenol, dopamine, glucagon and dibutyryl cyclic AMP (DB-cAMP) increase renin release at low but not at control blood pressure. These findings suggest that autoregulated afferent arteriolar dilation is a prerequisite of renin release mediated by intracellular generation of cyclic AMP. To examine this hypothesis further the effects on renin release of theophylline, which would maintain high intracellular concentration of cAMP by inhibiting phosphodiesterase, were studied in anesthetized dogs. After inhibiting beta-adrenergic stimulation with propranolol, theophylline increased renin release significantly from 0.7 +/- 0.2 to 1.8 +/- 0.7 micrograms/min at control blood pressure and from 23 +/- 4 to 41 +/- 5 micrograms/min at a renal perfusion pressure of about 50 mmHg. The greater effect at low blood pressure occurred despite adjustment of the infusion rate of theophylline to keep arterial plasma concentration of theophylline unaltered. Isoproterenol infusion at low blood pressure raised renin release from 41 +/- 11 to 76 +/- 19 micrograms/min before and 54 +/- 13 to 108 +/- 31 micrograms/min during continuous infusion of theophylline. The renin release response to infusion of theophylline at low blood pressure was not enhanced by DB-cAMP infusion. We conclude that arteriolar dilation provides a condition for stimulation of renin release during the theophylline infusion. Theophylline infusion may augment the effect of isoproterenol on renin release by delaying the intracellular degradation of cAMP.     

Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog

Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.