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1. The cardiovascular effects by gamma(2)-melanocyte-stimulating hormone (gamma(2)-MSH) are probably not due to any of the well-known melanocortin subtype receptors. We hypothesize that the receptor for Phe-Met-Arg-Phe-amide (FMRFa) or Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide (neuropeptide FF; NPFFa), other Arg-Phe containing peptides, is the candidate receptor. Therefore, we studied various Arg-Phe containing peptides to compare their haemodynamic profile with that of gamma(2)-MSH(6 - 12), the most potent fragment of gamma(2)-MSH. 2. Mean arterial pressure (MAP) and heart rate (HR) changes were measured in conscious rats after intravenous administration of gamma(2)-MSH related peptides. 3. Phe-Arg-Trp-Asp-Arg-Phe-Gly (gamma(2)-MSH(6 - 12)), FMRFa, NPFFa, Met-enkephalin-Arg-Phe-amide (MERFa), Arg-Phe-amide (RFa), acetyl-Phe-norLeu-Arg-Phe-amide (acFnLRFa) and desamino-Tyr-Phe-norLeu-Arg-Phe-amide (daYFnLRFa) caused a dose-dependent increase in MAP and HR. gamma(2)-MSH(6 - 12) showed the most potent cardiovascular effects (ED(50)=12 nmol kg(-1) for delta MAP; 7 nmol kg(-1) for delta HR), as compared to the other Arg-Phe containing peptides (ED(50)=177 - 292 nmol kg(-1) for delta MAP; 130 - 260 nmol kg(-1) for delta HR). 4. Peptides, which lack the C-terminal Arg-Phe sequence (Lys-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Pro-Gly (gamma(2)-pro(11)-MSH), desamino-Tyr-Phe-norLeu-Arg-[L-1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid]-amide (daYFnLR[TIC]a) and Met-enkephalin (ME)), were devoid of cardiovascular actions. 5. The results indicate that the baroreceptor reflex-mediated reduction of tonic sympathetic activity due to pressor effects is inhibited by gamma(2)-MSH(6 - 12) and that its cardiovascular effects are dependent on the presence of a C-terminal Arg-Phe sequence. 6. It is suggested that the FMRFa/NPFFa receptor is the likely candidate receptor, involved in these cardiovascular effects.

The effects of the proopiomelanocortin-(POMC)-derived peptide gamma 2-melanocyte-stimulating hormone (gamma 2-MSH) on mean arterial blood pressure (BP: MAP), heart rate (HR), internal and total carotid blood flow (BF) (CFint and CFtot, respectively), and regional cerebrocortical blood flow (CBF) were measured in urethane-anesthetized rats after intravenous (i.v.) and intracarotid (i.car.) administration of the peptide. gamma 2-MSH (1.5-100 nmol/kg) administered i.v. and i.car. caused a dose-dependent increase in MAP and HR. Injection of the peptide i.car. in the middose range resulted in a more pronounced pressor effect. Furthermore, the earlier onset of the hemodynamic effects after i.car. injection suggests that forebrain structures play a role in these effects. In addition to the pressor response, gamma 2-MSH produced a strong increase in CFint, CFtot, and CBF after both routes of administration, suggesting an increased intracerebral BF. Whereas the effects of the higher doses of gamma 2-MSH on MAP and CFtot were quantitatively comparable after either the intravenous or intracarotid administration, the effect on regional CBF and CFint was about twice as high after i.car. infusion, indicating a centrally mediated phenomenon underlying this effect on CBF. The increase in CFint cannot in itself be ascribed to a gamma 2-MSH-mediated higher perfusion pressure (i.e., BP), since an equipressor dose of norepinephrine (NE) caused a significant decrease in CFint. The significant and more than twofold higher increase in CBF after intracarotid administration of gamma 2-MSH in comparison with administration of NE by the same route also suggests a central origin for the enhancement of microcirculatory flow due to the peptide.

A method is described for providing chronic access to the right renal artery of unrestrained rats. It consists of insertion of a very thin (OD 0.2 mm) catheter into the right suprarenal artery of Wistar rats. The suprarenal artery originates from the right renal artery. After the cannula has been guided subcutaneously to the neck, it is connected to an Alzet osmotic minipump. The method has a success ratio of over 90% for periods up to 14 days. In the present study, we investigated the effects of catheter implantation on renal hemodynamics in uninephrectomized rats that were infused with saline for 2, 6, or 14 days. Values were compared with those obtained in control rats. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated from plasma clearances of 51Crethylenediaminetetraacetic acid and 125I-p-aminohippuric acid, respectively. Mean arterial pressure was between 107 +/- 2 and 116 +/- 2 mmHg in all animals. Neither GFR nor ERPF was influenced by catheter implantation. It is concluded that the method does not interfere with renal function.

Nonadrenaline was infused intravenously for 5 days into conscious, unrestrained normotensive rats. Infusion of 40 μg per kg body weight per hour caused a chronic elevation of blood pressure, reaching a maximum increase of 28 ± 5 mm Hg on the fifth day. This hypertension is characterized by a labile blood pressure: periods of normotension are followed by rapid outbursts of hypertension. Resting plasma levels of noradrenaline ranged from 0.20–1.25 ng/ml. Infusion of 40 μg per kg body weight per hour caused a 4–5 fold increase. These observations suggest that chronic elevations of plasma noradrenaline are associated with labile hypertension.

In this study, we investigated the central as well as the regional hemodynamics of spontaneous hypertension in different phases using the reference sample microsphere method in conscious, unrestrained spontaneously hypertensive rats (SHR) using age-matched progenitor Wistar Kyoto rats (WKy) as controls. Moreover, in order to study the role of intravascular fluid volumes and their regional distribution in the early hemodynamics of spontaneous hypertension, we measured albumin distribution spaces at different ages in SHR and WKy. Microsphere studies showed an increase of cardiac output in 5 weeks old SHR when compared to age-matched WKy. This increased flow was mainly transmitted to the muscular and skin vascular bed. The kidney vascular resistance was increased significantly already in 5 weeks old SHR. In 7-8 weeks old animals, cardiac output was not significantly different in SHR and WKy. The increase in blood pressure was then characterized by a generalized increase in vascular resistance in almost all tissues. Plasma volume (PV) measurements indicate a significantly higher PV in 5 weeks old SHR when compared to age-matched WKy. At later ages (7-16 weeks), PV was lower in SHR than in WKy. Regional measurements show a consistently lower PV in gut, muscle, testes, and skin in SHR. It is concluded that the early increase in cardiac output in SHR is related to an increased central intravascular volume, possibly because of renal fluid retention. Moreover, the later further rise in blood pressure and increase in total peripheral resistance seem to be caused by an independent secondary rise in vascular resistance of all vascular beds.

1. Sodium chloride solution (0.9%) or noradrenaline in doses of 4, 12 and 36 μgh−1 kg−1 was infused for five consecutive days, either intrarenally (by a new technique) or intravenously into rats with one kidney removed. 2. Intrarenal infusion of noradrenaline caused hypertension at doses which did not do so when infused intravenously. 3. Intrarenal compared with intravenous infusion of noradrenaline caused higher plasma noradrenaline concentrations and a shift of the plasma noradrenaline concentration-blood pressure effect curve towards lower plasma noradrenaline levels. 4. These results suggest that hypertension after chronic intrarenal noradrenaline infusion is produced by relatively higher levels of circulating noradrenaline and by triggering of an additional intrarenal pressor mechanism.

The present study was designed to determine the hemodynamic changes underlying the hypertension induced by chronic intrarenal infusion of norepinephrine (NE) in conscious rats. NE was infused for a 5-day period intrarenally with osmotic minipumps via a chronic catheter in the right suprarenal artery at rates of 4 and 36 micrograms . kg-1 . hr-1 or intravenously at a rate of 36 micrograms . kg-1 . hr-1. Control rats received a 1 microliter . hr-1 intrarenal infusion of pyrogen-free 0.9% NaCl. In separate experiments, short-term effects were measured continuously during a 22- to 24-hour intrarenal infusion of 4 and 36 micrograms NE . kg-1 . hr-1 or intravenous infusion of 36 micrograms NE . kg-1 . hr-1. Intrarenal infusion of NE produced a more pronounced long-term hypertensive effect than infusion of the same dose intravenously. This hypertension was characterized by a rapid and sustained increase in total peripheral resistance index (TPRI). Despite of the initial renal vasoconstriction, specifically produced during the first 24 hours of intrarenal NE application, cardiac index (CI) in parallel to stroke volume index (SVI) decreased significantly during intrarenal as well as during intravenous NE infusion. Furthermore, no signs of sodium retention were observed. Both rates of intrarenal NE infusion have been shown previously to produce a significant long-term increase in plasma potassium concentration, and the present study indicates that this is presumably the result of decreased urinary potassium output. It is concluded that chronic hypertension produced by intrarenal or intravenous infusion is not volume-dependent. The relatively greater increase in TPRI during intrarenal NE infusion is attributed to vascular wall receptor sensitization by increased plasma potassium levels resulting from effects of intrarenally present NE on tubular cation exchange mechanisms.

In order to obtain a better insight into the hemodynamic changes during beta-blockade, we measured central hemodynamics, plasma volume, and renal function during both acute and long-term beta-blockade in conscious spontaneously hypertensive rats (SHR). Acutely, both 1 and 5 mg/kg propranolol immediately decreased heart rate (HR) and cardiac output (CO). However, total peripheral resistance (TPR) rose sharply, thus preventing mean arterial pressure (MAP) from falling during the first hours after injection. After 4 h TPR had returned to control values and, because CO was still reduced, MAP was lowered. This decrease of MAP persisted for more than 20 h. During 5-day infusion of propranolol (5 mg/kg/day) CO fell on the 1st day and remained lowered during the 5-day period. MAP was lowered from the second day onward. Despite the reduced CO and MAP, plasma volume (PV) did not increase during the 5-day infusion. Acute injection of 5 mg/kg/day did, however, result in a decreased PV at 1 h postinjection. In this time span central venous pressure remained unchanged. Quantitation of water and sodium excretion revealed an immediate diuresis and natriuresis after acute administration of propranolol. This occurred despite a reduced glomerular filtration rate and effective renal plasma flow, as quantitated by indicator clearance methods. We conclude that propranolol reduced tubular sodium reabsorption, possibly through blockade of tubular beta-receptors. This effect may be essential for the long-term antihypertensive efficacy of beta-blockers because it prevents sodium and water retention in a state of reduced MAP and CO.