Biomedical subjects

M Gellai

Publications and source records attributed to M Gellai.

At least 37 records · Page 2Linked to original sources

PubMed1994

Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat.

Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg.min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicle-treated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na+ and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism. Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Na+ reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance.

Acute Kidney Injury↗

PubMed1994

BQ-123, a selective endothelin subtype A-receptor antagonist, lowers blood pressure in different rat models of hypertension.

OBJECTIVE: To investigate the role of endothelin-1 in the pathogenesis of hypertension directly by using the selective endothelin subtype A-receptor antagonist BQ-123. METHODS: The antihypertensive and hemodynamic effects of sustained BQ-123 administration were examined in conscious, unrestrained spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) rats and renin hypertensive rats. RESULTS: Sustained infusions of BQ-123 (0.16-164 nmol/kg per min, intravenously, for 6 h) produced dose-dependent reductions in mean arterial pressure in SHR, the maximal reduction being obtained with a dose of 16 nmol/kg per min. This reversible response was evident up to 14 h after the cessation of antagonist infusion. The antihypertensive response to a maximal dose of BQ-123 was associated with bradycardia, but only a minimal reduction in cardiac output (since the stroke volume was elevated) in the SHR. Therefore, the antihypertensive effect of BQ-123 resulted from a decrease in total peripheral resistance. In contrast, in WKY rats the infusion of the high dose (164 nmol/kg per min, intravenously for 6 h) produced a small but significant reduction in mean arterial pressure. BQ-123 did not alter the pressor response or tachycardia observed in pithed SHR following stimulation of the thoracolumbar sympathetic outflow. BQ-123 was also antihypertensive in renin hypertensive rats, lowering the blood pressure to an extent similar to that observed in SHR. CONCLUSION: The data presented indicate a role for endothelin in the pathophysiology of hypertension.

Animals↗

PubMed1994

Nonpeptide endothelin receptor antagonists. III. Effect of SB 209670 and BQ123 on acute renal failure in anesthetized dogs.

Endothelin (ET) is a potent vasoconstrictor that has been implicated in the pathogenesis of acute renal failure (ARF). In order to investigate the potential role of ET in ARF in the dog, the effect of a mixed ETA and ETB receptor antagonist, (+/-)-SB 209670, [(1RS-2SR,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-5- (prop-1-yloxy) indane-2-carboxylic acid], and a selective ETA antagonist, BQ123, were evaluated in anesthetized uninephrectomized dogs undergoing 60 min of renal occlusion. (+/-)-SB 209670 (1 microgram/kg/min) and BQ123 (10 micrograms/kg/min) were infused directly into the renal artery (intrarenal) for 30 min before renal occlusion, during occlusion and for 60 min after reperfusion at doses that inhibited the renal vasoconstrictor effects of intrarenal renal artery infusions of ET-1. Renal occlusion resulted in a significant reduction in inulin clearance (from 26.2 +/- 1.8 to 3.2 +/- 1.1 ml/min). This response was significantly (P < .05) attenuated by (+/-)-SB 209670 (from 23.5 +/- 2.2 to 7.6 +/- 2.0 ml/min) but not by BQ123 (from 23.5 +/- 1.7 to 4.9 +/- 1.2 ml/min). Endogenous creatinine clearance showed the same pattern. After renal artery occlusion, fractional sodium and fractional potassium excretions were increased significantly. (+/-)-SB 209670, but not BQ123, resulted in a significant reduction in fractional sodium; however, neither compound altered fractional potassium excretion. The data suggest that ET receptor antagonists, possibly by altering tubular sodium reabsorption, may be beneficial in ischemia-induced ARF.

Acute Kidney Injury↗

PubMed1993

Influence of oxytocin on renal hemodynamics and sodium excretion.

Acute administration of physiological doses of synthetic OT to conscious Long-Evans and Brattleboro homozygous diabetes insipidus rats produced a modest increase in GFR and effective filtration fraction. Chronic administration of OT to DI rats for 9 days in dosages that were antidiuretic (plasma OT ca. 100 pg/ml) increased both GFR and ERPF by 40%. Table 1 summarizes these renal hemodynamic changes and compares them to the renal effects of VP. Further investigation is needed to define the mechanisms responsible for the changes in GFR and/or ERPF produced by acute and chronic administration of OT to conscious rats. Acute administration of physiological doses of synthetic OT to conscious LE and DI rats also produced a brisk natriuresis with a marked increase in the fractional excretion of sodium. A natriuresis was also observed in conscious Sprague-Dawley rats administered physiological amounts of OT by subcutaneous osmotic minipump. The natriuretic effect of the hormone was short lived, however, being observed only during the first 24-hr period of treatment. The nephron site where OT exerts its natriuretic action, either directly or indirectly, is unknown. Renal prostaglandins may contribute to OT-induced natriuresis, but other mechanisms such as increased renal production of nitric oxide and cGMP have not been tested. Although the natriuretic response to OT has also been described for conscious dogs, it probably does not occur in humans and nonhuman primates. Precise localization of specific renal OT receptors has recently been reported for the rat. OT receptors were identified in the macula densa cells of the adult, rat kidney. This location suggests a possible role for OT in the regulation of tubuloglomerular feedback and solute transport. The signal transduction of the renal OT receptor has been recently evaluated in various kidney epithelial cells in culture. OT stimulates phosphoinositide hydrolysis and increases cytosolic calcium concentrations. In fact, VP produces similar cellular responses in renal epithelia, possibly through the OT receptor. Also, OT stimulates soluble guanylate cyclase and increases intracellular cGMP. Whether OT activates soluble guanylate cyclase secondarily through the production of nitric oxide has not been tested. An important role for OT in renal sodium homeostasis under basal conditions is likely, at least for the rat. Moreover, OT possibly mediates dehydration natriuresis in lower animal species. The contribution of OT to renal physiology in humans and in nonhuman primates, if any, remains uncertain.

Animals↗

PubMed1993

Antihypertensive effects of the endothelin receptor antagonist BQ-123 in conscious spontaneously hypertensive rats.

Until recently, a role for endothelin-1 (ET-1) in the development and/or maintenance of hypertension has been based solely on indirect findings, e.g., elevated circulating levels of peptide. However, with the development of specific ET-1 receptor antagonists it is now possible to examine this relationship directly. The present study describes the hemodynamic effects of systemic infusions of BQ-123, a selective endothelin (ETA)-receptor antagonist, in conscious, freely moving spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sustained infusions of BQ-123 (0.16-164 nmol/kg/min i.v. for 6 h) produced dose-dependent reductions in mean arterial pressure (approximately 30 mm Hg) in SHRs that were long-lasting (> 18 h) and reversible. Whereas cardiac output remained unaltered during BQ-123 infusion, the observed reduction in blood pressure was accompanied by a significant decrease (16%) in total peripheral resistance, indicating that the fall in blood pressure (an effect that was independent of the vehicle used and was not observed in WKY rats) was related primarily to peripheral vasodilation. Thus, the present study provides direct evidence showing that ET-1-receptor antagonists are effective antihypertensive (rather than hypotensive) agents and that endogenous ET-1 is involved in the pathophysiology of hypertension.

Animals↗

PubMed1993

Mechanisms for the diuresis of acute cold exposure: role for vasopressin?

The hypothesis that inhibition of vasopressin (VP) secretion initiates cold-induced diuresis was tested in six Brattleboro homozygous (diabetes insipidus, DI) rats exposed to 60 min at 5 degrees C. For 9-14 days before cold exposure (CE) the rats were treated with VP (750 pg.kg-1.min-1) subcutaneously via osmotic minipumps. Eight vehicle-treated Long-Evans (LE) rats characterized the response to acute exposure at 5 degrees C. Additional groups of six to eight LE and six DI rats were infused with VP (30-90 pg.kg-1.min-1 iv) on the day of CE. The DI rats receiving chronic VP replacement and untreated LE rats exhibited cold-induced diuresis, with peak increases in urine flow (V) of 63 +/- 12 (DIs) and 29 +/- 4 (LEs) microliters.min-1 x 100 g body wt-1. LE rats acutely infused with VP exhibited a diuresis at the two lower doses (peak V was 18 +/- 3 at the 30 and 18 +/- 4 microliters.min-1 x 100 g body wt-1 at the 60 pg.kg-1.min-1 dose), but the diuretic response was completely blunted at the uppermost dose of VP. Cold-induced diuresis was absent at the lowest VP dose in the acutely infused DI rats. A pressor response (30-36 mmHg) to CE was noted with all treatment groups, including those that did not exhibit a diuresis. No changes in glomerular filtration rate (GFR) with CE were observed. These data suggest that when plasma VP levels are controlled by prolonged infusion of VP in the DI rats, other mechanisms can operate to initiate cold-induced diuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Alpha 2-adrenoceptor antagonism attenuates the diuretic response to acute cold exposure.

Renal alpha 2-adrenoreceptors modulate the hydrosmotic action of arginine vasopressin (AVP) through suppression of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. Circulating catecholamines, likely candidates for the endogenous ligand, are elevated during cold exposure (CE). These studies therefore tested the hypothesis that the diuresis observed with acute CE in rats is due in part to modulation of AVP's tubular action via alpha 2-adrenoceptor activation. Subjects were five male Brattleboro homozygous diabetes insipidus (DI) rats (358 +/- 8 g) receiving chronic AVP replacement (1 microgram.kg-1 x day-1) and seven Long-Evans (LE) normal rats (395 +/- 5 g). In a CE protocol, baseline measurements at room temperature (RT, 24 +/- 0.3 degrees C) were followed by 60-min exposure to 5 +/- 0.5 degrees C. Results were compared with those from a RT time control protocol. The selective alpha 2-antagonist yohimbine (YOH; 10 micrograms.kg-1 x min-1) or vehicle (VEH) was infused throughout the CE and RT protocols. In VEH-infused rats, CE increased urine flow by 63 +/- 12 (DI rats) and 31 +/- 4 microliters.min-1 x 100 g body wt-1 (LE rats), and mean arterial pressure by 36 +/- 1 (DI rats) and 32 +/- 2 mmHg (LE rats). The increased flow was largely a water diuresis, with changes in free water clearance averaging 45 +/- 11 (DI rats) and 28 +/- 3 microliters.min-1 x 100 g body wt-1 (LE rats). YOH treatment completely blunted the cold-induced diuresis in both strains but did not alter the CE-induced hypertension. Glomerular filtration rate was not affected by either CE or YOH infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1993

Impairment of renal function precedes establishment of hypertension in spontaneously hypertensive rats.

To determine renal function throughout development of hypertension in the spontaneously hypertensive rat (SHR) and its normotensive counterpart, the Wistar-Kyoto rat (WKY), renal clearance studies were performed at 2-wk intervals from 4 to 12 wk and again at 16 wk of age in conscious chronically instrumented rats after recovery (4-6 days) from surgery. The data indicate that the critical period for the development of hypertension in SHR was between 4 and 6 wk of age. Mean arterial pressure sharply increased from 107 +/- 5 (n = 6) to 145 +/- 6 mmHg (n = 6) between 4 and 6 wk of age, did not change between 6 and 10 wk of age, and gradually rose between 10 and 16 wk of age to 183 +/- 3 mmHg. In WKYs, blood pressure increased only slightly from 97 +/- 3 mmHg at 4 wk of age (n = 8) to 110 +/- 3 mmHg at 8 wk of age (n = 8), where it remained through adulthood. Glomerular filtration rate (GFR) in the 4-wk-old SHR was significantly decreased compared with WKY (0.94 +/- 0.03 vs. 1.11 +/- 0.04 ml.min-1 x g wet kidney wt-1), and it recovered to normal level and stabilized by 6 wk of age (1.14 +/- 0.04 ml.min-1 x g wet kidney wt-1). Renal blood flow was lower in the SHR only at 4 and 16 wk; it increased with age in both groups. Renal vascular resistance was higher in the SHR at 4 wk and remained elevated throughout the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Opiate receptors within the blood-brain barrier mediate kappa agonist-induced water diuresis.

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significantly less potent than BRL 52656 and BRL 53114 in causing a water diuresis in conscious rats. The ED10S (i.v. doses to cause a positive free water clearance of 10 microliters/min.100 g) for BRL 52974, BRL 52656 and BRL 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 micrograms/kg i.v.) were able to cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-induced water diuresis and possibly inhibition of AVP secretion.

Animals↗

PubMed1993

Rat kidney endothelin receptors in ischemia-induced acute renal failure.

The current study was designed to assess the possible changes in kidney endothelin (ET) receptors in a model of ischemia-induced acute renal failure. In unilaterally nephrectomized (right kidney) Sprague-Dawley rats, the left renal artery was occluded for 30 min under pentobarbital anesthesia (40 mg/kg i.p.). Body temperature was maintained at 37 degrees C. Sham-operated rats were used as control. Plasma creatinine levels were measured and ET receptors were quantitated by binding of [125I]ET-1 to membranes prepared from the renal cortex at 0, 2, 5 and 24 hr after reperfusion. There was a time-dependent increase in plasma creatinine levels as well as in [125I]ET-1 binding to cortical membranes at 2, 5 and 24 hr postreperfusion. Saturation binding experiments using [125I]ET-1 and [125I]ET-3 indicated that this increase in binding was due to an increase in affinity without significant change in maximum binding. The affinities were 219, 134, 100, 69 and 80 pM for [125I]ET-1 and 320, 273, 130, 168 and 80 pM for [125I]ET-3 and, for sham, 0, 2, 5 and 24 hr postreperfusion, respectively. These data support the hypothesis of ET involvement in the pathophysiology of acute renal failure in rats.

Acute Kidney Injury↗

PubMed1992

Antihypertensive activity of the non-peptide angiotensin II receptor antagonist, SK&F 108566, in rats and dogs.

The antihypertensive activity of the nonpeptide angiotensin II receptor antagonist, SK&F 108566 (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophene propanoic acid), was examined in rats and dogs. SK&F 108566 produced dose-dependent decreases in blood pressure in renin-dependent hypertensive rats. At 10 mg/kg intraduodenally, mean arterial blood pressure fell from between 150-160 mm Hg to approximately 124 mm Hg. A sustained infusion of SK&F 108566 at 25 micrograms/min intraduodenally normalized blood pressure during 3 days of infusion and for 18 h following cessation of the infusion. Evaluation of the systemic hemodynamic effects of SK&F 108566 in chronically instrumented renin-dependent hypertensive rats demonstrated that the antihypertensive effects of SK&F 108566 were accompanied by a significant increase in cardiac output with little change in stroke volume. In dogs made acutely hypertensive by an intravenous infusion of angiotensin I, SK&F 108566 resulted in dose-dependent decreases in blood pressure. The antihypertensive activity of SK&F 108566 at 10 mg/kg p.o. was maintained for between 13-15 h, a similar duration of action as observed with enalapril (1 mg/kg, p.o.). Administration of DuP 753 (losartan) intravenously caused a small and short-lived fall in blood pressure in the angiotensin I-infused hypertensive dog. However, the active metabolite of losartan, EXP 3174, resulted in a response of longer duration. In dogs made hypertensive by placement of an ameroid constrictor on the left renal artery, SK&F 108566 (10 mg/kg, p.o.) or enalapril (1 mg/kg, p.o.) resulted in antihypertensive responses of at least 12 h duration. The data indicate that SK&F 108566 is a long-acting antihypertensive agent in the rat and dog.

Acrylates↗

PubMed1992

Dopamine DA1 receptor agonist, fenoldopam, reverses glycine-induced hyperfiltration in rats.

Stimulation of dopamine DA1 receptors can prevent glomerular hyperfiltration in streptozotocin-induced diabetic rats. In the present study we have therefore investigated whether the DA1 agonist, fenoldopam, can prevent glycine-induced hyperfiltration. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate clearances in conscious chronically instrumented rats. Glycine (3.7 mg/min iv; n = 8) significantly increased GFR by 37% (from 1.09 +/- 0.53 to 1.49 +/- 0.11 ml.100 g-1.min-1, P less than 0.01), ERPF by 23% (from 2.96 +/- 0.30 to 3.64 +/- 0.43 ml.100 g-1.min-1, P less than 0.05), and filtration fraction (FF) by 13% (from 0.39 +/- 0.04 to 0.44 +/- 0.05, P less than 0.05). Fenoldopam, at a dose (1 microgram.kg-1.min-1 iv; n = 8) that increased ERPF by 26%, decreased FF by 13%, but did not change GFR, significantly attenuated the glycine-induced hyperfiltration. In the presence of fenoldopam, glycine resulted in only an 8% increase in GFR (from 1.08 +/- 0.07 to 1.17 +/- 0.09 ml.100 g-1.min-1; n = 8). ERPF increased by 20% (from 3.34 +/- 0.24 to 4.00 +/- 0.21 ml.100 g-1.min-1, P less than 0.05), and FF decreased by 13% (from 0.34 +/- 0.03 to 0.29 +/- 0.02, P less than 0.05). Infusion of the DA1-selective antagonist, Sch 23390, abolished the effects of fenoldopam. Thus DA1 receptor activation can prevent glomerular hyperfiltration induced by glycine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Inhibition of vasopressin-sensitive cAMP accumulation by alpha 2-adrenoceptor agonists in collecting tubules is species dependent.

The ability of alpha 2-adrenoceptor agonists to inhibit vasopressin (VP)-stimulated cAMP accumulation in collecting tubules and to inhibit the antidiuretic effect of VP in rats is clearly established. However, in other species, such as the dog, alpha 2-adrenoceptor-induced inhibition of VP action has not been convincingly demonstrated. In the present study, we examined the effects of epinephrine and other alpha 2-adrenoceptor agonists on VP-stimulated cAMP accumulation in inner medullary collecting tubule cells and/or cortical collecting tubules from a number of species. Epinephrine, oxymetazoline, clonidine, and guanabenz inhibited VP-induced cAMP formation in rat inner medullary collecting tubule cells with IC50s ranging from 10 to 30 nM. However, epinephrine or guanabenz had no effect on VP-stimulated cAMP formation in cells from dog, pig, rhesus monkey, or human inner medulla. Similarly, epinephrine inhibited VP-induced cAMP accumulation in cortical collecting tubules dissected from rat kidneys but not from dog or rabbit kidneys. We conclude that there is a marked species difference in the ability of alpha 2-adrenoceptor agonists to inhibit VP-induced cAMP formation at the tubular level. This may explain the difficulty in demonstrating an alpha 2-adrenoceptor agonist-induced inhibition of VP action in other species such as dog and man.

Adrenergic alpha-Agonists↗

PubMed1992

The antihypertensive effect of the angiotensin II receptor antagonist DuP 753 may not be due solely to angiotensin II receptor antagonism.

The angiotensin II (AII) receptor antagonist, DuP 753 (10 mg/kg intraduodenal), produced a sustained and long-lasting antihypertensive effect in conscious renin-dependent hypertensive rats. Blood pressures were still reduced markedly 24 to 72 hr after administration of a single dose of DuP 753. However, pressor responses elicited by either angiotensin I or AII were not blocked at these times despite the continued antihypertensive effect of DuP 753. In a model of orthostatic hypotension, DuP 753 and the selective alpha-1 adrenoceptor antagonist prazosin produced a marked orthostatic hypotension response in renin-dependent hypertensive rats as demonstrated by potentiation of the decrease in blood pressure induced by a 90 degrees tilt. The nonpeptide AII receptor antagonist SK&F 108566 (10 mg/kg intraduodenal) did not produce orthostatic hypotension and the angiotensin converting enzyme inhibitor enalapril produced only a slight orthostatic response to tilting. In conscious spontaneously hypertensive rats (SHR), allowed 3 to 4 days to recover from surgery, administration of either enalapril (1 mg/kg i.v.) or SK&F 108566 (10 mg/kg i.v.) did not significantly effect blood pressure. In SHR tested within 24 hr of surgery, enalapril was effective in lowering blood pressure. In contrast, in surgically recovered SHR, DuP 753 (10 mg/kg i.v.) produced an antihypertensive effect that was slow in onset, sustained and extremely long in duration. Blood pressures did not return to predrug levels until 48 hr after administration of DuP 753. Stimulation of the thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses that were significantly potentiated by continuous infusion of a subpressor dose of AII.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗

PubMed1991

Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol.

The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1991

Modulation of vasopressin antidiuretic action by alpha 2-adrenoceptors is species specific.

There is evidence in the rat that stimulation of renal alpha 2-adrenoceptors modulates vasopressin antidiuretic action and vasopressin-stimulated adenylate cyclase activity. In the present study, we tested the ability of various alpha 2-adrenoceptor agonists to antagonize vasopressin-induced antidiuresis in the conscious hydrated dog and to inhibit vasopressin-induced adenosine 3',5'-cyclic monophosphate (cAMP) generation in rat and dog cortical collecting tubules. Vasopressin infusion (0.01 ng.kg-1.min-1) in five dogs resulted in a decrease in free water clearance from 2.90 +/- 0.42 to -0.34 +/- 0.08 ml/min. The vasopressin receptor antagonist SKF 105494 inhibited this response. Administration of norepinephrine (0.5 microgram.kg-1.min-1) or clonidine (20 micrograms/kg), however, failed to alter the vasopressin-induced antidiuresis. In vitro studies demonstrated that epinephrine caused a dose-dependent reduction in vasopressin-stimulated cAMP levels in cortical collecting tubules from the rat (50% effective concentration 32 nM) but not from the dog. The data indicate that there is a species difference in alpha 2-adrenoceptor modulation of vasopressin action.

Adenylyl Cyclases↗

PubMed1991

The water diuretic effect of the alpha-2 adrenoceptor agonist, AGN 190851, is species-dependent.

The effect of the novel alpha-2 adrenoceptor agonist, AGN 190851, was evaluated for its diuretic action in the rat, dog and cynomolgus monkey and its ability to inhibit vasopressin-stimulated cyclic AMP accumulation in rat and dog cortical collecting tubules in vitro. The data indicate that in the rat, AGN 190851 resulted in a dose-dependent water diuresis, which was accompanied by an increase in blood pressure and osmolar clearance. In addition, AGN 190851 resulted in a dose-dependent inhibition of vasopressin-stimulated cyclic AMP accumulation in rat cortical collecting tubules in vitro. In contrast, AGN 190851 was unable to cause either a water diuresis in conscious dogs or inhibit vasopressin-stimulated adenylate cyclase activity in canine tissue in vitro. In the lightly anesthetized cynomolgus monkey, AGN 190851 also failed to alter renal function significantly. Administration of the vasopressin receptor antagonist, SK&F 105494, to either dogs or cynomolgus monkeys demonstrated that antagonism of the vasopressin V2 receptor could result in a brisk water diuresis in both species. The data demonstrate that alpha-2 adrenoceptors can functionally antagonize vasopressin antidiuretic activity in the rat, but not in the dog or cynomolgus monkey.

Adrenergic alpha-Agonists↗

PubMed1990

The pharmacology of carvedilol.

Carvedilol is a potent antihypertensive agent with a dual mechanism of action. At relatively low concentrations it is a competitive beta-adrenoceptor antagonist and a vasodilator, whereas at higher concentrations it is also a calcium channel antagonist. The antihypertensive activity of carvedilol is characterized by a decrease in peripheral vascular resistance, resulting from the vasodilator activity of the compound, with no reflex tachycardia, as a result of beta-adrenoceptor blockade. The antihypertensive activity of carvedilol is associated with an apparent "renal sparing" effect in that the reduction in mean arterial blood pressure does not compromise renal blood flow or urinary sodium excretion. Studies on the mechanism of action of carvedilol indicate that the compound is a potent competitive antagonist of beta 1- and beta 2-adrenoceptors with a dissociation constant (KB) of 0.9 nM at both beta-adrenoceptor subtypes. Carvedilol is also a potent alpha 1-adrenoceptor antagonist (KB = 11 nM), which accounts for most, if not all, of the vasodilating response produced by the compound. At concentrations above 1 microM, carvedilol is a calcium channel antagonist. This activity can be demonstrated in vivo at doses that represent the higher end of the antihypertensive dose-response curve. Although the calcium-channel blocking activity of carvedilol may not contribute to the antihypertensive activity of the compound, it may play a prominent role in certain peripheral vascular beds, such as the cutaneous circulation, where marked increases in blood flow are observed. The data indicate that carvedilol is an antihypertensive agent that is both a beta-adrenoceptor antagonist and a vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗