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Aims: To review trade agreements, their relation to alcohol control policy and examine the role of the alcohol industry in supporting and attempting to influence trade policy., Methods: Review of peer review, public health advocacy literature (both pro and con on free trade), business, press and government documents on trade agreements, assess current and potential challenges by trade agreements to alcohol control policy and investigate the means and extent of industry influence in trade agreements., Findings: 'Free' trade agreements reduce trade barriers, increase competition, lower prices and promote alcohol consumption. However, international treaties, negotiated by free trade experts in close consultation with corporate lobbyists and without significant, if any, public health input, governments and corporations contain significant provisions that will result in increased alcohol consumption and may challenge public health measures of other nations as constraints on trade. Conversely, alcohol control measures seek to reduce access and consumption, raise prices and restrict advertising and product promotion. The prospect is for increased alcohol consumption and concomitant problems throughout the world., Conclusions: Trade agreements challenge effective alcohol control policies. The alcohol industry seeks to influence agreements and can be expected to work through trade agreements to reduce tariffs, increase market access and seek to restrict effective domestic regulations. Further research is needed on the impact of trade agreements and the ongoing role of the industry. Advocates must recognize the inherent conflicts between unbridled free trade and public health, work to exclude alcohol from trade agreements, counter industry influence and protect alcohol control policies.

This report reviews aspects of trade agreements that challenge tobacco and alcohol control policies. Trade agreements reduce barriers, increase competition, lower prices and promote consumption. Conversely, tobacco and alcohol control measures seek to reduce access and consumption, raise prices and restrict advertising and promotion in order to reduce health and social problems. However, under current and pending international agreements, negotiated by trade experts without public health input, governments and corporations may challenge these protections as constraints on trade. Advocates must recognise the inherent conflicts between free trade and public health and work to exclude alcohol and tobacco from trade agreements. The Framework Convention on Tobacco Control has potential to protect tobacco policies and serve as a model for alcohol control.

Background: Adolescents and college students are at high risk for initiating alcohol use and high-risk (or binge) drinking. There is a growing body of literature on neurotoxic and harmful cognitive effects of drinking by young people. On average, youths take their first drink at age 12 years., Methods: MEDLINE search on neurologic and cognitive effects of underage drinking., Results: Problematic alcohol consumption is not a benign condition that resolves with age. Individuals who first use alcohol before age 14 years are at increased risk of developing alcohol use disorders. Underage drinkers are susceptible to immediate consequences of alcohol use, including blackouts, hangovers, and alcohol poisoning and are at elevated risk of neurodegeneration (particularly in regions of the brain responsible for learning and memory), impairments in functional brain activity, and the appearance of neurocognitive deficits. Heavy episodic or binge drinking impairs study habits and erodes the development of transitional skills to adulthood., Conclusions: Underage alcohol use is associated with brain damage and neurocognitive deficits, with implications for learning and intellectual development. Impaired intellectual development may continue to affect individuals into adulthood. It is imperative for policymakers and organized medicine to address the problem of underage drinking.

The renal response to volume expansion (VE) has been shown to be impaired in streptozotocin (STZ)-induced diabetes. This may contribute to the abnormal maintenance of fluid balance in diabetics. Since calcium channel blockade (CaCb) has been shown to improve renal hemodynamic and tubular functions, the present studies were designed to examine the ability of CaCb to enhance the response of kidneys from diabetic rats to a volume load. Rats were made diabetic by a single injection of STZ (65 mg i.p.), while the control rats received only a vehicle injection. Nisoldipine, a CaCb agent was given to half of the diabetic rats in a dose of 0.015 microgram/kg per min during the acute experiment. The left kidney was denervated in each rat while the right kidney remained innervated. Glomerular filtration rate (GFR) was elevated during VE in all of the rats except in the denervated kidneys of diabetic rats. Nisoldipine improved GFR in most cases. Urine flow increased markedly during VE. This response was enhanced by denervation but depressed in the diabetic rats. Nisoldipine improved the defective volume reflex in primarily the denervated kidneys. Changes in net urinary excretion of water and sodium during VE were significantly lower in the diabetic rats than in the control group. In the nisoldipine treated diabetic rats the VE induced changes in water and sodium excretion returned toward normal in the denervated, but not in the innervated kidneys. The data are consistent with a blunted volume reflex in the diabetic rats that may be improved by CaCb. Impaired sympatho-inhibition in diabetic rats appears to oppose the effects of VE and nisoldipine treatment. CaCb may contribute to the volume reflex by enhanced filtration as well as by reduced tubular reabsorption.

To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with unilateral renal denervation. Rats were assigned to either a control group (108 +/- 6 mmHg), or one of two DOCA-salt groups (injected with deoxycorticosterone acetate, DOCA, 25 mg/week, and given 0.9% saline to drink for 4 weeks); a) DOCA-salt group (137 +/- 6 mmHg) and b) DOCA-salt-BPC group (with blood pressure controlled at the level of the femoral artery (102 +/- 3 mmHg) by an occluder on the abdominal aorta proximal to the right renal artery). Urine flow and sodium excretion in response to ANF infusion (0.3 micrograms/min/kg) were measured from intact and denervated kidneys of control and DOCA-salt treated rats. ANF infusion produced a significant increase in diuresis and natriuresis in all three groups of rats. Urine flow and sodium excretion in response to ANF were significantly less in the intact kidney but not the denervated kidneys of the DOCA-salt rats compared to control rats. These results indicate that renal nerves contribute to the blunted renal responses to ANF in DOCA-salt rats. Renal responses also were significantly smaller in both intact and denervated kidneys of DOCA-salt-BPC rats (in which arterial pressure was reduced) compared to DOCA-salt rats. Overall, these results indicate that both renal nerves and arterial pressure determine the natriuretic and diuretic actions of ANF in DOCA-salt hypertensive rats.

To determine whether renal nerves are involved in natriuresis or diuresis produced by the intracerebroventricular administration of clonidine (0.2, 2.0, and 8 micrograms/kg/min, and 2.0 microliters/min), urine flow, and sodium excretion were measured before and during clonidine administration from innervated and contralateral denervated kidneys in anesthetized (Inactin, 0.1 g/kg, ip) Sprague-Dawley rats. Baseline urine flow and sodium excretion were elevated after renal denervation prior to infusion of clonidine. Examining urine flow and sodium excretion before and during clonidine infusion indicated significant increases in urine flow and sodium excretion from the innervated kidneys but not from the denervated kidneys, possibly due to the renal sympatho-inhibition in the innervated kidney. However, the higher doses of clonidine (2 and 8 micrograms/kg/min) may have diffused out of the intracerebroventricular space into the peripheral circulation and produced their effect by a direct action on the kidney. Subsequently, two experiments were performed to distinguish between a central action and peripheral action. First, clonidine was administered centrally with concurrent administration of an alpha 2-blocker, yohimbine (8 micrograms/kg/min, i.v.), peripherally. In a second experiment the dose of clonidine was reduced 10-fold such that this reduced dose did not produce a peripheral action but still produced the renal responses to central administration. The results of the latter two studies further confirmed that natriuresis and diuresis produced by intracerebroventricular administration of clonidine is in part mediated by renal nerves.

The purpose of this study was to determine if the reflex response to a saline load is altered in the obese Zucker rat. The obese Zucker rat is a genetic model of obesity and insulin-resistant diabetes that has been reported to have high blood pressure. We examined the reflux renal responses to volume expansion in both anesthetized obese and lean Zucker rats. Initial blood pressure was significantly elevated in the obese Zucker rats compared with the lean controls. Urine flow and sodium excretion from innervated and denervated kidneys were measured before and after volume expansion with normal saline. Volume expansion resulted in significantly less urine flow and sodium excretion in the obese than the lean Zucker rats. This response was evident in both the intact and denervated kidneys. Rats were then infused with atrial natriuretic peptide (ANP) to determine if natriuretic and diuretic responses were altered in these rats. The diuretic action of ANP was not significantly reduced in the obese Zucker rat. However, the natriuretic action of ANP was significantly attenuated in the obese rats. These results indicate that the reflux response to an acute saline load is attenuated in the obese Zucker rat and that this decreased response may be due to a reduction in the direct action of ANP on the kidney.

The interaction of renal sympathetic nervous influences with the intrarenal kallikrein-kinin system was examined during graded expansion of the extracellular fluid volume in rats. One group of rats was pretreated with a specific and highly efficacious competitive antagonist of bradykinin receptor (BKRA), whereas the other group received only a vehicle infusion. The left kidney was denervated in each animal and the right kidney remained intact. After control observations, the extracellular fluid volume was expanded by a continuous i.v. infusion of 0.9% NaCl at a rate of 0.25% of body weight per minute for 40 min (VE). During VE urine flow and sodium excretion increased significantly from both kidneys in each of the two treatment groups. The diuretic response was greatest in the denervated kidneys of vehicle-pretreated rats, where urine flow increased by 70 +/- 13 microliters.min(-1).g kwt(-1). This exaggerated diuresis was blunted by pretreatment with the BKRA. In the denervated and BKRA-treated kidneys, the VE-induced mean urine flow increase was limited to 31 +/- 5 microliters.min(-1).g kwt(-1) (P less than .05 compared with vehicle-pretreated, denervated kidneys). The change in net sodium excretion produced by VE was also reduced by BKRA pretreatment in the denervated kidneys from 13.2 +/- 2.6 to 5.5 +/- 1.3 microEq.min-1.g kwt(-1) (P less than .05, vehicle vs. BKRA). In the intact kidneys the diuretic and natriuretic responses to VE were similar in the vehicle- and BKRA-pretreated rats. Glomerular filtration rate and filtration fraction were increased significantly and to the same extent by VE under all experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to examine pressor responsiveness in a rabbit model with adrenal perturbation. Adrenals in rabbits were stabbed with a needle, and the rabbits were given water (adrenal-water group) or 0.9% NaCl (adrenal-salt) to drink; additional rabbits were sham-operated and given water (sham-water group) or 0.9% NaCl (sham-salt group) to drink. Acute experiments were performed two weeks later on conscious rabbits. All four groups of rabbits had the same body weights, mean arterial pressures, heart rates, and plasma concentrations of Na+ and K+. Intravenous norepinephrine infusions at several doses produced greater pressor responses in the adrenal-water and adrenal-salt groups than in the sham-water or sham-salt groups. Administration 1-sarcosine-8-isoleucine angiotensin II ([Sar1, Ile8]Ang II) did not alter the pressor responses to norepinephrine in either the sham-water or the adrenal-salt groups. Cross-circulation of blood between adrenal-salt donor rabbits and normal recipient rabbits at 10 ml/min for 5 min resulted in enhanced pressor responses to norepinephrine in the recipients at 5 min after the cross-circulation. Similar cross-circulation experiments between sham-water donors and normal recipients did not alter the pressor responses to norepinephrine in the recipients. These studies demonstrated that rabbits with adrenal perturbations have pressor hyper-responsiveness to norepinephrine, which does not involve angiotensin II mechanisms, but is mediated by a fast-acting blood-borne factor.

Two series of experiments were conducted in anesthetized dogs to compare the vascular effects of the alpha 1-adrenoceptor antagonists urapidil and prazosin. In the first series of experiments vasoconstrictor responses to sympathetic nerve stimulation and phenylephrine injected intraarterially were elicited in the pump-perfused hindlimb. Urapidil and prazosin administered intravenously in the doses of 2 and 0.25 mg/kg, respectively, were equivalent in their ability to block these responses. Yohimbine, an alpha 2-adrenoceptor antagonist, in the dose of 0.05 mg/kg, had no additional effect on the responses, but did decrease the vascular resistance after prazosin infusion. This suggested that urapidil, but not prazosin, exerted an alpha 2-blocking effect which decreased vascular resistance. In the second series of experiments the effect of urapidil administered intravenously was determined on the innervated and denervated gracilis muscle, after maximal alpha 1-adrenoceptor blockade with prazosin. The purpose of these experiments was to confirm whether or not urapidil had an additional effect on vascular resistance attributable to alpha 2-antagonism. Prazosin, 0.25 mg/kg followed by 0.50 mg/kg i.v., decreased vascular resistance in both the innervated and denervated gracilis muscles, and maximal alpha 1-blockade was achieved based on the blockade of the pressor responses to phenylephrine. A further reduction in vascular resistance was found after urapidil infusion, 2 mg/kg, which appears to be due to blockade of the effect of circulating catecholamines on alpha 2-adrenoceptors. The difference between the vascular resistance seen immediately following acute sympathetic denervation and the level achieved 15 min afterward appears to be due to the influence of circulating catecholamines.

Conscious rabbits infused intravenously (i.v.) with isotonic saline at 1.5 to 1.8 ml/min for 24 hours had greater pressor responses to norepinephrine (NE) than did normal control rabbits. Infusion of the angiotension II (ANG II) antagonist [Sar1, Ile8] ANG II did not decrease the exaggerated pressor responses to NE in saline-infused rabbits. Measurements of cardiac output (CO) as well as the pressor responses to NE before and after saline infusion revealed that, although saline infusion increased the CO and decreased total peripheral resistance (TPR), CO did not change during NE infusion either before or after saline infusion, but NE produced significantly greater increases in mean arterial pressure (MAP) and TPR after saline infusion than before the saline infusion. The cross-circulation of blood at 10 ml/min for 5 minutes between saline-infused donor rabbits and normal recipient rabbits resulted in pressor hyperresponsiveness to NE in the normal recipients. Similar cross-circulation experiments between pairs of normal rabbits did not alter the pressor responses to NE. These studies provided direct evidence that expansion of body fluid volumes by saline infusion results in pressor and vascular hyperresponsiveness. There was no evidence to indicate that ANG II was involved in the mechanisms producing this pressor hyperresponsiveness. Some circulating hormonal factor, however, was involved in mediating the pressor hyperresponsiveness following saline infusion. The results of this study are compatible with the concept that natriuretic hormone may play a role in promoting pressor hyperresponsiveness in saline-expanded animals.

This study consisted of five different experiments with conscious rabbits. In experiment 1, the angiotensin II (ANG II) antagonist [Sar1-Ala8]ANG II infused iv into one-kidney rabbits with renal artery stenosis (RAS) of 3 days' duration, at a dose that blocked pressor responses to ANG II, did not decrease the exaggerated pressor responses to norepinephrine (NE). In experiment 2, captopril infused iv into one-kidney, 3-day, RAS rabbits blocked pressor hyperresponsiveness to NE, and the concurrent infusion of [Sar1-Ala8]ANG II did not reestablish pressor hyperresponsiveness, indicating that this ANG II analogue had no agonistic action to promote hyperresponsiveness to NE. In experiment 3, infusion of ANG II at a subpressor dose (6.7 pmol . min-1 . kg body wt-1) into normal rabbits resulted in pressor hyperresponsiveness to NE, which was blocked by [Sar1-Ala8]ANG II. Experiment 4 involved infusing [Sar1-Ala8]ANG II or [Sar1-Ile8]ANG II at various doses into 3-day RAS rabbits, to determine their abilities to attenuate the pressor responses to ANG II (100 ng/kg) and the pressor hyper-responses to NE (800 ng . min-1 . kg-1). [Sar1-Ile8]ANG II decreased the ANG II pressor responses at an ID50 dose of 64 +/- 5 (SEM) pmol . min-1 . kg-1 and attenuated the NE pressor hyper-response at an ID50 dose of 65 +/- 5 pmol . min-1 . kg-1; [Sar1-Ala8]ANG II diminished the ANG II pressor response at an ID50 dose of 757 +/- 247 and the NE pressor hyper-response at an ID50 dose of 10,061 +/- 944 pmol . min-1 . kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine was infused iv at several doses into four groups of conscious rabbits (six per group), and the pressor responses were recorded. The groups were 3-day sham-operated rabbits; 3-day, two-kidney rabbits with unilateral renal artery stenosis (RAS); 3-day, two-kidney rabbits with unilateral renal denervation; and 3-day, two-kidney rabbits with unilateral renal denervation plus RAS of the denervated kidney. The rabbits with RAS of an innervated kidney and those with RAS of a denervated kidney had the same pressor responses to norepinephrine, which were greater than the pressor responses in the sham-operated rabbits or in the rabbits with a denervated kidney but without RAS. Four additional groups of similarly prepared rabbits were infused with norepinephrine at 800 ng/min/kg body wt, and mean arterial pressure and cardiac output were determined before and during norepinephrine infusion. The rabbits with RAS of an innervated or of a denervated kidney had greater increases in total peripheral resistance as well as in mean arterial pressure during norepinephrine infusion than did the two groups of rabbits without RAS. This indicated that the rabbits with RAS also had increased vascular responses to norepinephrine. The concentration of norepinephrine in six denervated kidneys was extremely low as compared to that of six innervated kidneys. Because renal denervation did not diminish pressor and vascular hyperresponsiveness in 3-day RAS rabbits, the signal that originates in the kidney following RAS and that results ultimately in pressor and vascular hyperresponsiveness is not mediated by renal nerves.

This study examined body fluid volumes, the pressor responses to norepinephrine (NE), and the cardiovascular responses to NE before and during infusion of an angiotensin II (ANG II) antagonist in two-kidney rabbits with unilateral renal artery stenosis (RAS) of 3 and 30 day duration. Three separate experiments were performed. In the first experiment, plasma volume, extracellular fluid volume, and total body water were measured by the distribution volumes of radioiodinated serum albumin, 35SO4, and tritiated water, respectively. No differences were seen for any of these volumes between the 3- or 30-day RAS rabbits and their controls. In the second experiment, pressor responses to infusions of several doses of NE were examined; rabbits with 3- and 30-day RAS had exaggerated pressor responses to all doses of NE when compared with the control rabbits. In the third experiment, infusion of NE at 800 ng.min-1.kg body wt-1 resulted in more pronounced increases in mean arterial pressure and total peripheral resistance (TPR) in the 3- and 30-day RAS rabbits than in the controls; after infusion of [Sar1-Ile8] ANG II the increases in mean arterial pressure and TPR during NE infusion were blunted and were of the same magnitude as in the control group. In all experiments the 30-day RAS rabbits were hypertensive, whereas the 3-day RAS rabbits were normotensive; also, plasma renin activity (PRA) values were normal in both the 3- and 30-day RAS groups. These studies demonstrated that increases in body fluid volumes are not necessary for pressor and vascular hyperresponsiveness probably is mediated by ANG II, despite normal PRA values.

The central effect of urapidil on mean arterial blood pressure, heart rate, and reflex tachycardia was studied in anesthetized normotensive and Goldblatt hypertensive dogs and anesthetized cats. The administration of 1 mg intracisternally of urapidil decreased blood pressure and heart rate in normotensive dogs, whereas 2 and 4 mg decreased heart rate and returned blood pressure to the control level. Reflex tachycardia evoked by the intravenous administration of bradykinin was suppressed in a dose-dependent manner by urapidil. In the anesthetized cat, urapidil was administered intracisternally (50 to 400 micrograms) and had no effect on heart rate. The reflex bradycardia elicited by central vagal nerve stimulation was accentuated by urapidil given intracisternally, but this only occurred in the presence of beta adrenoceptor blockade with propranolol.

Because estrogens have been reported to produce sodium retention, this study investigated the possibility that hypertension in rats resulting from the ingestion of an estrogen used as an oral contraceptive could be due to increases in body fluid volumes. Female rats were given feed containing mestranol for 1, 3, and 6 mo; control rats were given the feed without mestranol. The mestranol-treated rats had higher arterial pressures than the controls only after 6 mo of treatment. Plasma volume, extracellular fluid volume, and total body water were measured in each rat by the distribution volumes of radioiodinated serum albumin, 35SO4, and tritiated water, respectively. Values for blood volume, interstitial fluid volume, and intracellular fluid volume were derived from these measurements. These body fluid volumes, expressed per 100 g of body weight, were not different between the mestranol-treated rats and their controls at any of the three treatment times. Due to differences in body weight and lean body mass between the mestranol-treated and the control rats, these volumes also were expressed per 100 g of lean body mass. Again, no differences were observed between the mestranol-treated rats and the control rats for any of these body fluid compartments at any of the treatment times. These studies, therefore, were unable to provide evidence that increases in body fluid volumes contributed to the elevated arterial pressure in this rat model of oral contraceptive hypertension.

Prehypertensive rabbits with renal artery stenosis of 3 days' duration (one-kidney, one clip) are known to have increased pressor responses to norepinephrine and vasopressin; this pressor hyperresponsiveness is restored to normal by the angiotensin II (AII) antagonist, [ Sar1, Ile8 ] AII, even though plasma renin activity (PRA) and plasma AII concentrations are not elevated. In the present study, the cross-circulation of blood between conscious one-kidney, 3-day renal artery stenosis rabbits and conscious normal rabbits resulted in the transfer of pressor hyperresponsiveness to the normal rabbits, although both groups of rabbits had normal values for PRA. A similar cross-circulation of blood between one-kidney rabbits without renal artery stenosis and normal rabbits did not alter the pressor responsiveness of the normal rabbits to norepinephrine. It was concluded that a circulating humoral factor is involved in mediating pressor hyperresponsiveness in 3-day renal artery stenosis rabbits. To evaluate the interrelationship between AII and the hormonal hyperresponsiveness factor, an additional experiment was performed in which blood was cross-circulated between one-kidney, 3-day renal artery stenosis rabbits and normal rabbits, with the normal rabbits receiving [ Sar1, Ile8 ] AII immediately following cross-circulation. Administration of this AII antagonist to the normal rabbits prevented them from showing pressor hyperresponsiveness following the cross-circulation of blood. It is concluded that in this prehypertensive renal artery stenosis model the humoral hyperresponsiveness factor exerts its effect through AII mechanisms, rather than AII acting to increase the release or secretion of the hyperresponsiveness factor.

The renal tubular effect of nisoldipine (10 micrograms/kg/h) was evaluated using clearance and micropuncture techniques in spontaneously hypertensive rats made diuretic by i.v. infusion of 2.5% NaCl. In one group of 11 rats the renal innervation was intact, whereas in a second group of 10 rats the left kidney was denervated. The drug reduced mean blood pressure in both groups of rats without a significant change in heart rate or glomerular filtration rate. Nisoldipine increased urine flow from 22.3 +/- 2.1 to 26.8 +/- 2.5 microliter/min/100 g BW and from 23.8 +/- 1.3 to 31.5 +/- 1.4 microliter/min/100 g BW in the innervated and denervated rats, respectively (p less than 0.05 for both). Fractional excretion of sodium and total solute were significantly higher under nisoldipine action in both groups of rats, indicating reduced reabsorption of water as well as solute by the nephron. Potassium excretion was unaltered in the innervated rats while in the denervated group it was significantly reduced by the drug. Fractional water excretion was enhanced from 3.3 +/- 0.3% to 4.1 +/- 0.4% of the filtrate in the innervated rats and from 3.4 +/- 0.2% to 4.6 +/- 0.3% in the denervated rats. Tubular fluid to plasma inulin concentration ratios at late distal puncture sites were lowered by nisoldipine in both the innervated kidneys (from 10.5 +/- 1.6 to 8.3 +/- 0.8, with p less than 0.05) and denervated kidneys (from 8.8 +/- 0.5 to 6.7 +/- 0.5, with p less than 0.05). The mean percentage of filtrate reabsorbed between late proximal and late distal tubular fluid collection sites was lowered in both groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Instrumented normotensive and two-kidney, one clip Goldblatt hypertensive dogs were placed on normal salt, high salt and DOCA-salt regimens and the effect on mean arterial blood pressure (MAP) and iliac vascular resistance (IVR) determined. High salt and DOCA-salt did not alter these variables in the Goldblatt hypertensive group. DOCA-salt increased MAP in the normotensives by 12 mmHg; however, IVR was not significantly increased by this treatment. In order to determine the degree of sympathetic tone in the iliac vascular bed, the change in IVR evoked by the alpha 1-adrenoceptor antagonists, urapidil and prazosin, was assessed. There were similar reductions in MAP and IVR after alpha 1-blockade in both groups of dogs, regardless of the salt regimen. However, urapidil caused a greater decrease in MAP in the normotensives than in the hypertensives. Captopril administration after alpha 1-blockade caused further reductions in MAP and IVR in the hypertensives, and in the MAP of the normotensive dogs on normal or high salt, indicating that the renin-angiotensin system maintained blood pressure in these groups. These results suggest that sympathetic tone is not increased by high salt- or DOCA-salt in normotensive or Goldblatt hypertensive dogs for the 8-11 day duration of these treatments.

In eight hypertensive patients treated with transdermal clonidine for one year, there was plasma dilution, as shown by a reduction in serum sodium, hemoglobin, and serum protein levels. Free water clearance did not change significantly. Plasma dilution was likely sustained by increased water intake due to "dry mouth", as frequently seen with central acting drugs such as clonidine.

Six rabbits were sham operated and were given water to drink (sham-water group); six additional rabbits were sham operated and were given saline to drink (sham-salt group); another six rabbits received an implant of deoxycorticosterone (DOCA) and were given water to drink (DOCA-water group); a final group of six rabbits received implants of DOCA and were given saline to drink (DOCA-salt group). Two weeks later, all four groups of rabbits had approximately the same mean arterial pressures, and the sham-salt, DOCA-water, and DOCA-salt groups all had plasma renin activity values less than the sham-water group. The DOCA-salt group had greater pressor responses to norepinephrine (NE) at several doses than did the other three groups of rabbits. In another group of six sham-water and six DOCA-salt rabbits, measurements of cardiac output before and during infusions of NE at 800 ng/min/kg body wt revealed no changes in cardiac output before or during NE infusion, but the DOCA-salt group had significantly greater increases in mean arterial pressure and total peripheral resistance during NE than did the sham-water group. In another group of six DOCA-salt rabbits, the pressor response to several doses of NE were determined during infusion of the angiotensin II (AII) antagonist, [Sar1, Ile8] AII; this AII antagonist failed to alter the enhanced pressor responses to NE. A final experiment examined pressor responses to NE in six normal rabbits before and after cross circulation of blood with six DOCA-salt rabbits. After blood cross circulation the normal rabbits had exaggerated pressor responses to NE at 5, 15, and 30 min, but not at 60 min. Similar cross-circulation experiments between six pairs of normal rabbits did not show any transfer of pressor hyperresponsiveness. These studies indicated that pressor and vascular hyperresponsiveness in DOCA-salt rabbits is conveyed by a fast-acting hormonal factor and that AII probably is not involved in mediating this hyperresponsiveness.

This study examined the possibility that the renal tubules are the site of the sensors that respond to renal artery stenosis (RAS) and which initiate the events leading to pressor hyperresponsiveness. A nonfiltering kidney (NFK) was produced in 32 rabbits by 2 hr of total renal ischemia plus permanent ligation of the ureter; the opposite kidney remained undisturbed. Sixteen of these rabbits also received RAS of the NFK. An additional 16 rabbits received RAS without production of a NFK, and 16 more rabbits were sham-operated controls. In acute experiments 3 days later in conscious rabbits, infusions of norepinephrine at several doses resulted in greater increases in mean arterial pressure in the RAS rabbits, with filtering kidneys (2-K, 1-clip) and with NFKs (2-K, 1-clip with NFK), than in the NFK rabbits without RAS (2-K control with NFK) or in the control rabbits (2-K control). Measurements of cardiac output revealed greater increases in total peripheral resistance as well as in mean arterial pressure in response to norepinephrine in the RAS rabbits both without and with a NFK. Because production of a NFK in rabbits did not prevent the development of pressor and vascular hyperresponsiveness 3 days after RAS, these studies indicated that the renal sensors that detect changes in the kidney following RAS and which initiate the series of events leading to pressor and vascular hyperresponsiveness, probably are not located in the renal tubules.