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.

Antihypertensive actions of the novel nonpeptide endothelin receptor antagonist SB 209670.

Indirect evidence has implicated endothelin-1 in the pathogenesis of hypertension. In the present study we examined such a role directly with SB 209670, a novel nonpeptide endothelin receptor antagonist. The antihypertensive and hemodynamic effects of SB 209670 were examined in conscious, unrestrained spontaneously hypertensive (SHR), normotensive Wistar-Kyoto (WKY), and renin-hypertensive rats. Sustained intravenous infusion of SB 209670 (10 micrograms.kg-1.min-1 for 6 hours) produced a significant, reversible reduction in mean arterial pressure in SHR but not in WKY rats. The antihypertensive response to 10 micrograms.kg-1.min-1 SB 209670 (approximately 25 mm Hg reduction in blood pressure) was associated with bradycardia (16% decrease in heart rate) but only a minimal reduction (3%) in cardiac output, because stroke volume was evaluated (by 15%). Therefore, the antihypertensive effect of SB 209670 resulted from a decrease (13%) in total peripheral resistance. A sustained antihypertensive effect could also be observed after intraduodenal administration of SB 209670 (3 mg/kg) in conscious SHR (reduction of approximately 35 mm Hg 5 hours after administration). SB 209670 (3 mg/kg intravenous bolus) did not alter the pressor response or tachycardia observed in pithed SHR after stimulation of thoracolumbar sympathetic outflow. SB 209670 was also antihypertensive in renin-hypertensive rats, lowering blood pressure to an extent similar to that observed in SHR. Thus, the data presented provide evidence to support a role for endothelin-1 in the pathophysiology of two animal models of hypertension.

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.

The role of vasopressin in the control of renal hemodynamics. The Brattleboro rat as an experimental model.

It has been demonstrated through the use of new techniques that the action of vasopressin on the kidneys is not limited to changing the water permeability of distal tubules and collecting ducts. However, it has yet to be established whether these additional actions, such as lowering Kf (possibly by contracting mesangial cells), or increasing postglomerular vascular resistance, are important factors in the control of GFR and renal blood flow. The use of animals with diabetes insipidus, particularly the Brattleboro homozygous (DI) rat, may help to circumvent a number of methodological problems and provide a useful model for assessing the role of vasopressin in the control of renal hemodynamics. Although that role may be exerted through a direct effect on the vascular tone, it may be an indirect effect in which the antidiuretic action of vasopressin alters fluid balance and elicits secondary changes in other vasoactive hormones. The complexity of this latter possibility suggests that other methodological problems (in the measurement and/or control of the related variables) may complicate the final resolution of this issue for some time to come.

Replacement therapy with arginine vasopressin in homozygous Brattleboro rats.

We studied the replacement therapy of different doses of AVP in DI rats. It is surprising that relatively high levels of plasma AVP were needed to achieve significant antidiuretic effects. Measured plasma AVP concentrations are less than those predicted from the release rates of AVP by the minipumps. This difference may be due to the subcutaneous mode of release of AVP. The study also provides evidence that urinary excretion of AVP is a good indicator of the plasma AVP level.

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.

Identification of ETB receptor subtypes using linear and truncated analogs of ET.

Using canine spleen and lung membranes as model systems, we have shown the presence of subtypes of ETB receptors. This classification was done based on the binding profiles of various analogs of ET-1 that have been identified as ETB-selective. Saturation binding experiments performed with [125I] ET-3 and [125I] IRL-1260 (ETB-selective ligands) indicated that [125I] IRL-1620 labeled 80-90% of [125I] ET-3 binding sites in canine lung, whereas in canine spleen, the binding of [125I] IRL-1620 was 10-20% of [125I] ET-3 binding. In addition, competition binding experiments using ETB-selective agonists [Ala1,3,11,15]-ET-1 (also known as 4-Ala ET-1), N-acetyl-[Ala11,15] ET-1 (6-21) also known as BQ3020 and Suc-[Glu9, Ala11,15] ET-1 (8-21) also known as IRL-1620 indicated that all three ligands displaced [125I] ET-3 from canine lung membranes with approximately 500-1000 fold greater affinity than canine spleen membranes. On the other hand, ET-1, ET-3, S6a, S6b, and S6d displayed very similar IC50 values in both preparations, except S6c which was approximately 20 fold less potent in canine spleen compared to lung. These data indicate that ETB receptors present in canine spleen are different from those present in lung and that ETB-selective linear as well as truncated analogs of ET-1 are good tools to identify these subtypes of ETB receptors.

Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist.

The angiotensin II antagonistic activity of SB 203220, [E-alpha-[[2-butyl-1-(4-carboxy-1-naphthalenyl)methyl]-1H- imidazol-5-yl]-methylene]-2-thiophene-propanic acid], was examined in several in vitro and in vivo assays. SB 203220 displaced [125I]angiotensin II binding from a variety of tissues including the cloned human AT1 receptor (IC(50)5-15 nM). SB 203220 (10 microM) did not interact with AT2, endothelin (ETA and ETB) or calcitonin gene-related peptide receptors. [3H]SB 203220 bound with high affinity to the AT1 receptor (Kd = 4.9 nM), but dissociated from the receptor at a much slower rate when compared to [3H]SK&F 108566. SB 203220 antagonized intracellular Ca2+ mobilization induced by angiotensin II in rat vascular smooth muscle cells and exhibited a selective and partially insurmountable antagonism of angiotensin II-induced contraction in isolated rabbit aorta. In the aorta, SB 203220 produced a concentration-dependent parallel shift in the concentration-response curve to angiotensin II [EC30 = 5.94 +/- 1.6 10(-11) M] and depressed the maximal contractile response to angiotensin II by approximately 35%. The antagonistic effect of SB 203220 in rabbit aorta was slowly reversible compared to SK&F 108566. SB 203220 displayed no agonist activity and had no effect on the contractile responses to KCl, endothelin-1 or norepinephrine. In rats, SB 203220 at 10 mg/kg i.v. inhibited angiotensin II-induced aldosterone release. Intraduodenal or oral administration of SB 203220 (1-10 mg/kg) to conscious rats and dogs inhibited the pressor responses to exogenous angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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)

Physiological role of endothelin in cardiovascular and renal hemodynamics: studies in animals.

Even though the pharmacology of the endothelin receptor subtypes ETB and ETB is well characterized, their physiological role in the control of basal vascular tone is poorly understood. It has been proposed that a tonic vasoconstriction mediated by endothelin counterbalances a vasodilator tone mediated by nitric oxide, the major endothelium-derived relaxing factor. Recent evidence suggest that the endogenous endothelin-1, released from the endothelial cells, mediates both vasodilation and vasoconstriction and indicates the existence of a negative feedback system involving endothelin-1, the endothelial ETB receptor and nitric oxide.

Modulation of vasopressin antidiuretic action by renal alpha 2-adrenoceptors.

It has been almost 40 years since the diuretic effect of alpha-adrenoceptor agonists was first demonstrated. Two possible mechanisms were proposed: inhibition of vasopressin secretion and antagonism of the cellular hydrosmotic actions of vasopressin. The debate could not be settled then for the lack of appropriate experimental models and pharmacological tools. Advances made in adrenoceptor pharmacology in the 1970s such as 1) subdivision of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes; 2) development of selective agonists and antagonists; and 3) localization of both adrenoceptor subtypes in the kidney, including the proximal and collecting tubules, stimulated new research. With regard to renal adrenoceptors, selective alpha 2-agonists have been shown to induce diuresis in dogs and rats. Whereas in the dog the increase in urine flow results mostly from an increase in osmolal clearance, in the rat the diuresis results in large part from an increase in the excretion of solute-free water. In vitro studies on isolated collecting tubules from rats and rabbits (none from dogs) have shown that alpha 2-agonists inhibit vasopressin-induced adenosine 3',5'-cyclic monophosphate formation and that this effect is mediated by the inhibitory guanine nucleotide regulatory protein and abolished by pertussis toxin treatment. In vivo evidence in support of such a mechanism was presented from conscious Brattleboro homozygous rats in which a selective alpha 2-agonist inhibited the antidiuretic effect of exogenous vasopressin, and this effect was abolished by pertussis toxin. The physiological importance of renal alpha 2-adrenoceptors was identified by use of adrenal medullectomized rats and the alpha 2-antagonist, yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic responses to leukotriene receptor stimulation in conscious rats.

We evaluated the effects of leukotrienes (LTs) C4 and D4 on systemic and renal hemodynamics in conscious rats. Intravenous injections of LTC4 or LTD4 (0.5-10 micrograms/kg) caused dose-dependent decreases in cardiac output (CO), renal blood flow (RBF), and heart rate (HR). Flow alterations were accompanied by increased systemic and renal vascular resistances (SVR and RVR) and mean arterial blood pressure (MAP). No secondary hypotensive effect was observed. The HR response was biphasic, with tachycardia replacing the initial brief bradycardia. The changes in RBF and CO were not concurrent; the maximum RBF decrease (47.6 +/- 9.5%, P less than 0.05) occurred when CO was down only by 9.1 +/- 3.6% (P less than 0.05) and RBF had fully recovered in 3-4 min, while CO was still down by 26.3 +/- 3.5% (P less than 0.001). Hematocrit (HCT) increased after the injection of 5 and 10 micrograms/kg doses of LTC4 or LTD4, and its time course of recovery to basal level (30-60 min) paralleled that of CO. Sustained intravenous infusion of the selective LT receptor antagonist, SK&F 104353, dose-dependently inhibited the immediate hemodynamic changes after LTD4 injections. SK&F 104353 also attenuated the increase in vascular permeability and the prolonged decrease in CO, suggesting that the observed cardiac and vascular effects of LTs were mediated by stimulation of LT receptors.

Inhibition of vasopressin-stimulated cyclic AMP accumulation by alpha-2 adrenoceptor agonists in isolated papillary collecting ducts.

The effects of selective alpha adrenoceptor agonists and antagonists on vasopressin (VP)-sensitive cyclic AMP (cAMP) formation in microdissected rat papillary collecting ducts were examined. In the presence of 10(-10) M VP, norepinephrine and the selective alpha-2 adrenoceptor agonist, B-HT 933, produced almost total inhibition of VP-stimulated cAMP accumulation. Half-maximal inhibition occurred at 1 x 10(-8) M and 6 x 10(-7) M for norepinephrine and B-HT 933, respectively. Cirazoline, a selective alpha-1 adrenoceptor agonist, had no significant effect on VP-stimulated cAMP accumulation. The inhibitory effects of norepinephrine and B-HT 933 were antagonized by rauwolscine but not by prazosin. The antagonism of B-HT 933-induced inhibition of VP-stimulated cAMP accumulation was competitive with an antagonist dissociation constant (KB) of 10.9 x 10(-9) M. Preincubation of papillary collecting ducts with pertussis toxin (1 microgram/ml for 1 hr at 37 degrees C) attenuated, by 65%, the inhibitory effect of B-HT 933 on VP-stimulated cAMP levels. These results demonstrate that alpha-2 adrenoceptors capable of inhibiting VP action are present on the papillary collecting duct. Furthermore, the alpha-2 adrenoceptor-induced inhibition of VP-stimulated cAMP accumulation is pertussis-toxin sensitive. This suggests that alpha-2 adrenoceptors are coupled negatively to adenylate cyclase, via the guanine nucleotide binding protein, in the collecting tubule.

Mechanism of alpha 2-adrenoceptor agonist-induced diuresis.

In vivo and in vitro studies were performed to assess the mechanism of the diuretic effect of B-HT 933, a selective alpha 2-adrenoceptor agonist. In conscious Sprague-Dawley rats whose plasma vasopressin (AVP) levels were increased by infusion of hypertonic NaCl, B-HT 933 had no effect on AVP secretion. In Brattleboro homozygous (DI) rats, the antidiuretic dose response to AVP was shifted to the right by B-HT 933. In addition, a sustained antidiuresis induced in rats by infusion of 10 pg/min AVP was attenuated by B-HT 933 in a concentration-dependent manner. Pretreatment of DI rats with pertussis toxin (2 micrograms/kg iv) 4-5 days before testing abolished the inhibitory effect of B-HT 933 on AVP-induced antidiuresis. In outer medullary collecting ducts of DI rats, norepinephrine and B-HT 933 produced significant inhibition of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. In contrast, the selective alpha 1-adrenoceptor agonist cirazoline had no effect on AVP-induced cAMP formation. The inhibitory effect of norepinephrine was antagonized by the selective alpha 2-adrenoceptor antagonist rauwolscine but not by prazosin, a selective alpha 1-antagonist. In outer medullary collecting ducts dissected from the pertussis toxin-treated DI rats used in the in vivo studies, the inhibitory effect of norepinephrine and B-HT 933 on AVP-stimulated cAMP accumulation was abolished. The results indicate that the hydrosmotic action of AVP is inhibited by alpha 2-agonists via a pertussis toxin-sensitive mechanism.

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)

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)

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)